Cocrystals and salts of 8-chloro-n-(4-(trifluoromethoxy)phenyl)quinolin-2-amine

Abstract

The present invention relates to co-crystals and pharmaceutically acceptable salts of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine, to pharmaceutical compositions comprising the same, and to the use thereof as a medicament, and more particularly for the prevention and / or treatment of inflammatory diseases, diseases caused by viruses and / or cancer or dysplasia. The present invention also relates to processes for the preparation of said co-crystals and said pharmaceutically acceptable salts.

Description

Invention Field

[0001] This invention relates to the pharmaceutical field, and more specifically to novel cocrystals and novel pharmaceutically acceptable salts of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine (also known as ABX464), methods for their preparation, their use as pharmaceuticals, and particularly for the prevention and / or treatment of inflammatory diseases such as inflammatory bowel disease, rheumatoid arthritis, pulmonary hypertension, NASH (non-alcoholic steatohepatitis), and multiple sclerosis, viral diseases, and / or cancers or developmental abnormalities. The invention also relates to pharmaceutical compositions comprising the aforementioned cocrystals and / or pharmaceutically acceptable salts of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine. Background of the Invention

[0003] WO2010 / 143169 describes the preparation and use of compounds, particularly quinoline derivatives, including certain pharmaceutically acceptable salts that can be used to treat HIV infection. The application specifically discloses 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine, also known as (8-chloro-quinoline-2-yl)-(4-trifluoromethoxy-phenyl)-amine, which is currently in clinical development. The inventors have noted that ABX464 is naturally highly crystalline and therefore spontaneously exists in a specific, unique, stable, and crystalline form referred to as "Crystal Form I".

[0004] Application WO2017 / 158201 relates to certain inorganic acids or sulfonates of ABX464.

[0005] ABX464 has poor solubility in aqueous solution. The main disadvantage of this poor solubility is that if the drug remains undissolved in the gastrointestinal system, the active ingredient cannot fully reach its target in the body.

[0006] Therefore, new methods are needed to improve the solubility of ABX464. Invention Overview

[0008] The inventors were surprised to discover that the implementation of new eutectic and pharmaceutically acceptable salts for ABX464 provided new opportunities to improve the performance of pharmaceutical products, such as in terms of solubility and dissolution rate control. The inventors have now developed new pharmaceutically acceptable salts and new eutectic forms for ABX464.

[0009] As mentioned above, there is always a need to improve the performance of pharmaceutical products, such as in terms of solubility, and especially when the free base is insoluble in water, as is the case with ABX464. It has been observed that when the salts and cocrystals according to this application are suspended in water, they dissociate and tend to precipitate due to the very weak nature of the corresponding free base (i.e., 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine itself). Therefore, to avoid the formation of precipitates and such instability during solubility measurements, these salts and cocrystals are typically formulated in the presence of at least one precipitation inhibitor, as described in more detail below. As shown in the experimental section (Example 10), the salts and cocrystals according to this application exhibit surprisingly significantly higher solubility compared to ABX464 crystalline form I (i.e., the free base). Furthermore, Example 11 of this application confirms that the salts according to this application exhibit surprisingly significantly higher solubility in an intestinal model compared to ABX464 crystalline form I (i.e., the free base).

[0010] Therefore, the present invention aims to provide a cocrystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine and a pharmaceutically acceptable salt thereof, and pharmaceutical compositions comprising the cocrystal of ABX464 and / or a pharmaceutically acceptable salt thereof (including its solvates and / or hydrates). The cocrystal of ABX464, the pharmaceutically acceptable salt thereof, and the pharmaceutical compositions comprising them can be used as medicines, and more particularly for the treatment and / or prevention of inflammatory diseases such as inflammatory bowel disease, rheumatoid arthritis, pulmonary hypertension, NASH (non-alcoholic steatohepatitis), and multiple sclerosis, viral diseases, and / or cancers or developmental abnormalities.

[0011] Therefore, the present invention provides a cocrystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine, wherein the cocrystal is selected from:

[0012] -8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine:L-proline, having a powder X-ray diffraction pattern showing peaks at 16.5, 20.6, 21.4 and 22.1 (±0.2 each time) in 2θ angle, and / or having a single endothermic onset temperature of 172.0 °C (±2 °C);

[0013] -8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine: gentic acid, having a powder X-ray diffraction pattern showing peaks at 7.9, 14.0, 15.2 and 25.2 (±0.2 each time) in 2θ angle, and / or having a single endothermic onset temperature of 133.0 °C (±2 °C);

[0014] -8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine:malonic acid, having a powder X-ray diffraction pattern showing peaks at 9.5, 12.2, 15.8, 17.3, 19.7, 22.8, 24.8 and 25.6 (±0.2 each) in 2θ angles, and / or having a single endothermic onset temperature of 109.0 °C (±2 °C); and

[0015] -8-Chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine:4,4'-bipyridine, having a powder X-ray diffraction pattern showing peaks at 12.0, 19.2, 21.2 and 24.3 (±0.2 each time) in 2θ angle, and / or having a single endothermic onset temperature of 127.0 °C (±2 °C).

[0016] Therefore, the present invention also provides pharmaceutically acceptable salts of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine, including their solvates and / or hydrates, selected from lactates, oleates, oxalates, palmitates, stearates, valerates, pantothenates, picrates, butyrates, malonates, succinates, tartrates, malates, mandelates, benzoates, edetates, gluceptates, gluconates, lacturonates, salicylates, disalicylates, mucilages, and dihydroxynaphthalenes. Salts, adipates, alginates, aspartates, camphorates, cyclopentanepropionates, digluconate, glucoheptonate, heptanate, hexanoate, laurate, nicotinate, dihydroxynaphthyl salt, neopentanoate, propionate, undecanoate, etc., phosphates, camphor sulfonate, 2-hydroxy-ethanesulfonate, estolate, naphthalene sulfonate, ethanesulfonate, naphthalene disulfonate, dodecyl sulfate, etc., perchlorates, borates, glycerol phosphates, nitrates, persulfates, etc.

[0017] This article also provides:

[0018] - A method for preparing the cocrystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined in this invention;

[0019] - A method for preparing the pharmaceutically acceptable salt (including its solvates and / or hydrates) of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined in this invention;

[0020] - A pharmaceutical composition comprising the eutectic as defined in this invention and / or the pharmaceutically acceptable salt (including its solvates and / or hydrates) of ABX464 as defined in this invention and at least one pharmaceutically acceptable excipient;

[0021] - A pharmaceutically acceptable salt (including its solvates and / or hydrates) of ABX464 as defined herein, used as a medicament, the cocrystal as defined herein, or a pharmaceutical composition as defined herein; and

[0022] - The pharmaceutically acceptable salt (including its solvates and / or hydrates) of ABX464 as defined in this invention, the cocrystal as defined in this invention, or the pharmaceutical composition as defined in this invention, for the prevention or treatment of cancer, AIDS, HIV infection, and / or inflammatory diseases.

[0023] A eutectic is a crystalline complex composed of at least two neutral molecules bonded together in a crystal lattice through non-covalent interactions. The main difference between a solvate and a eutectic relates to the physical state of the pure components: if one component is liquid at ambient temperature, the molecular complex is a solvate; if all components are solid at ambient temperature, the complex is referred to by the term "eutectic." The main difference between a solvate and a eutectic is that a eutectic is much more stable than a solvate. A eutectic is characterized by the method of obtaining it and its ordered three-dimensional structure, which is confirmed, for example, by X-ray diffraction patterns. It is impossible to know a priori whether two given components will form a eutectic with a specific three-dimensional structure, or whether this simply results in the juxtaposition of the two powders.

[0024] As used in this article, the term "pharmaceutically acceptable" means a compound, substance, excipient, carrier, adjuvant, solvent, composition, or dosage form that, within reasonable medical judgment, is suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problematic complications, in proportion to a reasonable benefit / risk ratio.

[0025] In the context of this invention, the term "treatment" as used herein refers to reversing or alleviating inflammatory diseases such as inflammatory bowel disease, rheumatoid arthritis, pulmonary hypertension, NASH (non-alcoholic steatohepatitis), and multiple sclerosis, viral diseases and / or cancer or developmental abnormalities, inhibiting the progression of said diseases, or preventing said diseases.

[0026] As used herein, the term "prevention" means reducing the risk of a given phenomenon occurring, or slowing the onset of a given phenomenon, which in this invention are inflammatory diseases such as inflammatory bowel disease, rheumatoid arthritis, pulmonary hypertension, NASH (non-alcoholic steatohepatitis), and multiple sclerosis, viral diseases and / or cancers or developmental abnormalities. "Prevention" as used herein also encompasses "reducing the likelihood of occurrence" or "reducing the likelihood of recurrence."

[0027] "Subjects" (including patients) include mammals, such as humans, companion animals (e.g., dogs, cats, birds, etc.), livestock (e.g., cattle, sheep, pigs, horses, poultry, etc.) and laboratory animals (e.g., rats, mice, guinea pigs, birds, etc.).

[0028] As used in this article, the term “ambient temperature” or “room temperature” refers to a temperature ranging from 15°C to 30°C, and more particularly from 18°C ​​to 25°C.

[0029] Brief description of the attached diagram

[0030] Figure 1 This is an X-ray powder diagram of the cocrystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine:L-proline (see Example 1).

[0031] Figure 2 This is an X-ray powder diagram of the cocrystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine:gentic acid (see Example 2).

[0032] Figure 3 This is an X-ray powder diagram of the eutectic of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine:malonic acid (see Example 3).

[0033] Figure 4 This is an X-ray powder diagram of the cocrystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine:4,4'-bipyridine (see Example 4).

[0034] Figure 5 This is an X-ray powder diagram of anhydrous crystalline ABX464 heminaphthalene disulfonate (see Example 5).

[0035] Figure 6 This is an X-ray powder diagram of anhydrous crystalline ABX464 ethanesulfonate (see Example 6).

[0036] Figure 7 This is an X-ray powder diagram of the crystalline semi-THF (tetrahydrofuran) solvate of ABX464 semi-naphthalene disulfonate (see Example 7).

[0037] Figure 8 Three X-ray powder maps of the fasting dissolution / precipitation test for ABX464 crystalline form I are shown. The first map shows ABX464 crystalline form I (see top line), the second map shows the solid residue collected in the gastric chamber at time point G 30 minutes (see middle line), and the third map shows the solid residue collected in the intestinal chamber at time point I 120 minutes (see bottom line) (see Example 11).

[0038] Figure 9 Four X-ray powder diagrams of the fasting dissolution / precipitation test of anhydrous ABX464 heminaphthalene disulfonate are shown. The first diagram shows ABX464 crystalline form I (see top line), the second diagram shows anhydrous ABX464 heminaphthalene disulfonate (see second line from the top), the third diagram shows the solid residue collected in the gastric chamber at time point G 30 minutes (see third line from the top), and the fourth diagram shows the solid residue collected in the intestinal chamber at time point I 120 minutes (see bottom line, i.e., fourth line from the top) (see Example 11). Invention Details

[0040] As explained above, the inventors have demonstrated that the salt and eutectic according to this application exhibit improved solubility compared to the solubility of the crystalline form of ABX464 Form I.

[0041] As will be seen in Example 10 below, the improved solubility has been studied in two typical media, FaSSIF (i.e., fasting simulated intestinal fluid) and FeSSIF (i.e., eating simulated intestinal fluid).

[0042] As will be apparent from the described embodiments, a precipitation inhibitor, namely (polyvinylpyrrolidone-vinyl acetate) PVP-VA, is also present in the medium. The use of such a precipitation inhibitor is commonly employed in the well-known "spring and parachute" approach. In fact, the concept of gastrointestinal supersaturation can be used as a strategy to enhance the intestinal absorption of poorly water-soluble drugs. To utilize supersaturation, two fundamental steps need to be considered: the generation and maintenance of a metastable supersaturated state, also known as the spring and parachute method (see Guzmán et al.: A "spring and parachute" approach to designing solid celecoxib formulations having enhanced oral absorption. AAPS J 6, 2004, Abstract T2189). Once supersaturation (called the spring) has been induced, the drug molecule tends to precipitate through a kinetically or thermodynamically controlled process. To benefit from the supersaturated state, the increased concentration must be maintained for a sufficient period of time for absorption. This may require temporarily inhibiting precipitation by using pharmaceutical excipients or by other components that interfere with nucleation and / or crystal growth (i.e., "parachutes" or precipitation inhibitors).

[0043] Among precipitation inhibitors, polymers such as PVP-VA (polyvinylpyrrolidone-vinyl acetate), HPMC (hydroxypropyl methylcellulose), HPMC-AS, HPMC-P, and surfactants such as TPGS (d-α-tocopherol polyethylene glycol 1000 succinate) can be mentioned. F127 (also known as P407: poloxamer 407), hydroxypropyl cellulose (HPC), PVP (polyvinylpyrrolidone) such as PVP-K15, PVP-K30 or PVP-K90, 974P (a highly carboxylated polymer composed of lightly cross-linked polyacrylic acid), polyvinyl alcohol (PVA) and mixtures thereof, or sodium dodecyl sulfate (SDS) may also be mentioned.

[0044] As shown in Example 10, significantly higher solubility of all solid forms was observed in FeSSIF pH 5.0 + 1% PPVVA medium simulating ingested intestinal medium. In other words, the presence of the precipitation inhibitor in said medium prevented the precipitation of the free ABX464 base and opened up a pathway to implement it in a new galen formulation.

[0045] Example 11 tested the solubility behavior of ABX464 salts in a two-step dissolution-precipitation fasting in vitro human model (see, for example, Dressman et al., “Estimating drug solubility in the gastrointestinal tract”, Advanced Drug Delivery Reviews, 2007, Vol. 59, No. 7, pp. 591-602), which further validated that the salts of ABX464 according to this application exhibit improved solubility compared to ABX464 crystalline form I. Indeed, in this model, a significantly higher solubility (approximately 430 μg / ml) of ABX464 heminaphthalenedisulfonate in the intestinal compartment was clearly observed compared to the solubility (approximately 80 μg / ml) of ABX464 crystalline form I in the intestinal compartment.

[0046] Therefore, the inventors have discovered a new method for increasing the solubility of ABX464, which also allows for the preparation of a wider variety of galen formulations, thereby ensuring that ABX464 reaches its biological targets with optimal bioavailability, as detailed in the following paragraph, “Pharmaceutical Compositions”.

[0047] The subject of the salt and eutectic of ABX464 of the present invention is described in more detail below.

[0048] ABX464 salt

[0049] As described above, one object of the present invention is a pharmaceutically acceptable salt of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine, including its solvates and / or hydrates, selected from lactates, oleates, oxalates, palmitates, stearates, valerates, pantothenates, picrates, butates, malonates, succinates, tartrates, malates, mandelates, benzoates, edetates, gluconate, gluconate, lacturonates, salicylates, disalicylates, mucilages, bis(hydroxynaphthyl)ate, adipate, alginates, aspartate, camphorate, and cyclopentanepropionate. Digluconate, gluconate, heptanate, hexanoate, laurate, nicotinate, dihydroxynaphthalate, neopentanoate, propionate, undecanoate, etc., phosphates, camphor sulfonate, 2-hydroxy-ethanesulfonate, etolate, naphthalene sulfonate, ethanesulfonate, naphthalene disulfonate, dodecyl sulfate, etc., perchlorate, borate, glycerol phosphate, nitrate, persulfate, etc., especially selected from ethanesulfonate and naphthalene disulfonate, and even more especially selected from anhydrous crystalline ABX464 heminaphthalene disulfonate, anhydrous crystalline ABX464 ethanesulfonate and crystalline hemiTHF solvates of ABX464 heminaphthalene disulfonate.

[0050] Therefore, according to one embodiment, the pharmaceutically acceptable salt is anhydrous and selected from anhydrous crystalline ABX464 heminaphthalene disulfonate and anhydrous crystalline ABX464 ethanesulfonate.

[0051] Therefore, according to another embodiment, the pharmaceutically acceptable salt is in the form of a solvate or hydrate, more particularly in the form of a solvate, and even more particularly in the form of a crystalline semi-THF (tetrahydrofuran) solvate of ABX464 heminaphthalene disulfonate.

[0052] Therefore, in a particular embodiment, the pharmaceutically acceptable salt of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined in this invention is selected from anhydrous crystalline ABX464 heminaphthalene disulfonate, anhydrous crystalline ABX464 ethanesulfonate, and crystalline hemiTHF solvates of ABX464 heminaphthalene disulfonate, as described in Examples 5, 6, and 7 herein (and respectively in Appendix I). Figure 5 , 6 As illustrated in 7).

[0053] In a particularly preferred embodiment, the pharmaceutically acceptable salt of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined in this invention is anhydrous crystalline ABX464 heminaphthalene disulfonate.

[0054] For example, pharmaceutically acceptable salts of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine can be characterized by X-ray powder diffraction (XRPD) and differential scanning calorimetry (DSC).

[0055] More specifically, the anhydrous crystalline ABX464 heminaphthalene disulfonate of Example 5 has a powder X-ray diffraction pattern showing peaks at 9.8, 16.4, 18.2, 20.1, 21.2, 21.6, 23.5, and 26.3 (±0.2 each time) in 2θ angles, and optionally further showing the following additional peaks in 2θ angles: 12.4, 13.1, 17.8, 20.9, 22.6, 24.5, 24.7, 25.2, and 25.9 (±0.2 each time); and even optionally further showing the following additional peaks in 2θ angles: 8.8, 13.3, 15.1, 17.2, 17.5, 19.4, 19.5, and 19.8 (±0.2 each time), as in Figure 5 As shown in the powder X-ray diffraction pattern, and / or with a single endothermic event starting at a temperature of 269.0 °C (±2 °C).

[0056] The characteristic X-ray powder diffraction pattern of anhydrous crystalline ABX464 heminaphthalene disulfonate can be found in Figure 5 The data are given in the table below, and its characteristic signals are summarized in Table 1:

[0057] Table 1

[0058]

[0059] According to one embodiment, the powder X-ray diffraction pattern of the anhydrous crystalline ABX464 heminaphthalene disulfonate of the present invention shows at least one peak represented at a 2θ angle, said peak being selected from 9.8, 16.4, 18.2, 20.1, 21.2, 21.6, 23.5, 26.3, 12.4, 13.1, 17.8, 20.9, 22.6, 24.5, 24.7, 25.2, 25.9, 8.8, 13.3, 15.1, 17.2, 17.5, 19.4, 19.5, and 19.8 (±0.2 each time).

[0060] According to another embodiment, the powder X-ray diffraction pattern of the anhydrous crystalline ABX464 heminaphthalene disulfonate of the present invention shows at least two peaks at a 2θ angle, said peaks being selected from 9.8, 16.4, 18.2, 20.1, 21.2, 21.6, 23.5, 26.3, 12.4, 13.1, 17.8, 20.9, 22.6, 24.5, 24.7, 25.2, 25.9, 8.8, 13.3, 15.1, 17.2, 17.5, 19.4, 19.5, and 19.8 (±0.2 each).

[0061] According to another embodiment, the powder X-ray diffraction pattern of the anhydrous crystalline ABX464 heminaphthalene disulfonate of the present invention shows at least three peaks represented at 2θ angles, said peaks being selected from 9.8, 16.4, 18.2, 20.1, 21.2, 21.6, 23.5, 26.3, 12.4, 13.1, 17.8, 20.9, 22.6, 24.5, 24.7, 25.2, 25.9, 8.8, 13.3, 15.1, 17.2, 17.5, 19.4, 19.5, and 19.8 (±0.2 each).

[0062] According to another embodiment, the powder X-ray diffraction pattern of the anhydrous crystalline ABX464 heminaphthalene disulfonate of the present invention shows at least four peaks represented at 2θ angles, said peaks being selected from 9.8, 16.4, 18.2, 20.1, 21.2, 21.6, 23.5, 26.3, 12.4, 13.1, 17.8, 20.9, 22.6, 24.5, 24.7, 25.2, 25.9, 8.8, 13.3, 15.1, 17.2, 17.5, 19.4, 19.5, and 19.8 (±0.2 each).

[0063] According to another embodiment, the powder X-ray diffraction pattern of the anhydrous crystalline ABX464 heminaphthalene disulfonate of the present invention shows at least five peaks represented at 2θ angles, said peaks being selected from 9.8, 16.4, 18.2, 20.1, 21.2, 21.6, 23.5, 26.3, 12.4, 13.1, 17.8, 20.9, 22.6, 24.5, 24.7, 25.2, 25.9, 8.8, 13.3, 15.1, 17.2, 17.5, 19.4, 19.5, and 19.8 (±0.2 each).

[0064] According to another embodiment, the powder X-ray diffraction pattern of the anhydrous crystalline ABX464 heminaphthalene disulfonate of the present invention shows at least six peaks represented at 2θ angles, said peaks being selected from 9.8, 16.4, 18.2, 20.1, 21.2, 21.6, 23.5, 26.3, 12.4, 13.1, 17.8, 20.9, 22.6, 24.5, 24.7, 25.2, 25.9, 8.8, 13.3, 15.1, 17.2, 17.5, 19.4, 19.5, and 19.8 (±0.2 each).

[0065] According to another embodiment, the powder X-ray diffraction pattern of the anhydrous crystalline ABX464 heminaphthalene disulfonate of the present invention shows at least seven peaks represented at 2θ angles, said peaks being selected from 9.8, 16.4, 18.2, 20.1, 21.2, 21.6, 23.5, 26.3, 12.4, 13.1, 17.8, 20.9, 22.6, 24.5, 24.7, 25.2, 25.9, 8.8, 13.3, 15.1, 17.2, 17.5, 19.4, 19.5, and 19.8 (±0.2 each).

[0066] According to another embodiment, the powder X-ray diffraction pattern of the anhydrous crystalline ABX464 heminaphthalene disulfonate of the present invention shows at least eight peaks represented at 2θ angles, said peaks being selected from 9.8, 16.4, 18.2, 20.1, 21.2, 21.6, 23.5, 26.3, 12.4, 13.1, 17.8, 20.9, 22.6, 24.5, 24.7, 25.2, 25.9, 8.8, 13.3, 15.1, 17.2, 17.5, 19.4, 19.5, and 19.8 (±0.2 each).

[0067] According to another embodiment, the powder X-ray diffraction pattern of the anhydrous crystalline ABX464 heminaphthalene disulfonate of the present invention shows at least nine peaks represented at 2θ angles, said peaks being selected from 9.8, 16.4, 18.2, 20.1, 21.2, 21.6, 23.5, 26.3, 12.4, 13.1, 17.8, 20.9, 22.6, 24.5, 24.7, 25.2, 25.9, 8.8, 13.3, 15.1, 17.2, 17.5, 19.4, 19.5, and 19.8 (±0.2 each).

[0068] According to another embodiment, the powder X-ray diffraction pattern of the anhydrous crystalline ABX464 heminaphthalene disulfonate of the present invention shows at least 10 peaks represented at 2θ angles, said peaks being selected from 9.8, 16.4, 18.2, 20.1, 21.2, 21.6, 23.5, 26.3, 12.4, 13.1, 17.8, 20.9, 22.6, 24.5, 24.7, 25.2, 25.9, 8.8, 13.3, 15.1, 17.2, 17.5, 19.4, 19.5, and 19.8 (±0.2 each).

[0069] According to another embodiment, the powder X-ray diffraction pattern of the anhydrous crystalline ABX464 heminaphthalene disulfonate of the present invention shows at least 11 peaks represented at 2θ angles, said peaks being selected from 9.8, 16.4, 18.2, 20.1, 21.2, 21.6, 23.5, 26.3, 12.4, 13.1, 17.8, 20.9, 22.6, 24.5, 24.7, 25.2, 25.9, 8.8, 13.3, 15.1, 17.2, 17.5, 19.4, 19.5, and 19.8 (±0.2 each).

[0070] According to another embodiment, the powder X-ray diffraction pattern of the anhydrous crystalline ABX464 heminaphthalene disulfonate of the present invention shows at least 12 peaks represented at 2θ angles, said peaks being selected from 9.8, 16.4, 18.2, 20.1, 21.2, 21.6, 23.5, 26.3, 12.4, 13.1, 17.8, 20.9, 22.6, 24.5, 24.7, 25.2, 25.9, 8.8, 13.3, 15.1, 17.2, 17.5, 19.4, 19.5, and 19.8 (±0.2 each).

[0071] According to another embodiment, the powder X-ray diffraction pattern of the anhydrous crystalline ABX464 heminaphthalene disulfonate of the present invention shows at least 13 peaks represented at 2θ angles, said peaks being selected from 9.8, 16.4, 18.2, 20.1, 21.2, 21.6, 23.5, 26.3, 12.4, 13.1, 17.8, 20.9, 22.6, 24.5, 24.7, 25.2, 25.9, 8.8, 13.3, 15.1, 17.2, 17.5, 19.4, 19.5, and 19.8 (±0.2 each).

[0072] According to another embodiment, the powder X-ray diffraction pattern of the anhydrous crystalline ABX464 heminaphthalene disulfonate of the present invention shows at least 14 peaks represented at 2θ angles, said peaks being selected from 9.8, 16.4, 18.2, 20.1, 21.2, 21.6, 23.5, 26.3, 12.4, 13.1, 17.8, 20.9, 22.6, 24.5, 24.7, 25.2, 25.9, 8.8, 13.3, 15.1, 17.2, 17.5, 19.4, 19.5, and 19.8 (±0.2 each).

[0073] According to another embodiment, the powder X-ray diffraction pattern of the anhydrous crystalline ABX464 heminaphthalene disulfonate of the present invention shows at least 15 peaks represented at 2θ angles, said peaks being selected from 9.8, 16.4, 18.2, 20.1, 21.2, 21.6, 23.5, 26.3, 12.4, 13.1, 17.8, 20.9, 22.6, 24.5, 24.7, 25.2, 25.9, 8.8, 13.3, 15.1, 17.2, 17.5, 19.4, 19.5, and 19.8 (±0.2 each).

[0074] According to another embodiment, the anhydrous crystalline ABX464 heminaphthalene disulfonate of the present invention has the same... Figure 5 The XRPD shown is essentially the same.

[0075] More specifically, the powder X-ray diffraction pattern of the anhydrous crystalline ABX464 ethanesulfonate of Example 6 shows peaks at 12.2 and 22.2 (±0.2 each time) in 2θ angles, and optionally further shows the following additional peaks in 2θ angles: 6.2, 12.9, 13.1, 15.3, 16.3, 18.2, 18.6, 19.5, 20.0, and 20.7 (±0.2 each time); and even optionally further shows the following additional peaks in 2θ angles: 10.1, 15.8, 17.7, 17.9, 20.3, and 21.4 (±0.2 each time), as in Figure 6 As shown in the powder X-ray diffraction pattern, and / or with a single endothermic event starting at a temperature of 108.0 °C (±2 °C).

[0076] The characteristic X-ray powder diffraction pattern of anhydrous crystalline ABX464 ethanesulfonate can be found in... Figure 6 The data are given in the table below, and its characteristic signals are summarized in Table 2:

[0077] Table 2

[0078]

[0079] According to one embodiment, the powder X-ray diffraction pattern of the anhydrous crystalline ABX464 ethanesulfonate of the present invention shows at least one peak represented at a 2θ angle, said peak being selected from 12.2, 22.2, 6.2, 12.9, 13.1, 15.3, 16.3, 18.2, 18.6, 19.5, 20.0, 20.7, 10.1, 15.8, 17.7, 17.9, 20.3, and 21.4 (±0.2 each time).

[0080] According to another embodiment, the powder X-ray diffraction pattern of the anhydrous crystalline ABX464 ethanesulfonate of the present invention shows at least two peaks at a 2θ angle, said peaks being selected from 12.2, 22.2, 6.2, 12.9, 13.1, 15.3, 16.3, 18.2, 18.6, 19.5, 20.0, 20.7, 10.1, 15.8, 17.7, 17.9, 20.3, and 21.4 (±0.2 each).

[0081] According to another embodiment, the powder X-ray diffraction pattern of the anhydrous crystalline ABX464 ethanesulfonate of the present invention shows at least three peaks represented at 2θ angles, said peaks being selected from 12.2, 22.2, 6.2, 12.9, 13.1, 15.3, 16.3, 18.2, 18.6, 19.5, 20.0, 20.7, 10.1, 15.8, 17.7, 17.9, 20.3, and 21.4 (±0.2 each).

[0082] According to another embodiment, the powder X-ray diffraction pattern of the anhydrous crystalline ABX464 ethanesulfonate of the present invention shows at least four peaks represented at 2θ angles, said peaks being selected from 12.2, 22.2, 6.2, 12.9, 13.1, 15.3, 16.3, 18.2, 18.6, 19.5, 20.0, 20.7, 10.1, 15.8, 17.7, 17.9, 20.3, and 21.4 (±0.2 each).

[0083] According to another embodiment, the powder X-ray diffraction pattern of the anhydrous crystalline ABX464 ethanesulfonate of the present invention shows at least five peaks represented at 2θ angles, said peaks being selected from 12.2, 22.2, 6.2, 12.9, 13.1, 15.3, 16.3, 18.2, 18.6, 19.5, 20.0, 20.7, 10.1, 15.8, 17.7, 17.9, 20.3, and 21.4 (±0.2 each).

[0084] According to another embodiment, the powder X-ray diffraction pattern of the anhydrous crystalline ABX464 ethanesulfonate of the present invention shows at least six peaks represented at 2θ angles, said peaks being selected from 12.2, 22.2, 6.2, 12.9, 13.1, 15.3, 16.3, 18.2, 18.6, 19.5, 20.0, 20.7, 10.1, 15.8, 17.7, 17.9, 20.3, and 21.4 (±0.2 each).

[0085] According to another embodiment, the powder X-ray diffraction pattern of the anhydrous crystalline ABX464 ethanesulfonate of the present invention shows at least seven peaks represented at 2θ angles, said peaks being selected from 12.2, 22.2, 6.2, 12.9, 13.1, 15.3, 16.3, 18.2, 18.6, 19.5, 20.0, 20.7, 10.1, 15.8, 17.7, 17.9, 20.3, and 21.4 (±0.2 each).

[0086] According to another embodiment, the powder X-ray diffraction pattern of the anhydrous crystalline ABX464 ethanesulfonate of the present invention shows at least eight peaks represented at 2θ angles, said peaks being selected from 12.2, 22.2, 6.2, 12.9, 13.1, 15.3, 16.3, 18.2, 18.6, 19.5, 20.0, 20.7, 10.1, 15.8, 17.7, 17.9, 20.3, and 21.4 (±0.2 each).

[0087] According to another embodiment, the powder X-ray diffraction pattern of the anhydrous crystalline ABX464 ethanesulfonate of the present invention shows at least nine peaks represented at 2θ angles, said peaks being selected from 12.2, 22.2, 6.2, 12.9, 13.1, 15.3, 16.3, 18.2, 18.6, 19.5, 20.0, 20.7, 10.1, 15.8, 17.7, 17.9, 20.3, and 21.4 (±0.2 each).

[0088] According to another embodiment, the powder X-ray diffraction pattern of the anhydrous crystalline ABX464 ethanesulfonate of the present invention shows at least 10 peaks represented at 2θ angles, said peaks being selected from 12.2, 22.2, 6.2, 12.9, 13.1, 15.3, 16.3, 18.2, 18.6, 19.5, 20.0, 20.7, 10.1, 15.8, 17.7, 17.9, 20.3, and 21.4 (±0.2 each).

[0089] According to another embodiment, the powder X-ray diffraction pattern of the anhydrous crystalline ABX464 ethanesulfonate of the present invention shows at least 11 peaks represented at 2θ angles, said peaks being selected from 12.2, 22.2, 6.2, 12.9, 13.1, 15.3, 16.3, 18.2, 18.6, 19.5, 20.0, 20.7, 10.1, 15.8, 17.7, 17.9, 20.3, and 21.4 (±0.2 each).

[0090] According to another embodiment, the powder X-ray diffraction pattern of the anhydrous crystalline ABX464 ethanesulfonate of the present invention shows at least 12 peaks represented at 2θ angles, said peaks being selected from 12.2, 22.2, 6.2, 12.9, 13.1, 15.3, 16.3, 18.2, 18.6, 19.5, 20.0, 20.7, 10.1, 15.8, 17.7, 17.9, 20.3, and 21.4 (±0.2 each).

[0091] According to another embodiment, the powder X-ray diffraction pattern of the anhydrous crystalline ABX464 ethanesulfonate of the present invention shows at least 13 peaks represented at 2θ angles, said peaks being selected from 12.2, 22.2, 6.2, 12.9, 13.1, 15.3, 16.3, 18.2, 18.6, 19.5, 20.0, 20.7, 10.1, 15.8, 17.7, 17.9, 20.3, and 21.4 (±0.2 each).

[0092] According to another embodiment, the powder X-ray diffraction pattern of the anhydrous crystalline ABX464 ethanesulfonate of the present invention shows at least 14 peaks represented at 2θ angles, said peaks being selected from 12.2, 22.2, 6.2, 12.9, 13.1, 15.3, 16.3, 18.2, 18.6, 19.5, 20.0, 20.7, 10.1, 15.8, 17.7, 17.9, 20.3, and 21.4 (±0.2 each).

[0093] According to another embodiment, the powder X-ray diffraction pattern of the anhydrous crystalline ABX464 ethanesulfonate of the present invention shows at least 15 peaks represented at 2θ angles, said peaks being selected from 12.2, 22.2, 6.2, 12.9, 13.1, 15.3, 16.3, 18.2, 18.6, 19.5, 20.0, 20.7, 10.1, 15.8, 17.7, 17.9, 20.3, and 21.4 (±0.2 each).

[0094] According to another embodiment, the anhydrous crystalline ABX464 ethanesulfonate of the present invention has the same... Figure 6 The XRPD shown is essentially the same.

[0095] More specifically, the crystalline semi-THF solvate of ABX464 heminaphthalene disulfonate of Example 7 has a powder X-ray diffraction pattern showing peaks at 8.4, 12.3, 14.0, 19.2, 21.3, 22.6, and 24.6 (±0.2 each) in 2θ angles, and optionally further showing the following additional peaks in 2θ angles: 9.6, 13.0, 13.5, 14.8, 17.2, 17.8, 23.4, 24.1, 24.9, and 25.2 (±0.2 each); and even optionally further showing the following additional peaks in 2θ angles: 16.7, 18.1, 18.8, 19.5, 20.9, and 22.3 (±0.2 each), as in Figure 7 As shown in the powder X-ray diffraction pattern, and / or with a single endothermic event starting at a temperature of 172.0 °C (±2 °C).

[0096] The characteristic X-ray powder diffraction pattern of the crystalline semi-THF solvate of ABX464 heminaphthalene disulfonate can be found in... Figure 7 The data are given in [the table], and its characteristic signals are summarized in Table 3 below:

[0097] Table 3

[0098]

[0099]

[0100] According to one embodiment, the powder X-ray diffraction pattern of the crystalline semi-THF solvate of ABX464 heminaphthalene disulfonate of the present invention shows at least one peak represented at a 2θ angle, said peak being selected from 8.4, 12.3, 14.0, 19.2, 21.3, 22.6, 24.6, 9.6, 13.0, 13.5, 14.8, 17.2, 17.8, 23.4, 24.1, 24.9, 25.2, 16.7, 18.1, 18.8, 19.5, 20.9, and 22.3 (±0.2 each time).

[0101] According to another embodiment, the powder X-ray diffraction pattern of the crystalline semi-THF solvate of the ABX464 heminaphthalene disulfonate of the present invention shows at least two peaks at a 2θ angle, said peaks being selected from 8.4, 12.3, 14.0, 19.2, 21.3, 22.6, 24.6, 9.6, 13.0, 13.5, 14.8, 17.2, 17.8, 23.4, 24.1, 24.9, 25.2, 16.7, 18.1, 18.8, 19.5, 20.9, and 22.3 (±0.2 each).

[0102] According to another embodiment, the powder X-ray diffraction pattern of the crystalline semi-THF solvate of the ABX464 heminaphthalene disulfonate of the present invention shows at least three peaks at 2θ angles, the peaks being selected from 8.4, 12.3, 14.0, 19.2, 21.3, 22.6, 24.6, 9.6, 13.0, 13.5, 14.8, 17.2, 17.8, 23.4, 24.1, 24.9, 25.2, 16.7, 18.1, 18.8, 19.5, 20.9, and 22.3 (±0.2 each).

[0103] According to another embodiment, the powder X-ray diffraction pattern of the crystalline semi-THF solvate of the ABX464 heminaphthalene disulfonate of the present invention shows at least four peaks represented at 2θ angles, said peaks being selected from 8.4, 12.3, 14.0, 19.2, 21.3, 22.6, 24.6, 9.6, 13.0, 13.5, 14.8, 17.2, 17.8, 23.4, 24.1, 24.9, 25.2, 16.7, 18.1, 18.8, 19.5, 20.9, and 22.3 (±0.2 each).

[0104] According to another embodiment, the powder X-ray diffraction pattern of the crystalline semi-THF solvate of the ABX464 heminaphthalene disulfonate of the present invention shows at least five peaks represented at 2θ angles, said peaks being selected from 8.4, 12.3, 14.0, 19.2, 21.3, 22.6, 24.6, 9.6, 13.0, 13.5, 14.8, 17.2, 17.8, 23.4, 24.1, 24.9, 25.2, 16.7, 18.1, 18.8, 19.5, 20.9, and 22.3 (±0.2 each).

[0105] According to another embodiment, the powder X-ray diffraction pattern of the crystalline semi-THF solvate of the ABX464 heminaphthalene disulfonate of the present invention shows at least six peaks represented at 2θ angles, said peaks being selected from 8.4, 12.3, 14.0, 19.2, 21.3, 22.6, 24.6, 9.6, 13.0, 13.5, 14.8, 17.2, 17.8, 23.4, 24.1, 24.9, 25.2, 16.7, 18.1, 18.8, 19.5, 20.9, and 22.3 (±0.2 each).

[0106] According to another embodiment, the powder X-ray diffraction pattern of the crystalline semi-THF solvate of the ABX464 heminaphthalene disulfonate of the present invention shows at least seven peaks represented at 2θ angles, said peaks being selected from 8.4, 12.3, 14.0, 19.2, 21.3, 22.6, 24.6, 9.6, 13.0, 13.5, 14.8, 17.2, 17.8, 23.4, 24.1, 24.9, 25.2, 16.7, 18.1, 18.8, 19.5, 20.9, and 22.3 (±0.2 each).

[0107] According to another embodiment, the powder X-ray diffraction pattern of the crystalline semi-THF solvate of ABX464 heminaphthalene disulfonate of the present invention shows at least eight peaks represented at 2θ angles, said peaks being selected from 8.4, 12.3, 14.0, 19.2, 21.3, 22.6, 24.6, 9.6, 13.0, 13.5, 14.8, 17.2, 17.8, 23.4, 24.1, 24.9, 25.2, 16.7, 18.1, 18.8, 19.5, 20.9, and 22.3 (±0.2 each).

[0108] According to another embodiment, the powder X-ray diffraction pattern of the crystalline semi-THF solvate of the ABX464 heminaphthalene disulfonate of the present invention shows at least nine peaks represented at 2θ angles, said peaks being selected from 8.4, 12.3, 14.0, 19.2, 21.3, 22.6, 24.6, 9.6, 13.0, 13.5, 14.8, 17.2, 17.8, 23.4, 24.1, 24.9, 25.2, 16.7, 18.1, 18.8, 19.5, 20.9, and 22.3 (±0.2 each).

[0109] According to another embodiment, the powder X-ray diffraction pattern of the crystalline semi-THF solvate of the ABX464 heminaphthalene disulfonate of the present invention shows at least 10 peaks represented at 2θ angles, said peaks being selected from 8.4, 12.3, 14.0, 19.2, 21.3, 22.6, 24.6, 9.6, 13.0, 13.5, 14.8, 17.2, 17.8, 23.4, 24.1, 24.9, 25.2, 16.7, 18.1, 18.8, 19.5, 20.9, and 22.3 (±0.2 each).

[0110] According to another embodiment, the powder X-ray diffraction pattern of the crystalline semi-THF solvate of the ABX464 heminaphthalene disulfonate of the present invention shows at least 11 peaks represented at 2θ angles, said peaks being selected from 8.4, 12.3, 14.0, 19.2, 21.3, 22.6, 24.6, 9.6, 13.0, 13.5, 14.8, 17.2, 17.8, 23.4, 24.1, 24.9, 25.2, 16.7, 18.1, 18.8, 19.5, 20.9, and 22.3 (±0.2 each).

[0111] According to another embodiment, the powder X-ray diffraction pattern of the crystalline hemi-THF solvate of ABX464 hemi-naphthalene disulfonate of the present invention shows at least 12 peaks represented at 2θ angles, said peaks being selected from 8.4, 12.3, 14.0, 19.2, 21.3, 22.6, 24.6, 9.6, 13.0, 13.5, 14.8, 17.2, 17.8, 23.4, 24.1, 24.9, 25.2, 16.7, 18.1, 18.8, 19.5, 20.9, and 22.3 (±0.2 each).

[0112] According to another embodiment, the powder X-ray diffraction pattern of the crystalline semi-THF solvate of the ABX464 heminaphthalene disulfonate of the present invention shows at least 13 peaks represented at 2θ angles, said peaks being selected from 8.4, 12.3, 14.0, 19.2, 21.3, 22.6, 24.6, 9.6, 13.0, 13.5, 14.8, 17.2, 17.8, 23.4, 24.1, 24.9, 25.2, 16.7, 18.1, 18.8, 19.5, 20.9, and 22.3 (±0.2 each).

[0113] According to another embodiment, the powder X-ray diffraction pattern of the crystalline hemi-THF solvate of ABX464 hemi-naphthalene disulfonate of the present invention shows at least 14 peaks represented at 2θ angles, said peaks being selected from 8.4, 12.3, 14.0, 19.2, 21.3, 22.6, 24.6, 9.6, 13.0, 13.5, 14.8, 17.2, 17.8, 23.4, 24.1, 24.9, 25.2, 16.7, 18.1, 18.8, 19.5, 20.9, and 22.3 (±0.2 each).

[0114] According to another embodiment, the powder X-ray diffraction pattern of the crystalline semi-THF solvate of the ABX464 heminaphthalene disulfonate of the present invention shows at least 15 peaks represented at 2θ angles, said peaks being selected from 8.4, 12.3, 14.0, 19.2, 21.3, 22.6, 24.6, 9.6, 13.0, 13.5, 14.8, 17.2, 17.8, 23.4, 24.1, 24.9, 25.2, 16.7, 18.1, 18.8, 19.5, 20.9, and 22.3 (±0.2 each).

[0115] According to another embodiment, the crystalline semi-THF solvate of the ABX464 heminaphthalene disulfonate of the present invention has the same... Figure 7 The XRPD shown is essentially the same.

[0116] Method for preparing pharmaceutically acceptable salts of ABX464

[0117] This article further provides a method for preparing pharmaceutically acceptable salts (including their solvates or hydrates) of ABX464, comprising the following steps:

[0118] a) Dissolve ABX464 in a solvent or a mixture of solvents;

[0119] b) Add counterions in the form of an acid to the mixture thus obtained in step a), wherein the acid itself may have been dissolved in a solvent or a mixture of solvents, thereby obtaining an ABX464:counterion molar ratio between 3:1 and 1:2, particularly between 5:2 and 1:2, even more particularly between 2:1 and 1:2 and even more particularly between 2:1 or 1:1.

[0120] c) Optionally, the solvent(s) are evaporated at a temperature between 0°C and the boiling point of the (multiple) selected solvents or solvent mixtures of steps a) and b), particularly between room temperature and 60°C, and even more particularly between room temperature and 50°C.

[0121] d) Optionally, add a solvent or a mixture of solvents.

[0122] e) Apply temperature program;

[0123] f) Optional filtering; and

[0124] g) Then optionally dry at a temperature between room temperature and 60°C to obtain the desired salt of ABX464.

[0125] According to one embodiment, the solvents used in steps a), b), and d) are any solvents conventionally used in the crystallization step, particularly organic solvents, more particularly selected from C1-C6 aliphatic alcohols, methyl ethyl ketones (also known as butanone or MEK), cyclohexane, alkanes such as heptane, dichloromethane, chloroform, formic acid, DMSO, 1-methyl-2-pyrrolidone, acetone, acetonitrile, tetrahydrofuran (THF), diethyl ether, dioxane, toluene, ethyl acetate, optionally mixed with water, and mixtures thereof, even more particularly selected from C1-C6 aliphatic alcohols, mixtures of H2O / C1-C6 aliphatic alcohols, and mixtures thereof, and even more particularly selected from methanol, ethanol, isopropanol, H2O / methanol, H2O / ethanol, and mixtures thereof.

[0126] Technicians know how to determine the more suitable (multiple) solvents in each step a), b), and d) to obtain the desired pharmaceutically acceptable salt.

[0127] According to one implementation, the (multiple) solvents used in steps a), b) and / or d) are the same.

[0128] According to another embodiment, the solvents used in steps a), b), and / or d) are different.

[0129] Advantageously, the counterion in the acid form of step b) is ethanesulfonic acid or naphthalene 1,5-disulfonic acid.

[0130] Therefore, in some embodiments, the solvent for steps a), b), and / or d) is any solvent conventionally used in the crystallization step, particularly an organic solvent, more particularly selected from C1-C6 aliphatic alcohols, methyl ethyl ketone (also known as butanone or MEK), cyclohexane, alkanes such as heptane, dichloromethane, chloroform, formic acid, DMSO, 1-methyl-2-pyrrolidone, acetone, acetonitrile, tetrahydrofuran (THF), diethyl ether, dioxane, toluene, ethyl acetate, optionally mixed with water, and mixtures thereof, even more particularly selected from C1-C6 aliphatic alcohols, mixtures of H2O / C1-C6 aliphatic alcohols, and mixtures thereof, and even more particularly selected from methanol, ethanol, isopropanol, H2O / methanol, H2O / ethanol, and mixtures thereof; and / or

[0131] The counterion in the acid form of step b) is ethanesulfonic acid or naphthalene 1,5-disulfonic acid.

[0132] According to one embodiment, evaporation step c is carried out under an inert gas such as N2.

[0133] According to one embodiment, step e) related to the temperature procedure includes a heating phase of reflux to a certain temperature, said certain temperature being between room temperature and the boiling point of (a variety of) solvents, particularly between room temperature and 60°C.

[0134] According to one embodiment, step e) related to the temperature program includes a cooling phase at a certain rate after refluxing to a certain temperature, wherein the certain temperature is between 0°C and 60°C, particularly between 5°C and 40°C, and even more particularly between room temperature and 40°C, and the certain rate is between 30°C / min and 0.05°C / min, particularly between 10°C / min and 0.05°C / min, and even more particularly between 5°C / min and 0.05°C / min.

[0135] According to one embodiment, step e) related to the temperature program includes: i) heating to a reflux temperature, said temperature being between room temperature and the boiling point of (a variety of) solvents, particularly between room temperature and 60°C, and / or ii) cooling to a reflux temperature at a rate, said temperature being between 0°C and 60°C, particularly between 5°C and 40°C, more particularly between room temperature and 40°C, said rate being between 30°C / min and 0.05°C / min, particularly between 10°C / min and 0.05°C / min, more particularly between 5°C / min and 0.05°C / min.

[0136] According to a particular embodiment, step e) related to the temperature program includes i) heating to a certain temperature, said certain temperature being between room temperature and 60°C, and ii) cooling to a certain temperature at a certain rate, said certain temperature being between 5°C and 40°C, said certain rate being between 30°C / min and 0.05°C / min, particularly between 10°C / min and 0.05°C / min, and even more particularly between 5°C / min and 0.05°C / min.

[0137] According to one embodiment, step f of filtration is performed using conventional glass fiber, conventional cellulose filter paper, PTFE (polytetrafluoroethylene) or PVDF (polyvinylidene fluoride), particularly cellulose filter paper with a 0.45 μm or 0.2 μm filter mesh.

[0138] According to one embodiment, the drying step (g) is carried out under vacuum at a temperature between 30°C and 60°C, particularly at 40°C.

[0139] According to one embodiment, the drying step (g) is carried out in an ambient atmosphere at a temperature between 30°C and 60°C, particularly at 40°C.

[0140] It should be understood that, in order to prepare a pharmaceutically acceptable salt of ABX464 as defined in this invention, 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine can be obtained in advance by the method described in WO2010 / 143169 or by any other suitable method.

[0141] According to certain embodiments, a method for preparing pharmaceutically acceptable salts (including their solvates or hydrates) of ABX464 includes the following steps:

[0142] a) Dissolve ABX464 in a solvent or a mixture of solvents;

[0143] b) Add counterions in the form of an acid to the mixture thus obtained in step a), wherein the acid itself may have been dissolved in a solvent or a mixture of solvents, thereby obtaining an ABX464:counterion molar ratio between 3:1 and 1:2, particularly between 5:2 and 1:2, even more particularly between 2:1 and 1:2 and even more particularly between 2:1 or 1:1.

[0144] c) Optionally, the solvent(s) are evaporated at a temperature between 0°C and the boiling point of the selected solvent(s) or solvent(mixtures) in steps a) and b), particularly between room temperature and 60°C, and even more particularly between room temperature and 50°C.

[0145] d) Optionally, add a solvent or a mixture of solvents.

[0146] e) Applying a temperature program, which includes i) heating at a reflux temperature, said temperature being between room temperature and the boiling point of (a variety of) solvents, particularly between room temperature and 60°C, and / or ii) cooling at a reflux temperature at a rate, said temperature being between 0°C and 60°C, particularly between 5°C and 40°C, even more particularly between room temperature and 40°C, said rate being between 30°C / min and 0.05°C / min, particularly between 10°C / min and 0.05°C / min, even more particularly between 5°C / min and 0.05°C / min;

[0147] f) Optionally, filtration is performed using conventional glass fiber, conventional cellulose filter paper, PTFE (polytetrafluoroethylene) or PVDF (polyvinylidene fluoride), particularly cellulose filter paper with a mesh size of 0.45 μm or 0.2 μm; and

[0148] g) Then optionally, drying is carried out under vacuum at a temperature between 30°C and 60°C, particularly at 40°C, or under an ambient atmosphere at a temperature between 30°C and 60°C, particularly at 40°C, to obtain the desired salt of ABX464.

[0149] According to certain embodiments, a method for preparing a pharmaceutically acceptable salt of ABX464 includes the following steps:

[0150] a) Dissolve ABX464 in methanol;

[0151] b) Add counterions, namely ethanesulfonic acid or naphthalenesulfonic acid, which are already dissolved in water / ethanol or ethanol, to the mixture thus obtained in step a), thereby obtaining an ABX464:counterion molar ratio between 3:1 and 1:2, particularly between 5:2 and 1:2, even more particularly between 2:1 and 1:2 and even more particularly between 2:1 or 1:1.

[0152] c) Optionally, the solvent(s) are evaporated at a temperature between 0°C and the boiling point of the (multiple) selected solvents or solvent mixtures of steps a) and b), particularly between room temperature and 60°C, and even more particularly between room temperature and 50°C.

[0153] d) Optionally, a solvent selected from ethyl acetate, THF, acetone, and mixtures thereof is added.

[0154] e) Applying a temperature program, which includes (i) a heating phase of reflux to a certain temperature, said certain temperature being between room temperature and the boiling point of (a variety of) solvents, particularly between room temperature and 60°C, and / or (ii) a cooling phase of reflux to a certain temperature at a certain rate, said certain temperature being between 0°C and 60°C, particularly between 5°C and 40°C, even more particularly between room temperature and 40°C, said certain rate being between 30°C / min and 0.05°C / min, particularly between 10°C / min and 0.05°C / min, even more particularly between 5°C / min and 0.05°C / min;

[0155] f) Optional filtering; and

[0156] g) Then optionally dry at a temperature between room temperature and 60°C to obtain the desired salt of ABX464.

[0157] According to certain embodiments, a method for preparing a pharmaceutically acceptable salt of ABX464 includes the following steps:

[0158] a) Dissolve ABX464 in methanol;

[0159] b) Add counterions, namely ethanesulfonic acid or naphthalenesulfonic acid, which are already dissolved in water / ethanol or ethanol, to the mixture thus obtained in step a), thereby obtaining an ABX464:counterion molar ratio between 3:1 and 1:2, particularly between 5:2 and 1:2, even more particularly between 2:1 and 1:2 and even more particularly between 2:1 or 1:1.

[0160] c) Optionally, the solvent(s) are evaporated at a temperature between 0°C and the boiling point of the (multiple) selected solvents or mixtures of (multiple) solvents in steps a) and b), particularly between room temperature and 60°C, and even more particularly between room temperature and 50°C.

[0161] d) Optionally, add a solvent selected from ethyl acetate, THF, acetone, and mixtures thereof.

[0162] e) Apply a temperature program, which includes (i) a heating phase at a temperature of 60°C during reflux, and / or (ii) a cooling phase at a certain rate during reflux at a certain temperature, said certain temperature being between 5°C and 40°C, more particularly between room temperature and 40°C, said certain rate being 1°C / min.

[0163] f) Optional filtering; and

[0164] g) Then optionally dry at 40°C to obtain the desired salt of ABX464.

[0165] According to a particular embodiment, ABX464 is dissolved in a C1-C6 aliphatic alcohol, particularly methanol, and then naphthalene-1,5-disulfonic acid, which is itself dissolved in a C1-C6 aliphatic alcohol, particularly ethanol, is added to the mixture, thereby obtaining an ABX464:counterion molar ratio between 3:1 and 1:2, particularly between 5:2 and 1:2, more particularly between 2:1 and 1:2, and even more particularly between 2:1 or 1:1. The mixture is then evaporated at room temperature (25°C) under N2, followed by the addition of acetone, application of a temperature program, filtration through 0.2 μm, and vacuum drying at 40°C to obtain anhydrous crystalline ABX464 heminaphthalenedisulfonate.

[0166] According to another specific embodiment, ABX464 is dissolved in a C1-C6 aliphatic alcohol, particularly methanol, and then ethanesulfonic acid, which is itself dissolved in a mixture of H2O / C1-C6 aliphatic alcohol, particularly water / ethanol, is added to the mixture, thereby obtaining an ABX464:counterion molar ratio between 3:1 and 1:2, particularly between 5:2 and 1:2, more particularly between 2:1 and 1:2, and even more particularly 1:1. The mixture is then evaporated at room temperature (25°C) under N2, followed by the addition of ethyl acetate, and then, with a temperature program applied, evaporated again at room temperature (25°C) under N2 to obtain anhydrous crystalline ABX464 ethanesulfonate.

[0167] According to another embodiment, ABX464 is dissolved in a C1-C6 aliphatic alcohol, particularly methanol, and then naphthalene-1,5-disulfonic acid, which is itself dissolved in a C1-C6 aliphatic alcohol, particularly ethanol, is added to the mixture, thereby obtaining an ABX464:counterion molar ratio between 3:1 and 1:2, particularly between 5:2 and 1:2, more particularly between 2:1 and 1:2, and even more particularly between 2:1. The mixture is then evaporated at 40°C under N2, followed by the addition of THF, then a temperature program is applied, followed by filtration at 0.2 μm and vacuum drying at 40°C to obtain a crystalline hemi-THF solvate of ABX464 hemi-naphthalene disulfonate.

[0168] ABX464 eutectic

[0169] As described above, in another aspect, the present invention relates to a eutectic of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine, selected from:

[0170] -8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine:L-proline, having a powder X-ray diffraction pattern showing peaks at 16.5, 20.6, 21.4, and 22.1 (±0.2 each time) in 2θ angles, and optionally further showing the following additional peaks in 2θ angles: 11.0, 15.9, 18.3, and 19.4 (±0.2 each time); and even optionally further showing the following additional peaks in 2θ angles: 6.1, 12.2, 12.6, 13.3, 13.7, 15.4, 17.3, and 22.4 (±0.2 each time), optionally further characterized by as Figure 1 The powder X-ray diffraction pattern shown and / or the single endothermic reaction with an initial temperature of 172.0 °C (±2 °C) are shown.

[0171] -8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine: gentic acid, having a powder X-ray diffraction pattern showing peaks at 7.9, 14.0, 15.2, and 25.2 (±0.2 each) in 2θ angles, and optionally further showing the following additional peaks in 2θ angles: 15.8, 16.9, 18.5, 19.9, 20.3, 23.0, and 24.7 (±0.2 each); and even optionally further showing the following additional peaks in 2θ angles: 7.6, 14.7, 16.1, 19.7, 21.6, 22.0, 22.3, 23.7, and 24.0 (±0.2 each), optionally further characterized by... Figure 2 The powder X-ray diffraction pattern shown and / or the single endothermic reaction with an initial temperature of 133.0 °C (±2 °C) are shown.

[0172] -8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine:malonic acid, having a powder X-ray diffraction pattern showing peaks at 9.5, 12.2, 15.8, 17.3, 19.7, 22.8, 24.8, and 25.6 (±0.2 each time) in 2θ angles, and optionally further showing the following additional peaks in 2θ angles: 19.0, 21.4, 24.6, 26.8, 27.6, and 29.9 (±0.2 each time); and even optionally further showing the following additional peaks in 2θ angles: 16.8, 17.8, 20.9, 23.8, 28.0, and 29.6 (±0.2 each time), optionally further characterized by... Figure 3 The powder X-ray diffraction pattern shown and / or the single endothermic reaction with an initial temperature of 109.0 °C (±2 °C); and

[0173] -8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine:4,4'-bipyridine, having a powder X-ray diffraction pattern showing peaks at 12.0, 19.2, 21.2, and 24.3 (±0.2 each time) in 2θ angles, and optionally further showing the following additional peaks in 2θ angles: 16.0, 17.0, 17.8, 20.3, 22.5, and 22.7 (±0.2 each time); and even optionally further showing the following additional peaks in 2θ angles: 8.5, 13.0, 15.7, 16.7, 20.9, 22.0, 23.1, 23.6, and 24.7 (±0.2 each time), optionally further characterized by... Figure 4 The powder X-ray diffraction pattern shown and / or the single endothermic reaction with an initial temperature of 127.0 °C (±2 °C) are shown.

[0174] In a particularly preferred embodiment, the cocrystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine is 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine:L-proline, having a powder X-ray diffraction pattern showing peaks at 16.5, 20.6, 21.4, and 22.1 (±0.2 each time) in 2θ angles, and optionally further showing the following additional peaks in 2θ angles: 11.0, 15.9, 18.3, and 19.4 (±0.2 each time); and even optionally further showing the following additional peaks in 2θ angles: 6.1, 12.2, 12.6, 13.3, 13.7, 15.4, 17.3, and 22.4 (±0.2 each time), optionally further characterized by... Figure 1 The powder X-ray diffraction pattern shown and / or the single endothermic reaction with an initial temperature of 172.0 °C (±2 °C) are shown.

[0175] The four eutectics are described in Example 1 (and) of this paper. Figure 1 Example 2 and Figure 2 Example 3 and Figure 3 ) and Example 4 (and Figure 4 This will be explained in the following section.

[0176] The characteristic X-ray powder diffraction pattern of the cocrystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine:L-proline can be found in Figure 1 The data are given in the table below, and its characteristic signals are summarized in Table 4:

[0177] Table 4

[0178]

[0179] According to one embodiment, the powder X-ray diffraction pattern of the cocrystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine:L-proline of the present invention shows at least one peak represented by a 2θ angle, said peak being selected from 16.5, 20.6, 21.4, 22.1, 11.0, 15.9, 18.3, 19.4, 6.1, 12.2, 12.6, 13.3, 13.7, 15.4, 17.3 and 22.4 (±0.2 each time).

[0180] According to another embodiment, the powder X-ray diffraction pattern of the eutectic of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine:L-proline of the present invention shows at least two peaks represented by a 2θ angle, said peaks being selected from 16.5, 20.6, 21.4, 22.1, 11.0, 15.9, 18.3, 19.4, 6.1, 12.2, 12.6, 13.3, 13.7, 15.4, 17.3 and 22.4 (±0.2 each).

[0181] According to another embodiment, the powder X-ray diffraction pattern of the eutectic of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine:L-proline of the present invention shows at least three peaks represented by a 2θ angle, said peaks being selected from 16.5, 20.6, 21.4, 22.1, 11.0, 15.9, 18.3, 19.4, 6.1, 12.2, 12.6, 13.3, 13.7, 15.4, 17.3 and 22.4 (±0.2 each).

[0182] According to another embodiment, the powder X-ray diffraction pattern of the eutectic of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine:L-proline of the present invention shows at least four peaks represented by a 2θ angle, said peaks being selected from 16.5, 20.6, 21.4, 22.1, 11.0, 15.9, 18.3, 19.4, 6.1, 12.2, 12.6, 13.3, 13.7, 15.4, 17.3 and 22.4 (±0.2 each).

[0183] According to another embodiment, the powder X-ray diffraction pattern of the eutectic of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine:L-proline of the present invention shows at least five peaks represented by a 2θ angle, said peaks being selected from 16.5, 20.6, 21.4, 22.1, 11.0, 15.9, 18.3, 19.4, 6.1, 12.2, 12.6, 13.3, 13.7, 15.4, 17.3 and 22.4 (±0.2 each).

[0184] According to another embodiment, the powder X-ray diffraction pattern of the cocrystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine:L-proline of the present invention shows at least six peaks represented by a 2θ angle, said peaks being selected from 16.5, 20.6, 21.4, 22.1, 11.0, 15.9, 18.3, 19.4, 6.1, 12.2, 12.6, 13.3, 13.7, 15.4, 17.3 and 22.4 (±0.2 each).

[0185] According to another embodiment, the powder X-ray diffraction pattern of the cocrystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine:L-proline of the present invention shows at least seven peaks represented by a 2θ angle, said peaks being selected from 16.5, 20.6, 21.4, 22.1, 11.0, 15.9, 18.3, 19.4, 6.1, 12.2, 12.6, 13.3, 13.7, 15.4, 17.3 and 22.4 (±0.2 each).

[0186] According to another embodiment, the powder X-ray diffraction pattern of the eutectic of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine:L-proline of the present invention shows at least eight peaks represented by a 2θ angle, said peaks being selected from 16.5, 20.6, 21.4, 22.1, 11.0, 15.9, 18.3, 19.4, 6.1, 12.2, 12.6, 13.3, 13.7, 15.4, 17.3 and 22.4 (±0.2 each).

[0187] According to another embodiment, the powder X-ray diffraction pattern of the eutectic of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine:L-proline of the present invention shows at least nine peaks represented by a 2θ angle, said peaks being selected from 16.5, 20.6, 21.4, 22.1, 11.0, 15.9, 18.3, 19.4, 6.1, 12.2, 12.6, 13.3, 13.7, 15.4, 17.3 and 22.4 (±0.2 each).

[0188] According to another embodiment, the powder X-ray diffraction pattern of the eutectic of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine:L-proline of the present invention shows at least 10 peaks represented by a 2θ angle, said peaks being selected from 16.5, 20.6, 21.4, 22.1, 11.0, 15.9, 18.3, 19.4, 6.1, 12.2, 12.6, 13.3, 13.7, 15.4, 17.3 and 22.4 (±0.2 each).

[0189] According to another embodiment, the powder X-ray diffraction pattern of the eutectic of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine:L-proline of the present invention shows at least 11 peaks represented by a 2θ angle, said peaks being selected from 16.5, 20.6, 21.4, 22.1, 11.0, 15.9, 18.3, 19.4, 6.1, 12.2, 12.6, 13.3, 13.7, 15.4, 17.3 and 22.4 (±0.2 each).

[0190] According to another embodiment, the powder X-ray diffraction pattern of the eutectic of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine:L-proline of the present invention shows at least 12 peaks represented by 2θ angles, said peaks being selected from 16.5, 20.6, 21.4, 22.1, 11.0, 15.9, 18.3, 19.4, 6.1, 12.2, 12.6, 13.3, 13.7, 15.4, 17.3 and 22.4 (±0.2 each).

[0191] According to another embodiment, the powder X-ray diffraction pattern of the eutectic of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine:L-proline of the present invention shows at least 13 peaks represented by 2θ angles, said peaks being selected from 16.5, 20.6, 21.4, 22.1, 11.0, 15.9, 18.3, 19.4, 6.1, 12.2, 12.6, 13.3, 13.7, 15.4, 17.3 and 22.4 (±0.2 each).

[0192] According to another embodiment, the powder X-ray diffraction pattern of the eutectic of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine:L-proline of the present invention shows at least 14 peaks represented by 2θ angles, said peaks being selected from 16.5, 20.6, 21.4, 22.1, 11.0, 15.9, 18.3, 19.4, 6.1, 12.2, 12.6, 13.3, 13.7, 15.4, 17.3 and 22.4 (±0.2 each).

[0193] According to another embodiment, the powder X-ray diffraction pattern of the eutectic of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine:L-proline of the present invention shows at least 15 peaks represented by a 2θ angle, said peaks being selected from 16.5, 20.6, 21.4, 22.1, 11.0, 15.9, 18.3, 19.4, 6.1, 12.2, 12.6, 13.3, 13.7, 15.4, 17.3 and 22.4 (±0.2 each).

[0194] According to another embodiment, the 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine:L-proline cocrystal of the present invention has a similarity to... Figure 1 The XRPD shown is essentially the same.

[0195] The characteristic X-ray powder diffraction pattern of the eutectic of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine:gentic acid can be found in Figure 2 The characteristics are given in the table below, and their feature signals are summarized in Table 5:

[0196] Table 5

[0197]

[0198] According to one embodiment, the powder X-ray diffraction pattern of the eutectic of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine:gentic acid of the present invention shows at least one peak represented by a 2θ angle, said peak being selected from 7.9, 14.0, 15.2, 25.2, 15.8, 16.9, 18.5, 19.9, 20.3, 23.0, 24.7, 7.6, 14.7, 16.1, 19.7, 21.6, 22.0, 22.3, 23.7 and 24.0 (±0.2 each time).

[0199] According to another embodiment, the powder X-ray diffraction pattern of the eutectic of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine:gentic acid of the present invention shows at least two peaks represented by a 2θ angle, said peaks being selected from 7.9, 14.0, 15.2, 25.2, 15.8, 16.9, 18.5, 19.9, 20.3, 23.0, 24.7, 7.6, 14.7, 16.1, 19.7, 21.6, 22.0, 22.3, 23.7 and 24.0 (±0.2 each).

[0200] According to another embodiment, the powder X-ray diffraction pattern of the eutectic of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine:gentic acid of the present invention shows at least three peaks represented by a 2θ angle, said peaks being selected from 7.9, 14.0, 15.2, 25.2, 15.8, 16.9, 18.5, 19.9, 20.3, 23.0, 24.7, 7.6, 14.7, 16.1, 19.7, 21.6, 22.0, 22.3, 23.7 and 24.0 (±0.2 each).

[0201] According to another embodiment, the powder X-ray diffraction pattern of the eutectic of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine:gentic acid of the present invention shows at least four peaks represented by a 2θ angle, said peaks being selected from 7.9, 14.0, 15.2, 25.2, 15.8, 16.9, 18.5, 19.9, 20.3, 23.0, 24.7, 7.6, 14.7, 16.1, 19.7, 21.6, 22.0, 22.3, 23.7 and 24.0 (±0.2 each).

[0202] According to another embodiment, the powder X-ray diffraction pattern of the eutectic of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine:gentic acid of the present invention shows at least five peaks represented by a 2θ angle, said peaks being selected from 7.9, 14.0, 15.2, 25.2, 15.8, 16.9, 18.5, 19.9, 20.3, 23.0, 24.7, 7.6, 14.7, 16.1, 19.7, 21.6, 22.0, 22.3, 23.7 and 24.0 (±0.2 each).

[0203] According to another embodiment, the powder X-ray diffraction pattern of the eutectic of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine:gentic acid of the present invention shows at least six peaks represented by a 2θ angle, said peaks being selected from 7.9, 14.0, 15.2, 25.2, 15.8, 16.9, 18.5, 19.9, 20.3, 23.0, 24.7, 7.6, 14.7, 16.1, 19.7, 21.6, 22.0, 22.3, 23.7 and 24.0 (±0.2 each).

[0204] According to another embodiment, the powder X-ray diffraction pattern of the eutectic of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine:gentic acid of the present invention shows at least seven peaks represented by a 2θ angle, said peaks being selected from 7.9, 14.0, 15.2, 25.2, 15.8, 16.9, 18.5, 19.9, 20.3, 23.0, 24.7, 7.6, 14.7, 16.1, 19.7, 21.6, 22.0, 22.3, 23.7 and 24.0 (±0.2 each).

[0205] According to another embodiment, the powder X-ray diffraction pattern of the eutectic of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine:gentic acid of the present invention shows at least eight peaks represented by a 2θ angle, said peaks being selected from 7.9, 14.0, 15.2, 25.2, 15.8, 16.9, 18.5, 19.9, 20.3, 23.0, 24.7, 7.6, 14.7, 16.1, 19.7, 21.6, 22.0, 22.3, 23.7 and 24.0 (±0.2 each).

[0206] According to another embodiment, the powder X-ray diffraction pattern of the eutectic of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine:gentic acid of the present invention shows at least nine peaks represented by a 2θ angle, said peaks being selected from 7.9, 14.0, 15.2, 25.2, 15.8, 16.9, 18.5, 19.9, 20.3, 23.0, 24.7, 7.6, 14.7, 16.1, 19.7, 21.6, 22.0, 22.3, 23.7 and 24.0 (±0.2 each).

[0207] According to another embodiment, the powder X-ray diffraction pattern of the eutectic of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine:gentic acid of the present invention shows at least 10 peaks represented by a 2θ angle, said peaks being selected from 7.9, 14.0, 15.2, 25.2, 15.8, 16.9, 18.5, 19.9, 20.3, 23.0, 24.7, 7.6, 14.7, 16.1, 19.7, 21.6, 22.0, 22.3, 23.7 and 24.0 (±0.2 each).

[0208] According to another embodiment, the powder X-ray diffraction pattern of the eutectic of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine:gentic acid of the present invention shows at least 11 peaks represented by a 2θ angle, said peaks being selected from 7.9, 14.0, 15.2, 25.2, 15.8, 16.9, 18.5, 19.9, 20.3, 23.0, 24.7, 7.6, 14.7, 16.1, 19.7, 21.6, 22.0, 22.3, 23.7 and 24.0 (±0.2 each).

[0209] According to another embodiment, the powder X-ray diffraction pattern of the eutectic of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine:gentic acid of the present invention shows at least 12 peaks represented at 2θ angles, said peaks being selected from 7.9, 14.0, 15.2, 25.2, 15.8, 16.9, 18.5, 19.9, 20.3, 23.0, 24.7, 7.6, 14.7, 16.1, 19.7, 21.6, 22.0, 22.3, 23.7 and 24.0 (±0.2 each).

[0210] According to another embodiment, the powder X-ray diffraction pattern of the eutectic of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine:gentic acid of the present invention shows at least 13 peaks represented by a 2θ angle, said peaks being selected from 7.9, 14.0, 15.2, 25.2, 15.8, 16.9, 18.5, 19.9, 20.3, 23.0, 24.7, 7.6, 14.7, 16.1, 19.7, 21.6, 22.0, 22.3, 23.7 and 24.0 (±0.2 each).

[0211] According to another embodiment, the powder X-ray diffraction pattern of the eutectic of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine:gentic acid of the present invention shows at least 14 peaks represented by 2θ angles, said peaks being selected from 7.9, 14.0, 15.2, 25.2, 15.8, 16.9, 18.5, 19.9, 20.3, 23.0, 24.7, 7.6, 14.7, 16.1, 19.7, 21.6, 22.0, 22.3, 23.7 and 24.0 (±0.2 each).

[0212] According to another embodiment, the powder X-ray diffraction pattern of the eutectic of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine:gentic acid of the present invention shows at least 15 peaks represented by a 2θ angle, said peaks being selected from 7.9, 14.0, 15.2, 25.2, 15.8, 16.9, 18.5, 19.9, 20.3, 23.0, 24.7, 7.6, 14.7, 16.1, 19.7, 21.6, 22.0, 22.3, 23.7 and 24.0 (±0.2 each).

[0213] According to another embodiment, the eutectic of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine:gentic acid of the present invention has a similarity to... Figure 2 The XRPD shown is essentially the same.

[0214] The characteristic X-ray powder diffraction pattern of the eutectic of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine:malonic acid can be found in Figure 3 The characteristics are given in the table below, and their feature signals are summarized in Table 6:

[0215] Table 6

[0216]

[0217]

[0218] According to one embodiment, the powder X-ray diffraction pattern of the eutectic of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine:malonic acid of the present invention shows at least one peak represented by a 2θ angle, said peak being selected from 9.5, 12.2, 15.8, 17.3, 19.7, 22.8, 24.8, 25.6, 19.0, 21.4, 24.6, 26.8, 27.6, 29.9, 16.8, 17.8, 20.9, 23.8, 28.0, and 29.6 (±0.2 each time).

[0219] According to another embodiment, the powder X-ray diffraction pattern of the eutectic of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine:malonic acid of the present invention shows at least two peaks at a 2θ angle, said peaks being selected from 9.5, 12.2, 15.8, 17.3, 19.7, 22.8, 24.8, 25.6, 19.0, 21.4, 24.6, 26.8, 27.6, 29.9, 16.8, 17.8, 20.9, 23.8, 28.0, and 29.6 (±0.2 each).

[0220] According to another embodiment, the powder X-ray diffraction pattern of the eutectic of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine:malonic acid of the present invention shows at least three peaks represented by a 2θ angle, said peaks being selected from 9.5, 12.2, 15.8, 17.3, 19.7, 22.8, 24.8, 25.6, 19.0, 21.4, 24.6, 26.8, 27.6, 29.9, 16.8, 17.8, 20.9, 23.8, 28.0, and 29.6 (±0.2 each).

[0221] According to another embodiment, the powder X-ray diffraction pattern of the eutectic of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine:malonic acid of the present invention shows at least four peaks represented by a 2θ angle, said peaks being selected from 9.5, 12.2, 15.8, 17.3, 19.7, 22.8, 24.8, 25.6, 19.0, 21.4, 24.6, 26.8, 27.6, 29.9, 16.8, 17.8, 20.9, 23.8, 28.0, and 29.6 (±0.2 each).

[0222] According to another embodiment, the powder X-ray diffraction pattern of the eutectic of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine:malonic acid of the present invention shows at least five peaks represented by a 2θ angle, said peaks being selected from 9.5, 12.2, 15.8, 17.3, 19.7, 22.8, 24.8, 25.6, 19.0, 21.4, 24.6, 26.8, 27.6, 29.9, 16.8, 17.8, 20.9, 23.8, 28.0, and 29.6 (±0.2 each).

[0223] According to another embodiment, the powder X-ray diffraction pattern of the eutectic of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine:malonic acid of the present invention shows at least six peaks represented by a 2θ angle, said peaks being selected from 9.5, 12.2, 15.8, 17.3, 19.7, 22.8, 24.8, 25.6, 19.0, 21.4, 24.6, 26.8, 27.6, 29.9, 16.8, 17.8, 20.9, 23.8, 28.0, and 29.6 (±0.2 each).

[0224] According to another embodiment, the powder X-ray diffraction pattern of the eutectic of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine:malonic acid of the present invention shows at least seven peaks represented by a 2θ angle, said peaks being selected from 9.5, 12.2, 15.8, 17.3, 19.7, 22.8, 24.8, 25.6, 19.0, 21.4, 24.6, 26.8, 27.6, 29.9, 16.8, 17.8, 20.9, 23.8, 28.0, and 29.6 (±0.2 each).

[0225] According to another embodiment, the powder X-ray diffraction pattern of the eutectic of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine:malonic acid of the present invention shows at least eight peaks represented by a 2θ angle, said peaks being selected from 9.5, 12.2, 15.8, 17.3, 19.7, 22.8, 24.8, 25.6, 19.0, 21.4, 24.6, 26.8, 27.6, 29.9, 16.8, 17.8, 20.9, 23.8, 28.0, and 29.6 (±0.2 each).

[0226] According to another embodiment, the powder X-ray diffraction pattern of the eutectic of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine:malonic acid of the present invention shows at least nine peaks represented by a 2θ angle, said peaks being selected from 9.5, 12.2, 15.8, 17.3, 19.7, 22.8, 24.8, 25.6, 19.0, 21.4, 24.6, 26.8, 27.6, 29.9, 16.8, 17.8, 20.9, 23.8, 28.0, and 29.6 (±0.2 each).

[0227] According to another embodiment, the powder X-ray diffraction pattern of the eutectic of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine:malonic acid of the present invention shows at least 10 peaks represented by a 2θ angle, said peaks being selected from 9.5, 12.2, 15.8, 17.3, 19.7, 22.8, 24.8, 25.6, 19.0, 21.4, 24.6, 26.8, 27.6, 29.9, 16.8, 17.8, 20.9, 23.8, 28.0, and 29.6 (±0.2 each).

[0228] According to another embodiment, the powder X-ray diffraction pattern of the eutectic of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine:malonic acid of the present invention shows at least 11 peaks represented by a 2θ angle, said peaks being selected from 9.5, 12.2, 15.8, 17.3, 19.7, 22.8, 24.8, 25.6, 19.0, 21.4, 24.6, 26.8, 27.6, 29.9, 16.8, 17.8, 20.9, 23.8, 28.0, and 29.6 (±0.2 each).

[0229] According to another embodiment, the powder X-ray diffraction pattern of the eutectic of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine:malonic acid of the present invention shows at least 12 peaks represented by a 2θ angle, said peaks being selected from 9.5, 12.2, 15.8, 17.3, 19.7, 22.8, 24.8, 25.6, 19.0, 21.4, 24.6, 26.8, 27.6, 29.9, 16.8, 17.8, 20.9, 23.8, 28.0, and 29.6 (±0.2 each).

[0230] According to another embodiment, the powder X-ray diffraction pattern of the eutectic of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine:malonic acid of the present invention shows at least 13 peaks represented by a 2θ angle, said peaks being selected from 9.5, 12.2, 15.8, 17.3, 19.7, 22.8, 24.8, 25.6, 19.0, 21.4, 24.6, 26.8, 27.6, 29.9, 16.8, 17.8, 20.9, 23.8, 28.0, and 29.6 (±0.2 each).

[0231] According to another embodiment, the powder X-ray diffraction pattern of the eutectic of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine:malonic acid of the present invention shows at least 14 peaks represented by 2θ angles, said peaks being selected from 9.5, 12.2, 15.8, 17.3, 19.7, 22.8, 24.8, 25.6, 19.0, 21.4, 24.6, 26.8, 27.6, 29.9, 16.8, 17.8, 20.9, 23.8, 28.0, and 29.6 (±0.2 each).

[0232] According to another embodiment, the powder X-ray diffraction pattern of the eutectic of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine:malonic acid of the present invention shows at least 15 peaks represented by a 2θ angle, said peaks being selected from 9.5, 12.2, 15.8, 17.3, 19.7, 22.8, 24.8, 25.6, 19.0, 21.4, 24.6, 26.8, 27.6, 29.9, 16.8, 17.8, 20.9, 23.8, 28.0, and 29.6 (±0.2 each).

[0233] According to another embodiment, the eutectic of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine:malonic acid of the present invention has a similarity to... Figure 3 The XRPD shown is essentially the same.

[0234] The characteristic X-ray powder diffraction pattern of the eutectic of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine:4,4'-bipyridine can be found in Figure 4 The data are given in [the table], and its characteristic signals are summarized in Table 7 below:

[0235] Table 7

[0236]

[0237]

[0238] According to one embodiment, the powder X-ray diffraction pattern of the eutectic of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine:4,4'-bipyridine of the present invention shows at least one peak represented by a 2θ angle, said peak being selected from 12.0, 19.2, 21.2, 24.3, 16.0, 17.0, 17.8, 20.3, 22.5, 22.7, 8.5, 13.0, 15.7, 16.7, 20.9, 22.0, 23.1, 23.6 and 24.7 (±0.2 each time).

[0239] According to another embodiment, the powder X-ray diffraction pattern of the eutectic of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine:4,4'-bipyridine of the present invention shows at least two peaks at a 2θ angle, said peaks being selected from 12.0, 19.2, 21.2, 24.3, 16.0, 17.0, 17.8, 20.3, 22.5, 22.7, 8.5, 13.0, 15.7, 16.7, 20.9, 22.0, 23.1, 23.6 and 24.7 (±0.2 each).

[0240] According to another embodiment, the powder X-ray diffraction pattern of the eutectic of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine:4,4'-bipyridine of the present invention shows at least three peaks represented by a 2θ angle, said peaks being selected from 12.0, 19.2, 21.2, 24.3, 16.0, 17.0, 17.8, 20.3, 22.5, 22.7, 8.5, 13.0, 15.7, 16.7, 20.9, 22.0, 23.1, 23.6 and 24.7 (±0.2 each).

[0241] According to another embodiment, the powder X-ray diffraction pattern of the eutectic of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine:4,4'-bipyridine of the present invention shows at least four peaks represented by a 2θ angle, said peaks being selected from 12.0, 19.2, 21.2, 24.3, 16.0, 17.0, 17.8, 20.3, 22.5, 22.7, 8.5, 13.0, 15.7, 16.7, 20.9, 22.0, 23.1, 23.6 and 24.7 (±0.2 each).

[0242] According to another embodiment, the powder X-ray diffraction pattern of the eutectic of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine:4,4'-bipyridine of the present invention shows at least five peaks represented by a 2θ angle, said peaks being selected from 12.0, 19.2, 21.2, 24.3, 16.0, 17.0, 17.8, 20.3, 22.5, 22.7, 8.5, 13.0, 15.7, 16.7, 20.9, 22.0, 23.1, 23.6 and 24.7 (±0.2 each).

[0243] According to another embodiment, the powder X-ray diffraction pattern of the eutectic of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine:4,4'-bipyridine of the present invention shows at least six peaks represented by a 2θ angle, said peaks being selected from 12.0, 19.2, 21.2, 24.3, 16.0, 17.0, 17.8, 20.3, 22.5, 22.7, 8.5, 13.0, 15.7, 16.7, 20.9, 22.0, 23.1, 23.6 and 24.7 (±0.2 each).

[0244] According to another embodiment, the powder X-ray diffraction pattern of the eutectic of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine:4,4'-bipyridine of the present invention shows at least seven peaks represented by a 2θ angle, said peaks being selected from 12.0, 19.2, 21.2, 24.3, 16.0, 17.0, 17.8, 20.3, 22.5, 22.7, 8.5, 13.0, 15.7, 16.7, 20.9, 22.0, 23.1, 23.6 and 24.7 (±0.2 each).

[0245] According to another embodiment, the powder X-ray diffraction pattern of the eutectic of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine:4,4'-bipyridine of the present invention shows at least eight peaks represented by a 2θ angle, said peaks being selected from 12.0, 19.2, 21.2, 24.3, 16.0, 17.0, 17.8, 20.3, 22.5, 22.7, 8.5, 13.0, 15.7, 16.7, 20.9, 22.0, 23.1, 23.6 and 24.7 (±0.2 each).

[0246] According to another embodiment, the powder X-ray diffraction pattern of the eutectic of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine:4,4'-bipyridine of the present invention shows at least nine peaks represented by a 2θ angle, said peaks being selected from 12.0, 19.2, 21.2, 24.3, 16.0, 17.0, 17.8, 20.3, 22.5, 22.7, 8.5, 13.0, 15.7, 16.7, 20.9, 22.0, 23.1, 23.6 and 24.7 (±0.2 each).

[0247] According to another embodiment, the powder X-ray diffraction pattern of the eutectic of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine:4,4'-bipyridine of the present invention shows at least 10 peaks represented at 2θ angles, said peaks being selected from 12.0, 19.2, 21.2, 24.3, 16.0, 17.0, 17.8, 20.3, 22.5, 22.7, 8.5, 13.0, 15.7, 16.7, 20.9, 22.0, 23.1, 23.6 and 24.7 (±0.2 each).

[0248] According to another embodiment, the powder X-ray diffraction pattern of the eutectic of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine:4,4'-bipyridine of the present invention shows at least 11 peaks represented at 2θ angles, said peaks being selected from 12.0, 19.2, 21.2, 24.3, 16.0, 17.0, 17.8, 20.3, 22.5, 22.7, 8.5, 13.0, 15.7, 16.7, 20.9, 22.0, 23.1, 23.6 and 24.7 (±0.2 each).

[0249] According to another embodiment, the powder X-ray diffraction pattern of the eutectic of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine:4,4'-bipyridine of the present invention shows at least 12 peaks represented at 2θ angles, said peaks being selected from 12.0, 19.2, 21.2, 24.3, 16.0, 17.0, 17.8, 20.3, 22.5, 22.7, 8.5, 13.0, 15.7, 16.7, 20.9, 22.0, 23.1, 23.6 and 24.7 (±0.2 each).

[0250] According to another embodiment, the powder X-ray diffraction pattern of the eutectic of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine:4,4'-bipyridine of the present invention shows at least 13 peaks represented at 2θ angles, said peaks being selected from 12.0, 19.2, 21.2, 24.3, 16.0, 17.0, 17.8, 20.3, 22.5, 22.7, 8.5, 13.0, 15.7, 16.7, 20.9, 22.0, 23.1, 23.6 and 24.7 (±0.2 each).

[0251] According to another embodiment, the powder X-ray diffraction pattern of the eutectic of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine:4,4'-bipyridine of the present invention shows at least 14 peaks represented by a 2θ angle, said peaks being selected from 12.0, 19.2, 21.2, 24.3, 16.0, 17.0, 17.8, 20.3, 22.5, 22.7, 8.5, 13.0, 15.7, 16.7, 20.9, 22.0, 23.1, 23.6 and 24.7 (±0.2 each).

[0252] According to another embodiment, the powder X-ray diffraction pattern of the eutectic of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine:4,4'-bipyridine of the present invention shows at least 15 peaks represented at 2θ angles, said peaks being selected from 12.0, 19.2, 21.2, 24.3, 16.0, 17.0, 17.8, 20.3, 22.5, 22.7, 8.5, 13.0, 15.7, 16.7, 20.9, 22.0, 23.1, 23.6 and 24.7 (±0.2 each).

[0253] According to another embodiment, the eutectic of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine:4,4'-bipyridine of the present invention has a similarity to... Figure 4 The XRPD shown is essentially the same.

[0254] Method for preparing ABX464 eutectic

[0255] According to another aspect, the present invention further relates to a method for preparing a cocrystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined herein, the method comprising the following steps:

[0256] a) Dissolve ABX464 in a solvent or a mixture of solvents;

[0257] b) Add a co-former to the mixture thus obtained in step a), which may be already dissolved in a solvent or solvent mixture and is selected from L-proline, gentian acid, malonic acid and 4,4'-bipyridine, thereby obtaining ABX464:co-former in a molar ratio between 3:1 and 1:2, particularly between 5:2 and 1:2, more particularly between 2:1 and 1:2 and even more particularly between 2:1 or 1:1;

[0258] c) Optionally, the solvent(s) are evaporated at a temperature between 0°C and the boiling point of the (multiple) selected solvents or mixtures of (multiple) solvents in steps a) and b), particularly between room temperature and 60°C, and even more particularly between room temperature and 50°C.

[0259] d) Optionally, add a solvent or a mixture of solvents.

[0260] e) Apply temperature program;

[0261] f) Optional filtering; and

[0262] g) Then optionally dry at a temperature between room temperature and 60°C to obtain the desired eutectic of ABX464.

[0263] According to one embodiment, the solvents used in steps a), b), and d) are any solvents conventionally used in the crystallization step, particularly organic solvents, more particularly selected from C1-C6 aliphatic alcohols, methyl ethyl ketones (also known as butanone or MEK), cyclohexane, alkanes such as heptane, dichloromethane, chloroform, formic acid, DMSO, 1-methyl-2-pyrrolidone, acetone, acetonitrile, tetrahydrofuran (THF), diethyl ether, dioxane, toluene, ethyl acetate, optionally mixed with water, and mixtures thereof, even more particularly selected from C1-C6 aliphatic alcohols, mixtures of H2O / C1-C6 aliphatic alcohols, acetonitrile and mixtures thereof, and even more particularly selected from methanol, ethanol, isopropanol, H2O / methanol, H2O / ethanol, acetonitrile and mixtures thereof.

[0264] Technicians know how to determine the more suitable (multiple) solvents in each step a), b), and d) to obtain the desired eutectic.

[0265] According to one implementation, the (multiple) solvents used in steps a), b) and / or d) are the same.

[0266] According to another embodiment, the solvents used in steps a), b), and / or d) are different.

[0267] According to one embodiment, evaporation step c is carried out under an inert gas such as N2.

[0268] According to one embodiment, step e) related to the temperature procedure includes a heating phase of reflux to a certain temperature, said certain temperature being between room temperature and the boiling point of (a variety of) solvents, particularly between room temperature and 60°C.

[0269] According to one embodiment, step e) related to the temperature program includes a cooling phase at a certain rate after refluxing to a certain temperature, wherein the certain temperature is between 0°C and 60°C, particularly between 5°C and 40°C, and even more particularly between room temperature and 40°C, and the certain rate is between 30°C / min and 0.05°C / min, particularly between 10°C / min and 0.05°C / min, and even more particularly between 5°C / min and 0.05°C / min.

[0270] According to one embodiment, step e) related to the temperature program includes i) heating at a reflux temperature, said temperature being between room temperature and the boiling point of (multiple) solvents, particularly between room temperature and 60°C, and / or ii) cooling at a reflux temperature at a rate, said temperature being between 0°C and 60°C, particularly between 5°C and 40°C, more particularly between room temperature and 40°C, said rate being between 30°C / min and 0.05°C / min, particularly between 10°C / min and 0.05°C / min, more particularly between 5°C / min and 0.05°C / min.

[0271] According to a particular embodiment, step e) related to the temperature program includes i) heating to a certain temperature, said certain temperature being between room temperature and 60°C, and ii) cooling to a certain temperature at a certain rate, said certain temperature being between 5°C and 40°C, said certain rate being between 30°C / min and 0.05°C / min, particularly between 10°C / min and 0.05°C / min, and even more particularly between 5°C / min and 0.05°C / min.

[0272] According to one embodiment, step f of filtration is performed using conventional glass fiber, conventional cellulose filter paper, PTFE (polytetrafluoroethylene) or PVDF (polyvinylidene fluoride), particularly cellulose filter paper with a 0.45 μm or 0.2 μm filter mesh.

[0273] According to one embodiment, the drying step (g) is carried out under vacuum at a temperature between 30°C and 60°C, particularly at 40°C.

[0274] According to one embodiment, the drying step (g) is carried out in an ambient atmosphere at a temperature between 30°C and 60°C, particularly at 40°C.

[0275] According to a specific embodiment, the method for preparing the cocrystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined in this invention includes the following steps:

[0276] a) Dissolve ABX464 in a solvent or a mixture of solvents;

[0277] b) Add a eutectic form to the mixture thus obtained in step a), which may be already dissolved in a solvent or solvent mixture and is selected from L-proline, gentian acid, malonic acid and 4,4'-bipyridine, thereby obtaining ABX464: eutectic form in a molar ratio between 3:1 and 1:2, particularly between 5:2 and 1:2, more particularly between 2:1 and 1:2 and even more particularly between 2:1 or 1:1;

[0278] c) Optionally, the solvent(s) are evaporated at a temperature between 0°C and the boiling point of the (multiple) selected solvents or mixtures of (multiple) solvents in steps a) and b), particularly between room temperature and 60°C, and even more particularly between room temperature and 50°C.

[0279] d) Optionally, add a solvent or a mixture of solvents.

[0280] e) Applying a temperature program, which includes i) heating at a reflux temperature, the certain temperature being between room temperature and 60°C, and / or ii) cooling at a reflux temperature at a certain rate, the certain temperature being between 5°C and 40°C, the certain rate being between 30°C / min and 0.05°C / min, particularly between 10°C / min and 0.05°C / min, and even more particularly between 5°C / min and 0.05°C / min;

[0281] f) Optionally, filtration is performed using conventional glass fiber, conventional cellulose filter paper, PTFE (polytetrafluoroethylene) or PVDF (polyvinylidene fluoride), particularly cellulose filter paper with a mesh size of 0.45 μm or 0.2 μm; and

[0282] g) Then optionally, drying is carried out under vacuum at a temperature between 30°C and 60°C, particularly at 40°C, or in an ambient atmosphere at a temperature between 30°C and 60°C, particularly at 40°C, in order to obtain the desired eutectic of ABX464.

[0283] According to another specific embodiment, the method for preparing the cocrystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined in this invention includes the following steps:

[0284] a) Dissolve ABX464 in methanol, ethanol, isopropanol, H2O / methanol, H2O / ethanol, acetonitrile, or a mixture thereof;

[0285] b) Add the eutectic form to the mixture thus obtained in step a), which may be already dissolved in methanol, ethanol, isopropanol, H2O / methanol, H2O / ethanol, acetonitrile or mixtures thereof and is selected from L-proline, gentian acid, malonic acid and 4,4'-bipyridine, thereby obtaining ABX464:eutectic form comprising a molar ratio between 3:1 and 1:2, particularly between 5:2 and 1:2, more particularly between 2:1 and 1:2 and even more particularly between 2:1 or 1:1;

[0286] c) Optionally, the solvent is evaporated at a temperature between 0°C and the boiling point of the (multiple) selected solvents or mixtures of (multiple) solvents in steps a) and b), particularly between room temperature and 60°C, and even more particularly between room temperature and 50°C.

[0287] d) Optionally, a solvent selected from methanol, ethanol, isopropanol, H2O / methanol, H2O / ethanol, acetonitrile, and mixtures thereof are added.

[0288] e) Apply temperature program;

[0289] f) Optional filtering; and

[0290] g) Then optionally dry at a temperature between room temperature and 60°C to obtain the desired eutectic of ABX464.

[0291] According to another specific embodiment, the method for preparing the cocrystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined in this invention includes the following steps:

[0292] a) Dissolve ABX464 in methanol, ethanol, isopropanol, H2O / methanol, H2O / ethanol, acetonitrile, or a mixture thereof;

[0293] b) Add the eutectic form to the mixture thus obtained in step a), which may be already dissolved in methanol, ethanol, isopropanol, H2O / methanol, H2O / ethanol, acetonitrile or mixtures thereof and is selected from L-proline, gentian acid, malonic acid and 4,4'-bipyridine, thereby obtaining ABX464:eutectic form in a molar ratio between 3:1 and 1:2, particularly between 5:2 and 1:2, more particularly between 2:1 and 1:2 and even more particularly between 2:1 or 1:1;

[0294] c) Optionally, the solvent(s) are evaporated at a temperature between 0°C and the boiling point of the (multiple) selected solvents or mixtures of (multiple) solvents in steps a) and b), particularly between room temperature and 60°C, and even more particularly between room temperature and 50°C.

[0295] d) Optionally, a solvent selected from methanol, ethanol, isopropanol, H2O / methanol, H2O / ethanol, acetonitrile, and mixtures thereof are added.

[0296] e) Applying a temperature program, which includes i) heating at a reflux temperature, the certain temperature being between room temperature and 60°C, and / or ii) cooling at a reflux temperature at a certain rate, the certain temperature being between 5°C and 40°C, the certain rate being between 30°C / min and 0.05°C / min, particularly between 10°C / min and 0.05°C / min, and even more particularly between 5°C / min and 0.05°C / min;

[0297] f) Optionally, filtration is performed using conventional glass fiber, conventional cellulose filter paper, PTFE (polytetrafluoroethylene) or PVDF (polyvinylidene fluoride), particularly cellulose filter paper with a mesh size of 0.45 μm or 0.2 μm; and

[0298] g) Then optionally, drying is carried out under vacuum at a temperature between 30°C and 60°C, particularly at 40°C, or in an ambient atmosphere at a temperature between 30°C and 60°C, particularly at 40°C, in order to obtain the desired eutectic of ABX464.

[0299] According to another aspect, the present invention further relates to a method for preparing a cocrystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined herein, the method comprising the following steps:

[0300] -a') In a suitable solvent or solvent mixture, 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine is physically mixed with a cocrystal formed from L-proline, gentian acid, malonic acid, and 4,4'-bipyridine in a molar ratio between 2:1 and 1:2, particularly in a molar ratio of 1:1; and

[0301] -b') In the presence of a drop of solvent or a mixture of solvents, grind the physical mixture thus obtained from step a) to obtain a eutectic.

[0302] Technicians know how to determine the more suitable (multiple) solvents in each step a') and b') to obtain the desired eutectic.

[0303] According to one embodiment, the solvents used in steps a') and b') are any solvents conventionally used in the crystallization step, particularly organic solvents, more particularly selected from C1-C6 aliphatic alcohols, methyl ethyl ketones (also known as butanone or MEK), cyclohexane, alkanes such as heptane, dichloromethane, chloroform, formic acid, DMSO, 1-methyl-2-pyrrolidone, acetone, acetonitrile, tetrahydrofuran (THF), diethyl ether, dioxane, toluene, ethyl acetate, optionally mixed with water, and mixtures thereof, even more particularly selected from C1-C6 aliphatic alcohols, mixtures of H2O / C1-C6 aliphatic alcohols, acetonitrile and mixtures thereof, and even more particularly selected from methanol, ethanol, isopropanol, H2O / methanol, H2O / ethanol, acetonitrile and mixtures thereof.

[0304] In some implementations, the grinding is performed using a Retsch MM200 instrument, milling at 20 Hz for 45 min.

[0305] According to one embodiment, the grinding is performed using non-oxidizable balls.

[0306] According to one embodiment, the grinding is performed by using horizontal motion, particularly horizontal motion with a frequency in the range of 20-30 Hz.

[0307] Advantageously, horizontal exercise can be applied for a period of time, ranging from 15 minutes to 3 hours, especially 45 minutes.

[0308] According to a particular embodiment, the present invention further relates to a method for preparing a cocrystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined herein, the method comprising the following steps:

[0309] -a') In a suitable solvent selected from methanol, ethanol, isopropanol, H2O / methanol, H2O / ethanol, acetonitrile, and mixtures thereof, 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine is physically mixed with a cocrystal formed from L-proline, gentianic acid, malonic acid, and 4,4'-bipyridine in a molar ratio between 2:1 and 1:2, particularly in a molar ratio of 1:1; and

[0310] -b') In the presence of a drop of a solvent selected from methanol, ethanol, isopropanol, H2O / methanol, H2O / ethanol, acetonitrile, and mixtures thereof, grind the physical mixture obtained from step a) to obtain a eutectic.

[0311] It should be understood that, in order to prepare the eutectic of ABX464, 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine can be obtained in advance from the method described in WO2010 / 143169 or from any other suitable method.

[0312] Eutectic of ABX464 according to the present invention, pharmaceutically acceptable salt of ABX464, and the drug for use as a pharmaceutical. Composition

[0313] According to another aspect, the present invention further relates to pharmaceutical compositions comprising at least one cocrystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined herein and / or at least one pharmaceutically acceptable salt (including its solvates and / or hydrates) of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as one or more active ingredients, and at least one pharmaceutically acceptable excipient.

[0314] According to another aspect, the present invention further relates to pharmaceutical compositions, wherein the pharmaceutical composition comprises at least one of at least one cocrystal as defined in the present invention and / or at least one of a pharmaceutically acceptable salt (including its solvates and / or hydrates) of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined in the present invention, as the sole (multiple) pharmaceutically active ingredient.

[0315] The pharmaceutically acceptable compositions of the present invention can be administered to humans and other animals orally, rectally, parenterally, intracerebrospinally, intravaginally, intraperitoneally, topically (e.g., by powder, ointment, or drops), sublingually, or as oral or nasal sprays, depending on the severity of the infection to be treated. The term "parentereal" as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional, and intracranial injection or infusion techniques. In some embodiments, the active ingredient ABX464 contained in a cocrystal or salt of the present invention may be administered orally or parenterally once or more at dose levels of about 0.01 mg / kg to about 50 mg / kg and preferably about 1 mg / kg to about 25 mg / kg of the subject's body weight per day, to achieve the desired therapeutic effect.

[0316] 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 cocrystals of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined in this invention and / or pharmaceutically acceptable salts (including solvates and / or hydrates) of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined in this invention, liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers, and emulsifiers such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butanediol, dimethylformamide, oils (specifically, cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerin, tetrahydrofurfuryl alcohol, fatty acid esters of polyethylene glycol and sorbitol, and mixtures thereof. In addition to inert diluents, oral compositions may also contain adjuvants such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents, coloring agents, and aroma agents. When an aqueous suspension is required for oral use, a cocrystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined in this invention and / or a pharmaceutically acceptable salt (including its solvates and / or hydrates) of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined in this invention may be combined with emulsifiers and suspending agents.

[0317] According to known techniques, injectable formulations, such as sterile injectable aqueous or oily suspensions, can be formulated using suitable dispersants or wetting agents and suspending agents. The sterile injectable formulations can also be sterile injectable solutions, suspensions, or emulsions in non-toxic, parenteral-acceptable diluents or solvents, such as solutions in 1,3-butanediol. Acceptable solvents and media that can be used include water, USP Ringer's solution, and isotonic sodium chloride solution. Furthermore, sterile non-volatile oils are commonly used as solvents or suspending media. For this purpose, any mild non-volatile oil can be used, including synthetic monoglycerides or diglycerides. Additionally, fatty acids such as oleic acid are used in the preparation of injectable formulations.

[0318] Injectable formulations can be sterilized, for example, by filtration through a bacterial trap or by incorporating a sterilizing agent in the form of a sterile solid composition, which can be dissolved or dispersed in sterile water or other sterile injectable media prior to use.

[0319] The composition for rectal or vaginal administration is preferably a suppository, which can be prepared by mixing a cocrystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined in this invention and / or a pharmaceutically acceptable salt (including its solvates and / or hydrates) of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined in this invention with a suitable non-irritating excipient or carrier (such as cocoa butter, polyethylene glycol, or suppository wax), which is solid at ambient temperature and liquid at body temperature, and thus melts and releases active ABX464 in the rectal or vaginal cavity.

[0320] Solid dosage forms for oral administration include capsules, tablets, pills, powders, lozenges, chewing gum, and granules. In such solid dosage forms, a cocrystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined in this invention and / or a pharmaceutically acceptable salt (including its solvates and / or hydrates) of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined in this invention is mixed with: at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate, and / or a) fillers or extenders such as starch (e.g., corn starch), lactose, sucrose, glucose, mannitol, and silicate; b) binders such as carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; c) humectants such as glycerin; d) disintegrants such as agar, calcium carbonate, potato or cassava starch, alginate, certain silicates, and sodium carbonate; e) solution retarding agents. (a) agents such as paraffin wax, (b) absorption enhancers such as quaternary ammonium compounds, (c) wetting agents such as cetyl alcohol and glyceryl monostearate, (d) absorbents such as kaolin and bentonite, and (e) 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 forms may also contain buffers. If desired, certain sweeteners, flavoring agents, or coloring agents may also be added.

[0321] Similar solid compositions can also be used as fillers in soft and hard-filled gelatin capsules using excipients such as lactose or milk sugar and high molecular weight polyethylene glycol. Solid dosage forms such as tablets, sugar-coated pills, capsules, pellets, and granules can be prepared using coatings and shells such as enteric coatings and other coatings well-known in the pharmaceutical industry. These may optionally contain light-blocking agents and may also be compositions that optionally release (multiple) active ingredients in a delayed manner, either only or preferably in a specific portion of the intestine. Examples of usable encapsulation compositions include polymeric substances and waxes. Similar solid compositions can also be used as fillers in soft and hard-filled gelatin capsules using excipients such as lactose or milk sugar and high molecular weight polyethylene glycol.

[0322] The cocrystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined in this invention and / or pharmaceutically acceptable salts of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined in this invention (including their solvates and / or hydrates) may also be in microencapsulated form with one or more excipients as described above. Solid dosage forms such as tablets, sugar-coated pills, capsules, pellets, and granules can be prepared using coatings and shells such as enteric coatings, controlled-release coatings, and other coatings well known in the pharmaceutical formulation field. In such solid dosage forms, the cocrystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined in this invention and / or pharmaceutically acceptable salts of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined in this invention (including their solvates and / or hydrates) may be mixed with at least one inert diluent such as sucrose, lactose, or starch.

[0323] In accordance with conventional practice, such dosage forms may also contain substances other than inert diluents, such as tableting lubricants and other tableting aids, such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets, and pills, the dosage forms may also contain buffers. They may optionally contain light-blocking agents and may also be compositions that optionally release (multiple) active ingredients in a delayed manner, either only or preferentially, in specific portions of the intestine. Examples of usable encapsulation compositions include polymers and waxes.

[0324] The pharmaceutically acceptable compositions of the present invention can also be applied topically, particularly when the therapeutic target includes areas or organs that can be easily reached by topical application, including diseases of the eyes, skin, or lower intestine. Suitable topical formulations can be readily prepared for each of these areas or organs.

[0325] It can be applied topically to the lower intestine using rectal suppositories (see above) or as a suitable enema. Topical transdermal patches can also be used.

[0326] For topical application, the provided pharmaceutically acceptable compositions may be formulated in suitable ointments containing an active ingredient suspended or dissolved in one or more carriers. Topical application carriers for eutectic forms of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined in this invention and / or pharmaceutically acceptable salts (including their solvates and / or hydrates) of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined in this invention include, but are not limited to, mineral oils, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsified waxes, and water. Alternatively, the provided pharmaceutically acceptable compositions may be formulated in suitable lotions or creams containing an active ingredient suspended or dissolved in one or more pharmaceutically acceptable carriers.

[0327] Suitable carriers include, but are not limited to: mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecyl alcohol, benzyl alcohol, and water.

[0328] Additionally, the present invention contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of the compound to the body. Such dosage forms can be prepared by dissolving or dispensing a cocrystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined in the present invention and / or a pharmaceutically acceptable salt (including its solvates and / or hydrates) of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined in 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 providing a rate-controlled membrane or by dispersing a cocrystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined in the present invention and / or a pharmaceutically acceptable salt (including its solvates and / or hydrates) of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined in the present invention in a polymer matrix or gel.

[0329] Topical or transdermal dosage forms of eutectic forms of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined in this invention and / or pharmaceutically acceptable salts (including their solvates and / or hydrates) of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined in this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalers, or patches.

[0330] The cocrystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined in this invention and / or a pharmaceutically acceptable salt (including its solvates and / or hydrates) of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined in this invention are mixed under sterile conditions with a pharmaceutically acceptable carrier and any desired preservatives or buffers that may be required.

[0331] Ophthalmic preparations, ear drops, and eye drops are also considered within the scope of this invention.

[0332] In practice, for ophthalmic applications, the pharmaceutically acceptable compositions provided can be formulated as micronized suspensions in isotonic, pH-adjusted sterile saline, or preferably, solutions in isotonic, pH-adjusted sterile saline, with or without preservatives such as benzalkonium chloride. Alternatively, for ophthalmic applications, the pharmaceutically acceptable compositions can be formulated in ointments such as petrolatum.

[0333] The pharmaceutically acceptable compositions of the present invention can also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the field of pharmaceutical formulation and can be prepared as solutions in saline containing benzyl alcohol or other suitable preservatives, bioavailability enhancers, fluorocarbons, and / or other conventional solubilizers or dispersants. Most preferably, the pharmaceutically acceptable compositions of the present invention are formulated for oral administration. Such formulations can be administered with or without food.

[0334] Therefore, according to a particular embodiment, a pharmaceutical composition comprising a cocrystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined in this invention and / or a pharmaceutically acceptable salt (including its solvates and / or hydrates) of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined in this invention and at least one pharmaceutically acceptable excipient is particularly in the form of tablets, capsules, pills, lozenges, chewing gum, powders, granules, suppositories, emulsions, microemulsions, solutions such as aqueous solutions, suspensions such as aqueous suspensions, syrups, elixirs, ointments, drops, pastes, creams, lotions, gels, sprays, inhalants, or patches.

[0335] In some embodiments, the pharmaceutically acceptable composition of the present invention is administered without food. In other embodiments, the pharmaceutically acceptable composition of the present invention is administered with food.

[0336] The amount of a cocrystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined in this invention and / or a pharmaceutically acceptable salt (including its solvates and / or hydrates) of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined in this invention, which can be combined with excipients or carrier substances in a single dosage form to produce a composition, will vary depending on the host being treated and the specific administration method.

[0337] In the pharmaceutical compositions according to the invention, more particularly references may be made to those suitable for oral, parenteral (intravenous or subcutaneous) or nasal administration, tablets or sugar-coated pills, granules, sublingual tablets, capsules, lozenges, suppositories, creams, ointments, dermal gels, injectable formulations, drinkable suspensions, and chewing gum.

[0338] According to a particular embodiment, the pharmaceutical composition according to the invention is an oral pharmaceutical composition.

[0339] The oral pharmaceutical compositions of the present invention may be in the form of capsules, tablets, or sacs comprising a composition in powder form. The therapeutically effective oral dosage of the formulations of the present invention is determined by a medical practitioner using standard clinical techniques.

[0340] According to one embodiment, when eutectic forms of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined in this invention and / or pharmaceutically acceptable salts (including their solvates and / or hydrates) of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined in this invention are formulated into capsules, tablets, suspensions, solutions, or syrups using conventional methods, they are protected in blister packs. Another advantage of using blister packs is that the capsules or tablets are also protected from oxygen and other contaminants.

[0341] The capsules may be soft gel capsules or hard gel capsules. When the capsules are soft gel capsules or hard gel capsules, they may advantageously contain liquid excipients, particularly:

[0342] -Lipophilic liquid solvent,

[0343] - Semi-solid lipophilic solvents / viscosity modifiers for use in lipophilic liquid solvents

[0344] - Solubilizers, surfactants, emulsifiers, and adsorption enhancers,

[0345] Among these excipients, the following can be mentioned:

[0346] - Refined specialty oils such as:

[0347] Peanut oil

[0348] -castor oil

[0349] cottonseed oil

[0350] -Corn oil

[0351] -olive oil

[0352] - Sesame oil

[0353] - Soybean oil

[0354] -Sunflower seed oil

[0355] -Medium-chain triglycerides and related esters such as:

[0356] - Caprylic / capric triglycerides (Akomed E, Akomed R, Miglyol 810, and Captex 355)

[0357] Medium-chain triglycerides (Labrafac CC)

[0358] - Propylene glycol diester of caprylic / capric acid (Labrafac PG)

[0359] -Propylene glycol monolaurate (Lauroglycol FCC)

[0360] - Fractionated coconut oil (Miglyol 812)

[0361] - Caprylic / Capric / Succinate Diglyceride (Miglyol 829)

[0362] - Medium-chain diester of propylene glycol (Miglyol 840)

[0363] - Diglycerides and natural fatty acid esters (Softisan 645).

[0364] - Solubilizers, surfactants, emulsifiers, and adsorption enhancers such as:

[0365] -Propylene glycol monooctanoate (Capryol 90)

[0366] - Polyglycolic acid esters (Gelucire 44 / 14 and 50 / 13)

[0367] -Polyoxyethylene-40 hydrogenated castor oil (Cremophor RH 40)

[0368] - Glyceryl monostearate / diglyceride / triglyceride + glycerol (Imwitor 191)

[0369] - Caprylic / Caprylic Acid Glyceryl Monoester (Imwitor 308*)

[0370] - Glyceryl cocoate / glyceryl citrate / glyceryl lactate (Imwitor 380)

[0371] - Caprylic / Caprylic / Capric Triglyceride (Imwitor 742)

[0372] -Isostearyl diglyceride succinate (Imwitor 780K)

[0373] - Glyceryl cocoate (Imwitor 928)

[0374] - Caprylic / Caprylic Glyceryl Triglyceride (Imwitor 988)

[0375] -Oleoyl polyethylene glycol-8 glyceride (Labrafil M 1944CS)

[0376] - Linoleoyl polyethylene glycol glyceride (Labrafil M 2125CS)

[0377] -PEG-8 Caprylic / Capric Glyceryl Acetate (Labrasol)

[0378] -Lauric acid

[0379] -Propylene glycol lauroyl 90

[0380] -Oleic acid

[0381] -Polyethylene glycol

[0382] -Propylene glycol

[0383] - Polyglycerol dioleate (Plurol Oleique CC 497)

[0384] - Polyoxyethylene-polyoxypropylene copolymer (Poloxamer 124 and 188)

[0385] α-hydroxylated unsaturated fatty acid metaglycerides (Softigen 701)

[0386] -PEG-6 caprylic / capric triglyceride (Softigen 767)

[0387] - Trioleoyl polyoxyethylene glycerol (Tagat TO)

[0388] - Polyoxyethylene (20) dehydrated sorbitol monooleate (Tween 80).

[0389] In some embodiments, the present invention provides tablets or capsules comprising a cocrystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined herein and / or a pharmaceutically acceptable salt (including its solvates and / or hydrates) of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined herein and at least one pharmaceutically acceptable excipient.

[0390] In certain specific embodiments, the present invention provides: capsules comprising a cocrystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined in the present invention and / or a pharmaceutically acceptable salt (including its solvates and / or hydrates) of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined in the present invention and at least one pharmaceutically acceptable excipient; or tablets comprising particles formed from a cocrystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined in the present invention and / or a pharmaceutically acceptable salt (including its solvates and / or hydrates) of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined in the present invention and particles formed from at least one in-particle excipient, said particles being compressed together with at least one out-of-particle excipient.

[0391] When the pharmaceutical composition according to the invention is a tablet, the tablet may be coated or uncoated. Preferably, the tablet is coated using any suitable film coating agent known in the art.

[0392] This document specifically provides an oral galenine formulation comprising at least one cocrystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined herein and / or at least one pharmaceutically acceptable salt (including its solvates and / or hydrates) of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined above and at least one precipitation inhibitor as defined above.

[0393] This article further provides coated oral dosage forms, particularly for delayed-release dosage forms, comprising at least one cocrystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined above and / or at least one pharmaceutically acceptable salt (including its solvates and / or hydrates) of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined above.

[0394] Delayed-release formulations are a special type of modified formulation that allows the active ingredient to be released from the formulation at a specific time after administration, such as once the active ingredient has reached the intestines.

[0395] The term "modulated release dosage form" refers to a dosage form that allows a specified amount of active ingredient to be released into the body over a specific time period, i.e., a specific pharmacokinetic profile. The term "modulated release" includes all types of release that have been modulated compared to immediate release. In other words, the term "controlled release" is equivalent to "modulated release" and includes extended release as well as delayed and pulsatile release.

[0396] Oral dosage forms can be in the form of multi-particle drug delivery systems or multilayer compressed coated tablets. The coating can be selected from polymers that allow the salt or cocrystal to dissolve rapidly and the polymer to dissolve once the dosage form reaches the biological target, and more specifically the intestine.

[0397] Therefore, the present invention further provides the use of at least one cocrystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined above and / or at least one pharmaceutically acceptable salt (including its solvates and / or hydrates) of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined above for the preparation of delayed-release oral dosage forms.

[0398] The available dosage can vary depending on the nature and severity of the disorder, the route of administration, and the patient's age and weight.

[0399] According to one embodiment, the pharmaceutical composition according to the invention enables the active ingredient ABX464 to be administered to a subject in need in one or more doses daily at a dose of 1 mg to 1 g, particularly 10 mg to 150 mg daily.

[0400] The excipient can be any conventionally used excipient, including in-particle excipients and / or out-of-particle excipients.

[0401] Excipients may be selected from fillers, flow aids, binders, antioxidants, disintegrants, lubricants, surfactants, precipitation inhibitors, film coating agents, and mixtures thereof.

[0402] Useful fillers according to the present invention include, but are not limited to, lactose (anhydrous), lactose monohydrate, spray-dried lactose; compressible sugars, dextrose, glucose binders; starch (including starch from any source such as corn, potato, rice, wheat, which can be fully pregelatinized and partially gelatinized); cellulose; microcrystalline cellulose; inorganic salts such as calcium phosphate, tricalcium phosphate, and calcium sulfate; and polyols such as mannitol, sorbitol, and xylitol.

[0403] In some embodiments, the filler may be 10% to 85% by weight, based on the total weight of the composition.

[0404] Lubricants useful according to the present invention include, but are not limited to, magnesium stearate, calcium stearate, zinc stearate, stearic acid, sodium stearoyl fumarate, hydrogenated vegetable oil, mineral oil, polyethylene glycol, talc, glyceryl behenate, glyceryl monostearate, glyceryl stearate palmitate, leucine, and magnesium lauryl sulfate.

[0405] In some embodiments, the lubricant may be in an amount of 0.3% to 2% by weight, based on the total weight of the composition.

[0406] Useful disintegrants according to the present invention include, but are not limited to, croscarmellose sodium, starch glycolate sodium, starch (including starch from any source such as corn, potato, rice, wheat, which is fully pregelatinized and partially gelatinized), crospovidone, alginates such as calcium alginate and sodium alginate, alginate and magnesium aluminum silicate.

[0407] In some embodiments, the disintegrant may be an amount of 30% to 60% by weight, based on the total weight of the composition.

[0408] Surfactants that can be used as additives in this invention include, but are not limited to, sodium lauryl sulfate, tocopherol, lecithin, lauryl sulfate, vitamin E, egg yolk phospholipid, sodium docusate, Capryol, Labrafil, Labrasol, Lauroglycol, Solutol (polyethylene glycol-15 hydroxystearate), and mixtures thereof.

[0409] In some embodiments, the surfactant may be in an amount of 1% to 3% by weight, based on the total weight of the composition.

[0410] Useful flow aids according to the present invention include, but are not limited to, colloidal silica.

[0411] In some embodiments, the flow aid may be in an amount of 0.3% to 2% by weight, based on the total weight of the composition.

[0412] In some embodiments, the adhesive may be an amount of 5% to 20% by weight, based on the total weight of the composition.

[0413] The pharmaceutical compositions according to the invention may be in a regulated, sustained, controlled, delayed, or immediate release form.

[0414] According to another aspect, the present invention also relates to a cocrystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined herein, a pharmaceutically acceptable salt (including its solvates and / or hydrates) of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined herein, or a pharmaceutical composition as defined herein, for use as a medicament.

[0415] According to another aspect, the present invention also relates to a cocrystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined herein, a pharmaceutically acceptable salt (including its solvates and / or hydrates) of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined herein, or a pharmaceutical composition as defined herein for the prevention and / or treatment of inflammatory diseases such as inflammatory bowel disease, rheumatoid arthritis, pulmonary hypertension, NASH (non-alcoholic steatohepatitis) and multiple sclerosis, viral diseases and / or cancer or developmental abnormalities.

[0416] According to another aspect, the present invention also relates to the use of a cocrystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined herein, a pharmaceutically acceptable salt (including its solvates and / or hydrates) of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined herein, or a pharmaceutical composition as defined herein for the preparation of a medicament.

[0417] According to another aspect, the present invention also relates to the use of a cocrystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined herein, a pharmaceutically acceptable salt (including its solvates and / or hydrates) of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined herein, or a pharmaceutical composition as defined herein for the preparation of a medicament for the prevention and / or treatment of inflammatory diseases such as inflammatory bowel disease, rheumatoid arthritis, pulmonary hypertension, NASH (non-alcoholic steatohepatitis) and multiple sclerosis, viral diseases and / or cancers or developmental abnormalities.

[0418] According to another aspect, the present invention also relates to treatments for and / or prevention of inflammatory diseases such as inflammatory bowel disease, rheumatoid arthritis, pulmonary hypertension, NASH (non-alcoholic steatohepatitis) and multiple sclerosis, viral diseases and / or cancer or developmental abnormalities, comprising administering a composition to a patient in need, said composition comprising a cocrystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined in the present invention and / or a pharmaceutically acceptable salt (including its solvates and / or hydrates) of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined in the present invention.

[0419] According to another aspect, the present invention also relates to treatments for treating and / or preventing inflammatory diseases such as inflammatory bowel disease, rheumatoid arthritis, pulmonary hypertension, NASH (non-alcoholic steatohepatitis) and multiple sclerosis, viral diseases and / or cancers or developmental abnormalities, comprising administering to a patient in need a therapeutically effective amount of a cocrystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined in the present invention and / or a pharmaceutically acceptable salt (including its solvates and / or hydrates) of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined in the present invention.

[0420] A method is provided for administering a eutectic of ABX464 to a subject in need, comprising:

[0421] - Provides an oral pharmaceutical composition comprising: a cocrystal of ABX464 as defined herein and / or a pharmaceutically acceptable salt (including its solvates and / or hydrates) of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine and at least one pharmaceutically acceptable excipient; and

[0422] - Administer a therapeutically effective amount of the pharmaceutical composition orally to the subject in need.

[0423] The ABX464 cocrystal as defined in this invention can be administered alone or in combination with other therapeutic agents that can act synergistically with the ABX464 cocrystal as defined in this invention. For example, another therapeutic agent may be a pharmaceutically acceptable salt (including its solvates and / or hydrates) of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined in this invention.

[0424] Similarly, pharmaceutically acceptable salts (including their solvates and / or hydrates) of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined in this invention can be administered alone or in combination with other therapeutic agents that can act synergistically with the pharmaceutically acceptable salts (including their solvates and / or hydrates) of ABX464 as defined in this invention. For example, another therapeutic agent could be a eutectic of ABX464 as defined in this invention.

[0425] Inflammatory diseases

[0426] Therefore, the present invention also relates to cocrystals of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined herein, pharmaceutically acceptable salts (including solvates and / or hydrates) of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined herein, or pharmaceutical compositions as defined herein, for the treatment and / or prevention of inflammatory diseases.

[0427] According to the present invention, "inflammation" is a protective response of the immune system to tissue damage and infection. However, in some cases, the inflammatory response can damage the body. In the acute phase, inflammation is characterized by pain, fever, redness, swelling, and loss of function. Inflammation may be caused by infection, irritation, or injury.

[0428] Therefore, "inflammatory diseases" refers to a group of diseases and / or disorders caused by excessive or disordered inflammation.

[0429] In a non-restrictive sense, inflammatory diseases include: inflammatory diseases associated with autoimmune diseases, inflammatory diseases of the central nervous system (CNS), arthritic diseases, inflammatory digestive tract diseases, inflammatory skin and other inflammatory diseases associated with epithelial cells such as bronchitis, inflammation associated with cancers such as colon cancer, irritation-related inflammation and injury-related inflammation.

[0430] According to the present invention, the inflammatory disease, disorder, or symptom is selected from:

[0431] (a) An inflammatory disease, disorder or condition of the pancreas, selected from type I diabetes, type II diabetes, acute and chronic pancreatitis;

[0432] (b) Inflammatory diseases, disorders or conditions of the kidney, selected from glomerulosclerosis, glomerulonephritis, nephritis, acute kidney injury, Berger's disease, Goodpasser syndrome, Wegener's granulomatosis and acute or chronic rejection of kidney transplantation;

[0433] (c) Inflammatory disease, disorder or condition of the liver, selected from non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), cholestatic liver disease, sclerosing cholangitis and acute or chronic rejection of liver transplantation.

[0434] (d) An inflammatory disease, disorder or condition of the lungs or heart, selected from chronic obstructive pulmonary disease (COPD), asthma, pulmonary fibrosis, pulmonary hypertension, sarcoidosis, myocarditis, pericarditis and acute or chronic rejection of lung or heart transplantation.

[0435] (e) Inflammatory diseases, disorders or conditions of the skin, selected from contact dermatitis, atopic dermatitis, urticaria, chronic dermatitis, psoriasis, eczema, alopecia areata, erythema multiforme, herpetic dermatitis, scleroderma, vitiligo, allergic vasculitis, urticaria, bullous pemphigoid, pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus, acquired epidermolysis bullosa, acne, keloid scars and other inflammatory or allergic conditions of the skin;

[0436] (f) Inflammatory diseases, disorders or conditions in the blood vessels / blood, selected from Behcet's disease, vasculitis, sepsis, tumor angiogenesis, atherosclerosis, proliferative vascular disease and restenosis;

[0437] (g) an inflammatory disease, disorder or condition of the eye, selected from conjunctivitis, scleritis, episcleritis, panuveitis, choroiditis, choroidoretinitis, optic nerve retinitis, uveitis, orbital inflammatory disease and optic neuritis.

[0438] (h) Inflammatory diseases, disorders or conditions of the central or peripheral nervous system, selected from nonviral and viral encephalitis and meningitis, depression, neuropathic pain, chronic pain, traumatic brain injury including stroke, Alzheimer's disease, Parkinson's disease, myelitis, peroneal muscular dystrophy type 1 (including CMT1A and CMT1B), multiple sclerosis, amyotrophic lateral sclerosis (ALS), Creutzfeldt-Jakob disease, demyelinating polyneuropathy and peripheral neuropathy;

[0439] (i) an autoimmune disease, disorder or condition selected from lupus (including in the skin and kidneys), Guillain-Barré syndrome, myasthenia gravis, Hashimoto's thyroiditis, idiopathic purpura, aplastic anemia, Graves' disease and myocarditis;

[0440] (j) Inflammatory diseases, disorders, or conditions of the intestine, selected from intestinal failure, ulcerative colitis (UC), and Crohn's disease.

[0441] (k) Inflammatory diseases, disorders, or conditions of the reproductive system, selected from endometriosis, uterine fibroids, prostatic dysplasia or growth, and cervical dysplasia; and

[0442] (l) Inflammatory diseases, disorders or conditions in bones and / or joints, selected from rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, periodontitis and arthritis and / or demineralization of the hands, feet, ankles, knees, hips, shoulders, elbows or spine.

[0443] In one particular implementation, the inflammatory disease may be selected from: inflammatory diseases related to autoimmune diseases, inflammatory diseases of the central nervous system (CNS), arthritic diseases, inflammatory digestive tract diseases, inflammatory skin diseases and other inflammatory diseases related to epithelial cells, cancer-related inflammation, irritation-related inflammation and injury-related inflammation.

[0444] Specifically, inflammatory diseases are selected from: inflammatory bowel disease, rheumatoid arthritis, Crohn's disease, ulcerative colitis, multiple sclerosis, Alzheimer's disease, Parkinson's disease, osteoarthritis, atherosclerosis, ankylosing spondylitis, psoriasis, dermatitis, Sjögren's syndrome, bronchitis, asthma, pulmonary hypertension, NASH, and inflammation associated with colon cancer.

[0445] More specifically, inflammatory diseases are selected from: inflammatory bowel disease, rheumatoid arthritis, Crohn's disease, ulcerative colitis, multiple sclerosis, osteoarthritis, ankylosing spondylitis, psoriasis, Sjögren's syndrome, bronchitis, pulmonary hypertension, NASH, and inflammation associated with colon cancer.

[0446] More specifically, inflammatory diseases are selected from: inflammatory bowel disease, rheumatoid arthritis, Crohn's disease, ulcerative colitis, multiple sclerosis, osteoarthritis, ankylosing spondylitis, pulmonary hypertension, NASH, and psoriasis.

[0447] Preferably, the inflammatory diseases according to the present invention include: inflammatory bowel disease, Crohn's disease, ulcerative colitis, rheumatoid arthritis, pulmonary hypertension, NASH, and multiple sclerosis.

[0448] Even more preferably, the inflammatory diseases according to the present invention include: inflammatory bowel disease, rheumatoid arthritis, pulmonary hypertension, NASH, and multiple sclerosis.

[0449] Inflammatory diseases can also include Alzheimer's disease, Parkinson's disease, asthma, atherosclerosis, and dermatitis.

[0450] As for dermatitis, eczema can be mentioned.

[0451] In view of the above, the present invention relates to a cocrystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined herein, a pharmaceutically acceptable salt (including its solvates and / or hydrates) of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined herein, or a pharmaceutical composition as defined herein for the treatment and / or prevention of inflammatory diseases, said inflammatory diseases including inflammation itself and inflammation associated with inflammatory diseases.

[0452] Therefore, the present invention also relates to the use of cocrystals of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined herein, pharmaceutically acceptable salts (including solvates and / or hydrates thereof) of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined herein, or pharmaceutical compositions as defined herein for the treatment and / or prevention of inflammatory diseases, said inflammatory diseases including inflammation itself and inflammation associated with inflammatory diseases.

[0453] The present invention also relates to the use of a cocrystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined herein, or a pharmaceutically acceptable salt (including its solvates and / or hydrates) of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined herein, for the preparation of compositions (such as pharmaceuticals) for the treatment and / or prevention of inflammation, including inflammation itself and inflammation associated with inflammatory diseases.

[0454] The present invention also relates to methods for treating and / or preventing inflammatory diseases, said inflammatory diseases including inflammation itself and inflammation associated with said inflammatory disease, and said methods comprising the steps of: administering to a patient in need a cocrystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined in the present invention, a pharmaceutically acceptable salt (including its solvates and / or hydrates) of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined in the present invention, or a pharmaceutical composition as defined in the present invention.

[0455] In some embodiments, the method of the invention for use as defined above, for treating inflammatory diseases, disorders, or conditions, or the cocrystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined in the invention, a pharmaceutically acceptable salt (including its solvates and / or hydrates) of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined in the invention, or a pharmaceutical composition as defined in the invention further comprises measuring and / or monitoring the presence and / or level of a biomarker in a patient, for example, in blood, plasma, tissue, saliva, and / or serum samples. In some embodiments, the biomarker measured and / or monitored in the method of the invention is miR-124.

[0456] In some embodiments, the method of the invention for use as defined above, for treating inflammatory diseases, disorders, or conditions, or a cocrystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined in the invention, a pharmaceutically acceptable salt (including its solvates and / or hydrates) of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined in the invention, or a pharmaceutical composition as defined in the invention further comprises measuring and / or monitoring the presence and / or expression level of miR-124 in a patient, such as in blood, plasma, tissue, saliva, and / or serum samples, and then administering, as described herein, a cocrystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined in the invention, a pharmaceutically acceptable salt (including its solvates and / or hydrates) of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined in the invention, or a pharmaceutical composition as defined in the invention.

[0457] In some embodiments, the method of the invention for the purpose as defined above, for the treatment of inflammatory diseases, disorders, or conditions, or in the cocrystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined in the invention, a pharmaceutically acceptable salt (including its solvates and / or hydrates) of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined in the invention, or a pharmaceutical composition as defined in the invention, further comprises measuring and / or monitoring the presence and / or expression level of miR-124 in a patient during treatment with the cocrystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined in the invention, a pharmaceutically acceptable salt (including its solvates and / or hydrates) of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined in the invention, or a pharmaceutical composition as defined in the invention.

[0458] In some embodiments, the method of the present invention for treating inflammatory diseases, disorders, or conditions, or for use as defined herein, a cocrystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined herein, a pharmaceutically acceptable salt (including its solvates and / or hydrates) of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined herein, or a pharmaceutical composition thereof as defined herein, further comprises selecting patients for treatment as described herein using a cocrystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined herein, a pharmaceutically acceptable salt (including its solvates and / or hydrates) of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined herein, or a pharmaceutical composition thereof as defined herein, by measuring and / or monitoring the presence and / or expression level of miR-124 in the patient.

[0459] The provided cocrystals of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined in this invention, or pharmaceutically acceptable salts (including their solvates and / or hydrates) of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined in this invention, may be administered alone or in combination with one or more other therapeutic compounds. Possible combination therapies may take the form of a fixed combination, or the application of the compounds of this invention with one or more other therapeutic compounds may be alternated or independent of each other, or a fixed combination may be administered in combination with one or more other therapeutic compounds. In addition, or furthermore, the compounds of this invention may be administered in combination with chemotherapy, radiotherapy, immunotherapy, phototherapy, surgical intervention, or combinations thereof, particularly for the treatment of cancer. Long-term therapy is also possible, such as adjuvant therapy in the context of other treatment strategies as described above. Other possible treatments are therapies to maintain the patient's condition after tumor regression, or even chemopreventive therapy, for example, in at-risk patients.

[0460] The additional agents may be administered separately as part of a multiple-dosing regimen with a cocrystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined herein, or with a pharmaceutically acceptable salt (including its solvates and / or hydrates) of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined herein. Alternatively, those agents may be part of a single dosage form, mixed in a single composition with a cocrystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined herein, or with a pharmaceutically acceptable salt (including its solvates and / or hydrates) of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined herein. If administered as part of a multiple-dosing regimen, the two active agents may be delivered simultaneously, sequentially, or at intervals between each other (typically within five hours).

[0461] As used herein, the terms “combined,” “conjunctive,” and related terms indicate simultaneous or sequential administration of the therapeutic agent according to the invention. For example, a cocrystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined herein, or a pharmaceutically acceptable salt (including its solvates and / or hydrates) of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined herein, may be administered simultaneously or sequentially with another therapeutic agent in separate unit dosage forms, or together in a single unit dosage form. Therefore, the present invention provides a single unit dosage form comprising a cocrystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined herein, or a pharmaceutically acceptable salt (including its solvates and / or hydrates) of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined herein, a further therapeutic agent, and a pharmaceutically acceptable carrier, adjuvant, or solvent.

[0462] In some embodiments, a cocrystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined in this invention, or a pharmaceutically acceptable salt (including its solvates and / or hydrates) of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined in this invention, may be administered in combination with one or more additional therapeutic agents. Such additional therapeutic agents may be small molecule or recombinant biological agents and include, for example, acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin, ibuprofen, naproxen, and etodoxacin. Celecoxib, colchicine Corticosteroids such as prednisone, prednisolone, methylprednisolone, hydrocortisone, probenecid, allopurinol, febuxostat sulfasalazine Antimalarial drugs such as hydroxychloroquine and chloroquine Methotrexate Gold salts such as glucosinolate gold gold thiomalate And Kinnofen D-Penicillamine ( or ), azathioprine Cyclophosphamide Chlorinated nitrogen mustard Cyclosporin Tacrolimus, Sirolimus, Mycophenolate Mofetil, Leflunomide And "anti-TNF" agents such as etanercept Infliximab Golimumab Becelizumab and adalimumab Anti-IL-1 agents such as anakinin and Linasipu Anti-T cell antibodies such as thymoglobin, IV immunoglobulin (IVIg), and cananumab Anti-Jak inhibitors such as tofacitinib, antibodies such as rituximab Anti-T cell agents such as abatacept Anti-IL-6 agents such as tocilizumab Diclofenac, cortisone, hyaluronic acid or Monoclonal antibodies such as tanizumab, anticoagulants such as heparin ( or ) and warfarin Antidiarrheal drugs such as diphenoxylate and loperamide Bile acid binders such as cholestyramine and allosetron Lubiprostone Laxatives such as magnesium oxide emulsion, polyethylene glycol and Anticholinergic drugs or antispasmodics such as dicyclovir β-2 agonists such as salbutamol ( HFA, HFA), L-salbutamol Osinarin Pyrboterol Acetate Terbutaline sulfate Salmeterol senna and Formotero Anticholinergic agents such as ipratropium bromide and tiotropium bromide Inhaled corticosteroids such as beclomethasone dipropionate ( and ), Triamcinolone Momison Buddyne and flunisulfanil Sodium cromoglycate Methylxanthines such as theophylline ( And aminophylline, IgE antibodies such as omalizumab Nucleoside reverse transcriptase inhibitors such as zidovudine Abacave Abacave / Lamivudine Abacavir / Lamivudine / Zidovudine Dehydroxyinosine Enqutabin Lamivudine Lamivudine / Zidovudine Staffidin Hezashitabin Non-nucleoside reverse transcriptase inhibitors such as diraviridine According to Weilen Nevairapine He Yiquweilin Nucleotide reverse transcriptase inhibitors such as tenofovir Protease inhibitors such as ampravir Azanavir Darunavir Fosanavir Indinavir Lopinavir and ritonavir Nefernavir Litonavir Saquinavir or ) and telanavir Entry inhibitors such as enfuviride and Maravero Integrase inhibitors such as retegvir Dorothy Star Changchun New Alkali Bortezomib and lenalidomide Dexamethasone Anti-IL36 agents such as BI655130, dihydroorotate dehydrogenase inhibitors such as IMU-838, anti-OX40 agents 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 dakanitide, sphingosine kinase inhibitors such as oppanib, and anti-IL-12 / IL-23 agents such as AK-1 01. 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, and LAG-3 antibodies such as GS K-2831781, RIP2 kinase inhibitors such as GSK-2983559, 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 alifossen, anti-IL23 agents such as gusecucurumab, brecurumab, and mijigridumab, anti-IL- 15 agents such as AMG-714, TYK-2 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 icotinib, or any combination thereof.

[0463] Diseases caused by viruses

[0464] The cocrystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined in this invention, pharmaceutically acceptable salts (including solvates and / or hydrates) of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined in this invention, or pharmaceutical compositions as defined in this invention, may be used to treat or prevent various diseases caused by viruses, particularly retroviruses and more particularly HIV, and more particularly to reduce viral load in patients infected with viruses, particularly HIV or virus-related conditions, with durable effects and without resistance.

[0465] Examples of viruses considered in this invention include enveloped viruses and naked viruses, including DNA viruses, RNA viruses and retroviruses, including dsDNA viruses, ssDNA viruses, dsRNA viruses, (+)ssRNA viruses, (-)ssRNA viruses, ssRNA-RT viruses and dsDNA-RT viruses.

[0466] More particularly favored viruses are RNA viruses and retroviruses, including lentiviruses, preferably HIV. Therefore, more particularly favored virus-related illnesses are those associated with RNA viruses or retroviruses, preferably HIV. HIV can include HIV-1, HIV-2, and all their subtypes, including HIV-1 strains belonging to HIV-1 subtype B, HIV-1 subtype C, and HIV-1 recombinants. Examples include HIV-1 strains selected from Ad8, AdaM, isolate B, isolate C, CRF01, CRF02, and CRF06. According to a preferred embodiment, the virus-related illness is AIDS.

[0467] The retrovirus family can be divided into three subfamilies: tumor viruses, lentiviruses, and foam viruses. HIV belongs to the lentivirus family.

[0468] According to a specific implementation scheme, retroviruses include HIV (HIV1 and HIV2), Vesna / Medy virus or MVV / Vesna, equine infectious anemia virus or EIAV, caprine arthritis encephalitis virus or CAEV, simian immunodeficiency virus or SIV, avian leukosis virus or ALV, murine leukosis virus (also known as Moloney virus or MULV), Eberson leukosis virus, murine mammary tumor virus, Mason-Pfizer monkey virus or MPMV, feline leukosis virus or FELV, human leukosis virus HTLV-I, human leukosis virus HTLV-II, simian leukosis virus or STLV, bovine leukosis virus or BLV, and primates. Type D tumor virus, Type B tumor virus, Rous sarcoma virus or RSV, simian foam virus or SFV or chimpanzee simian virus, human foam virus and feline immunodeficiency virus, human foam virus or HFV, bovine syncytial virus or BSV, feline syncytial virus FSV, feline immunodeficiency virus, avian leukemia virus, pocharis cutaneous sarcoma virus, T-cell lymphoma, acute ATL, lymphomatous ATL, chronic ATL, stagnant ATL, neurological disorders, tropical spastic paraplegia or HTLV-related myelopathy, inflammatory diseases and autoimmune diseases such as uveitis, dermatitis, pneumonia, rheumatoid arthritis and polymyositis, blood and skin diseases, lung diseases, encephalopathy and / or immunodeficiency.

[0469] As described herein, the term tumor virus may include α-retroviruses (e.g., avian leukosis virus and Rous sarcoma virus); β-retroviruses (e.g., mouse mammary tumor virus); γ-retroviruses (e.g., murine leukosis virus and feline leukosis virus); δ-retroviruses (e.g., bovine leukosis virus and human T-lymphotropic virus); and ε-retroviruses (e.g., bigeye perch cutaneous sarcoma virus).

[0470] More generally, the retroviruses described herein can be, for example, Vesna / Medy virus or MVV / Vesna, equine infectious anemia virus or EIAV, caprine arthritis encephalitis virus or CAEV, simian immunodeficiency virus or SIV, avian leukosis virus or ALV, murine leukosis virus (also known as Moloney virus or MULV), Eberson leukosis virus, murine mammary tumor virus, Mason-Pfizer monkey virus or MPMV, feline leukosis virus or FELV, human leukosis virus HTLV-I, human leukosis virus HTLV-II, simian leukosis virus or STLV, bovine leukosis virus or BLV, primate type D tumor virus, type B tumor virus, Rous sarcoma virus or RSV and / or simian foam virus or SFV or chimpanzee simian virus, human foam virus and feline immunodeficiency virus, human foam virus (or HFV), bovine syncytial virus (or BSV), feline syncytial virus (FSV) and feline immunodeficiency virus.

[0471] More specifically, HTLV-I causes T-cell lymphoma (ATL stands for adult T-cell leukemia / lymphoma, including different forms of ATL such as acute ATL, lymphomatous ATL, chronic ATL, and stasis ATL), neurological disorders, tropical spastic paraplegia (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; and HTLV-II can play a role in certain neurological, hematological, and dermatological diseases; HIV (HIV1 and HIV2) causes AIDS; Vesna virus causes lung and brain diseases in sheep; feline immunodeficiency virus causes immunodeficiency in cats; and Rous sarcoma virus and mouse mammary tumor virus cause tumor growth and cancer.

[0472] This invention also relates to methods for treating and / or preventing diseases caused by viruses, particularly retroviruses and more particularly HIV, and said methods comprising the steps of administering to a patient in need a cocrystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined in this invention, a pharmaceutically acceptable salt (including its solvates and / or hydrates) of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined in this invention, or a pharmaceutical composition as defined in this invention.

[0473] Furthermore, the object of the present invention is to reduce viral load in patients infected with viruses, particularly HIV or virus-related conditions, with a sustained effect and without resistance by using a cocrystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined in the present invention, a pharmaceutically acceptable salt (including its solvates and / or hydrates) of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined in the present invention, or a pharmaceutical composition as defined in the present invention.

[0474] In one embodiment, the present invention relates to a cocrystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined in this invention, a pharmaceutically acceptable salt (including its solvates and / or hydrates) of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined in this invention, or a pharmaceutical composition as defined in this invention for the treatment or prevention of retroviral infection or retroviral-related conditions in patients, particularly HIV infection or HIV-related conditions, for which previous antiretroviral treatments have been described as ineffective or less effective.

[0475] In another embodiment, the present invention relates to a cocrystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined in this invention, a pharmaceutically acceptable salt (including its solvates and / or hydrates) of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined in this invention, or a pharmaceutical composition as defined in this invention for the treatment or prevention of retroviral infection or retroviral-related conditions in patients, particularly HIV infection or HIV-related conditions, wherein the patients are infected with drug-resistant viral strains, and more particularly with drug-resistant HIV strains.

[0476] Furthermore, the present invention relates to novel dosages and regimens of the cocrystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined herein, or of the pharmaceutically acceptable salts (including solvates and / or hydrates) of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined herein, and their use in the treatment or prevention of viral infections, particularly HIV or virus-related conditions, more particularly in maintaining a low viral load after treatment is terminated. Therefore, according to one embodiment, the present invention relates to a cocrystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined in this invention, a pharmaceutically acceptable salt (including its solvates and / or hydrates) of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined in this invention, or a pharmaceutical composition as defined in this invention, for the treatment or prevention of viral infections or virus-related conditions in patients, particularly HIV infection or HIV-related conditions, wherein: a low or undetectable viral load is maintained after treatment termination; and / or the CD4+ cell count is stable or increased.

[0477] According to another embodiment, the present invention relates to a cocrystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined in this invention, a pharmaceutically acceptable salt (including its solvates and / or hydrates) of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined in this invention, or a pharmaceutical composition as defined in this invention for the treatment or prevention of viral infections or virus-related conditions in patients, particularly HIV infection or HIV-related conditions, for which previous antiretroviral therapy has been ineffective or has decreased in effectiveness.

[0478] According to yet another embodiment, the present invention relates to a cocrystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined in this invention, a pharmaceutically acceptable salt (including its solvates and / or hydrates) of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined in this invention, or a pharmaceutical composition as defined in this invention for the treatment or prevention of viral infection or virus-related conditions in patients, particularly HIV infection or HIV-related conditions, wherein the patients are infected with a drug-resistant strain.

[0479] Within the framework of this invention, a cocrystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined herein, or a pharmaceutically acceptable salt (including its solvates and / or hydrates) of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined herein, may be administered in combination with another antiretroviral agent. According to one embodiment, ART (antiretroviral therapy) or HAART (highly active antiretroviral therapy) can be performed using one or more of the following antiretroviral compounds:

[0480] (i) Nucleoside / nucleotide reverse transcriptase inhibitors, also known as nucleoside analogs, such as abacavir, emtricitabine and tenofovir;

[0481] (ii) Non-nucleoside reverse transcriptase inhibitors (NNRTIs), such as efavirenz, ectrevirine, and nevirapine;

[0482] (iii) Protease inhibitors (PIs), such as atazanavir, darunavir and ritonavir;

[0483] (iv) Inhibitors, such as entfuvirtide and maraviro;

[0484] (v) Integrase inhibitors, such as dolutegravir and retegvir.

[0485] Other examples of antiretroviral agents include, in a non-limiting manner, zidovudine, lamivudine, emtricitabine, doxorinosine, stavudine, abacavir, zalcitabine, Racivir, amdoxavir, aripipridine, eftabine, efavirenz, nevirapine, ectavirine, deraviridine, rilpivirine, tenofovir, fosalvudine, ampravir, telanavir, indinavir, saquinavir, fosanavir, ritonavir, darunavir, atazanavir, nelfinavir, lopinavir, retegvir, averavir, dolutegravir, entfuvirtide, maraviro, velivirol, and combinations thereof.

[0486] In some embodiments, a cocrystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined in this invention, or a pharmaceutically acceptable salt (including its solvates and / or hydrates) of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined in this invention, may be administered in combination with one or more additional therapeutic agents selected from nucleoside reverse transcriptase inhibitors such as zidovudine. Abacave Abacave / Lamivudine Abacavir / Lamivudine / Zidovudine Dehydroxyinosine Enqutabin Lamivudine Lamivudine / Zidovudine Staffidin Hezashitabin Non-nucleoside reverse transcriptase inhibitors such as diraviridine According to Weilen Nevellappi He Yiquweilin Nucleotide reverse transcriptase inhibitors such as tenofovir Protease inhibitors such as ampravir Azanavir Darunavir Fosanavir Indinavir Lopinavir and ritonavir Nefernavir Litonavir Saquinavir or ) and telanavir Entry inhibitors such as enfuviride and Maravero Integrase inhibitors such as retegvir And their combinations.

[0487] Cocrystals of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined in this invention, pharmaceutically acceptable salts (including solvates and / or hydrates) of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined in this invention, or pharmaceutical compositions as defined in this invention may also be used to treat and / or prevent diseases caused by viruses belonging to the Coronaviridae family or infections caused by the Coronaviridae family, and related conditions, particularly severe acute respiratory syndrome caused by SARS-CoV or SARS-CoV-2 infection (including strains and mutants of the virus that cause COVID-19 (also referred to herein as coronavirus disease 2019)).

[0488] More specifically, SARS-CoV-2, formerly known as 2019-nCoV, belongs to the Coronaviridae family and is part of Group IV of the Baltimore Classification.

[0489] For reference, the content of the “Baltimore classification” reported in this article further references the virus classification listed in the database of the International Committee on Taxonomy of Viruses (ICTV), which was made available online on March 20, 2020 at https: / / talk.ictvonline.org / taxonomy / (email approval February 2019 and MSL#34). This classification is incorporated herein in its entirety.

[0490] Therefore, this classification divides viruses into families (or "groups") based on their genome type. As in 2018, the current virus classification includes seven distinct groups:

[0491] - Group I: Double-stranded DNA virus (dsDNA);

[0492] - Group II: Single-stranded DNA viruses (ssDNA);

[0493] - Group III: Double-stranded RNA viruses (dsRNA);

[0494] - Group IV: (+) strand or sense RNA virus ((+) ssRNA);

[0495] - Group V: (-) strand or antisense RNA virus ((-)ssRNA);

[0496] - Group VI: Single-stranded RNA viruses with DNA intermediates (ssRNA-RT);

[0497] - Group VII: Double-stranded DNA viruses with RNA intermediates (dsDNA-RT).

[0498] Furthermore, the cocrystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined in this invention, pharmaceutically acceptable salts (including their solvates and / or hydrates) of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined in this invention, or pharmaceutical compositions as defined in this invention are particularly useful for treating and / or preventing severe forms of SARS-CoV-2 infection: anti-inflammatory effects against cytokine storms, mucosal effectiveness, and promotion of tissue repair to avoid long-term post-ventilation sequelae.

[0499] According to a particular embodiment, a cocrystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined in this invention, a pharmaceutically acceptable salt (including its solvates and / or hydrates) of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined in this invention, or a pharmaceutical composition as defined in this invention may be used in the early stages of COVID-19.

[0500] In clinical practice, SARS-CoV-2 infection can lead to cytokine storm syndrome, acute respiratory distress syndrome (ARDS), and multiple organ failure. Notably, cytokine storm (i.e., an excessive inflammatory syndrome) has been associated with the severity of COVID-19 disease (including increased levels of MCP1, IL-1β, TNFα, IL-17, G-CSF, and IL-6). Early treatment and action targeting viral replication and various cytokine pathways can successfully reduce cytokine storm syndrome and “excessive inflammation,” and prevent ARDS and multiple organ failure.

[0501] Therefore, in one embodiment, the present invention relates to a cocrystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined in this invention, a pharmaceutically acceptable salt (including its solvates and / or hydrates) of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined in this invention, or a pharmaceutical composition as defined in this invention, used in a method for treating a group of patients prior to the onset of acute respiratory distress syndrome associated with coronavirus infection. These patients may be hospitalized or not.

[0502] Therefore, in one embodiment, the present invention relates to a cocrystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined in this invention, a pharmaceutically acceptable salt (including its solvates and / or hydrates) of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined in this invention, or a pharmaceutical composition as defined in this invention, used in a method for treating or preventing the occurrence of acute respiratory distress syndrome associated with coronavirus infection.

[0503] According to a specific embodiment, a cocrystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined in this invention, a pharmaceutically acceptable salt (including its solvates and / or hydrates) of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined in this invention, or a pharmaceutical composition as defined in this invention, is used in a method for treating or preventing coronavirus infections, for the treatment or prevention of vascular, cardiovascular, neurological, or gastrointestinal symptoms associated with coronavirus infections.

[0504] Advantageously, the cocrystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined in this invention, or a pharmaceutically acceptable salt (including its solvates and / or hydrates) of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined in this invention, alone or in combination with any other active agent, particularly any activator protein inhibitor, especially any activator protein-2 inhibitor, may be considered for the treatment or prevention of coronavirus infections.

[0505] The “symptoms associated with coronavirus infections” used in this article, particularly those associated with coronaviruses such as SARS-CoV2 that are associated with severe acute respiratory syndrome, may be selected from or comprised of the following: severe respiratory distress syndrome, cardiovascular disease, vascular disease, gastrointestinal disease, or neurological disease.

[0506] Advantageously, patients with symptoms associated with coronavirus infection or at risk of developing symptoms associated with coronavirus infection may also be considered.

[0507] According to the exemplary implementation, conditions specifically considered in relation to coronavirus infections include: pulmonary fibrosis, vasculitis, Kawasaki disease, and tissue damage or destruction, particularly lung tissue damage and destruction.

[0508] Unless otherwise stated, all disclosed cocrystals of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined in this invention, pharmaceutically acceptable salts (including their solvates and / or hydrates) of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined in this invention, and pharmaceutical compositions as defined in this invention are specifically considered herein for the treatment or prevention of the Coronaviridae family, which may therefore refer generally to any member of the Coronaviridae family in the sense of the Baltimore Convention, although specific selections of viruses will be considered below as preferred embodiments.

[0509] As used in this article, the term "coronavirus family" refers to the corresponding family of RNA viruses belonging to Group IV of the Baltimore classification, which itself is part of the suborder Coronidovirineae and the order Nidovirales. The coronavirus family includes the subfamily Letovirinae and the subfamily Orthocoronavirinae.

[0510] The term “letovirus subfamily” as used in this article refers to the corresponding family in the Baltimore classification, which includes the genus Alphaletovirus, subgenus Milecovirus, which includes (in a non-exhaustive manner) one species of Microhyla letovirus.

[0511] The term “Orthocoronavirus subfamily” as used in this article refers to the corresponding family in the Baltimore classification, which includes the genera Alphacoronavirus, Betacoronavirus, Deltacoronavirus, and Gammacoronavirus.

[0512] The term “A coronavirus” as used in this article refers to the corresponding family in the Baltimore classification, which includes the subgenus Colacovirus, Decacovirus, Duvinacovirus, Luchacovirus, Minacovirus, Minunacovirus, Myotacovirus, Myctacovirus, Pedacovirus, Rhinacovirus, Setracovirus, and Tegacovirus. In a non-exhaustive manner, this includes the following species: bat coronavirus CDPHE15, bat coronavirus HKU10, Rhinolophus ferrumequinum A coronavirus HuB-2013, human coronavirus 229E, Lucheng Rn rat coronavirus, ferret coronavirus, mink coronavirus 1, long-winged bat coronavirus 1, long-winged bat coronavirus HKU8, Myotis ricketti A coronavirus Sax-2011, Nyctalus velutinus A coronavirus SC-2013, swine epidemic diarrhea virus, yellow bat coronavirus 512, Rhinolophus ferrumequinum bat coronavirus HKU2, human coronavirus NL63, NL63-related bat coronavirus strain BtKYNL63-9b, and A coronavirus 1.

[0513] As used in this article, the term "betacoronavirus" refers to the corresponding family in the Baltimore classification, which includes the subgenera Embecovirus, Hibecovirus, Merbecovirus, Nobecovirus, and Sarbecovirus. In a non-exhaustive manner, this includes the following species: betacoronavirus 1, China Rattus coronavirus HKU24, human coronavirus HKU1, mouse coronavirus, bat Hp-betacoronavirus Zhejiang 2013, hedgehog coronavirus 1, Middle East Respiratory Syndrome-related coronavirus, bat coronavirus HKU5, bat coronavirus HKU4, hedgehog coronavirus 1, Middle East Respiratory Syndrome-related coronavirus, bat coronavirus HKU5, bat coronavirus HKU4, bat coronavirus HKU4, fruit bat coronavirus GCCDC1, fruit bat coronavirus HKU9, and severe acute respiratory syndrome-related coronavirus.

[0514] The term “severe acute respiratory syndrome-associated coronavirus” or SARS virus as used in this article includes, in a non-exhaustive manner, SARS-CoV, SARSr-CoV WIV1, SARSr-CoV HKU3, SARSr-CoV RP3, and SARS-CoV-2; including the strains that cause COVID-19 and their mutants.

[0515] As used in this article, the term "D-coronavirus" refers to the corresponding family in the Baltimore classification, which includes the subgenera Andecovirus, Buldecovirus, Herdecovirus, and Moordecovirus. In a non-exhaustive manner, this includes the following species: Duck Coronavirus HKU20, Bulbul Coronavirus HKU11, Coronavirus HKU15, Java Finch Coronavirus HKU13, White-eye Coronavirus HKU16, Black-crowned Night Heron Coronavirus HKU19, and Common Moorhen Coronavirus HKU21.

[0516] As used in this article, the term "cytironocoronavirus" refers to the corresponding family in the Baltimore classification, which includes the subgenus Cegacovirus and the subgenus Igacovirus. In a non-exhaustive manner, this includes the following species: beluga whale coronavirus SW1 and avian coronaviruses.

[0517] According to a specific embodiment, a cocrystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined in this invention, a pharmaceutically acceptable salt (including its solvates and / or hydrates) of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined in this invention, or a pharmaceutical composition as defined in this invention, used in methods for treating or preventing coronavirus infections, is used to reduce inflammation associated with coronavirus infections.

[0518] According to a specific embodiment, a cocrystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined in this invention, a pharmaceutically acceptable salt (including its solvates and / or hydrates) of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined in this invention, or a pharmaceutical composition as defined in this invention, used in methods for treating or preventing coronavirus infections, is used to reduce viral load in coronaviruses.

[0519] According to a specific embodiment, a cocrystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined in this invention, a pharmaceutically acceptable salt (including its solvates and / or hydrates) of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined in this invention, or a pharmaceutical composition as defined in this invention, used in a method for treating or preventing coronavirus infections, in combination with the following agents:

[0520] -Inhibitors of activating proteins, such as Dynasore; and / or

[0521] - Antibiotics, such as those selected from one of the following: β-lactams, fluoroquinolones, and macrolides, such as azithromycin;

[0522] - Remdesivir;

[0523] -Ribavirin;

[0524] -Litonavir;

[0525] -Lopinavir;

[0526] -Chloroquine or hydroxychloroquine;

[0527] -β-interferon;

[0528] -Anti-inflammatory compounds, such as those selected from one of the following: anti-TNF, Jak inhibitors, anti-IL6 antibodies, IL6 receptor antagonists; and / or

[0529] - Calcium inhibitors such as diltiazem.

[0530] According to certain specific implementations, the coronavirus family is selected from the Letovirinae and Orthocoronavirus subfamilies.

[0531] According to certain specific implementations, the Coronavirus Family is a type A coronavirus, a type B coronavirus, a type D coronavirus, or a type C coronavirus.

[0532] According to certain specific implementations, the coronavirus family is Embecovirus, Hibecovirus, Merbecobivirus, Nobecovirus, or Sarbecovirus.

[0533] According to certain specific implementations, the coronavirus family is selected from Sarbecovirus, a coronavirus associated with severe acute respiratory syndrome.

[0534] According to certain specific implementation schemes, the severe acute respiratory syndrome (SARS) related coronavirus is selected from: SARS-CoV, SARSr-CoV WIV1, SARSr-CoV HKU3, SARSr-CoV RP3, and SARS-CoV-2.

[0535] According to certain preferred embodiments, the severe acute respiratory syndrome (SARS)-related coronavirus is selected from SARS-CoV and SARS-CoV-2; including strains that cause COVID-19 and their mutants.

[0536] According to certain embodiments, a cocrystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined in this invention, a pharmaceutically acceptable salt (including its solvates and / or hydrates) of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined in this invention, or a pharmaceutical composition as defined in this invention is used in a method for treating or preventing coronavirus infections, wherein the level of free base equivalent of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine is measured in a patient's blood, plasma, tissue, saliva, pharynx, trachea, bronchoalveolar, and / or serum samples during use.

[0537] cancer

[0538] The cocrystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined in this invention, pharmaceutically acceptable salts (including solvates and / or hydrates) of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined in this invention, or pharmaceutical compositions as defined in this invention may be used to treat or prevent various cancers.

[0539] Unless otherwise stated, the term "cancer" as used herein may refer to any disorder associated with abnormal cell growth, including malignant and benign tumors, metastatic and non-metastatic tumors, solid and non-solid tumors, such as blood-related cancers, which may therefore include leukemia, lymphoma, and myeloma; it may also refer to central nervous system (CNS) cancers and non-CNS cancers. Unless otherwise stated, the term "cancer" also includes juvenile and non-juvenile cancers, recurrent and non-recurrent cancers, and cancer recurrence.

[0540] Among cancers, the following may be mentioned: blood-related cancers, pancreatic cancer, urinary tract cancers, 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, stomach cancer, endometrial cancer, esophageal cancer, head and neck cancer, melanoma, neuroendocrine cancer, central nervous system cancer, brain tumors (e.g., glioma, anaplastic oligodendroglioma, adult glioblastoma multiforme, and adult anaplastic astrocytoma), bone cancer, soft tissue sarcoma, retinoblastoma, neuroblastoma, peritoneal effusion, malignant pleural effusion, mesothelioma, nephroblastoma, trophoblastic tumor, hemangiopericytoma, Kaposi's sarcoma, myxoid carcinoma, round cell carcinoma, squamous cell carcinoma, esophageal squamous cell carcinoma, oral cancer, adrenocortical carcinoma, or tumors that produce ACTH.

[0541] According to one implementation plan, 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, gastrointestinal cancer, colorectal cancer, esophageal cancer, colorectal cancer, bladder cancer, gallbladder cancer, thyroid cancer, melanoma, uterine / cervical cancer, ovarian cancer, bone cancer, and kidney cancer.

[0542] According to another embodiment, the cancer may be selected from head and neck cancer, head and neck squamous cell carcinoma, neck squamous cell carcinoma, acute lymphoblastic leukemia (ALL) in adults or children, acute myeloid leukemia (AML) in adults or children, acute lymphoblastic leukemia in adults, adrenal cancer, anal cancer, astrocytic glioma, astrocytoma (grade I, II, III or IV), B- or NK / T-cell lymphoma, basal and squamous cell carcinoma of the skin, biliary tract cancer, bladder cancer, bone cancer, brain cancer, brain and spinal cord tumors, brain and spinal cord tumors in children, anaplastic astrocytoma in women, breast cancer, gastrointestinal cancer, breast cancer, breast cancer in young women, breast cancer in men, and recurrent breast cancer in adolescents. Primary breast cancer, hereditary breast cancer, HER2-positive breast cancer, breast cancer with lymph node metastasis, ER-α-positive breast cancer, cancer in children, cancer in young adults, cancer of unknown primary origin, Castleman's disease, cervical cancer, cervical intraepithelial neoplasia, cholangiocarcinoma, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic myelomonocytic leukemia (CMML), colorectal cancer, colorectal adenoma, squamous cell carcinoma of the skin, endometrial cancer, epithelial ovarian cancer, epithelial ovarian cancer with metastasis, esophageal cancer, esophageal squamous cell carcinoma, Ewing sarcoma, Ewing familial tumor, lymphoblastic leukemia (ALL), eye cancer such as melanoma. Tumors and lymphomas, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumors, gastrointestinal stromal tumors (GIST), gestational trophoblastic disease, glioblastoma, glioblastoma multiforme (GBM), hairy cell leukemia, glioma, high-grade glioma, hepatocellular carcinoma, intrahepatic cholangiocarcinoma, invasive breast ductal carcinoma, Hodgkin's lymphoma, Kaposi's sarcoma, kidney cancer, laryngeal and hypopharyngeal cancer, leiomyosarcoma, leukemia, leukemia in children, liver cancer, lung cancer, lung carcinoid tumors, 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 nose Paraplegic sinus carcinoma, nasopharyngeal carcinoma, recurrent or metastatic nasopharyngeal carcinoma, neuroblastoma, glioma, non-Hodgkin lymphoma, non-Hodgkin lymphoma in children, non-small cell lung cancer, gefitinib-resistant non-small cell lung cancer, oral cancer, oral and oropharyngeal cancer, osteosarcoma, metastatic osteosarcoma of the lung, ovarian cancer, pancreatic cancer, thyroid cancer, papillary thyroid carcinoma, pediatric spinal ependymoma, penile cancer, pituitary adenoma, pituitary adenoma, proneural tumor, prostate cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skin cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma of the tongue, gastric cancer, testicular cancer, thymic carcinoma, thyroid cancer, uterine sarcoma, vaginal cancer, vulvar cancer, kidney cancer, retinoblastoma.Waldenström macroglobulinemia and nephroblastoma.

[0543] According to another embodiment, the cancer may be selected from head and neck squamous cell carcinoma, cervical squamous cell carcinoma, acute lymphoblastic leukemia (ALL) in adults or children, acute myeloid leukemia (AML) in adults or children, acute lymphoblastic leukemia in adults, adrenal cancer, anal cancer, astrocytic glioma, astrocytoma (grade I, II, III or IV), B- or NK / T-cell lymphoma, basal and squamous cell carcinoma of the skin, biliary tract cancer, bone cancer, brain cancer, brain and spinal cord tumors, brain and spinal cord tumors in children, anaplastic astrocytoma, gastrointestinal cancer, breast cancer in women, breast cancer in young women, and breast cancer in men. Recurrent breast cancer in adolescents, hereditary breast cancer, HER2-positive breast cancer, breast cancer with lymph node metastasis, ER-α-positive breast cancer, cancer in children, cancer in young adults, cancer of unknown primary origin, Kassler's disease, cervical intraepithelial neoplasia, cholangiocarcinoma, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic myelomonocytic leukemia (CMML), colorectal adenoma, squamous cell carcinoma of the skin, endometrial cancer, epithelial ovarian cancer, epithelial ovarian cancer with metastasis, esophageal squamous cell carcinoma, Ewing sarcoma, Ewing familial tumors, lymphoblastic leukemia (ALL), eye cancer such as Eye melanoma and lymphoma, gastric cancer, gastrointestinal carcinoid tumors, gastrointestinal stromal tumors (GIST), gestational trophoblastic disease, glioblastoma, glioblastoma multiforme (GBM), hairy cell leukemia, glioma, high-grade glioma, hepatocellular carcinoma, intrahepatic cholangiocarcinoma, invasive breast ductal carcinoma, Hodgkin's lymphoma, Kaposi's sarcoma, laryngeal and hypopharyngeal cancer, leiomyosarcoma, leukemia, leukemia in children, lung carcinoid tumors, lymphoma, cutaneous lymphoma, malignant mesothelioma, mantle cell lymphoma, medulloblastoma, malignant melanoma, meningioma, Merkel cell skin carcinoma, multiple myeloma, multiple myeloma with osteonecrosis of the jaw, myelodysplastic syndrome, nasal Cavity and paranasal sinus carcinoma, nasopharyngeal carcinoma, recurrent or metastatic nasopharyngeal carcinoma, neuroblastoma, glioma, non-Hodgkin lymphoma, non-Hodgkin lymphoma in children, gefitinib-resistant non-small cell lung cancer, oral cancer, oral and oropharyngeal cancer, osteosarcoma, metastatic osteosarcoma of the lung, thyroid cancer, papillary thyroid cancer, pediatric spinal ependymoma, penile cancer, pituitary adenoma, pituitary adenoma, proneuronal tumor, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skin cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma of the tongue, testicular cancer, thymic cancer, uterine sarcoma, vaginal cancer, vulvar cancer, renal cancer, retinoblastoma, Waldenström macroglobulinemia, and nephroblastoma.

[0544] According to another embodiment, the cancer may be selected from head and neck cancer, head and neck squamous cell carcinoma, neck squamous cell carcinoma, malignant melanoma, gastric cancer, breast cancer, breast cancer in women, breast cancer in young women, basal and squamous cell carcinoma of the skin in adults or children, liver cancer, brain cancer, 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 I, II, III or IV), colorectal cancer, colorectal adenoma, squamous cell carcinoma of the skin, bladder cancer, bone cancer, recurrent breast cancer, hereditary breast cancer, HER2-positive breast cancer, breast cancer associated with lymph node metastasis, ER-α-positive breast cancer, kidney cancer, cervical intraepithelial neoplasia, cholangiocarcinoma, leiomyosarcoma, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic myelomonocytic leukemia (CMML), acute myeloid leukemia (AML). ML), Acute lymphoblastic leukemia, B- or NK / T-cell lymphoma, cervical cancer, glioblastoma, glioblastoma multiforme (GBM), hairy cell leukemia, glioma, high-grade glioma, hepatocellular carcinoma, intrahepatic cholangiocarcinoma, invasive breast ductal carcinoma, renal cell carcinoma, endometrial cancer, ovarian cancer, epithelial ovarian cancer, metastatic epithelial ovarian cancer, esophageal cancer, esophageal squamous cell carcinoma, Ewing sarcoma, lymphoblastic leukemia (ALL), and sclerosis. Cytokine lymphoma, medulloblastoma, lymphoma, myelodysplastic syndrome, meningioma, multiple myeloma (MM), multiple myeloma with osteonecrosis of the jaw, nasopharyngeal carcinoma, recurrent or metastatic nasopharyngeal carcinoma, neuroblastoma, glioma, papillary thyroid carcinoma, pediatric spinal ependymoma, osteosarcoma, metastatic osteosarcoma of the lung, pancreatic cancer, thyroid cancer, sarcoma, pituitary adenoma, pituitary adenoma, proneuronal tumor, squamous cell carcinoma of the tongue, mesothelioma, retinoblastoma, and prostate cancer.

[0545] According to another embodiment, the cancer may be selected from head and neck cancer, head and neck squamous cell carcinoma, neck squamous cell carcinoma, malignant melanoma, astrocytic glioma, glioma, gastric cancer, breast cancer, bile duct cancer, recurrent or metastatic nasopharyngeal carcinoma, basal and squamous cell carcinoma of the skin, liver cancer, brain cancer, anaplastic astrocytoma, lung cancer, non-small cell lung cancer, gefitinib-resistant non-small cell lung cancer, oral cancer, glioblastoma, osteosarcoma, metastatic osteosarcoma of the lung, pancreatic cancer, eye cancer, gastrointestinal cancer, colorectal cancer, colorectal adenoma, squamous cell carcinoma of the skin, endometrial cancer, epithelial ovarian cancer, esophageal cancer, Ewing sarcoma, gastric cancer, hepatocellular carcinoma, HER2-positive breast cancer, bladder cancer, bone cancer, prostate cancer, retinoblastoma, and kidney cancer.

[0546] According to another embodiment, the cancer may be selected from anaplastic astrocytoma, astrocytic glioma, bladder cancer, breast cancer, bile duct cancer, colorectal cancer, colorectal adenoma, squamous cell carcinoma of the skin, endometrial cancer, epithelial ovarian cancer, esophageal cancer, Ewing 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 (recurrence or metastasis), cervical squamous cell carcinoma, non-small cell lung cancer, oral cancer, osteosarcoma, osteosarcoma (lung metastasis), prostate cancer, and retinoblastoma.

[0547] According to another embodiment, the cancer may be selected from anal cancer, biliary tract cancer, gastrointestinal cancer, bile duct cancer, colorectal cancer, colorectal adenoma, esophageal cancer, esophageal squamous cell carcinoma, gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), hepatocellular carcinoma, intrahepatic bile duct cancer, liver cancer, lung cancer, lung carcinoid tumor, non-small cell lung cancer, gefitinib-resistant non-small cell lung cancer, metastatic osteosarcoma of the lung, gastric cancer, pancreatic cancer, small cell lung cancer, and small bowel cancer.

[0548] According to one embodiment, the patient does not have clinically detectable metastases, particularly if the patient has precancerous lesions, early-stage cancer, or non-metastatic cancer, or if the patient has clinically detectable metastases, and the cocrystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined in this invention, or the pharmaceutically acceptable salt (including its solvates and / or hydrates) of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined in this invention, does not directly target the invasion of metastases.

[0549] In view of the above, the present invention relates to a cocrystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined in this invention, a pharmaceutically acceptable salt (including its solvates and / or hydrates) of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined in this invention, or a pharmaceutical composition as defined in this invention for the treatment and / or prevention of cancers (such as those listed above) and developmental abnormalities.

[0550] Therefore, the present invention also relates to the use of eutectic crystals of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined herein, pharmaceutically acceptable salts (including solvates and / or hydrates) of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined herein, or pharmaceutical compositions as defined herein for the treatment and / or prevention of cancers (such as those listed above) and developmental disorders.

[0551] The present invention also relates to the use of eutectic crystals of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined herein, and pharmaceutically acceptable salts (including solvates and / or hydrates thereof) of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined herein for the preparation of compositions (such as pharmaceuticals) for the treatment and / or prevention of cancers (such as those listed above) and developmental abnormalities.

[0552] This invention also relates to methods for preventing, inhibiting, or treating cancer or developmental abnormalities, the methods comprising at least one step: administering to a patient suffering from cancer or a developmental abnormality an effective amount of a cocrystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined in this invention, a pharmaceutically acceptable salt (including its solvates and / or hydrates) of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined in this invention, or a pharmaceutical composition as defined in this invention.

[0553] In some embodiments, the present invention relates to the method of the invention or to a cocrystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined in the invention, a pharmaceutically acceptable salt (including its solvates and / or hydrates) of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined in the invention, or a pharmaceutical composition as defined in the invention for use as defined above, for the treatment and / or prevention of cancer or developmental abnormalities, wherein the presence and / or expression level of miR-124 in a patient's blood and / or tissue samples are measured prior to and / or during said use.

[0554] In some embodiments, the present invention relates to the methods of the present invention or to a cocrystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined in the present invention, a pharmaceutically acceptable salt (including its solvates and / or hydrates) of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined in the present invention, or a pharmaceutical composition as defined in the present invention for use as defined above, for the treatment and / or prevention of cancer or developmental abnormalities, wherein the presence and / or expression level of miR-124 in blood and / or tissue samples is measured to guide dosage or monitor response to treatment.

[0555] In some embodiments, the present invention relates to the method of the invention or to a cocrystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined in the invention, a pharmaceutically acceptable salt (including its solvates and / or hydrates) of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined in the invention, or a pharmaceutical composition as defined in the invention for use as defined above, for the treatment and / or prevention of cancer or developmental abnormalities, wherein the level of free base equivalent of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine in a patient's blood, plasma, tissue, saliva, and / or serum samples is measured during use.

[0556] In some embodiments, the present invention relates to the method of the invention or to a cocrystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined in the invention, a pharmaceutically acceptable salt (including its solvates and / or hydrates) of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined in the invention, or a pharmaceutical composition as defined in the invention for use as defined above, for the treatment and / or prevention of cancer or developmental abnormalities, in combination with another antitumor agent.

[0557] In some embodiments, the present invention relates to the method of the invention or to a cocrystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined in the invention, a pharmaceutically acceptable salt (including its solvates and / or hydrates) of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined in the invention, or a pharmaceutical composition as defined in the invention for use as defined above, for the treatment and / or prevention of cancer or developmental abnormalities, in combination with another therapy selected from chemotherapy, immunotherapy, radiotherapy, surgery, ultrasound, monoclonal antibodies, and cancer vaccines.

[0558] Among other anticancer drugs, the following can be mentioned:

[0559] - Androgen receptor inhibitors, such as enzalutamide ( Astellas / Medivation), Abiraterone ( Centocor / Ortho, gonadotropin-releasing hormone (GnRH) receptor antagonists such as degaralix ( Ferring Pharmaceuticals);

[0560] - Anti-apoptotic agents, such as venetoclax ( AbbVie / Genentech), Bonatumab ( Amgen), navitoclax (ABT-263, Abbott);

[0561] - Anti-proliferating and anti-mitotic agents, such as vinca alkaloids (including vincristine and vinblastine);

[0562] - Antibiotics such as daunorubicin, doxorubicin, idarubicin, anthracycline antibiotics, mitoxantrone, bleomycin, procainox (photomycin) and mitomycin;

[0563] -L-Asparaginase;

[0564] -Antibacterial agents;

[0565] - Antiproliferative / antimitotic alkylating agents such as nitrogen mustard cyclophosphamides and analogs (including melphalan, chlorambucil, hexamethylmelamine and thiotepa), alkylnitrosoureas (including carmustine) and analogs, strazoxine and triazines (including dacarbazine);

[0566] - Antiproliferative / antimitotic antimetabolites such as folic acid analogs (including methotrexate), aromatase inhibitors; anti-estrogens; topoisomerase I inhibitors; topoisomerase II inhibitors; microtubule-active compounds; alkylating compounds; histone deacetylase inhibitors; compounds that induce cell differentiation; cyclooxygenase inhibitors; MMP inhibitors; mTOR inhibitors; antitumor antimetabolites; platinum compounds; compounds that target / reduce the activity of protein or lipid kinases and other anti-angiogenic compounds; compounds that target, reduce or inhibit the activity of protein or lipid phosphatases; gonadotropin-releasing hormone agonists; anti-androgens; methionine aminopeptidase inhibitors; matrix Metalloproteinase inhibitors; bisphosphonates; biological response modulators; antiproliferative antibodies; heparinase inhibitors; inhibitors of Ras oncogenic isotypes; telomerase inhibitors; proteasome inhibitors; compounds for the treatment of hematologic malignancies; compounds that target, reduce, or inhibit Flt-3 activity; Hsp90 inhibitors such as 17-AAG (17-allylaminogeldemycin, NSC330507), 17-DMAG (17-dimethylaminoethylamino-17-demethoxy-geldemycin, NSC707545), IPI-504, CNF1010, CNF2024, CNF1010 (from Conforma Therapeutics); temozolomide Kinesin-spindle protein inhibitors, such as SB715992 or SB743921 (from GlaxoSmithKline), or pentamiprid / chlorpromazine (from CombinatoRx); MEK inhibitors such as ARRY142886 (from Array BioPharma), AZd6244 (from AstraZeneca), PD181461 (from Pfizer), and leucovorin;

[0567] -Anti-transfer agents;

[0568] -Angiogenesis inhibitors, such as TNP-470;

[0569] -Aromatase inhibitors, such as letrozole and anastrozole, exemestane;

[0570] -Angiotensin

[0571] - Antisense oligonucleotides, such as antisense nucleic acids targeting miR-124;

[0572] - Anticoagulants, such as heparin, synthetic heparin salts and other thrombin inhibitors;

[0573] - Arginine inhibitors, such as AEB1102 (polyethylene glycolated recombinant arginase, Aeglea Biotherapeutics) and CB-1158 (Calithera Biosciences);

[0574] - Bone resorption inhibitors, such as denosumab ( Amgen), diphosphonates such as zoledronic acid ( Novartis);

[0575] -CC chemokine receptor 4 (CCR4) inhibitors, such as mojazumab ( Kyowa Hakko Kirin, Japan);

[0576] -CDK inhibitors, such as CDK4 / CDK6 inhibitors, such as palbociclib ( Pfizer); Rebosini Novartis; abecine (Ly2835219, Eli Lilly); and trilaciclib (G1T28, G1 therapeutic agent);

[0577] - Cell cycle inhibitors and differentiation inducers, such as retinoic acid;

[0578] - Corticosteroids, such as cortisone, dexamethasone, hydrocortisone, methylprednisolone, prednisolone and prednisolone;

[0579] DNA damaging agents such as actinomycin, acridine, busulfan, carboplatin, chlorambucil, cisplatin, and cyclophosphamide. Dystomatitis, daunorubicin, doxorubicin, epirubicin, ifosfamide, melphalan, merchlorethamine, mitomycin, mitoxantrone, nitrosourea, procarbazine, tamethasone, teniposide, etoposide, and triethylamine thiophosphate.

[0580] - Fibrinolytic agents, such as tissue plasminogen activator, streptokinase, urokinase, aspirin, dipyridamole, ticlopidine, and clopidogrel;

[0581] -Folic acid antagonists;

[0582] -FLT3 receptor inhibitors, such as enzalutamide, abiraterone, apalutamide, erlotinib, crizotinib, niraparib, olaparib, osimertinib, regorafenib, sunitinib, letotinib, midotutolin, gilteritinib, semasanib, linivani, fantatinib, pericidatinib, sorafenib, cabozantinib, ponatinib, ilorasertib, paritinib, famitinib, pericidatinib, quezartinib;

[0583] - Glutaminase inhibitors, such as CD-839 (Calithera Biosciences);

[0584] - Growth factor signal transduction kinase inhibitors;

[0585] - Growth factor inhibitors, such as vascular endothelial growth factor inhibitors and fibroblast growth factor inhibitors, such as olarumab ( Eli Lilly), cetuximab ( Eli Lilly); Nexituzumab ( Eli Lilly), Panitumumab ( Amgen); and osimertinib (targeting activated EGFR, AstraZeneca);

[0586] -Hedgehog pathway inhibitors, such as sinedipine ( Sun Pharmaceuticals); and vismodegib ( Genentech);

[0587] - Histone deacetylases (HDAC) inhibitors, such as vorinostat ( Merck); Romidesin Celgene); Papirostabrine ( Novartis; Belistar ( Spectrum Pharmaceuticals); Entenoxate (SNDX-275, Syndax Pharmaceuticals) (NCT00866333); and Chidamide ( HBI-8000, Chipscreen Biosciences, China);

[0588] - Hormones and their analogues, such as estrogen, tamoxifen, goserelin, bicalutamide, and nilutet;

[0589] -Isocitrate dehydrogenase (IDH) inhibitors, such as AG120 (Celgene; NCT02677922); AG221 (Celgene, NCT02677922; NCT02577406); BAY1436032 (Bayer, NCT02746081); IDH305 (Novartis, NCT02987010)

[0590] -Isoflavones, such as genistein;

[0591] - Immunosuppressants, such as tacrolimus, sirolimus, azathioprine, and mycophenolate mofetil;

[0592] -Inhibitors of p53-repressing proteins, such as ALRN-6924 (Aileron);

[0593] - Inhibitors of transforming growth factor-β (TGF-β or TGFβ), such as NIS793 (Novartis), fusumumab (GC1008; Sanofi-Genzyme), M7824 (Merck KgaA – formerly MSB0011459X);

[0594] -iNKT cell agonists such as ABX196 (5Abivax)

[0595] -mTOR inhibitors, such as everolimus ( Novartis; Tauromus ( Pfizer); and Sirolimus ( Pfizer);

[0596] - Drugs that inhibit microtubules, such as taxanes (including paclitaxel, docetaxel), vincristine, nocodazole, epothilone, vinorelbine) And podophyllotoxins (etoposide, teniposide);

[0597] - Nitric oxide donor;

[0598] - Nucleoside inhibitors, such as trabectedin (a guanidine alkylating agent), Janssen Oncology), dichloromethyldiethylamine (alkylating agent), Aktelion Pharmaceuticals); Vincristine ( Eli Lilly; Teva Pharmaceuticals; Talon Therapeutics); Temozolomide (an alkylating agent, a prodrug of 5-(3-methyltriazine-1-yl)-imidazol-4-carboxamide (MTIC)). Merck); Cytarabine injection (ara-C, an antimetabolite cytarabine analog, Pfizer); Lomustine (alkylating agent, Bristol-Myers Squibb; NextSourceBiotechnology); Azacitidine (a pyrimidine nucleoside analog of cytidine, Celgene); omacetaxine mepesuccinate (cephalothinyl ester) (protein synthesis inhibitor) Teva Pharmaceuticals); Asparaginase Erwinia chrysanthemi (an enzyme used to deplete asparaginine). Lundbeck; EUSA Pharma); Eribulin Mesylate (a microtubule inhibitor, a tubulin-based antimitotic agent, Eisai); Cabazitaxel (microtubule inhibitor, a tubulin-based antimitotic agent, Sanofi-Aventis; capecitabine (thymidine synthase inhibitor) Genentech); Bendamustine (a bifunctional dichloromethyldiethylamine derivative believed to form interstrand DNA crosslinks). Cephalon / Teva); Ixaspiron (a semi-synthetic analogue of epothilone B, a microtubule inhibitor, a tubulin-based antimitotic agent), Bristol-Myers Squibb); Nerapine (a prodrug of deoxyguanosine analogue, a nucleoside metabolism inhibitor) Novartis); Clofarabine (a prodrug of ribonucleotide reductase inhibitors, a competitive inhibitor of deoxycytidine, Sanofi-Aventis); and trifluuridine and tepyrimidine (nucleoside analogs and thymidine phosphorylase inhibitors based on thymidine). Taiho Oncology);

[0599] -PI3K inhibitors, such as ederaris ( Gilead, Apelis (BYL719, Novartis), Tacelicillin (GDC-0032, Genentech / Roche); Piclasticis (GDC-0941, Genentech / Roche); Cupannisin (BAY806946, Bayer); Daveliximab (formerly IPI-145, Infinity Pharmaceuticals); PQR309 (Piqur Therapeutics, Switzerland); and TGR1202 (formerly RP5230, TG Therapeutics);

[0600] - Platinum coordination complexes (such as cisplatin, oxaliplatin, carboplatin, nedaplatin, pyridine, procarbazine, mitotane, saplatin and ammonia glutathione);

[0601] - Poly(ADB) ribose polymerase (PARP) inhibitors, such as those selected from the following: olaparib ( AstraZeneca); Lucapani Clovis Oncology); Nirapani Tesaro); taporabani (MDV3800 / BMN673 / LT00673, Medivation / Pfizer / Biomarin); velipanib (ABT-888, AbbVie); and BGB-290 (BeiGene, Inc.);

[0602] - Proteasome inhibitors, such as everolimus ( Novartis; Tauromus ( Pfizer); and Sirolimus ( Pfizer), Bortezomib Takeda); Carfilzomi ( Amgen); and Isazomi (Amgen); Takeda);

[0603] -Pyrimidine and purine analogues, such as fluorouridine, capecitabine and cytarabine;

[0604] -Receptor blockers, antisecretory agents, such as breveldin;

[0605] - Selective estrogen receptor modulators (SERMs), such as raloxifene ( Eli Lilly);

[0606] - Therapeutic antibodies, such as those selected from the following: anti-TNF antibody, anti-VEGF antibody, anti-EGFR antibody, anti-PD-1 antibody, anti-HER2 antibody, anti-CD20 antibody, anti-IL17 antibody and anti-CTLA4 antibody, anti-PDL1, anti-CD25, anti-α4 integrin, anti-IL6R, anti-C5, anti-IL1, 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-P CSK9, anti-IL5, anti-CD22, anti-IL4, anti-PDGFRα, anti-IL17RA, and anti-TcdB, and those selected from the following: abavoxel, abatacept, abciximab, arbiturumab, aliluximab, accorduzumab, adalimumab, adecatumab, adunaximab, aflibercept, afutuzymab, arazetil, alexiximab, alenzaximab, aliciximab, atomoximab, amatoximab, memetuzumab, anetoximab, anifromumab, arbiturumab, aporuzumab, asimomumab, avasumab, acezoliumab, atezolizumab, atezolizumab, atezolizumab, atezolizumab, atezolizumab, Alti zumab, atorumab, bavixazumab, baribizumab, bavitizumab, betumab, begoloxab, berazip, belimumab, benaribizumab, bertilimumab, besolazumab, bevacizumab, belotoxumab, bezlotoxumab, bisimazumab, bimaluzumab, bimegazumab, bivalzazumab, bonatumab, butozumab, bercosizumab, brentuximab, briakimumab, brodazumab, broxolizumab, bronoxizumab, cananumab, mecanzumab, calacizumab, calocizumab, calcimeroxumab, cetuximab, cetozumab, cetozumab mab, citatuzumab, citaltuzumab, clazazumab, cristatumab, cristatumab, cotrastuzumab, cotrastuzumab, cinnamumab, concyzumab, crenezumab, dacizumab, dalotuzumab, dapirizumab, dapirizumab, dedextuzumab, dencizumab, dinituzumab, denoxumab, derlotixumab, demumab, dastatumab, dilivomarab, trezituzumab, dupilumab, duvalumab, dustastuzumab, emexizumab, eculizumab, edalozabEfrazumab, ifencoumarb, ediluzumab, elgemtumab, ilezumab, esimomomarb, emactuzumab, emamatozumab, enavatuzumab, enrofloxacin, enrofloxacin, enrofloxacin, enrofloxacin, enrofloxacin, enrofloxacin, enrofloxacin, enrofloxacin, enrofloxacin, enrofloxacin, enrofloxacin, ipratuzumab, erlizumab, ermasomarb, etanercept, edaluzumab, etrolizumab, evinacumab, evolocumab, ivirumab, fasomumab, faramomab, fatroxacin (letuzomab), Fasimumab, Fezkimumab, Ficlatuzumab, Fentuzumab, Frivumab, Flantozumab, Fulecuzumab, Flantozumab, Fraltozumab, Fraltozumab, Fusomumab, Fulramumab, Vortoxicam, Garlicimumab, Ganitinumab, Garlicimumab, Gelotuzumab, Gelotuzumab, Gelotuzumab, Glembatumumab, Golimuumab, Golixicam, Gusecuzumab, Ibazumab, Tiimumab, Elucumab, Idacilizumab Igovomarab, Imalumab, Incemarab, Imatrozumab, Inclacumab, Indatuximab, Indutuximab, Infliximab, Intolimab, Intolimab, Innomumab, Izizumab, Ipilimumab, Itolimab, Ixatoximab, Ilizumab, Izizumab, Keliximumab, Labezizumab, Pembrolizumab, Lampalizumab, Lejinzumab, Lemasoxumab, Lenzruzumab, Lesamumab, Riviera, Lifatozumab, Ligliglizumab, Rilotorab, Lintozumab, Lirelurumab, Lodixacillin, Logivir, Lovotozumab, Lucarumab, Lulizumab Antibiotics, Luciximab, Lutozumab, Mapanizumab, Magutuximab, Massomumab, Mafullimumab, Matozumab, Meperizumab, Metemumab, Milazumab, Minetumomab, Mitoximab, Mitomoumab, Mogazumab, Moromumab, Movizumab, Moxetumomab, Morozumab-CD3, Nacolomab, Nameluzumab, Naputumab, Natralumab, Natralumab, Nabacuzzi, Nebacuzzi, Nemolizumab, Neremozumab, Nevasumab, Nitozumab, Navonab, Romozumab, Otosaczaximab, Atorizumab, Oxalutuximab, OrezumabOdumomumab, Ofamumab, Olamumab, Olozumab, Omaluzumab, Ontoxizumab, Opinuzumab, Oportuzumab, Ogovomumab, Otetuzumab, Oltertuzumab, Oceluzumab, Ozanazumab, Orlyzumab, Paxizumab, Palizumab, Panokomab, Panokumab, Pasatuzumab, Paco Pertuzumab, Pertuzumab, Pallizumab, Pertrastuzumab, Pembrolizumab, Pemtumomab, Perregizumab, Pertuzumab, Pericarizumab, Pidocizumab, Pinatozumab, Pituituzumab, Polotozumab, Ponizumab, Priliximab, Priliximab, Quinolizumab, Raltomozumab, Raltrastuzumab, Ravizumab, Rapamiluzumab, Ramucirumab, Ralcizumab, Ralcizumab, Refaniluzumab, Rega Vermitusab, Relizumab, Linasip, Rituximab, Linusuzumab, Rituximab, Rostrum, Roledoumab, Romozumab, Rolizumab, Roveizumab, Rulizumab, Sacitozumab, Samalizumab, Sarilumab, Satumumab, Secukinumab, Seretizumab, Sertosaxicumab, Seveximab, Sirozizumab, Sifamumab, Secuximab Sirulizumab, Sirukumab, Sofitelumab, Sulanzumab, Soritolumab, Sonepizumab, Sorbitolumab, Stacalumab, Thioxalumab, Suvezumab, Tabeluzab, Tazumab, Taduzumab, Talizumab, Talizumab, Taritumab, Taritumab, Taritumab, Taretozumab, Teflizumab, Atemozolomide, Tetumab, Tenexizumab, Teflizumab, Terduluumab, TGN 1412, Ticlimumab, Tictragizumab, TNX-650, Tocilizumab, Tolisizumab, Tosatosulimumab, Tosimo, Tovitumab, Trastuzumab, TRBS07, Trastuzumab, Trametesumab, Tragolumbumab, Tucotuzumab, Tovirumab, Utoxicam, Urolumbumab, Urolumbumab, Utekimumab, Vantoxicam Tocilizumab, Ventetuzumab, Varuceluzumab, Varliximab, Varlimumab, Verliximab, Vertozumab, Vertuzumab, Verpamomab, Vesenocurumab, Vexiximab, Volocixumab, Voseltuzumab, Votelmumab, Zatulimumab, Zatumumab, Zatulimumab, Zatulimumab, Zolimomab;

[0607] - Topoisomerase inhibitors, such as doxorubicin, daunorubicin, cytomegaloxin, eniposide, epirubicin, etoposide, idarubicin, irinotecan, mitoxantrone, topotecan, and irinotecan;

[0608] -Toxins, such as cholera toxin, ricin, Pseudomonas exotoxin, Bordetella pertussis adenylate cyclase toxin, diphtheria toxin and caspase activator.

[0609] Kinase or VEGF inhibitors, such as regorafenib ( Bayer); Vantanib ( AstraZeneca; Axitinib Pfizer); and Lenvatinib ( Eisai); Raf inhibitors, such as sorafenib ( Bayer AG and Onyx); Darafini ( Novartis; and Verofini ( Genentech / Roche); MEK inhibitors, such as cobimetinib ( Exelexis / Genentech / Roche); Trametinib ( Novartis; Bcr-Abl tyrosine kinase inhibitors, such as imatinib ( Novartis; Nilotinib Novartis; Dasatinib Bristol Myers Squibb); Bosutinib Pfizer); and ponatinib ( Ariad Pharmaceuticals); Her2 and EGFR inhibitors, such as gefitinib ( AstraZeneca); Erlotinib Genentech / Roche / Astellas); Lapatinib ( Novartis; Afatinib Boehringer Ingelheim); osimertinib (targeting activated EGFR, AstraZeneca; and brigatinib ( Ariad Pharmaceuticals); c-Met and VEGFR2 inhibitors, such as cabozantinib ( Exelexis; and multi-kinase inhibitors, such as sunitinib (Exelexis); and multiple kinase inhibitors, such as sunitinib (Exelexis); Pfizer); Pazopanib Novartis; ALK inhibitors, such as crizotinib ( Pfizer); Ceritinib Novartis; and alectinib ( Genentech / Roche); Bruton's tyrosine kinase inhibitors, such as ibrutinib ( Pharmacyclics / Janssen); and Flt3 receptor inhibitors, such as midostaurin ( Novartis, Tevozanib (Aveo Pharmaceuticals); Varanil (Bayer / Novartis); Deritinib (Clovis Oncology); Duvitinib (TKI258, Novartis); Cioronib (Chipscreen Biosciences); CEP-11981 (Cephalon); Linivanib (Abbott Laboratories); Neratinib (HKI-272, Puma Biotechnology); Randolinib ( IY5511 (Il-Yang Pharmaceuticals, South Korea); Ruxotetinib ( Incyte Corporation); PTC299 (PTC Therapeutics); CP-547,632 (Pfizer); Falotinib (Exelexis, GlaxoSmithKline); Quizatinib (Daiichi Sankyo); and Moticanib (Amgen / Takeda).

[0610] In a non-limiting manner, the eutectic or salt of the present invention can be used alone or in combination with one or more of the following anticancer drugs or compounds, either in kit form: ABVD, AC, ACE, abiraterone. Albumin-bound paclitaxel (Abraxane), Abstral, Actinomycin D, Fentanyl, Doxorubicin, Afatinib Afinitor (Everolimus), Aflibercept Idalor, Aldehyde Interleukin (IL-2, Proleukin or Interleukin 2), Alenduzumab (MabCampath), Ecclare, Amsidine (m-AMSA), Amsidine, Anastrozole Ara C, Ardaco, Renin, Arnoxin, Arsenic trioxide ( ATO), asparaginase ( Axitinib Azacitidine BEACOPP, BEAM, Bendamustine Bevacizumab (Avastin), Bexarotin Bicalutamide Bleomycin, bleomycin, etoposide and platinum (BEP), bortezomib Bosulif, also known as bosutinib or brentuximab. Ibuprofen (Brufen), Buserelin Busilvex, Busilvex (Maryland), CAPE-OX, CAPOX, CAV, CAVE, CCNU, CHOP, CMF, CMV, CVP, Cabazitaxel Cabozantinib Caelyx, Calpol, Campto, capecitabine ( Caprelsa, Carbo MV, CarboTaxol, Carboplatin, Carboplatin and Etoposide, Carboplatin and Paclitaxel, Carmustine (BCNU) ), Casode, Ceritinib Zhengdingmycin, Cetuximab ChlVPP, Chlorobutyrate Nitrogen Mustard Cisplatin, cisplatin and Teysuno, cisplatin and capecitabine (CX), cisplatin, etoposide and ifosfamide (PEI), cisplatin, fluorouracil (5-FU) and trastuzumab, cladribine ( LITAK), Clasteon, chlorofrabin Co-codamol ( Cometriq, cytomegalovirus, crisantaspase, crizotinib Cyclophosphamide, thalidomide and dexamethasone (CTD), Cyprostat, cyproterone acetate Cytarabine (Ara C, cytosine cytarabine), cytarabine entering the spinal fluid, cytosine cytarabine, DHAP, DTIC, dabrafenib Dacarbazine (DTIC), Dacogen, Actinomycin D ), Dasatinib (Sprycel), Daunorubicin, De Gramont, Decapeptyl SR, Decitabine Degarek denosumab ( Depocyte, dexamethasone, diacemorphine, pamidronate disodium, Disprol, docetaxel Docetaxel, cisplatin and fluorouracil (TPF), Doxifos, Doxil, doxorubicin (doxorubicin), doxorubicin and ifosfamide (Doxifos), Drogenil, Durogesic, EC, ECF, EOF, EOX, EP, ESHAP, Effentora, Efudix, vindesine (Eldisine), oxaliplatin (Eloxatin), enzalutamide, epirubicin Epirubicin, cisplatin and capecitabine (ECX), Epirubicin, carboplatin and capecitabine (ECarboX), Eposin, Erbitux, Eribulin Erlotinib Erwinase, Estracyt, Vanipexole, Etoposide ( Everolimus Evoltra, Isimestan FAD, FEC, FEC-T chemotherapy, FMD, FOLFIRINOX, FOLFOX, Faslodex, Fentanyl, Fentanyl, Firmagon, Fentanyl, Fludarabine Fludarabine, cyclophosphamide and rituximab (FCR), fluorouracil (5FU), flutamide, leucovorin, fluorouracil and irinotecan (FOLFIRI), fulvestrant G-CSF, Gefitinib (Iressa), GemCarbo (gemcitabine and carboplatin), GemTaxol, Gemcitabine (Gemzar), Gemcitabine and capecitabine (GemCap), Gemcitabine and cisplatin (GC), Gemcitabine and paclitaxel Gemzar, Giotrif, Gliadel, Glivec, Gonapeptyl, Depot, Gösherelin Gosherelin ( Granulocyte colony-stimulating factor (G-CSF), Halaven, Herceptin, Hycamtin, Hydroxyurea Hydroxyurea, I-DEX, ICE, IL-2, IPE, Ibandronic acid, Tiimomab Ibrutinib Ibuprofen ), Iclusig, Idabi Star Idabi Star and Dexamethasone, Adelaris Ifosfamide Imatinib Imiquimod cream Imnovid, Instanyl, Interferon (Intron A), Interleukin, Intron A, Ipilimumab Iressa, Irinotecan Irinotecan and capecitabine Irinotecan de Gramont, Irinotecan modified de Gramont, Javlor, Jevtana, Kadcyla, Kapake, Keytruda, Lanreitide Lapatinib Lenalidomide Letrozole Leukeran, Leukeran Leustat, Levact, Liposome Doxorubicin, Litak, Lomustine (CCNU), Lynparza, Lysodren, MIC, MMM, MPT, MST Continus, MVAC, MVP, MabCampath, Mabthera, Maxtrex, Medroxyprogesterone Acetate (Provera), Megace, Medroxyprogesterone Acetate American flammable Mepact, mercaptopurine Methotrexate (Maxtrex), Methylprednisolone, Mifamotide Mitomycin C, Mitoxana, Mitoxantrone Morphgesic SR, morphine, malaria, myocet, albumin-bound paclitaxel, albumin-bound paclitaxel Navelbine Nexavar, nilotinib Nidanip Nipent, nivolumab Novgos, Nurofen, Atorizumab Octreotide, ocfamumab Olapani Oncovin, Onkotrone, Opdivo, Oramorph, Eloxatin, and capecitabine PAD, PC (paclitaxel and carboplatin), PCV, PE, PMitCEBO, POMB / ACE, paclitaxel Paclitaxel and carboplatin, pamidronate, Panadol, panitumab Acetaminophen, Pazopanib Pemetrexed (Keytruda) Pemetrexed and Carboplatin, Pemetrexed and Cisplatin, Pentostatin Perjeta, Pertuzumab Picks & Chilli Pixuvri, pomalidomide Ponatinib, Potactasol, Prednisolone, Procarbazine, Aldehyde Interleukin, Prolia, Prostap, Provera, Mercaptopurine, R-CHOP, R-CVP, R-DHAP, R-ESHAP, R-GCVP, Rice, Raloxifene, Raltitrexed Regorafenib Revlimid, rituximab Sevredol, sodium chlorphosphate ( Solpadol, Sorafenib Steroids (dexamethasone, prednisolone, methylprednisolone), levozocin Sunitinib Sutent, TAC, TIP, Tafinlar, Tamoxifen, Tarceva, Targretin, Tasigna, Taxol, Taxotere, Taxotere and Cyclophosphamide (TC), Temodal, Temozolomide Tamarox Tepadina, Teysuno, Thalidomide, Thiotepa Thioguanine ( 6-TG (6-thioguanine), Topotecan, Topotecan (Potactasol), Torisel, Trabectin (Yondelis), Trastuzumab Trastuzumab Enmi Quoshufan, retinoic acid ( ATRA), Triptorelin Gonapeptyl Trisenox, Tylex, Tyverb, VIDE, Vantanib Vargatef, VeIP, Vectibix, Velbe, Velcade, Vemurafenib Vepesid, Vesanoid, Vidaza, Vincristine Vincristine, Vincristine, Actinomycin D And cyclophosphamide (VAC), vincristine, actinomycin and ifosfamide (VAI), vincristine, doxorubicin and dexamethasone (VAD), vindesine Changchun Fluorine Changchun Ruibin Vimodji Votrient, XELOX, Xalkori, Xeloda, Xgeva, Xtandi, Yervoy, Yondelis, Z-DEX, Zaltrap, Zanosar, Zavedos, Zelboraf, Zevalin, Zoladex (breast cancer), Zoladex (prostate cancer), zoledronic acid Zometa, Zomorph, Zydelig, Zytiga.

[0611] According to a particular embodiment, a cocrystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined herein, or a pharmaceutically acceptable salt (including its solvates and / or hydrates) of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined herein, can be combined with various chemotherapy therapies, immunotherapies (e.g., checkpoint inhibitors, monoclonal antibodies), antitumor vaccines, RNA vaccines, magnetic particles, intravascular microrobots, radiotherapy, surgery, ultrasound, or other antitumor therapies.

[0612] Therefore, the present invention further provides a cocrystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined in the present invention, a pharmaceutically acceptable salt (including its solvates and / or hydrates) of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine as defined in the present invention, or a pharmaceutical composition as defined in the present invention, which is used as an antitumor agent intended for patients also treated with any of the following antitumor therapies: immunotherapy, antitumor vaccines, RNA vaccines, radiotherapy, surgery, ultrasound, or other antitumor therapies.

[0613] According to one embodiment, the present invention relates to a cocrystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine for use as defined above, a pharmaceutically acceptable salt of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine for use as defined above, or a pharmaceutical composition for use as defined above, wherein the free base equivalent level of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine is measured in a patient’s blood, plasma, tissue, saliva, and / or serum samples during use.

[0614] According to another embodiment, the present invention also relates to a cocrystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine for use as defined above, a pharmaceutically acceptable salt of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine for use as defined above, or a pharmaceutical composition for use as defined above, wherein said use is intended for use in patients in which the level of the free base equivalent of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine in blood, plasma, tissue, saliva, and / or serum samples of said patients is measured during use.

[0615] According to yet another embodiment, the present invention also relates to a cocrystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine for use as defined above, a pharmaceutically acceptable salt of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine for use as defined above, or a pharmaceutical composition for use as defined above, wherein the presence and / or expression level of miR-124 in a patient’s blood and / or tissue samples is measured before and / or during said use, particularly for monitoring the efficacy of use and / or response to use.

[0616] The invention will be described in more detail below with reference to the following embodiments. These embodiments are provided to illustrate the invention and should not be construed as limiting the scope and spirit of the invention. Example

[0617] Materials and methods

[0618] I. Differential scanning calorimetry (DSC)

[0619] -TA Instruments Q200

[0620] - Aluminum sealed sample tray (non-sealed)

[0621] - Atmosphere: Nitrogen

[0622] - Heating rate: 10K / min

[0623] - Data processing: Universal Analysis 2000 v4.3

[0624] Samples were analyzed by DSC from 0°C up to 300°C.

[0625] II. X-ray powder diffraction (XRPD)

[0626] - Bruker D8 Advance diffractometer;

[0627] - Copper reverse cathode, tension 35KV, strength 40mA

[0628] -Bragg-Brentano configuration, for sample fixation

[0629] -Analysis range: 2° to 40°

[0630] -Step increment: 0.04°

[0631] - Step-by-step measurement time: 1s

[0632] - Data was processed experimentally using EVA software (v 11.0).

[0633] The position and intensity of X-ray peaks were extracted from the analyzed sample.

[0634] III. HPLC-UV method

[0635] The sample was analyzed by HPLC-UV using the following method:

[0636] - Instruments: Agilent 1200 and 1100 equipped with PDA detectors

[0637] -Column: Waters XTerra MS C18 3.5μm 4.6x50 mm

[0638] - Flow rate: 1.5 ml / min

[0639] -UV detection: 220nm, 270nm, 290nm

[0640] - Column temperature: 40℃

[0641] -Injection volume: 1 μl

[0642] -Mobile phase: Use a gradient of solutions A and B prepared according to the following:

[0643] - Eluent A: Ultrapure water adjusted to pH 2 with 85% orthophosphoric acid

[0644] - Elution buffer B: Acetonitrile

[0645] Table 7a below shows the HPLC gradient methods used for kinetic solubility measurements and in vitro dissolution / precipitation models.

[0646] Table 7a

[0647] Time (minutes) ％A ％B 0 90 10 4 5 95 7.9 5 95 8 90 10 10 90 10

[0648] Example 1: Preparation of a cocrystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine:L-proline

[0649] 6.6 mg of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine was mixed with 1.6 mg of L-proline as a co-crystal form and 2 μl of acetonitrile. The resulting mixture was then milled at 20 Hz for 45 min using a Retsch MM200 instrument to obtain a co-crystal of 7 mg of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine:L-proline.

[0650] The 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine:L-proline cocrystal was characterized by X-ray powder diffraction (XRPD) to confirm the cocrystal formation and by differential scanning calorimetry (DSC) to determine the thermal behavior of the new solid form.

[0651] More specifically, the powder X-ray diffraction pattern of the 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine:L-proline cocrystal shows peaks at 16.5, 20.6, 21.4, and 22.1 (±0.2 each time) in 2θ angles, and it may optionally further show the following additional peaks in 2θ angles: 11.0, 15.9, 18.3, and 19.4 (±0.2 each time); and even optionally further show the following additional peaks in 2θ angles: 6.1, 12.2, 12.6, 13.3, 13.7, 15.4, 17.3, and 22.4 (±0.2 each time), optionally further characterized by... Figure 1 The powder X-ray diffraction pattern shown and / or the single endothermic reaction with an initial temperature of 172.0 °C (±2 °C) are shown.

[0652] The same examples were carried out except that methanol was used instead of acetonitrile as the polar organic solvent, and a cocrystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine:L-proline was obtained.

[0653] Example 2: Preparation of a eutectic of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine:gentic acid

[0654] 8.9 mg of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine was mixed with 2.3 mg of gentic acid as a co-crystal form and 2 μl of acetonitrile. The resulting mixture was then milled at 20 Hz for 45 min using a Retsch MM200 instrument to obtain 7 mg of a co-crystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine:gentic acid.

[0655] The 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine:gentic acid eutectic was characterized by X-ray powder diffraction (XRPD) to confirm the formation of the eutectic and by differential scanning calorimetry (DSC) to determine the thermal behavior of the new solid form.

[0656] More specifically, the powder X-ray diffraction pattern of the 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine:gentic acid eutectic shows peaks at 7.9, 14.0, 15.2, and 25.2 (±0.2 each time) in 2θ angles, and it may optionally further show the following additional peaks in 2θ angles: 15.8, 16.9, 18.5, 19.9, 20.3, 23.0, and 24.7 (±0.2 each time); and even optionally further show the following additional peaks in 2θ angles: 7.6, 14.7, 16.1, 19.7, 21.6, 22.0, 22.3, 23.7, and 24.0 (±0.2 each time), optionally further characterized by... Figure 2 The powder X-ray diffraction pattern shown and / or the single endothermic reaction with an initial temperature of 133.0 °C (±2 °C) are shown.

[0657] Except for using methanol instead of acetonitrile as the polar organic solvent, the same examples were carried out, and a cocrystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine:gentic acid was obtained.

[0658] Example 3: Preparation of a eutectic of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine:malonic acid

[0659] 5.8 mg of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine was mixed with 1.5 mg of malonic acid as a co-crystal form and 2 μl of acetonitrile. The resulting mixture was then milled at 20 Hz for 45 min using a Retsch MM200 instrument to obtain 7 mg of a co-crystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine:malonic acid.

[0660] The 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine:malonic acid eutectic was characterized by X-ray powder diffraction (XRPD) to confirm the formation of the eutectic and by differential scanning calorimetry (DSC) to determine the thermal behavior of the new solid form.

[0661] More specifically, the powder X-ray diffraction pattern of the 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine:malonic acid eutectic shows peaks at 9.5, 12.2, 15.8, 17.3, 19.7, 22.8, 24.8, and 25.6 (±0.2 each) at a 2θ angle, and it may optionally further show the following additional peaks at 19.0, 21.4, 24.6, 26.8, 27.6, and 29.9 (±0.2 each) at a 2θ angle; and even optionally further show the following additional peaks at 16.8, 17.8, 20.9, 23.8, 28.0, and 29.6 (±0.2 each) at a 2θ angle, optionally further characterized by... Figure 3 The powder X-ray diffraction pattern shown and / or the single endothermic reaction with an initial temperature of 109.0 °C (±2 °C) are shown.

[0662] Except for using methanol instead of acetonitrile as the polar organic solvent, the same examples were carried out, and a cocrystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine:malonic acid was obtained.

[0663] Example 4: Preparation of a cocrystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine:4,4'-bipyridine

[0664] 8.6 mg of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine was mixed with 2.4 mg of 4,4'-bipyridine as a co-crystal form and 2 μl of acetonitrile. The resulting mixture was then milled at 20 Hz for 45 min using a Retsch MM200 instrument to obtain a co-crystal of 7 mg of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine:4,4'-bipyridine.

[0665] The eutectic of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine:4,4'-bipyridine was characterized by X-ray powder diffraction (XRPD) to confirm the formation of the eutectic and by differential scanning calorimetry (DSC) to determine the thermal behavior of the new solid form.

[0666] More specifically, the powder X-ray diffraction pattern of the 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine:4,4'-bipyridine eutectic shows peaks at 12.0, 19.2, 21.2, and 24.3 (±0.2 each time) in 2θ angles, and it may optionally further show the following additional peaks in 2θ angles: 16.0, 17.0, 17.8, 20.3, 22.5, and 22.7 (±0.2 each time); and even optionally further show the following additional peaks in 2θ angles: 8.5, 13.0, 15.7, 16.7, 20.9, 22.0, 23.1, 23.6, and 24.7 (±0.2 each time), optionally further characterized by... Figure 4 The powder X-ray diffraction pattern shown and / or the single endothermic reaction with an initial temperature of 127.0 °C (±2 °C) are shown.

[0667] The same examples were performed except that methanol was used instead of acetonitrile as the polar organic solvent, and a cocrystal of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine:4,4'-bipyridine was obtained.

[0668] Example 5: Preparation of anhydrous crystalline ABX464 heminaphthalene disulfonate

[0669] 11.9 mg of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine was dissolved in 500 μl of methanol. 175 μl of a 0.1 M naphthalene-1,5-disulfonic acid (counterion) ethanol solution was added to this mixture to obtain a 2:1 ABX464:counterion molar ratio.

[0670] The mixture was magnetically stirred at room temperature (25°C) for 1 / 2 hour. The solvent was evaporated under a nitrogen stream at room temperature (25°C). Acetone (1180 μl) was then added to the tube as a crystallization solvent. The tube was then hermetically sealed to prevent evaporation of the crystallization solvent and heated at 60°C for 1 hour while stirring the solution with a magnetic rod. To induce product crystallization, the tube was then cooled to 5°C at a rate of 0.1°C / min while stirring the solution with a magnetic rod. The resulting suspension was then filtered through a 0.2 μm mesh and dried under vacuum at 40°C.

[0671] Thus, 8 mg of anhydrous crystalline ABX464 heminaphthalene disulfonate was obtained.

[0672] As already mentioned herein, the powder X-ray diffraction pattern of this salt shows peaks at 9.8, 16.4, 18.2, 20.1, 21.2, 21.6, 23.5, and 26.3 (±0.2 each) in 2θ angles, and optionally further shows the following additional peaks in 2θ angles: 12.4, 13.1, 17.8, 20.9, 22.6, 24.5, 24.7, 25.2, and 25.9 (±0.2 each); and even optionally further shows the following additional peaks in 2θ angles: 8.8, 13.3, 15.1, 17.2, 17.5, 19.4, 19.5, and 19.8 (±0.2 each), as in Figure 5 As shown in the powder X-ray diffraction pattern, and / or with a single endothermic event starting at a temperature of 269.0 °C (±2 °C).

[0673] Therefore in Figure 5 The characteristic X-ray powder diffraction pattern of anhydrous crystalline ABX464 heminaphthalene disulfonate is given in the paper.

[0674] Example 6: Preparation of anhydrous crystalline ABX464 ethanesulfonate

[0675] 11.4 mg of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine was dissolved in 500 μl of methanol. 337 μl of a 0.1 M ethanesulfonic acid (counterion) solution in water / ethanol (1 / 10) was added to this mixture to obtain a 1:1 ABX464:counterion molar ratio.

[0676] The mixture was magnetically stirred at room temperature (25°C) for 1 / 2 hour. The solvent was evaporated at room temperature (25°C) under a nitrogen stream. Then, 480 μl of ethyl acetate was added to the tube as a crystallization solvent. The tube was then hermetically sealed to prevent evaporation of the crystallization solvent and heated at 60°C for 1 hour while stirring the solution with a magnetic rod. To induce crystallization of the product, the tube was then cooled to 5°C at a rate of 0.1°C / min while stirring the solution with a magnetic rod. The resulting solution was then evaporated at room temperature under a nitrogen stream.

[0677] Thus, 12 mg of anhydrous crystalline ABX464 ethanesulfonate was obtained.

[0678] As already mentioned herein, the powder X-ray diffraction pattern of this salt shows peaks at 12.2 and 22.2 (±0.2 each time) in 2θ angles, and optionally further shows the following additional peaks in 2θ angles: 6.2, 12.9, 13.1, 15.3, 16.3, 18.2, 18.6, 19.5, 20.0, and 20.7 (±0.2 each time); and even optionally further shows the following additional peaks in 2θ angles: 10.1, 15.8, 17.7, 17.9, 20.3, and 21.4 (±0.2 each time), as in Figure 6 As shown in the powder X-ray diffraction pattern, and / or with a single endothermic event starting at a temperature of 108.0 °C (±2 °C).

[0679] Therefore in Figure 6 The characteristic X-ray powder diffraction pattern of anhydrous crystalline ABX464 ethanesulfonate is given in the paper.

[0680] Example 7: Preparation of crystalline semi-THF (tetrahydrofuran) solvate of ABX464 heminaphthalene disulfonate

[0681] 10.6 mg of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine was dissolved in 500 μl of methanol. 313 μl of a 0.1 M naphthalene-1,5-disulfonic acid (counterion) ethanol solution was added to this mixture to obtain a 2:1 ABX464:counterion molar ratio.

[0682] The mixture was magnetically stirred at room temperature (25°C) for 1 / 2 hour. The solvent was evaporated under a nitrogen stream at room temperature (25°C). Then, 1030 μl of THF was added to the tube as a crystallization solvent. The tube was then hermetically sealed to prevent evaporation of the crystallization solvent and heated at 60°C for 1 hour while stirring the solution with a magnetic rod. To induce product crystallization, the tube was then cooled to 5°C at a rate of 0.1°C / min while stirring the solution with a magnetic rod. The resulting suspension was then filtered through a 0.2 μm mesh and dried under vacuum at 40°C.

[0683] Thus, 8 mg of ABX464 heminaphthalene disulfonate crystalline hemiTHF (tetrahydrofuran) solvate was obtained.

[0684] As already mentioned herein, the powder X-ray diffraction pattern of this salt shows peaks at 8.4, 12.3, 14.0, 19.2, 21.3, 22.6, and 24.6 (±0.2 each) in 2θ angles, and optionally further shows the following additional peaks in 2θ angles: 9.6, 13.0, 13.5, 14.8, 17.2, 17.8, 23.4, 24.1, 24.9, and 25.2 (±0.2 each); and even optionally further shows the following additional peaks in 2θ angles: 16.7, 18.1, 18.8, 19.5, 20.9, and 22.3 (±0.2 each), as in Figure 7 As shown in the powder X-ray diffraction pattern, and / or with a single endothermic event starting at a temperature of 172.0 °C (±2 °C).

[0685] Therefore in Figure 7 The characteristic X-ray powder diffraction pattern of the crystalline semi-THF solvate of ABX464 semi-naphthalene disulfonate is given in the figure.

[0686] Example 8: A capsule form of the drug according to the invention comprising a eutectic of ABX464 as defined herein. Composition

[0687] Prepare the following capsules using the corresponding amounts of ingredients specified in Table 8 below.

[0688] Table 8

[0689]

[0690] The pharmaceutical compositions according to the present invention can be used for the prevention and / or treatment of inflammatory diseases such as inflammatory bowel disease, rheumatoid arthritis, pulmonary hypertension, NASH (non-alcoholic steatohepatitis) and multiple sclerosis, viral diseases and / or cancer or developmental abnormalities.

[0691] Example 9: A pharmaceutically acceptable salt of ABX464 as defined in this invention according to the present invention. Pharmaceutical compositions in capsule form

[0692] Prepare the following capsules using the corresponding amounts of the ingredients specified in Table 9 below.

[0693] Table 9

[0694]

[0695] The pharmaceutical compositions according to the present invention can be used to treat and / or prevent inflammatory diseases such as inflammatory bowel disease, rheumatoid arthritis, pulmonary hypertension, NASH and multiple sclerosis, viral diseases and / or cancer or developmental abnormalities.

[0696] Example 10: At selected sampling times in two different specific aqueous media, ABX464 crystal form I... In comparison, the preparation and solubility dynamics of anhydrous ABX464 heminaphthalene disulfonate and ABX464:L-proline cocrystal according to this application... Mechanical measurement.

[0697] Anhydrous ABX464 heminaphthalene disulfonate and ABX464:L-proline cocrystal according to this application were prepared and tested according to the two schemes detailed below (see Example 10a and Example 10b respectively).

[0698] Example 10a: Preparation of anhydrous ABX464 heminaphthalene disulfonate

[0699] Anhydrous ABX464 heminaphthalene disulfonate was synthesized according to the following scheme:

[0700] Weigh 200 mg of ABX464 crystal form I into a 20 mL glass bottle;

[0701] - Add 10 ml of methanol to a glass bottle at room temperature and dissolve ABX464 crystal form I by magnetic stirring for 15 min;

[0702] -Then the ABX464 methanol solution was filtered through a PTFE 0.45μm filter.

[0703] - Add 5.9 mL of 0.05 M naphthalene-1,5-disulfonic acid in ethanol dropwise at room temperature;

[0704] - Stir the solution magnetically at room temperature for 60 minutes (note the clear yellow solution);

[0705] -Then the solvent was evaporated at room temperature under a nitrogen gas stream (to obtain a pale yellow solid);

[0706] - Add 10 mL of acetone to a glass bottle at room temperature to allow ABX464 heminaphthalene disulfonate to crystallize overnight while magnetically stirring the suspension;

[0707] - The suspension was filtered through a 0.2 μm cellulose sieve filter (to obtain a pale yellow solid);

[0708] - The resulting solid was finally dried under vacuum at room temperature to obtain anhydrous ABX464 heminaphthalene disulfonate.

[0709] To characterize the salt, X-ray powder diffraction analysis was performed. The corresponding XRPD pattern is characteristic of the crystalline solid and is consistent with... Figure 5 The results are quite similar.

[0710] Example 10b: Preparation of ABX464:L-proline cocrystal

[0711] Synthesize ABX464:L-proline cocrystal according to the following scheme:

[0712] - A powder physical mixture was prepared by mixing 200 mg of ABX464 crystalline form I and 68 mg of L-proline (1 / 1 molar stoichiometry) in a 10 ml stainless steel grinding jar;

[0713] - Introduce two 5mm diameter stainless steel grinding balls into the grinding jar;

[0714] Add 130 μl of methanol;

[0715] - Seal the container airtight immediately after adding the solvent;

[0716] -Then place the jar on a grinding instrument (Retsch MM200) and grind it at 20Hz for 45 minutes;

[0717] - Thus, ABX464:L-proline cocrystal was obtained.

[0718] To characterize this eutectic, X-ray powder diffraction analysis was performed. The corresponding XRPD pattern is characteristic of the crystalline solid and is consistent with... Figure 1 The result is equivalent to the above.

[0719] Example 10c: Kinetic solubility in two aqueous media

[0720] The kinetic solubility measurements of ABX464 crystalline form I, anhydrous ABX464 heminaphthalene disulfonate, and ABX464:L-proline cocrystal were performed using the following method.

[0721] Kinetic solubility scheme

[0722] - Samples for kinetic solubility measurements were prepared at room temperature in the dark at a target concentration of 2 mg / ml (equivalent to ABX464):

[0723] - Weigh 2 mg of the test substance equivalent to ABX464 into a 4 ml glass bottle;

[0724] - Add 1 ml of the selected medium at room temperature (see below for details);

[0725] - Perform orbital stirring at room temperature, away from light (see below);

[0726] - At selected sampling times (5 min, 30 min, 2 h, 4 h, and 24 h), soluble fractions are separated from insoluble fractions by filtration through a PTFE 0.45 μm membrane;

[0727] - Immediately after filtration, the HPLC-UV dose of the resulting filtrate was calibrated relative to an external single point. The HPLC-UV method selected for these measurements is described above (see also Table 7a above).

[0728] Preparation of ABX464 reference solution of -1 mg / ml:

[0729] Weigh 1 mg of ABX464 in crystalline form I;

[0730] Dissolve it in DMSO until a clear DMSO solution of 1 mg / ml is obtained.

[0731] What makes these two specific aqueous media even more special is:

[0732] -FaSSIF (i.e., fasting simulated intestinal fluid) pH = 6.5 + 1 wt% PPVVA (polyvinylpyrrolidone-vinyl acetate: precipitation inhibitor); and

[0733] -FeSSIF (i.e., intestinal fluid simulated during feeding) pH=5.0 + 1 wt% PVPVA (precipitation inhibitor)

[0734] To prepare 5 mL of FaSSIF, the steps are as follows:

[0735] Weigh 11.2 mg of SIF powder, add 175 μl of FaSSIF buffer concentrate, and then make up to 5.0 mL with ultrapure water; let stand for 2 hours; and add 1% w / w PVPVA.

[0736] To prepare 5 mL of FeSSIF, the steps are as follows:

[0737] Weigh 56.0 mg of SIF powder, add 350 μl of FeSSIF buffer concentrate, and then make up to 5.0 mL with ultrapure water; and add 1% w / w PVPVA.

[0738] kinetic solubility results

[0739] The kinetic solubility results of ABX464 crystalline form I, anhydrous ABX464 heminaphthalene disulfonate, and ABX464:L-proline cocrystal in FassiF and FessiF media at different sampling times are reported in Table 10 below.

[0740] Table 10

[0741]

[0742] As a conclusion to these solubility measurements, the following general observations can be emphasized:

[0743] - In both media and in each case, the solubility of anhydrous ABX464 heminaphthalene disulfonate and ABX464:L-proline cocrystal was higher than that of ABX464 crystalline form I.

[0744] - All solid forms exhibit significantly higher solubility in FeSSIF pH 5.0 + 1% PPVVA medium.

[0745] Finally, note that:

[0746] The solubility of anhydrous ABX464 heminaphthalene disulfonate in FeSSIF + 1% PPVVA medium rapidly reached a plateau of about 1.05 mg / ml at 2 h, and then continued to increase until it reached about 1.52 mg / ml at 24 h.

[0747] The solubility of -ABX464:L-proline cocrystal in FeSSIF+1%PVPVA medium rapidly reached a plateau of approximately 1.16 mg / ml at 2 h, and then continued to increase slightly until it reached approximately 1.28 mg / ml at 24 h.

[0748] The solubility of ABX464 crystalline form I in FeSSIF + 1% PPVVA medium plateaued at approximately 0.30 mg / mL after 2 hours, and then continued to increase slightly until it reached approximately 0.42 mg / mL after 24 hours.

[0749] Example 11: Compared with ABX464 crystalline form I, in the intestinal compartment of a two-step dissolution-precipitation fasting human in vitro model Solubility measurement of anhydrous ABX464 heminaphthalene disulfonate

[0750] ABX464 crystalline form I and anhydrous ABX464 heminaphthalene disulfonate have been evaluated in a two-step dissolution / precipitation in vitro human model.

[0751] The anhydrous ABX464 heminaphthalene disulfonate used in this test was a salt prepared according to the scheme detailed in Example 10a above.

[0752] The ABX464 crystal form I used in this test is the same form used in Example 10 above.

[0753] The model consists of the following steps:

[0754] - The selected substance was dispensed into a fasting simulated gastric medium containing 1% w PVPVA (precipitation inhibitor), and then after 30 minutes,

[0755] - Dilute the obtained suspension with simulated fasting intestinal medium.

[0756] Using this model, the risk of dissolution of the selected substance (ABX464 crystalline form I or anhydrous BX464 heminaphthalene disulfonate) in gastric media and precipitation of the API (active pharmaceutical ingredient) in the intestinal compartment was evaluated.

[0757] The crystalline properties of the solid residues collected at the end of each step (stomach and intestine) were determined by XRPD after centrifugation (18,000 rpm for 15 min).

[0758] Dissolution / precipitation model scheme under fasting human conditions

[0759] -Weigh 4.0 mg equivalent of the selected substance of ABX464 into 6 different vials.

[0760] - Solubility was measured in the gastric compartment (also known as G) after 15 min (G15 min) and after 30 min (G30 min), which included the following steps:

[0761] Add 1 mL of FaSSGF pH 1.2 medium containing 1% w PVPVA (ABX464 target concentration = 4 mg / mL) to each of the six vials.

[0762] - Vortex mixing at 37°C.

[0763] - Carefully observe one vial at 15 min and 30 min (label the vials for G15 min and G30 min respectively), and for each vial...

[0764] -Note the floating appearance,

[0765] - Centrifuge at 18000 rpm for 5 min and filter through a 0.45 μm filter (Millex LCR Ref.SLCR0,13NK).

[0766] - Measure the pH of the supernatant.

[0767] - Quantitative dosing of ABX464 soluble fractions by HPLC

[0768] - Record the XPRD image of the sample at the final time point.

[0769] - Solubility was measured in the intestinal compartment (also known as I) after 15 min (vial I 15 min), 30 min (vial I 30 min), 60 min (vial I 60 min), and 120 min (vial I 120 min), comprising the following steps:

[0770] - Add 1 mL of FaSSIF x2 pH 6.5 medium / sodium bicarbonate 90 / 10 (ABX464 target concentration = 2 mg / mL) to the 4 remaining vials.

[0771] - Vortex mixing at 37°C.

[0772] - Carefully observe one vial at times of 15 min, 30 min, 60 min, and 120 min (labeled as I 15 min, I 30 min, I 60 min, and I 120 min, respectively), and for each vial...

[0773] -Note the floating appearance,

[0774] - Centrifuge at 18000 rpm for 5 min and filter through a 0.45 μm filter (Millex LCR Ref.SLCR0,13NK).

[0775] - Measure the pH of the supernatant.

[0776] - Quantitative dispensing of ABX464 soluble fractions by HPLC

[0777] - Record the XPRD image of the sample at the final time point.

[0778] Composition and preparation of biological media under fasting conditions (see Tables 11 and 12):

[0779] - Fasting gastric medium = FaSSGF pH = 1.2 / 1% PVPVA w / v

[0780] Table 11

[0781]

[0782]

[0783] - Fasting intestinal medium (FaSSIF X2 pH=6.5 / sodium bicarbonate, at 80g / l 90 / 10v / v)

[0784] Composition / Preparation of FaSSIF x2 (the medium was concentrated 2-fold to account for dilution in the fasting model):

[0785] Table 12

[0786]

[0787] After dilution, a FaSSIF X2 / sodium bicarbonate 80 g / L (90 / 10; v / v) mixture was prepared in the intestinal compartment to maintain a pH of 6.5.

[0788] Results of a two-step dissolution / precipitation model in fasting humans. The solubility values ​​of ABX464 crystalline form I and anhydrous ABX464 heminaphthalene disulfonate were obtained in the two-step dissolution / precipitation human fasting model reported in Tables 13 to 16 below.

[0789] For the solid residues collected at the last time point in the gastric (G 30 min) and intestinal (I 120 min) compartments during the fasting dissolution / precipitation test, record the XRPD chromatograms of ABX464 crystalline form I and anhydrous ABX464 heminaphthalene disulfonate, and report them separately. Figure 8 (The bottom line) and Figure 9 (On the bottom line).

[0790] exist Figure 8For comparison, an X-ray powder diagram showing ABX464 crystalline form I (the top line) is also included.

[0791] exist Figure 9 For comparison, two X-ray powder diagrams are also included, showing ABX464 crystalline form I (top line) and anhydrous ABX464 heminaphthalene disulfonate (second line from the top).

[0792] Data and results for ABX464 crystalline form I (solubility measured in a fasting model containing 1% PPVVA at FaSSGF pH 1.2) are collected in Tables 13 and 14 below.

[0793] Table 13

[0794]

[0795] Table 14

[0796]

[0797]

[0798] Data and results for anhydrous ABX464 heminaphthalene disulfonate (solubility measured in a fasting model containing 1% PPVVA in FaSSGF pH 1.2) are collected in Tables 15 and 16 below.

[0799] Table 15

[0800]

[0801] Table 16

[0802]

[0803] These results highlight the following points:

[0804] - In the intestinal compartment at pH 6.5:

[0805] - Starting with ABX464 crystalline form I (approximately 80 μg / ml) in the intestinal compartment, the soluble fraction of ABX464 did not undergo significant evolution, and no phase transformation was detected by XRPD.

[0806] - Starting with anhydrous ABX464 heminaphthalene disulfonate, a significant increase in the soluble fraction of ABX464 in the intestinal compartment was noted (approximately 430 μg / ml), and no phase transformation was detected by XRPD.

[0807] The main conclusions of these solubility studies, as illustrated in Examples 10 and 11 above, are:

[0808] Compared to ABX464 crystalline form I, ABX464 heminaphthalene disulfonate and ABX464:L-proline cocrystal exhibit significantly higher solubility in Fassif and Fessif media.

[0809] -Compared to the solubility of ABX464 crystalline form I in the intestinal compartment of a two-step dissolution / precipitation fasting in vitro human model (approximately 80 μg / ml), the solubility of ABX464 heminaphthalene disulfonate in the intestinal compartment of this model is significantly higher (approximately 430 μg / ml).

Claims

A crystalline semi-THF solvate of 1,8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine heminaphthalene disulfonate, having a powder X-ray diffraction pattern showing peaks at 8.4, 12.3, 14.0, 19.2, 21.3, 22.6 and 24.6, expressed in 2θ angles ±0.

2.

2. The crystalline hemi-THF solvate of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine heminaphthalene disulfonate according to claim 1, exhibiting the following additional peaks at ±0.2 degrees in 2θ angles: 9.6, 13.0, 13.5, 14.8, 17.2, 17.8, 23.4, 24.1, 24.9, and 25.

2.

3. The crystalline hemi-THF solvate of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine hemi-naphthalene disulfonate according to claim 1, exhibiting the following additional peaks at ±0.2 degrees in 2θ angles: 16.7, 18.1, 18.8, 19.5, 20.9, and 22.

3.

4. The crystalline semi-THF solvate of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine heminaphthalene disulfonate according to claim 1, having a powder X-ray diffraction pattern as shown in Figure 7.

5. The crystalline semi-THF solvate of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine heminaphthalene disulfonate according to claim 1, having a single endothermic onset temperature of 172.0 °C ± 2 °C.

6. A method for preparing the crystalline hemi-THF solvate of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine heminaphthalenedisulfonate as described in any one of claims 1-5, the method comprising the following steps: a) Dissolve 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine in a solvent or mixture of solvents selected from C1-C6 aliphatic alcohols; b) Add naphthalene-1,5-disulfonic acid to the mixture thus obtained in step a), wherein the acid itself may have been dissolved in a solvent or solvent mixture selected from C1-C6 aliphatic alcohols, thereby obtaining an 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine:antiion molar ratio between 3:1 and 1:

2. c) Optionally, the solvent is evaporated at a temperature between 0°C and the boiling point of the selected solvent or solvent mixture in steps a) and b); d) Optionally add tetrahydrofuran; e) Apply temperature program; f) Optional filtering; and g) Then optionally dry at a temperature between room temperature and 60°C to obtain the desired salt of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine.

7. The method of claim 6, wherein step e) related to the temperature program comprises: i) Heating under reflux at a specified temperature, the specified temperature being between room temperature and the boiling point of the solvent, and / or ii) Cooling under reflux at a specified rate, the specified temperature being between 0°C and 60°C, the specified rate being between 30°C / min and 0.05°C / min.

8. The method of claim 6, wherein step f of the filtration is performed using conventional glass fiber, conventional cellulose filter paper, polytetrafluoroethylene, or polyvinylidene fluoride.

9. The method according to any one of claims 6-8, wherein step g of drying is carried out under vacuum at a temperature between 30°C and 60°C, or under an ambient atmosphere at a temperature between 30°C and 60°C.

10. A pharmaceutical composition comprising a crystalline hemiTHF solvate of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine heminaphthalene disulfonate as defined in any one of claims 1-5, and at least one pharmaceutically acceptable excipient.

11. The pharmaceutical composition of claim 10, wherein the pharmaceutical composition is in the form of tablets, capsules, pills, lozenges, chewing gum, powders, granules, suppositories, emulsions, microemulsions, solutions, suspensions, syrups, elixirs, ointments, drops, pastes, creams, lotions, gels, sprays, inhalers, or patches.

12. The pharmaceutical composition according to claim 11, wherein the solution is an aqueous solution.

13. The pharmaceutical composition according to claim 11, wherein the suspension is an aqueous suspension.

14. Use of the crystalline hemi-THF solvate of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine hemi-naphthalenedisulfonate according to any one of claims 1-5, or the pharmaceutical composition according to any one of claims 10 to 13, in the preparation of a medicament for the prevention and / or treatment of inflammatory diseases.

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