Troriluzole hydrochloride salts

Abstract

Our invention relates to a process for the preparation of 2-amino-N-[2-[methyl-[2-oxo-2-[[6- (trifluoromethoxy)-1,3-benzothiazol-2-yl]amino]ethyl]amino]-2-oxoethyl]acetamide, to its new salts, its anhydrous forms, hydrates and solvates, to its new crystalline forms (in other words, polymorphic modifications or polymorphs), and to the preparation of all of these, to pharmaceutical compositions containing them, and to the medical applications of the new salts and crystalline forms according to the invention.

Description

[0001] Troriluzole hydrochloride salts

[0002] Technical background

[0003] Present invention refers to a new process for the preparation of 2-amino-N-[2-[methyl-[2- oxo-2-[[6-(trifluoromethoxy)-l,3-benzothiazol-2-yl]amino]ethyl]amino]-2- oxoethyl] acetamide, its new salts, their anhydrous forms, hydrates, and solvates, new crystalline forms (also known as polymorphic modifications or polymorphs), as well as the preparation of all these forms, the pharmaceutical compositions containing them, and the pharmaceutical applications of the new salts and crystalline forms according to the invention.

[0004] The chemical structure of the compound of formula (I), 2-amino-N-[2-[methyl-[2-oxo-2- [[6-(trifluoromethoxy)-l,3-benzothiazol-2-yl]amino]ethyl]amino]-2-oxoethyl]acetamide, as INN troriluzole (1) is as follows:

[0005] The formula (1) corresponds to the base of troriluzole. Clinical trials are currently being conducted for the treatment of obsessive-compulsive disorder (OCD) using the hydrochloride salt of troriluzole.

[0006] Background of the invention

[0007] Troriluzole (BHV-4157) is an investigational glutamate modulator and a third-generation prodrug of riluzole. When administered orally, aminopeptidase enzymes in the blood release riluzole from the tripeptide derivative. Unlike riluzole, troriluzole only needs to be administered once daily, and its effectiveness is not influenced by food intake. Troriluzole has been studied for various types of cancer and later for the treatment of Alzheimer's disease and spinocerebellar ataxia. Troriluzole was first described in the international patent application with publication number WO 2016 / 140879.

[0008] In this application, only the salt formed with trifluoroacetic acid (TFA) among the salts of troriluzole is mentioned. However, neither the description nor examples disclose the exact procedure for its preparation, and the characterization of the TFA salt is also missing. Similarly, there is neither description of the preparation of the troriluzole base, nor of its chemical or morphological properties.

[0009] Furthermore, new information regarding the final product base (1) or its salt is not disclosed in subsequent applications (US2021228549, US2021236470, US2022396555, WO2023230451) also.

[0010] Brief summary of the invention

[0011] In recent times, there has been a significant demand in the pharmaceutical industry to reproducibly produce pure and morphologically uniform products. This is a fundamental requirement to meet the needs of pharmaceutical formulation, quality assurance, and regulatory authorities. It is well known that different salts and polymorphs exhibit variations in essential properties such as solubility, chemical stability, polymorphic stability, dissolution rate, bioavailability, filterability, dryability, and tabletability. Furthermore, from the perspective of manufacturing economics, it is extremely important to produce the product using a process that is feasible on an industrial scale, easily reproducible, and results in a morphologically uniform and impurity-free salt. The aim was with the present invention to develop a troriluzole production process which is more advantageous than the previously known methods.

[0012] Our goal was to produce new troriluzole salts and polymorphic forms with high purity and uniform morphology, whose stability and physicochemical properties are more favorable than those of salts obtainable by a person skilled in the art using routine procedures. Their chemical stability also makes them suitable for use in pharmaceutical preparations. Currently, no proven clinically suitable base or salt form is known from the prior art. The trifluoroacetate salt described in patent application WO 2016 / 140879 is not suitable for medicinal use. In patent application WO2023230451, a troriluzole hydrochloride hydrate salt is mentioned and used in studies, which, according to its formula, contains troriluzole, hydrochloric acid, and water in a 1 : 1 : 1 ratio. However, apart from describing it, they do not characterize the material, nor do they provide information on its crystallinity or stability. Eddy and colleagues (Journal of Investigative Dermatology (2023) 143, 2007e2018) conducted in vivo studies on mice, using lyophilized troriluzole monohydrochloride obtained from Fox Chase Therapeutics Discovery (Doylestown, PA), dissolved in dimethyl sulfoxide. No data on the crystalline hydrochloride salt is provided here either.

[0013] It is still necessary to develop a solid form that has adequate morphological and chemical stability to be useful in pharmaceutical preparations. Considering that troriluzole contains a tripeptide side chain, it arises that the hydrochloride of the product may be hygroscopic, which could make complicate the drug formulation and makes the exact composition of the active ingredient uncertain. Therefore, salt forms that absorb minimal moisture from the air are particularly advantageous.

[0014] The above objective is achieved with the new salts according to our invention, specifically the salts formed with troriluzole and hydrochloric acid (including hydrates and solvates, amorphous and crystalline forms), and their production.

[0015] The present invention also refers to the advantageous production of a new troriluzole base for the use of troriluzole, as well as to pharmaceutical preparations containing the new salts and polymorphs, and to the processes for producing the salts, polymorphs, and pharmaceutical preparations, as well as to the medicinal applications of the salts and polymorphs.

[0016] The invention further relates to the use of the troriluzole salts and crystalline forms according to the invention as medicines, as well as to the use of the troriluzole salts and crystalline forms according to the invention for the production of pharmaceutical compositions. The invention also refers to the use of any troriluzole salt or crystalline form according to the present invention in the production of high-purity troriluzole base, as well as to the use of any troriluzole salt or crystalline form according to the invention as an intermediate in the production of troriluzole base, any of its salts, or any of their solvates.

[0017] Brief description of the figures

[0018] Figure la: Synthesis of troriluzole (TFA salt).

[0019] Figure lb: Production of troriluzole (salt and base) through tripeptide.

[0020] Figure 2: X-ray powder diffraction pattern of troriluzole base Form I polymorph form.

[0021] Figure 3: X-ray powder diffraction pattern of troriluzole base Form II polymorph form.

[0022] Figure 4: X-ray powder diffraction pattern of troriluzole base Form III polymorph form.

[0023] Figure 5: X-ray powder diffraction pattern of troriluzole base Form IV polymorph form.

[0024] Figure 6: X-ray powder diffraction pattern of troriluzole base Form V polymorph form. Figure 7: X-ray powder diffraction pattern of the crystalline form of troriluzole hydrochloride hydrate [(1:1:1) salt].

[0025] Figure 8: DVS diagram of the crystalline form of troriluzole hydrochloride hydrate [(1:1 : 1) salt] prepared according to Example 13.

[0026] Figure 9: TG diagram of the crystalline form of troriluzole hydrochloride hydrate [(1:1:1) salt] prepared according to Example 13.

[0027] Figure 10: DVS diagram of the crystalline form of troriluzole hydrochloride hydrate [(1:1:1) salt] prepared according to Example 14.

[0028] Figure 11 : TG diagram of the crystalline form of troriluzole hydrochloride hydrate [(1:1: 1) salt] prepared according to Example 14.

[0029] Figure 12: DVS diagram of the crystalline form of troriluzole hydrochloride hydrate [(1:1:1) salt] prepared according to Example 15.

[0030] Figure 13 : TG diagram of the crystalline form of troriluzole hydrochloride hydrate [(1:1: 1) salt] prepared according to Example 15.

[0031] Figure 14: X-ray powder diffraction pattern of the crystalline form of troriluzole hydrochloride hydrate [(1:2:1) salt].

[0032] Figure 15: DVS diagram of the crystalline form of troriluzole hydrochloride hydrate [(1:2:1) salt].

[0033] Figure 16: TG diagram of the crystalline form of troriluzole hydrochloride hydrate [(1:2: 1) salt]. Figure 17: X-ray powder diffraction pattern of troriluzole hydrochloride [(1:1) salt] Form A polymorph form.

[0034] Figure 18: DVS recording of troriluzole hydrochloride [(1:1) salt] Form A polymorph form.

[0035] Figure 19: TG recording of troriluzole hydrochloride [(1:1) salt] Form A polymorph form.

[0036] Figure 20: X-ray powder diffraction pattern of troriluzole hydrochloride [(1:1) salt] Form B polymorph form.

[0037] Figure 21: DVS recording of troriluzole hydrochloride [(1:1) salt] Form B polymorph form.

[0038] Figure 22: TG recording of troriluzole hydrochloride [(1:1) salt] Form B polymorph form.

[0039] Figure 23 : X-ray powder diffraction pattern of the crystalline form of troriluzole hydrochlorideacetic acid solvate [(1:1:1) salt].

[0040] Figure 24: TG recording of the crystalline form of troriluzole hydrochloride-acetic acid solvate [(1:1:1) salt].

[0041] Figure 25: X-ray powder diffraction pattern of the amorphous form of troriluzole hydrochloride [(1:1) salt]. Detailed description of the invention

[0042] The present invention thus relates, on the one hand, to a new, cost-effective process to produce troriluzole in fewer steps. The process for preparing troriluzole was first described in international patent application publication number WO 2016 / 140879, using the following synthesis route:

[0043] Figure la

[0044] The synthesis route starts from riluzole and yields the troriluzole trifluoroacetate salt in four steps. The resulting troriluzole trifluoroacetate salt is described as a light-yellow powder, characterized by LC / MS and NMR data. It is not clear whether the obtained product is amorphous or crystalline. However, the resulting trifluoroacetate salt is not suitable for use as a pharmaceutical active ingredient. The description of the application does not disclose how the base or a pharmaceutically suitable salt can be prepared from the resulting trifluoroacetate salt. Thus, the patent application does not describe a pharmaceutically applicable active ingredient form. Thus, no free base or pharmaceutically suitable salts of troriluzole and procedure for the production thereof are disclosed. It is clear that there is a need for producing troriluzole derivatives which are suitable for use in pharmaceutical compositions and which are stable and have a uniform morphological structure.

[0045] It is essential to achieve - from a cost-effective perspective - a high yield in the transformation of the starting material, riluzole, into the product troriluzole (salts or free base). Therefore, our aim was to develop a suitable procedure for the preparation of troriluzole from riluzole with an acceptable yield.

[0046] Surprisingly, we found that riluzole, when modified with the appropriate tripeptide side chain (3, BocGlyGlySarOH), can be converted into a troriluzole salt in a single step, without preparing the intermediate compound (4), according to the following scheme:

[0047] Figure lb According to the present invention, troriluzole of formula (1) or a salt thereof, can be produced by reacting riluzole of formula (2), or an acid addition salt thereof of general formula (2 * HnA), wherein A represents a mono- or polyvalent anion and n corresponds to the valency of A, with a compound of formula (3) (BocGlyGlySarOH) in the presence of a base and a peptide coupling agent. The thus obtained intermediate of formula (4) can be converted to troriluzole of the compound of formula (1) optionally without isolation, by removing the protecting group with acid, and the resulting troriluzole of formula (1) is separated in base or salt form. According to the present invention, troriluzole - separated in its base form - can be converted into any salt form. Alternatively, if separated in a salt form it can be converted into the base or into another salt form.

[0048] In a preferred embodiment of the process according to present invention, the peptide coupling agent is a carbodiimide-type compound, preferably di-cyclohexyl-carbodiimide (DCC), N,N'-di-isopropyl-carbodiimide (DIC), l-ethyl-3-(3-dimethylaminopropyl)- carbodiimide (EDC), l-cyclohexyl-(2-morpholinoethyl)-carbodiimide metho-p-toluol sulfonate (CMCT), preferably carbonyl-diimidazole, di-cyclohexyl-carbodiimide and / or

[0049] - aza-benzotriazole-type compounds, preferably l-hydroxy-7-azabenzotriazole (HO At), l-[bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-b]pyridinium-3-oxide- hexafluorophosphate (HATU), [benzotri azol -1 -yloxy(dimethylamino)methylene]-dimethyl- azanium hexafluorophosphate (HBTU), HBTU / TBTU, 2-(6-chloro-lH-benzotriazol-l-yl)- 1, 1,3,3-tetramethyl-amin-hexafluorophosphate (HCTU), (benzotri azol- 1-yloxy)- tripyrrolidino-phosphonium-hexafluorophosphate (PyBOP), (7-azabenzotriazol- 1 -yloxy)- tripyrrolidino-phosphonium-hexafluorophosphate (PyAOP), preferably 1- [bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-b]pyridinium-3-oxide- hexafluorophosphate (HATU) and / or

[0050] - most preferably, we can use l-[bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5- b]pyridinium-3-oxide-hexafluorophosphate (HATU). - most preferably, we can use l-[bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5- b]pyridinium-3-oxide-hexafluorophosphate (HATU).

[0051] In a preferred embodiment of the troriluzole production process according to present invention, an organic base is used to form the peptide bond, preferably tertiary amines, more preferably trialkyl amines, most preferably triethylamine (TEA), diisopropylethylamine (DIPEA), and most preferably diisopropylethylamine (DIPEA), or cyclic amines such as pyridine, 1,6-dimethylpyridine, most preferably diisopropylethylamine (DIPEA).

[0052] In the highly advantageous embodiment of our invention, the production of troriluzole is carried out in the presence of a solvent, such that the reaction is preferably carried out in a dipolar aprotic solvent, which dipolar aprotic solvent o preferably ester-type solvents, esters formed from Ci-Ce alcohols and Ci-Ce organic acids, more preferably methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n- or sec-butyl acetate, methyl-, n-propyl- or iso-propyl propionate, or methyl-, ethyl-, n-propyl- or iso-propyl butyrate, more preferably ethyl acetate, or o preferably formamide-type solvents, more preferably dimethylformamide, diethylformamide, dimethylacetamide, diethylacetamide, dimethyl or diethyl propionamide, most preferably dimethylformamide, cyclic amides, preferably N-methylpyrrolidone, or o preferably ether-type solvents, more preferably aliphatic ethers such as diethyl ether, diisopropyl ether, methyl ethyl ether, methyl isopropyl ether, more preferably cyclic ethers, preferably dioxane or tetrahydrofuran, methyl tetrahydrofuran, more preferably tetrahydrofuran, methyl tetrahydrofuran, most preferably tetrahydrofuran, or o - ketone-type solvents, preferably symmetric and asymmetric ketones containing Ci-Ce aliphatic carbon chains, more preferably acetone, methyl ethyl ketone, methyl isobutyl ketone, most preferably acetone, or cyclic ketones, preferably cyclopentanone, cyclohexanone, cycloheptanone, or cyclooctanone, or o - sulfoxide-type solvents, such as dimethyl sulfoxide, diethyl sulfoxide, or dioxolane, most preferably dimethyl sulfoxide, or o - nitrile-type solvents, such as acetonitrile, propionitrile, butyronitrile, isobutyronitrile most preferably acetonitrile, or

[0053] - preferably nonpolar aprotic solvents, which are saturated or unsaturated, open-chain or cyclic hydrocarbons, where saturated hydrocarbons are preferably Ci-Cs straight or branched chain alkanes, or mixtures thereof, preferably pentane, hexane, heptane isomers, or mixtures thereof, cyclic saturated hydrocarbons, preferably Cs-Cs cyclic hydrocarbons, more preferably cyclopentane, cyclohexane, methylcyclohexane, cycloheptane, cyclooctane, or mixtures thereof, or aromatic solvents, preferably toluene or xylene.

[0054] In the process according to the present invention, acids are used in the step of removing the Boc protecting group, preferably organic or inorganic acids are used. As inorganic acids, preferably hydrogen chloride, hydrogen bromide, hydrogen iodide, sulfuric acid, nitric acid, phosphoric acid, more preferably hydrogen chloride, most preferably aqueous hydrogen chloride solution, as organic acids, sulfonic acids, preferably ethanesulfonic acid, methanesulfonic acid, benzenesulfonic acid, para-toluenesulfonic acid, carboxylic acids, preferably C1-C4 aliphatic carboxylic acids, more preferably chlorinated or fluorinated acetic acid derivatives, most preferably trifluoroacetic acid are used.

[0055] In one of the highly advantageous embodiments of the present invention, the production of troriluzole uses riluzole acid addition salt of general formula (2 * HnA) as the starting material. In the formula (2 * HnA), A represents an inorganic or organic acid anion, where the inorganic acid is preferably hydrogen chloride, hydrogen bromide, hydrogen iodide, sulfuric acid, nitric acid, phosphoric acid, more preferably hydrogen chloride, or where the organic acid is sulfonic acids, preferably ethanesulfonic acid, methanesulfonic acid, benzenesulfonic acid, para-toluenesulfonic acid, or carboxylic acids, preferably C1-C4 aliphatic carboxylic acids, more preferably chlorinated or fluorinated acetic acid derivatives, most preferably trifluoroacetic acid.

[0056] In a preferred embodiment of the present invention, after the Boc-protecting group is removed in an acidic medium, the troriluzole converts to its salt form. This troriluzole salt of formula (1) is filtered from the reaction mixture, optionally dried, and recrystallized if necessary. Alternatively, the salt can be filtered from the reaction mixture, optionally dried, and reacted with an inorganic base in water, organic solvent, or their mixture, and the resulting troriluzole base of formula (1) is isolated and recrystallized if necessary. Another approach is to add a base to the troriluzole salt formed in the reaction mixture in situ to release the troriluzole base of formula (1), then isolate and recrystallize the base if necessary.

[0057] In the description of the present invention, isolation or separation means that the product to be isolated, which is present in solid form in the reaction mixture, or it is converted to solid form in the reaction mixture, and it is filtered from the reaction mixture. If the desired product is not present in solid form in the reaction mixture, it is converted to solid form before isolation. The possible methods for this are known to those skilled in the art. For example, we can convert it to a salt in the reaction mixture, or if it is in salt form, convert it to a base by adding a base. Alternatively, we can add an auxiliary solvent to the reaction mixture that changes the polarity of the mixture, causing the desired product to precipitate in solid form. Generally, the product can also be isolated by extracting the reaction mixture with a solvent that does not mix with it but dissolves the product. After separating the phases, the product can be separated from the solution by forming a salt or base as described above, or by evaporating the solvent to obtain the product. The selection of the appropriate isolation method is part of the general knowledge of the skilled person.

[0058] In the production of troriluzole salts, we can proceed by preparing a base from the separated salt as described above, or by isolating troriluzole as a base. The obtained base is then reacted with an acid in water, organic solvent, or their mixture to obtain the troriluzole salt, which is then separated and recrystallized if necessary. In one of the most advantageous embodiments of the present invention, after the acidic hydrolysis of the compound of formula (4), the troriluzole salt of formula (1) formed in the reaction mixture is separated.

[0059] In one of the most advantageous embodiments of the present invention, the intermediate of formula (4) is not isolated, but the Boc protecting group is cleaved by adding acid to the reaction mixture and, if necessary, additional solvent also added to the reaction mixture.

[0060] According to the present invention, we can also proceed in such a way that during the process, the troriluzole base of formula (1), e.g., amorphous or crystalline, anhydrous form, hydrate, solvate, or any isolated or non-isolated intermediate of the synthesis of the formula (4) reacts with hydrochloric acid in a suitable organic solvent. The resulting salt is then separated, optionally washed with an organic solvent, recrystallized if necessary, and dried at the appropriate temperature.

[0061] In the most advantageous embodiment of our invention, solvents such as aliphatic alcohols with 1-4 carbon atoms, straight-chain or cyclic ethers with 1-5 carbon atoms, esters with 1-6 carbon atoms, ketones with 1-5 carbon atoms, carboxylic acids with 1-6 carbon atoms, as well as acetonitrile, cyclohexane, and toluene, and mixtures of the listed solvents or their mixtures with water can also be used.

[0062] For carrying out the reaction, the organic solvent is preferably an ether, ester, or alcohol with 1-4 carbon atoms, or a dipolar aprotic solvent, particularly preferably THF, diethyl ether, ethyl acetate, acetonitrile, methyl alcohol, ethyl alcohol, acetone, methyl ethyl ketone, methyl isobutyl ketone, 2-propanol, acetic acid, cyclohexane, toluene, or mixtures thereof, including mixtures containing water.

[0063] In the process according to our invention, the coupling reaction step is preferably carried out at a temperature between 20-60°C, more preferably between 30-50°C, and most preferably between 35-45°C.

[0064] According to advantageous embodiments of the present invention, the acidic cleavage of the Boc-protecting group from the intermediate of formula (4) is carried out at a temperature between 0 and 30°C, preferably between 10 and 25°C, most preferably at 25°C.

[0065] In one of the highly advantageous embodiments of the present invention, the intermediate of formula (4) is not isolated. We proceed by reacting riluzole of formula (2), or its acid addition salt of general formula (2 * HnA) in an organic solvent, preferably aliphatic alcohols with 1-4 carbon atoms, straight-chain or cyclic ethers with 1-5 carbon atoms, esters with 1-6 carbon atoms, ketones with 1-5 carbon atoms, carboxylic acids with 1-6 carbon atoms, as well as acetonitrile, cyclohexane, or toluene, or mixtures of these solvents, at a temperature preferably between 20-60°C, more preferably between 30-50°C, and most preferably between 35-45°C, in the presence of a base and a peptide coupling agent with the compound of formula (3). After the completion of the reaction, the reaction mixture containing the intermediate of formula (4) is cooled to a temperature between 0 and 30°C, preferably between 10 and 25°C, most preferably to 25°C, and the Boc protecting group is cleaved by adding acid. The acid is preferably hydrochloric acid dissolved in a solvent, aqueous hydrochloric acid solution, or a mixture of solvent and aqueous hydrochloric acid solution.

[0066] The acid used for salt formation is preferably used in an amount of 0.5-5.0 mol equivalents, preferably 0.9-3.0 equivalents, calculated based on the amount of troriluzole (1).

[0067] The most advantageous hydrochloric acid for salt formation is preferably used in an amount of 0.5-5.0 mol equivalents, preferably 0.9-3.0 equivalents, calculated based on the amount of troriluzole (1).

[0068] The product is most advantageously isolated from the resulting reaction mixture by filtering it out. Hydrochloric acid is most advantageous for hydrolysis. According to our experiments, the crude hydrochloric salt obtained directly from the isolated or non-isolated intermediate (4) during the processing stage of troriluzole synthesis mostly results in a chemically and morphologically non-uniform troriluzole hydrochloride form.

[0069] The production of hydrochloric salts seemed advantageous because hydrochloric acid is an endogenous substance found in the human body. Additionally, due to its strongly acidic nature, it forms salts with a significant portion of basic compounds. This, along with its favorable toxicological properties, makes it a frequently used medicinal salt-forming agent. The salts, which are hydrochlorides of various stoichiometric compositions, their hydrates, anhydrates, and different crystalline modifications of the hydrochloride salts, are desirable and sought-after forms for most pharmaceutical active ingredients. However, their use as active pharmaceutical ingredients is not always possible due to reduced chemical or morphological stability. In the case of hydrochlorides, hygroscopicity or heat sensitivity, which occur more frequently, can prevent their use as active ingredients. For amino acid hydrochlorides, a typical problem is their hygroscopicity, which results in a composition dependent on manufacturing and environmental conditions, thereby limiting their synthesis, storage, and consequently their use.

[0070] Troriluzole is a tripeptide derivative of riluzole. In the case of salt formations on the tripeptide side chain, particularly with hydrochlorides, crystallization and stability issues can be expected due to the increased water absorption tendency of the active ingredient. This is perhaps one of the reasons why the hydrochloride salt separated from the reaction mixture is not directly suitable as a pharmaceutical active ingredient, as it mostly results in a chemically and morphologically non-uniform troriluzole hydrochloride form.

[0071] During the recrystallization of troriluzole hydrochlorides and the reaction of troriluzole base with hydrochloric acid, we found that the resulting hydrochlorides can appear in various crystalline forms or in mixtures thereof, depending on the conditions and as it is expected, these salts are hygroscopic. Thus, they can absorb significant amounts of moisture, up to 2-5% (in extreme cases up to 40%, Figure 15) by weight at higher humidity. When produced from solution, they typically have a small particle size and needle-like crystal structure, leading to gelation and filtration difficulties. Depending on the quality of the solvent used and the amount of hydrochloric acid, the troriluzole hydrochloride hydrate [(1 : 1 :1) salt] crystal form and the troriluzole hydrochloride hydrate [(1 :2:1) salt] crystal form can also be produced.

[0072] In the procedures according to the present invention, the formation of hydrochloric salts can be carried out with hydrochloric gas dissolved in an anhydrous organic solvent, or with hydrochloric acid in a mixture of water and organic solvent. Examples include hydrochloric acid dissolved in anhydrous ethyl acetate or a mixture of ethanol and aqueous hydrochloric acid. In the description, unless otherwise specified, hydrochloric acid solution refers to an aqueous hydrochloric acid solution with a concentration of 5-37% by weight, preferably 15- 37% by weight, most preferably 37% by weight.

[0073] Therefore, we aimed to produce morphologically uniform crystalline and amorphous forms that can be used as pharmaceutical active ingredients. Morphological uniformity is very important both from a pharmaceutical technology perspective and for the use of the drug. Different polymorphic forms can behave differently during formulation, for example, they may have different flow and compression properties, which can significantly affect the quality of capsule filling or tablet and granule pressing. Thus, if an unstable modification is used, the manufacturing results can vary from batch to batch, which is unacceptable in the pharmaceutical industry. If a modification change occurs during storage, or if the ratio of different forms changes in the preparation, the drug release and absorption properties of the pharmaceutical products can change due to the different solubilities of the individual forms, which is also unacceptable.

[0074] Therefore, the compounds produced and used according to the present invention - if they are in solid state - can be crystalline or amorphous in structure. Morphological uniformity is essential for usability, especially for pharmaceutical active ingredients, because active ingredients in different crystalline and amorphous forms have different physical properties, such as solubility, which can also affect drug absorption. But morphological properties are also important for intermediates and active ingredients, as a product with uniform morphology facilitates technological processing, such as weighing and tableting, since the material to be processed has uniform physical properties, such as flowability. A solid material is considered morphologically uniform, according to the description of the present invention present invention, if at least 95% of the material's mass, preferably 97%, more preferably 99%, and most preferably 99.5%, consists of a morphologically defined, uniform crystal structure. In other words, the solid material considered morphologically uniform according to the present invention if it comprises at most 5% of its mass, preferably 3%, more preferably at most 1%, and most preferably at most 0.5%, of different crystalline form or amorphous form from the main mass. According to the description of the present invention an amorphous product considered to be morphologically uniform if it contains at most 5% of its mass, preferably at most 3%, more preferably at most 1%, and most preferably at most 0.5%, of crystalline product. The identification of the crystal structure and the determination of the quantitative ratio of the individual crystal forms can be carried out by evaluating X-ray powder diffraction images, based on the general knowledge of the expert. We can also proceed by comparing the characteristic X-ray powder diffraction peaks of the different uniform crystal forms with the recording of the mixture.

[0075] The present invention relates the crystalline salts and hydrates formed by troriluzole with hydrochloric acid, in which the stoichiometric ratio of troriluzole to hydrochloric acid and water is 1 :1 (monohydrochloride), 1 : 1 : 1 (monohydrochloride monohydrate), or 1 :2: 1 (dihydrochloride monohydrate).

[0076] The solution-phase recrystallization of troriluzole hydrochlorides encounters several difficulties. Troriluzole hydrochlorides do not dissolve in most organic solvents except methanol, so for recrystallization, solvent mixtures that are miscible with water and also solvent mixtures containing water (acetone / water, THF / water), as well as highly polar DMSO and DMF systems, can be used.

[0077] Another difficulty is that the solutions above are not thermally stable; upon heating, troriluzole gradually decomposes into riluzole. Therefore, during crystallization by cooling a supersaturated solution, impurities may appear, and yield may significantly decrease. Additionally, as in the case of production from the base, the appearance of small particle-sized, needle-like crystal structures is also characteristic here, causing technological and filtration difficulties.

[0078] The hydrochloride salts of troriluzole (1) formed with hydrochloric acid according to the present invention are preferably prepared by suspending the troriluzole base in a suitable solvent, preferably in an alcohol, ester, or ketone with 1-6 carbon atoms, more preferably in methanol, ethanol, ethyl acetate, acetone, methyl isobutyl ketone, diethyl ether, tetrahydrofuran, acetic acid, cyclohexane, or toluene. Then, for the monohydrochloride, 0.9-1.2 mol of hydrochloric acid is added at temperatures between -10°C and 60°C (considering the melting and boiling points of the solvent). For the dihydrochloride, 1.8-3.0 mol of hydrochloric acid is added in an aqueous or suspension, preferably water-free solution / at temperatures between - 10°C and 60°C (considering the melting and boiling points of the solvent) / . If the salt precipitates from the solution or suspension at the addition temperature, the product is filtered, washed, and dried after the necessary crystallization time. If necessary, crystallization can be initiated using seed crystals.

[0079] Due to the aforementioned properties, producing the troriluzole hydrochloride hydrate [(1: 1 : 1) salt] crystal form with a high degree of crystallinity is not obvious. One possible method is to dissolve the troriluzole hydrochloride salt in a suitable volatile solvent and then allow the solvent to evaporate slowly at room temperature, providing sufficient time for the formation of the appropriate, stable crystal structure and form (Example 13, Figures 7-9). The troriluzole hydrochloride hydrate [(1 : 1 : 1) salt] crystal form according to our invention is morphologically uniform.

[0080] Taken into consideration of the known difficulties in crystallization, we were surprised to find that starting from hydrochloride forms and using organic acids as solvents, specifically low-carbon carboxylic acids (e.g. C1-C4 carboxylic acids), more specifically acetic acid - and hydrochloric acid if necessary - the solution can be heated without decomposition, and the given troriluzole hydrochloride hydrate [(1 :2: 1) salt] can be recrystallized in a classical manner. The product obtained in this way has high degree of crystallinity (plate-like structure), with high purity, which easily filterable, and morphologically uniform. Furthermore, it is produced in an industrially applicable technology, has uniform stoichiometry, and meets the purity requirements expected of pharmaceutical active ingredients (Figure 14).

[0081] We found surprisingly that the troriluzole hydrochloride hydrate [(1:2: 1) salt] crystal, under appropriate conditions and / or solvents, partially or completely loses half of its hydrochloric acid content and thus transforms into the troriluzole hydrochloride hydrate [(1 : 1 : 1) salt] crystal form. This property is surprising and unexpected. Accordingly, the troriluzole hydrochloride hydrate [(1 :2:1) salt] crystal can be considered a salt form prone to partial dissociation.

[0082] We unexpectedly observed that the mentioned transformation occurs not only in solution but also in suspension and solid-phase reactions. In the case of the product obtained from suspension, we obtained plate-like structured crystals, whose water absorption and thermal stability (Figures 10-11) are similar those of the samples obtained from recrystallization (Figures 8-9).

[0083] The crystal habit of the sample produced in the solid phase also differs from the needlelike structure; however, its thermal decomposition starts at a higher temperature (Figure 13) and it absorbs significantly less moisture across the entire (0-95% RH) range (Figure 12).

[0084] As a result, depending on the applied procedure, the favorable properties of the starting material (high degree of crystallinity, morphological uniformity, high chemical purity) are inherited by the resulting salt form, and we obtain a unique troriluzole hydrochloride hydrate [(1: 1 : 1) salt] crystal form. In addition to the previously mentioned properties, this form is characterized by greater thermal stability and less than 1% water absorption tendency, has uniform stoichiometry, and meets the purity requirements expected of pharmaceutical active ingredients, including chemical and morphological (morphologically uniform) stability criteria. Other preferred embodiment of the present invention also anhydrous forms of troriluzole hydrochlorides, which can be obtained from anhydrous media or by drying, and which are the Form A and B variant of troriluzole hydrochloride [(1 : 1) salt] (Figures 17-22). The Form A and B crystal phases of troriluzole hydrochloride [(1 : 1) salt] are prone to absorb ambient humidity at room temperature and transform into troriluzole hydrochloride hydrate (1 : 1 : 1) salt.

[0085] During our investigations, we found that the crystallization of troriluzole hydrochloride occurs in hydrate form under conditions where the presence of water is not excluded. For example, if we use anhydrous solvents and perform salt formation with anhydrous hydrochloric acid dissolved in ethyl acetate, if this operation is not carried out under dry protective gas, it absorbs the necessary water from the ambient humidity and precipitates as a hydrate salt.

[0086] We found surprisingly also that by modifying the procedure for the troriluzole hydrochloride hydrate [(1 :2:1) salt] crystal form, we obtained a solvate, the troriluzole hydrochloride-acetic acid solvate [(1 :1 : 1) salt] crystalline form. This acetic acid solvate can also be produced with a high degree of crystallinity, in a morphologically uniform form, and with high purity. Additionally, its thermal stability is outstanding within the temperature range typical for processing, storage, and use (Figures 23-24).

[0087] In addition to the typically crystalline hydrochloride salts, we were surprised to find that by selecting appropriate conditions, troriluzole hydrochloride [(1 : 1) salt] can also be produced in an amorphous form, simply by precipitation from an organic solvent (Figure 25). The amorphous salt obtained in this way is morphologically uniform and does not contain a crystalline phase.

[0088] Using the process according to the present invention, crystalline troriluzole base can also be produced. The troriluzole base can be used both as a pharmaceutical active ingredient and as a raw material for various salts.

[0089] One embodiment of the present invention is the troriluzole base. The troriluzole base can be produced by reacting a salt or a mixture of salts of troriluzole with a base in a suitable organic solvent, then isolating the resulting product, washing it with an organic solvent if necessary, recrystallizing it if needed, and then drying it at the appropriate temperature.

[0090] The release of the base can be carried out most advantageously by reacting the troriluzole hydrochloride, e.g., amorphous or crystalline, anhydrous form, hydrate, solvate, or mixtures thereof, with a base in a suitable organic solvent, then isolating the resulting product, washing it with an organic solvent if necessary, recrystallizing it if needed, and then drying it at the appropriate temperature. The release of the troriluzole base can be advantageously carried out in an organic solvent, such as aliphatic alcohols with 1-4 carbon atoms, straight-chain or cyclic ethers with 1-5 carbon atoms, esters with 1-6 carbon atoms, ketones with 1-5 carbon atoms, as well as in acetonitrile, water, or mixtures thereof.

[0091] For the reaction process, it is even more advantageous to use THF, diethyl ether, ethyl acetate, acetonitrile, methyl alcohol, ethyl alcohol, acetone, methyl ethyl ketone, methyl isobutyl ketone, 2-propanol, water, or mixtures thereof.

[0092] The release of troriluzole base from its salt preferably an inorganic base is used in an amount of 0.5-3.0 mol equivalents, preferably 1.0-2.2 equivalents, calculated based on the amount of troriluzole salt, preferably troriluzole hydrochloride salt.

[0093] In an advantageous embodiment of the present invention it can proceed by using a solution or suspension of troriluzole salt, and carry out the base liberation at a temperature between -20°C and the boiling point of the solvent, preferably between 0°C and the boiling point of the solvent, most preferably between 20°C and the boiling point of the solvent or at the boiling point of the solvent.

[0094] According to a more advantageous embodiment of the present invention it can proceed by reacting a suspension or solution of troriluzole hydrochloride in methanol, ethanol, or ethyl acetate, acetone, methyl isobutyl ketone (MIBK), diethyl ether, tetrahydrofuran, water, or mixtures of these solvents containing water, with 1.0-2.2 equivalents of base at a temperature between -10°C and 60°C (for diethyl ether: 36°C). The product precipitated from the reaction mixture is preferably obtained by filtration.

[0095] The appropriate polymorphic form of troriluzole base (1) can also be advantageously prepared by suspending a suitable form of troriluzole salt in an appropriate solvent, preferably in an alcohol, ester, or ketone with 1-6 carbon atoms, particularly preferably in methanol, ethanol, ethyl acetate, acetone, methyl isobutyl ketone, diethyl ether, tetrahydrofuran, water, or mixtures thereof. Then, between -10°C and 60°C (for diethyl ether: 36°C), 1.0-2.2 mol of alkali metal or alkaline earth metal carbonates or their bicarbonates, preferably alkali bicarbonates, are added in solution or solid form. If the free base precipitates from the solution phase or suspension at the addition temperature, the product is filtered, washed, and dried after the necessary crystallization time.

[0096] The new polymorphic forms according to the present invention can also be prepared by suspending and stirring the troriluzole base in an organic solvent, preferably in an ether, ester, alcohol, or dipolar aprotic solvent with 1-4 carbon atoms, particularly preferably in THF, diethyl ether, ethyl acetate, acetonitrile, methanol, ethanol, acetone, methyl ethyl ketone, methyl isobutyl ketone, 2-propanol, and additionally in toluene, at a temperature between -10°C and the boiling point of the solvent, typically between 25°C and 50°C. During this process, a solution or solid-phase transformation occurs in the product, resulting in a material with a crystal structure different from the original. The transformation can be accelerated by selecting a better solvent (or solvent mixture) for the appropriate modification or by using seed crystals of the desired form during the suspension.

[0097] A new form can also be obtained if the troriluzole base is dissolved in the mentioned solvents, and then the solvent is partially or completely removed by applying higher temperature and / or vacuum, and if necessary, replaced with another solvent.

[0098] Below, we describe the polymorphic forms obtained with the solvents and methods outlined above, without limiting the preparation of each polymorphic form to these procedures.

[0099] The present invention also relates the crystalline polymorphs of troriluzole base.

[0100] The new crystal forms according to the invention are characterized by their X-ray powder diffraction data. In the description and claims, the 29 values are expressed everywhere in degrees (°20)."

[0101] The characteristic X-ray powder diffraction peaks of the Form I modification of the troriluzole base according to the invention are as follows: 29 (±9.2 °29): 19.82; 22.42; 23.38. More specifically, we can characterize it with the following X-ray powder diffraction peaks: 29 (±9.2 °29): 19.49; 19.82; 22.42; 23.38; 24.45. Even more specifically, we can characterize it with the following X-ray powder diffraction peaks: 29 (±9.2 °29): 3.84; 5.48; 6.43; 7.99; 7.79; 9.95; 9.85; 11.35; 14.93; 15.29; 16.93; 16.69; 17.66; 18.29; 18.94; 19.49; 19.82; 29.43; 29.63; 21.97; 21.45; 21.89; 22.42; 23.38; 24.15; 24.45; 24.92; 25.35; 26.29; 26.48; 27.18; 27.34; 27.77; 28.33; 28.69; 29.39; 29.76; 39.48; 39.96; 31.55; 32.73; 32.93; 33.89; 34.16, or with the X-ray powder diffractogram shown in Figure 2. The signals with an intensity of 2% or higher are summarized in Table 1 below:

[0102] Table 1 : X-ray powder diffraction data of the Form I modification of troriluzole base (relative intensities >2%)

[0103] The Form I polymorph of the troriluzole base according to the present invention is morphologically uniform. Thus, at least 95%, preferably 97%, more preferably 99%, and most preferably 99.5% of the mass of the Form I polymorph of the base according to the present invention consists of a defined, uniform crystal structure characteristic of the Form I polymorph.

[0104] Another embodiment of the present invention the preparation of the Form I modification of troriluzole base. According to advantageous embodiment of the present invention it can proceed by mixing troriluzole salt, preferably hydrochloride salt in a mixture of water and ethyl acetate, and then dripping a sodium bicarbonate solution into the suspension at a temperature between 0°C and 30°C. The resulting suspension is stirred at room temperature, and the precipitated product is filtered, optionally washed, and dried.

[0105] A further embodiment of the present invention is the Form II base form of troriluzole. The characteristic X-ray powder diffraction peaks of the Form II polymorph form of the troriluzole base according to the invention are as follows: 29 (±0.2 °29): 2.51; 16.30; 22.86. More specifically, we can characterize it with the following X-ray powder diffraction peaks: 29 (±0.2 °29): 2.51; 4.20; 4.96; 16.30; 17.59; 22.86. Even more specifically, we can characterize it with the following X-ray powder diffraction peaks: 29 (±0.2 °29): 2.51; 4.20; 4.96; 16.30; 17.59; 18.41; 20.44; 22.86; 26.29; 27.22; 30.78; 31.87 and with the X-ray powder diffractogram shown in Figure 3. The signals with an intensity of 5% or higher are summarized in Table 2 below:

[0106] Table 2: X-ray powder diffraction data of the Form II polymorph form of troriluzole base (relative intensities >5%)

[0107] The Form II polymorph of the troriluzole base according to the present invention is morphologically uniform. Thus, at least 95%, preferably 97%, more preferably 99%, and most preferably 99.5% of the mass of the Form II polymorph of the base according to present invention consists of a defined, uniform crystal structure characteristic of the Form II polymorphic form.

[0108] The present invention also relates the preparation of the Form II amorphous form of troriluzole base. An advantageous process for the preparation of the Form II amorphous form of troriluzole base can be carried out according to the present invention mixing troriluzole hydrochloride in a mixture of water and acetone, and then dripping a sodium bicarbonate solution into the suspension at a temperature between 0°C and 30°C. The resulting suspension is stirred at room temperature, and the precipitated product is filtered, optionally washed, and dried.

[0109] A further embodiment of the present invention is the Form III base form of troriluzole. The characteristic X-ray powder diffraction peaks of the Form III modification of the troriluzole base according to the invention are as follows: 29 (±0.2 °29): 14.24; 18.44; 24.19. More specifically, we can characterize it with the following X-ray powder diffraction peaks: 29 (±0.2 °29): 9.19; 14.24; 18.44; 21.00; 21.96; 24.19. Even more specifically, we can characterize it with the following X-ray powder diffraction peaks: 29 (±0.2 °29): 4.95; 9.19; 9.97; 10.88; 12.84; 14.24; 16.78; 17.72; 18.06; 18.44; 18.66; 19.36; 20.05; 21.00; 21.37; 21.96; 22.12; 22.83; 23.31; 24.19; 25.01; 25.21; 25.77; 26.40; 26.61; 28.00; 28.52; 28.93; 29.70; 29.90; 31.31; 31.69; 32.13; 32.60; 32.98; 33.24; 34.79 and with the X-ray powder diffractogram shown in Figure 4.

[0110] The signals with an intensity of 3% or higher are summarized in Table 3 below:

[0111] Table 3: X-ray powder diffraction data of the Form III polymorph form of troriluzole base (relative intensities >3%)

[0112] The Form III polymorph of the troriluzole base according to the present invention is morphologically uniform. Thus, at least 95%, preferably 97%, more preferably 99%, and most preferably 99.5% of the mass of the Form III polymorph of the base according to present invention consists of a defined, uniform crystal structure characteristic of the Form III polymorphic form.

[0113] The present invention also relates the preparation of the Form III polymorph form of troriluzole base. The preparation of the Form III polymorph form of troriluzole base can be carried out advantageously by suspending the troriluzole base in methanol, then dissolving it by stirring at reflux temperature. Subsequently, the methanol is distilled off from the solution, while the evaporated solvent is replaced with ethanol. At the end of the solvent exchange (internal temperature of 75-80°C), the solution is cooled to a temperature between -5°C and 5°C and stirred. The precipitated product is filtered, optionally washed, and dried.

[0114] A further embodiment of the present invention is the Form IV base form of troriluzole.

[0115] The characteristic X-ray powder diffraction peaks of the Form IV modification of the troriluzole base according to the invention are as follows: 29 (±0.2 °29): 10.27; 18.87; 22.76. More specifically, we can characterize it with the following X-ray powder diffraction peaks: 29 (±0.2 °29): 4.10; 10.27; 12.50; 18.87; 19.33; 22.76; 22.92. Even more specifically, we can characterize it with the following X-ray powder diffraction peaks: 29 (±0.2 °29): 4.10; 10.27; 12.32; 12.50; 15.54; 16.48; 18.41; 18.87; 19.33; 19.46; 19.55; 20.64; 21.30; 21.67; 22.76; 22.92; 23.34; 23.74; 24.83; 25.63; 28.13; 28.80; 29.88; 30.35; 30.51; 32.11; 32.84; 33.29;

[0116] 34.08; 34.67 and with the X-ray powder diffractogram shown in Figure 5.

[0117] The signals with an intensity of 2% or higher are summarized in Table 4 below:

[0118] Table 4: X-ray powder diffraction data of the Form IV polymorph form of troriluzole base (relative intensities >2%)

[0119] The Form IV polymorph of the troriluzole base according to the present invention is morphologically uniform. Thus, at least 95%, preferably 97%, more preferably 99%, and most preferably 99.5% of the mass of the Form IV polymorph of the base according to present invention consists of a defined, uniform crystal structure characteristic of the Form IV polymorphic form.

[0120] The present invention also relates the preparation of the Form IV polymorph form of troriluzole base. The preparation of the Form IV polymorph form of troriluzole base can be carried out advantageously by dissolving the troriluzole base in methanol at a temperature between 20°C and 30°C, then removing the solvent under vacuum at 45°C. The precipitated product is filtered, washed with a small amount of methanol, and dried.

[0121] A further embodiment of the present invention is the Form V base form of troriluzole.

[0122] The characteristic X-ray powder diffraction peaks of the Form V modification of the troriluzole base according to the invention are as follows: 29 (±0,2 °29): 13,02; 17,36; 19,47. More specifically, we can characterize it with the following X-ray powder diffraction peaks: 29 (±0,2 °29): 4,52; 13,02; 16,99; 17,36; 19,47; 20,33; 21,67. Even more specifically, we can characterize it with the following X-ray powder diffraction peaks: 29 (±0,2 °29): 2,38; 4,52; 9,07; 13,02; 14,54; 16,46; 16,99; 17,36; 18,43; 19,04; 19,47; 20,07; 20,33; 20,57; 21,14; 21,67; 22,50; 22,69; 22,88; 23,25; 24,07; 24,41; 24,84; 25,08; 25,53; 26,46; 27,04; 27,61; 28,34; 28,80; 29,53; 31,12; 31,48; 31,88; 32,16; 33,58; 33,89; 34,11; 34,68; 34,93 and with the X-ray powder diffractogram shown in Figure 6.

[0123] The signals with an intensity of 2% or higher are summarized in Table 5 below:

[0124] Table 5: X-ray powder diffraction data of the Form V polymorph form of troriluzole base (relative intensities >2%)

[0125] The Form V polymorph of the troriluzole base according to the present invention is morphologically uniform. Thus, at least 95%, preferably 97%, more preferably 99%, and most preferably 99.5% of the mass of the Form V polymorph of the base according to present invention consists of a defined, uniform crystal structure characteristic of the Form V polymorphic form.

[0126] The present invention also relates the preparation of the Form V polymorph form of troriluzole base. The preparation of the Form V polymorph form of troriluzole base can advantageously proceed by suspending the Form II polymorph form of troriluzole base in toluene, then stirring at a temperature between 0°C and 30°C. The crystalline product is filtered, optionally washed, and dried.

[0127] As mentioned above, our invention includes the crystalline salts and hydrates of troriluzole formed with hydrochloric acid.

[0128] A further advantageous embodiment of the present invention is the crystalline form of troriluzole-hydrochloride-hydrate [(1: 1 : 1) salt], having characteristic X-ray powder diffraction peaks according to the present invention are as follows: 29 (±0.2 °29): 5.63; 15.80; 25.48. More specifically, we can characterize it with the following X-ray powder diffraction peaks: 29 (±0.2 °29): 5.63; 13.33; 15.80; 16.58; 18.39; 25.48; 25.75; 27.04. Even more specifically, we can characterize it with the following X-ray powder diffraction peaks: 29 (±0.2 °29): 5.63; 7.65; 11.05; 13.33; 14.25; 14.52; 15.80; 16.58; 17.96; 18.18; 18.39; 19.25; 20.09; 20.48; 20.62; 21.01; 21.78; 22.00; 22.66; 22.86; 23.08; 23.77; 24.27; 24.44; 25.16;

[0129] 25.48; 25.75; 26.11; 26.53; 27.04; 27.72; 27.90; 28.23; 28.72; 29.32; 29.71; 29.99; 30.17;

[0130] 30.80; 31.05; 31.37; 31.59; 31.91; 32.17; 32.37; 33.11; 33.41; 33,54; 34,17; 34,63 and with the X-ray powder diffractogram shown in Figure 7.

[0131] The signals with an intensity of 2% or higher are summarized in Table 6 below:

[0132] Table 6: X-ray powder diffraction data of crystalline form of troriluzole-hydrochlori dehydrate [(1: 1 :1) salt], (relative intensities >2%)

[0133] The troriluzole hydrochloride hydrate [(1: 1 : 1) salt], according to the present invention is morphologically uniform. Thus, at least 95%, preferably 97%, more preferably 99%, and most preferably 99.5% of the mass of troriluzole hydrochloride hydrate [(1 : 1 : 1) salt], according to present invention consists of a defined, uniform crystal structure characteristic of the troriluzole hydrochloride hydrate [(1 : 1 :1) salt].

[0134] The present invention also relates the preparation of the crystalline form of troriluzole hydrochloride hydrate [(1 : 1 : 1) salt]. The preparation of the crystalline form of troriluzole hydrochloride hydrate [(1 : 1 : 1) salt] can be carried out advantageously according to Example 6, by stirring the free base of troriluzole (1) in ethanol, then dripping hydrochloric acid solution into the suspension at a temperature between 0°C and 30°C. The resulting suspension is stirred at room temperature, and the precipitated product is filtered, optionally washed, and dried.

[0135] The preparation of the crystalline form of troriluzole hydrochloride hydrate [(1 : 1 : 1) salt] can also proceed without preparing the free base, and the salt formation can be carried out during the synthesis processing stage through the isolated or non-isolated intermediate (4) (Figure lb). In the procedure, the starting riluzole (2) or its salt (2 * HnA), preferably riluzole hydrochloride, and the BocGlyGlySarOH tripeptide derivative of the formula (3), coupling agent (carbonyl diimidazole, dicyclohexylcarbodiimide, T3P, HATU), preferably HATU, and base (TEA, DIPEA), preferably DIPEA, are stirred in an organic solvent (acetone, methyl ethyl ketone, methyl isobutyl ketone, THF, methyl-THF, toluene, cyclohexane, isopropyl acetate, ethyl acetate), preferably ethyl acetate, at 20-60°C. After the coupling reaction takes place, the reaction mixture is cooled, and anhydrous hydrochloric acid solution, preferably ethyl acetate saturated with hydrochloric acid, is added to the suspension at a temperature between 0°C and 30°C. The resulting suspension is stirred at room temperature, diluted with an organic solvent if necessary, and the precipitated product is filtered, optionally washed, and dried if necessary. The dried or still wet crude product is suspended in alcohol (ethanol, propanol, isopropyl alcohol, n-butanol, i-butanol, t-butanol), preferably t-butanol, heated, and stirred at 20-80°C. The purified product is cooled to room temperature, filtered, optionally washed, and then dried, and recrystallized if necessary (Example 7).

[0136] The advantageous preparation of the crystalline form of troriluzole hydrochloride hydrate [(1 : 1 : 1) salt] according to the present invention can be carried out by dissolving a hydrochloride of troriluzole in a solvent mixture of THF and methanol and allowing the solvent to slowly evaporate from the solution in an open and undisturbed container (Example 13).

[0137] The preparation of the crystalline form of troriluzole-hydrochloride-hydrate [(1 : 1 : 1) salt] can also advantageously proceed (Example 14) by suspending the crystalline form of troriluzole hydrochloride hydrate [(1:2: 1) salt] in isopropanol, seeding with the crystalline form of troriluzole hydrochloride hydrate [(1: 1 :1) salt] if necessary, stirring at a temperature between 20°C and 66°C, then filtering the product, optionally washing, and drying.

[0138] One particularly advantageous embodiment of the invention is the non-hygroscopic variant of the crystalline form of troriluzole hydrochloride hydrate [(1 :1 : 1) salt]. We found that the crystalline form of troriluzole hydrochloride hydrate [(1: 1 : 1) salt] has two variants with identical characteristic X-ray powder diffraction peaks. However, one highly advantageous variant, whose preparation is described in Example 15, is non-hygroscopic, meaning it absorbs less than 1% water by weight at 25°C and 95% relative humidity (RH) during DVS measurements. In contrast, the other variant described above absorbs at least 1.5% water at 20% RH and reaches 2-2.5% water absorption at 95% RH. This is significant because, as mentioned above, the stability of pharmaceutical compositions comprising troriluzole can be greatly affected by the presence of water. Furthermore, it is evident to person skilled in the art that hygroscopic substances pose a serious disadvantage in solid pharmaceutical preparations, such as tablets, because water absorption can change the volume of the active ingredient particles. Even small changes can cause tablets to crack or break during storage. Therefore, the unexpected advantageous fact that the crystalline form of troriluzole hydrochloride hydrate [(1: 1 : 1) salt] has a non-hygroscopic variant is of particular importance.

[0139] More particularly the non-hygroscopic version of crystalline form of troriluzole hydrochloride hydrate [(1 : 1 :1) salt], having characteristic X-ray powder diffraction peaks according to the present invention are as follows: 29 (±0.2 °29): 5.63; 15.80; 25.48. More specifically, we can characterize it with the following X-ray powder diffraction peaks: 29 (±0.2 °29): 5.63; 13.33; 15.80; 16.58; 18.39; 25.48; 25.75; 27.04. Even more specifically, we can characterize it with the following X-ray powder diffraction peaks: 29 (±0.2 °29): 5.63; 7.65; 11.05; 13.33; 14.25; 14.52; 15.80; 16.58; 17.96; 18.18; 18.39; 19.25; 20.09; 20.48;

[0140] 20.62; 21.01; 21.78; 22.00; 22.66; 22.86; 23.08; 23.77; 24.27; 24.44; 25.16; 25.48; 25.75;

[0141] 26.11; 26.53; 27.04; 27.72; 27.90; 28.23; 28.72; 29.32; 29.71; 29.99; 30.17; 30.80; 31.05;

[0142] 31.37; 31.59; 31.91; 32.17; 32.37; 33.11; 33.41; 33.54; 34.17; 34.63 and with the X-ray powder diffractogram shown in Figure 7. The signals with an intensity of 2% or higher are summarized in Table 6 above.

[0143] The present invention relates to the non-hygroscopic form of crystalline troriluzole hydrochloride hydrate [(1 : 1 : 1) salt]. In this patent description, we refer to those crystal forms as 'non-hygroscopic' crystal forms that, under the conditions of the DVS test presented in the experimental section, absorb less than or a maximum of 1% by weight of water relative to the mass of the measured crystals.

[0144] As an example, the DVS curve for the non-hygroscopic troriluzole hydrochloride hydrate [(1: 1 : 1) salt] crystal form is shown in Figure 12.

[0145] As an example, the DVS curve for the troriluzole hydrochloride hydrate [(1 : 1 : 1) salt] crystal form with higher water absorption - which, according to our invention, is not considered non- hygroscopic - is shown in Figure 19.

[0146] The present invention also relates to the non-hygroscopic form of crystalline troriluzole hydrochloride hydrate [(1 : 1: 1) salt], characterized by the fact that the crystal form does not absorb more than 1% by weight of water during the DVS test.

[0147] We can further characterize the subject of our invention by stating that another aspect of our invention is the non-hygroscopic form of crystalline troriluzole, characterized by the fact that the crystal form does not absorb more than 1% by weight of water during the DVS test, which is carried out under the following parameters:

[0148] Instrument: TA Q5000SA dynamic vapour sorption analyser (DVS)

[0149] Atmosphere: Nitrogen

[0150] Total gas flow: 200 mL / min

[0151] Solvent: Water

[0152] Balance purge flow: 10 mL / min

[0153] Balance temperature: 35 °C

[0154] Pan type: Platinum 100 pl, unsealed Method: Custom

[0155] Drying: No

[0156] Conditioning: 30 min

[0157] Temperature: 25 °C, isotherm

[0158] Relative humidity range: 0% to 95% RH

[0159] Initial humidity: 20% RH or 40% RH

[0160] Humidity step stages: Desorption - adsorption - desorption

[0161] Humidity step size: 5% RH

[0162] Stabilization criteria: < 0.01% for 10 min

[0163] Maximum dwell time: 360 min

[0164] Data sampling interval: 5 sec / point

[0165] Number of cycles: 2

[0166] Our invention also relates to the production of the non-hygroscopic form of crystalline troriluzole hydrochloride hydrate [(1 : 1 :1) salt].

[0167] For the producing the non-hygroscopic form of crystalline troriluzole hydrochloride hydrate [(1 : 1 : 1) salt], we can carried out advantageously by subjecting the crystalline form of troriluzole hydrochloride hydrate [(1:2: 1) salt] to drying, suspending, conditioning, or other processes during which it gradually transforms into the salt form of troriluzole hydrochloride hydrate [(1: 1 : 1) salt].

[0168] According to the particularly advantageous embodiment of the present invention the non-hygroscopic form of crystalline troriluzole hydrochloride hydrate [(1 : 1 : 1) salt], we can particularly advantageously proceed by conditioning the crystalline form of troriluzole hydrochloride hydrate [(1 :2: 1) salt] in a drying oven with alternating high humidity and dry air.

[0169] According to the present invention, conditioning means placing the sample in a drying chamber, then washing and saturating the vapor space with wet / dry air at a constant temperature and subsequently maintaining the gas flow for at least 10 minutes to allow the equilibrium process between the sample and the vapor space to occur.

[0170] In one particularly advantageous embodiment of the present invention, the non- hygroscopic form of crystalline troriluzole hydrochloride hydrate [(1 : 1 : 1) salt] can be obtained by a process in which the crystalline form of troriluzole hydrochloride hydrate [(1 :2:1) salt] is transformed into the crystalline form of troriluzole hydrochloride hydrate [(1 : 1 : 1) salt]. More specifically, the non-hygroscopic form of crystalline troriluzole hydrochloride hydrate [(1 : 1 : 1) salt] can advantageously be obtained by a process in which the crystalline form of troriluzole hydrochloride hydrate [(1 :2:1) salt] is conditioned at room temperature in a drying oven with alternating high humidity and dry air.

[0171] According to the present invention, by high humidity air, we mean air with a relative humidity (RH) between of 70% RH and saturated relative humidity (100% RH), preferably between 80% RH and 100% RH, more preferably between 85% RH and 95% RH. By dry air at room temperature, we mean air with a relative humidity between 0% and 25% RH, preferably between 0% and 10% RH, most preferably between 0% and 5% RH. For conditioning according to the present invention, inert gases with the above-mentioned moisture content, such as nitrogen or argon, can also be used instead of air.

[0172] During conditioning, in each cycle, the wet and dry air are alternately supplied for preferably 1-8 hours, more preferably 1-6 hours, and most preferably 4-6 hours. Since the dihydrochloride hydrate transforms into monohydrochloride hydrate, the end of weight loss indicates the end of the transformation. Generally, 1-5 cycles, preferably 2-4 cycles, are used for the transformation.

[0173] Particularly, the present invention relates to the crystalline, non-hygroscopic form of troriluzole hydrochloride hydrate [(1 :1 : 1) salt], which can be obtained through a process where the crystalline form of troriluzole hydrochloride hydrate [(1 :2: 1) salt] is conditioned in a drying oven alternately with high humidity and dry air, characterized by the fact that the non- hygroscopic form does not absorb more than 1% by weight of water during the DVS test conducted at 25°C, even at the stage of the test when the RH is 95%.

[0174] More particularly, the present invention relates to the crystalline, non-hygroscopic form of troriluzole hydrochloride hydrate [(1 : 1 :1) salt], which can be obtained by a process in which the crystalline form of troriluzole hydrochloride hydrate [(1 :2: 1) salt] is conditioned in a drying oven alternately with high humidity and dry air, characterized in that the non-hygroscopic form does not absorb more than 1% by weight of water during the DVS test performed at 25°C, even at the stage of the test when the RH is 95%, and the characteristic X-ray powder diffraction peaks of the crystalline product (which correspond to those described above) are as follows: 29 (±0.2 °29): 5.63; 15.80; 25.48. More specifically, we can characterize it with the following X- ray powder diffraction peaks: 29 (±0.2 °29): 5.63; 13.33; 15.80; 16.58; 18.39; 25.48; 25.75; 27.04. Even more specifically, we can characterize it with the following X-ray powder diffraction peaks: 29 (±0.2 °29): 5.63; 7.65; 11.05; 13.33; 14.25; 14.52; 15.80; 16.58; 17.96; 18.18; 18.39; 19.25; 20.09; 20.48; 20.62; 21.01; 21.78; 22.00; 22.66; 22.86; 23.08; 23.77; 24.27; 24.44; 25.16; 25.48; 25.75; 26.11; 26.53; 27.04; 27.72; 27.90; 28.23; 28.72; 29.32; 29.71; 29.99; 30.17; 30.80; 31.05; 31.37; 31.59; 31.91; 32.17; 32.37; 33.11; 33.41; 33.54; 34.17; 34.63 and with the X-ray powder diffractogram shown in Figure 7. The signals with an intensity of 2% or higher are summarized in Table 6 above.

[0175] More particularly, the present invention relates to the crystalline, non-hygroscopic form of troriluzole hydrochloride hydrate [(1 : 1 :1) salt], which can be obtained by a process in which the crystalline form of troriluzole hydrochloride hydrate [(1 :2: 1) salt] is conditioned in a drying oven alternately with high humidity and dry air, characterized in that the non-hygroscopic form does not absorb more than 1% by weight of water during the DVS test performed at 25°C, even at the stage of the test when the RH is 95%, which test is carried out by the method described above and in the experimental section.

[0176] A further advantageous embodiment of the present invention is the crystalline form of troriluzole hydrochloride hydrate [(1 :2: 1) salt] having characteristic X-ray powder diffraction peaks according to the present invention are as follows: 29 (±0.2 °29): 10.79; 14.15; 20.78. More specifically, we can characterize it with the following X-ray powder diffraction peaks: 29 (±0.2 °29): 9.27; 10.79; 12.06; 14.15; 20.78; 22.80; 23.26. Even more specifically, we can characterize it with the following X-ray powder diffraction peaks: 29 (±0.2 °29): 3.08; 9.27; 10.79; 12.06; 14.15; 14.34; 14.64; 15.18; 15.50; 15.73; 16.12; 16.57; 17.33; 18.37; 19.33;

[0177] 20.51; 20.78; 20.88; 21.32; 21.58; 22.02; 22.42; 22.80; 23.07; 23.26; 23.81; 24.62; 25.45;

[0178] 25.80; 26.18; 27.85; 28.16; 28.57; 28.89; 29.56; 29.91; 30.17; 30.36; 30.59; 31.04; 31.27;

[0179] 31.55; 31.84; 32.31; 32.76; 32.96; 33.50; 33.67; 33.88; 34.08; 34.49; 34.69. with the X-ray powder diffractogram shown in Figure 14. The signals with an intensity of 2% or higher are summarized in Table 7 below.

[0180] Table 7: X-ray powder diffraction data of crystalline form of troriluzole hydrochloride hydrate [(1:2:1) salt], (relative intensities >2%)

[0181] The troriluzole hydrochloride hydrate [(1:2: 1) salt], according to the present invention is morphologically uniform. Thus, at least 95%, preferably 97%, more preferably 99%, and most preferably 99.5% of the mass of troriluzole hydrochloride hydrate [(1 :2: 1) salt], according to present invention consists of a defined, uniform crystal structure characteristic of the troriluzole hydrochloride hydrate [(1 :2:1) salt].

[0182] The present invention also relates to the process for preparation of the crystalline form of troriluzole hydrochloride hydrate [(1 :2: 1) salt]. In the process for preparation of the crystalline form of troriluzole hydrochloride hydrate [(1 :2: 1) salt], it is advantageous to carry out the process by mixing the free base of troriluzole (1) in toluene, then dripping hydrochloric acid solution into the suspension at a temperature between 0 and 30°C. The resulting suspension is mixed at room temperature, the precipitated product is filtered, and if necessary, washed and dried. (Figure 14).

[0183] Alternatively, we can proceed by suspending the troriluzole hydrochloride salt in acetic acid, heating the suspension to a temperature between 60 and 100°C and mixing until complete dissolution. If necessary, hydrochloric acid solution is dripped in, then the solution is slowly cooled. The resulting suspension is mixed at room temperature, the precipitated product is filtered, and if necessary, washed and dried.

[0184] A further advantageous embodiment of the present invention is the crystalline form A polymorph of troriluzole hydrochloride [(1 :1) salt] having characteristic X-ray powder diffraction peaks according to the present invention are as follows: 29 (±0.2 °29): 9.57; 18.13; 20.89. More specifically, we can characterize it with the following X-ray powder diffraction peaks: 29 (±0.2 °29): 9.57; 13.48; 18.13; 19.28; 20.00; 20.89; 30.12. Even more specifically we can characterize it with the following X-ray powder diffraction peaks: 29 (±0.2 °29): 9.57; 12.79; 13.48; 14.04; 16.60; 17.59; 18.13; 19.28; 20.00; 20.89; 21.38; 21.98; 23.39; 24.12; 24.63; 25.14; 25.45; 26.22; 28.17; 29.11; 29.76; 30.12; 30.77; 31.58; 32.81; 33.13; 33.44; 34.12; 34.54 or with the X-ray powder diffractogram shown in Figure 17. The signals with an intensity of 3% or higher are summarized in Table 8 below:

[0185] Table 8: X-ray powder diffraction data of crystalline form A of troriluzole hydrochloride [(1 : 1) salt],

[0186] (relative intensities >3%)

[0187] The troriluzole hydrochloride [(1 : 1) salt] crystalline Form A, according to the present invention is morphologically uniform. Thus, at least 95%, preferably 97%, more preferably 99%, and most preferably 99.5% of the mass of troriluzole hydrochloride [(1: 1) salt] crystalline Form A, according to present invention consists of a defined, uniform crystal structure characteristic of the troriluzole hydrochloride [(1 :1) salt] crystalline Form A.

[0188] The present invention also relates to the production of a troriluzole hydrochloride [(1 : 1) salt] crystalline Form A polymorph form. In the production of the troriluzole hydrochloride [(1: 1) salt] crystalline Form A, it is advantageous to carry out the process by suspending a hydrochloride salt of troriluzole in toluene, mixing the suspension at a temperature between 0 and 30°C, seeding with 1-2% seed crystals if necessary with troriluzole hydrochloride [(1: 1) salt] crystalline Form A, then filtering the product, and if necessary, washing and drying it.

[0189] A further advantageous embodiment of the present invention is the crystalline form B polymorph of troriluzole hydrochloride [(1 :1) salt] having characteristic X-ray powder diffraction peaks according to the present invention are as follows: 29 (±0.2 °29): 3.53; 17.18; 19.48. More specifically, we can characterize it with the following X-ray powder diffraction peaks: 26 (±0.2 °29): 3.53; 7.06; 14.27; 17.18; 19.48; 20.38; 22.31; 25.03. Even more specifically we can characterize it with the following X-ray powder diffraction peaks: 29 (±0.2 °26): 3.53; 7.06; 10.57; 14.27; 14.61; 16.02; 17.18; 17.81; 18.51; 18.89; 19.48; 19.96; 20.38; 20.54; 21.24; 22.31; 22.76; 23.23; 23.70; 23.84; 24.47; 25.03; 25.30; 26.20; 27.28; 28.26; 28.79; 29.63; 30.44; 30.54; 30.70; 31.06; 31.56; 31.97; 32.39; 32.60; 32.94; 33.32; 33.81; 34.24; 34.61 or with the X-ray powder diffractogram shown in Figure 20. The signals with an intensity of 5% or higher are summarized in Table 9 below:

[0190] Table 9: X-ray powder diffraction data of crystalline form B of troriluzole hydrochloride [(1 : 1) salt], (relative intensities >5%)

[0191] The troriluzole hydrochloride [(1: 1) salt] crystalline Form B, according to the present invention is morphologically uniform. Thus, at least 95%, preferably 97%, more preferably 99%, and most preferably 99.5% of the mass of troriluzole hydrochloride [(1: 1) salt] crystalline Form B, according to present invention consists of a defined, uniform crystal structure characteristic of the troriluzole hydrochloride [(1 :1) salt] crystalline Form B.

[0192] The present invention also relates to the production of a troriluzole hydrochloride [(1 : 1) salt] crystalline Form B polymorph form. In the production of troriluzole hydrochloride [(1 : 1) salt] crystalline Form B, it is advantageous to proceed by placing the crystalline form of troriluzole hydrochloride hydrate [(1 :2: 1) salt] in a drying oven and drying it to constant weight at a temperature range between 140 and 170°C.

[0193] A further advantageous embodiment of the present invention is the crystalline form of troriluzole hydrochloride acetic acid solvate [(1 : 1 : 1) salt] having characteristic X-ray powder diffraction peaks according to the present invention are as follows: 29 (±0.2 °29): 11.47; 16.44; 27.34. More specifically, we can characterize it with the following X-ray powder diffraction peaks: 29 (±0.2 °29): 8.13; 11.47; 13.11; 16.44; 19.84; 21.93; 22.11; 27.34. Even more specifically we can characterize it with the following X-ray powder diffraction peaks: 29 (±0.2 °29): 8.13; 9.64; 11.47; 11.69; 11.82; 13.12; 13.99; 15.97; 16.15; 16.44; 17.33; 18.06; 18.71; 19.84; 20.27; 20.73; 21.31; 21.93; 22.11; 22.65; 22.92; 23.84; 24.23; 24.63; 24.86; 25.53; 25.74; 26.26; 26.44; 26.57; 26.91; 27.34; 28.16; 28.39; 28.90; 29.17; 29.30; 29.68; 30.32; 30.63; 31.38; 31.58; 32.64; 33.02; 33.23; 34.42; 34.93 or with the X-ray powder diffractogram shown in Figure 23. The signals with an intensity of 2% or higher are summarized in Table 10 below:

[0194] Table 10: X-ray powder diffraction data of crystalline form of troriluzole hydrochloride acetic acid solvate [(1 :1 : 1) salt], (relative intensities >2%)

[0195] The troriluzole hydrochloride acetic acid solvate [(1 :1 : 1) salt] crystalline Form, according to the present invention is morphologically uniform. Thus, at least 95%, preferably 97%, more preferably 99%, and most preferably 99.5% of the mass of crystalline troriluzole hydrochloride acetic acid solvate [(1 : 1 : 1) salt], according to present invention consists of a defined, uniform crystal structure characteristic of the troriluzole hydrochloride acetic acid solvate [(1 : 1 : 1) salt].

[0196] The present invention also relates to the production of the crystalline form of troriluzole hydrochloride acetic acid solvate [(1 : 1 : 1) salt]. In the production of the crystalline form of troriluzole hydrochloride acetic acid solvate [(1 : 1 : 1) salt], it is advantageous to carry out the procedure by suspending a hydrochloride salt of troriluzole in acetic acid, heating the suspension to a temperature between 60 and 100°C and mixing until complete dissolution. If necessary, a hydrochloric acid solution is dripped in, then the solution is slowly cooled. The resulting suspension is mixed at room temperature, while a continuous gas flow (nitrogen, argon, air) is provided above the mixed suspension, the precipitated product is filtered, and if necessary, washed and dried.

[0197] Further object of the present invention is amorphous form of troriluzole hydrochloride [(1: 1) salt], having the X-ray powder diffractogram shown in Figure 25.

[0198] The present invention also relates to the production of amorphous form of troriluzole hydrochloride [(1: 1) salt]. In the production of amorphous form of troriluzole hydrochloride [(1: 1) salt], it is advantageous to proceed by mixing the free base of troriluzole (1) in diethyl ether, then dripping a hydrochloric acid solution into the suspension at a temperature between 0 and 30°C. The resulting suspension is mixed at room temperature, the precipitated product is filtered, and if necessary, washed and dried.

[0199] The new polymorphic forms according to the invention can also be produced by mixing a salt of troriluzole in a polar solvent (alcohol, ketone, acetonitrile, carboxylic acids, DMSO, DMF, water, or their mixtures) at a temperature between -10°C and the boiling point of the solvent (taking into account the freezing points of DMSO and water), typically between 25- 100°C. During this process, a solution or solid-phase transformation occurs in the product, resulting in a material with a crystal structure different from the original. The transformation can be accelerated by selecting a better solvent (or solvent mixture) for the appropriate modification or by using the desired form as seed crystals during the suspension.

[0200] The new polymorphic modifications according to the invention can also be produced by conditioning or drying a suitable salt of troriluzole under appropriate conditions, so that the starting salt loses its solvent and / or hydrochloric acid content, or a part of it, in a controlled manner. During this process, a solid-phase transformation occurs in the product, resulting in a material with a crystal structure different from the original.

[0201] To the separation of salts or crystalline forms, any method used in the pharmaceutical industry for separating solid and liquid phases can be applied. For example, filtration can be performed under atmospheric conditions, using vacuum filtration, or under pressure. Additionally, centrifugation can be used.

[0202] The pharmaceutical compositions according to the invention contain any troriluzole salt and / or polymorph in a therapeutically effective amount, optionally together with one or more pharmaceutically acceptable carriers and / or excipients. More specifically, the present invention relates to a troriluzole-containing pharmaceutical composition, which as an active ingredient contains a therapeutically effective amount of the troriluzole base, preferably crystalline base, crystalline modifications Form I, II, III, IV or V of the crystalline base, or crystalline hydrochloride salts of troriluzole in which the stochiometric rate of components of troriluzole, hydrochloric acid and water are e.g. 1 : 1 (monohydrochloride), 1: 1 :1 : (monohydrochloride monohydrate), 1 :2: 1 (dihydrochloride monohydrate) or a hydrochloride salt acetic acid solvate [(1: 1 : 1) troriluzole:HCl: acetic acid)] or the amorphous form of 1 :1 (monohydrochloride).

[0203] The pharmaceutical compositions according to the invention are preferably administered orally. The orally administrable compositions can be, for example, tablets, capsules, dragees, solutions, elixirs, suspensions, or emulsions.

[0204] The pharmaceutical compositions according to the present invention can therefore contain conventional pharmaceutical carriers and / or excipients. Carriers can include, for example, magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, low melting point wax, PEG, cocoa butter, etc. In the case of capsules, the carrier often serves as the material of the capsule itself, and in such cases, no additional carrier is needed. Oral compositions also include sachets and lozenges. Tablets, powders, capsules, pills, sachets, and lozenges are particularly suitable solid dosage forms for oral administration.

[0205] Tablets can be produced by mixing the active ingredient with carriers that have suitable properties in appropriate proportions and then pressing the mixture into tablets of the desired shape and size.

[0206] Powders are prepared by mixing the finely powdered active ingredient with finely powdered carriers. Liquid formulations can include solutions, suspensions, and emulsions, from which the active ingredient can be released in a delayed manner if desired. Aqueous or aqueous propylene glycol solutions are preferred. Liquid formulations for parenteral administration are preferably prepared in the form of aqueous polyethylene glycol solutions.

[0207] The pharmaceutical compositions according to the invention can preferably be produced in dosage units. The dosage units contain the desired amount of the active ingredient. The dosage units can be marketed in packaged form, containing separate quantities of the preparations (e.g., packaged tablets, capsules, powder in vials or ampoules). The term dosage unit refers to the capsule, tablet, sachet, lozenge, and the packaging containing the appropriate number of unit doses.

[0208] In the process for producing the pharmaceutical compositions according to the present invention, one or more of the troriluzole base or salts and crystal forms thereof according to the invention are mixed with one or more pharmaceutically suitable solid or liquid diluents and / or excipients, and the mixture is brought into a galenic form.

[0209] The pharmaceutical compositions according to the invention can be produced using conventional pharmaceutical manufacturing methods. If necessary, the pharmaceutical compositions according to the invention can also contain additional pharmaceutical active ingredients that are compatible with the compounds according to the invention or their mixtures.

[0210] The salts and crystalline forms according to the invention can be used as glutamate modulators, for example, in obsessive-compulsive or generalized anxiety disorder syndrome, as well as in the treatment of atopic dermatitis, Takayasu's arteritis, psoriatic arthritis, temporal arteritis, alopecia areata, rheumatoid arthritis, spondylarthritis, juvenile rheumatoid arthritis, sleep disorders, systemic lupus erythematosus, ulcerative colitis, non-segmental vitiligo, vitiligo, hidradenitis suppurativa, ankylosing spondylitis, juvenile idiopathic arthritis, Crohn's disease, and immune system disorders.

[0211] More specifically, the present invention relates to use of troriluzole base, preferably crystalline base, crystal phases of Form I, II, III, IV or V of the crystalline base, or crystalline hydrochloride salts of troriluzole in which the stochiometric rate of components of troriluzole, hydrochloric acid and water are e.g. 1 : 1 (monohydrochloride), 1: 1 :1 : (monohydrochloride monohydrate), 1 :2: 1 (dihydrochloride monohydrate) or a hydrochloride salt acetic acid solvate [(1: 1 : 1) troriluzole :HC1: acetic acid)] or the amorphous form of 1 : 1 (monohydrochloride) as a glutamate modulator in obsessive-compulsive or generalized anxiety disorder syndrome.

[0212] The present invention has the advantage that the salts and crystalline forms according to the present invention are materials with uniform morphology and advantageous crystal shape. Accordingly, these materials have reproducible properties in terms of dissolution rate, bioavailability, chemical stability, and processability (filterability, drying, tableting, etc.).

[0213] The active ingredients according to the invention can be produced on an industrial scale using favorable, reproducible processes.

[0214] Further details of our solution according to the invention are presented in the following examples, without limiting the scope of protection of our invention in any way to the mentioned examples.

[0215] Measurement methods

[0216] X-ray powder diffraction (XRPD) measurement conditions

[0217] Instrument: PANalytical Empyrean X-ray powder diffractometer

[0218] Sample mode: Transmission

[0219] X-ray tube

[0220] Type: Empyrean Long Fine Focus High Resolution tube

[0221] Anode material: Cu

[0222] Wavelength: Ka (1.541874 A)

[0223] Focus mode: line focus

[0224] Incident beam optics

[0225] Divergence slit: Fixed slit 1 / 2 °

[0226] Mirror: Focusing elliptical mirror

[0227] Seller slit: 0.04 rad

[0228] Anti-scatter slit: Fixed slit 1 / 2 °

[0229] Diffracted beam optics

[0230] Anti-scatter slit: Programmable slit in fix mode: 1 / 2 °

[0231] Seller slit: 0.04 rad

[0232] Sample stage

[0233] Type: Reflection-transmission spinner stage

[0234] Sample rotation: 1 rps

[0235] Beam knife: Transmission beam stop used

[0236] Detector

[0237] Type: PIXcel 3D 1 x 1 area detector

[0238] Mode: Scanning line detector (ID) mode

[0239] Active length: 3.3473°

[0240] Sample preparation: place powder samples (without grinding) between two Mylar foils in the sample holder

[0241] Measurement settings

[0242] Temperature: room temperature

[0243] Accelerating voltage: 45 kV Anode heating current: 40 mA

[0244] Scan type: continuous gonio (9 / 9) scan

[0245] Measurement range: range: 2.0000 - 34.9964 °29

[0246] Step size: 0.0131 °29

[0247] Time per step: 109.650 s

[0248] Measurement cycles: 1

[0249] Measurement time: ~20 minutes

[0250] Thermogravimetry (TG) measurement conditions

[0251] Device: TA Instruments Discovery TGA thermogravimetric analyzer

[0252] Atmosphere: N2 flow: 25 mL / min (furnace)

[0253] 10 mL / min (balance)

[0254] Data sampling interval: 0.5 s / pt

[0255] Temperature program: 30 °C - 230 °C 10 °C / min

[0256] Pan: Platinum 100 pL

[0257] Dynamic vapor sorption (DVS) measurement conditions

[0258] Instrument: TA Q5000SA dynamic vapour sorption analyser (DVS)

[0259] Atmosphere: Nitrogen

[0260] Total gas flow: 200 mL / min

[0261] Solvent: Water

[0262] Balance purge flow: 10 mL / min

[0263] Balance temperature: 35 °C

[0264] Pan type: Platinum 100 pl, unsealed

[0265] Method: Custom

[0266] Drying: No

[0267] Conditioning: 30 min

[0268] Temperature: 25 °C, isotherm

[0269] Relative humidity range: 0% to 95% RH

[0270] Initial humidity: 20% RH or 40% RH

[0271] Humidity step stages: Desorption - adsorption - desorption

[0272] Humidity step size: 5% RH

[0273] Stabilization criteria: < 0.01% for 10 min

[0274] Maximum dwell time: 360 min Data sampling interval: 5 sec / point

[0275] Number of cycles: 2

[0276] NMR spectra

[0277] The3H and13C NMR spectra were recorded in DMSO-t / e solvent using a Bruker Avance III HD spectrometer (600 MHz for 'H NMR and approximately 150 MHz for13C NMR) in the presence of TMS as an internal standard.

[0278] Examples

[0279] In the following examples, the production of troriluzole bases and hydrochloride salts was achieved using commercially available reagents.

[0280] A possible and non-exclusive method for producing the form of troriluzole hydrochloride hydrate [(1 : 1 : 1) salt] is illustrated in Example 8. A possible and non-exclusive method for producing the troriluzole base, starting from the form of troriluzole hydrochloride hydrate [(1: 1 : 1) salt], is illustrated in Example 6.

[0281] In every detailed example where it is relevant, we specify which crystal modification of the starting material is used or in what form the product is produced. In cases where such information is not provided, the morphological properties of the starting or resulting material are not significant for the given reaction. In the given example, any salt or base form described in this application, or their mixtures (e.g., hydrochloride mixtures, base mixtures), can be used as starting materials.

[0282] Example 1

[0283] Preparation of Form I polymorph of troriluzole base

[0284] In a device providing intensive mixing 8 cm3of water, 0.5 cm3of ethyl acetate are measured and 0.20 g (0.4 mmol) of troriluzole hydrochloride suspended in it. To the reaction mixture 1.5 cm3of 5% (7.5 mmol) sodium bicarbonate solution is added, then stirred the suspension at room temperature for 6 hours. The crystalline product is filtered, washed with a small amount of water, and dried in a vacuum at 50°C.

[0285] Yield: 0,163 g (92,1%);

[0286] Purity (HPLC): 100%.

[0287] The X-ray powder diffraction pattern of the obtained product's powder sample is shown in Figure 2.

[0288] Example 2 Preparation of Form II polymorph of troriluzole base

[0289] In a device providing intensive mixing 120 cm3of water, 7.5 cm3of acetone are measured and 3.0 g (6.3 mmol) of troriluzole hydrochloride salt suspended in it. To the reaction mixture 22.5 cm3of 5% (13.4 mmol) sodium bicarbonate solution are added, then stirred the suspension at room temperature for 1 hour. The crystalline product is filtered, washed with a small amount of water, and dried in a vacuum at 50°C.

[0290] Yield: 2,55 g (95,5%);

[0291] Purity (HPLC): 100%.

[0292] The X-ray powder diffraction pattern of the obtained product's powder sample is shown in Figure 3.

[0293] Example 3

[0294] Preparation of Form III polymorph of troriluzole base

[0295] In a device providing intensive mixing - which is suitable for solvent distillation -70 cm3of methanol is measured and 0.84 g (2.0 mmol) of troriluzole base is suspended in it. The reaction mixture was heated to reflux temperature and stirring is continued until complete dissolution. At this point, the methanol began to evaporate from the reaction mixture while the evaporated solvent continuously replaced with ethanol. The boiling of the mixture maintained with heating and continued the solvent exchange until the internal temperature reached 75 °C. Then the solution cooled to a temperature between 0 and 5°C and the stirring continued for 1 additional hour. The crystalline product is filtered cold, washed with a small amount of ethanol, and dried in a vacuum at 50°C.

[0296] Yield: 0.425 g (50.6%);

[0297] Purity (HPLC): 100%.

[0298] The X-ray powder diffraction pattern of the obtained product's powder sample is shown in Figure 4.

[0299] Example 4

[0300] Preparation of Form IV polymorph of troriluzole base

[0301] In a device providing intensive mixing, 25 cm3of methanol are measured, and 0.15 g (0.4 mmol) of troriluzole base suspended in it. To the reaction mixture is stirred at room temperature until the troriluzole base fully dissolved, then the solvent is evaporated in vacuum, the residue is washed with small amount of solvent, filtered and dried in a vacuum at 50°C. Yield: 0.12 g (80.0%); Purity (HPLC): 100%.

[0302] The X-ray powder diffraction pattern of the obtained product's powder sample is shown in Figure 5.

[0303] Example 5

[0304] Preparation of Form V polymorph of troriluzole base

[0305] In a device providing intensive mixing 3 cm3of toluene measured and 0.15 g (0.4 mmol) of troriluzole base of Form II are suspended in it. The suspension is stirred at room temperature for 3 hours. The crystalline residue is filtered, washed with small amount of ethanol and dried in a vacuum at 50°C.

[0306] Yield: 0.13 g (85.3%);

[0307] Purity (HPLC): 99.32%.

[0308] The X-ray powder diffraction pattern of the obtained product's powder sample is shown in Figure 6.

[0309] Example 6

[0310] Process for preparation of troriluzole base from crystalline troriluzole hydrochloride hydrate [(1: 1 : 1) salt]

[0311] In a device providing intensive mixing 8 cm3of water, 0.5 cm3of isopropyl alcohol is measured and 0.200 g (0.42 mmol) of troriluzole hydrochloride salt suspended in it. To the reaction mixture 1.50 cm3of sodium bicarbonate solution (5% aqueous solution, 0.89 mmol) are added and the suspension is stirred at room temperature for additional 2 hours. The crystalline product is filtered, washed with a small amount of water, and dried in a vacuum at 50°.

[0312] Yield: 0.17 g (97.3%);

[0313] Purity (HPLC): 100%.

[0314] Example 7

[0315] Process for preparation crystalline troriluzole hydrochloride hydrate [(1 : 1 : 1) salt] from troriluzole base

[0316] In a device providing intensive mixing 3 cm3of ethanol are measured and 0.15 g (0.4 mmol) of troriluzole base are suspended in it. The suspension is stirred and 0.07 cm3of hydrochloric acid-saturated isopropyl alcohol (22.8% solution, 0.41 mmol) are added at room temperature, then continued stirring the suspension for 5 hours. The crystalline product is filtered, washed with a small amount of ethanol, and dried in a vacuum at 50°C.

[0317] Yield: 0.12 g (85.3%);

[0318] Purity (HPLC): 100%.

[0319] The X-ray powder diffraction pattern of the obtained product's powder sample is shown in Figure 7.

[0320] Example 8

[0321] Process for preparation crystalline troriluzole hydrochloride hydrate [(1 : 1 : 1) salt] from troriluzole base preparation from an in situ formed intermediate of formula (4)

[0322] In a preheated device providing intensive mixing, 3 cm3of ethyl acetate, 0.45 cm3(2.6 mmol) of DIPEA (diisopropylethylamine) are measured, and 0.53 g (1.1 mmol) of riluzole hydrochloride are suspended in it and 0.50 g (1.6 mmol) BocGlyGlySarOH (3; 2-[methyl-[2- [[2-[(2-methylpropan-2-l)oxycarbonylamino]acetyl]amino]acetyl]amino]acetic acid) tripeptide are added and the system made inert with argon gas at 40°C. The suspension is stirred until dissolved, then 0.63 g (2.6 mmol) of HATU ((dimethylamino)({3H-[l,2,3]triazolo[4,5- b]pyridin-3-yloxy})methylidene]dimethylazanium added; hexafluoro-X5-phosphanuide) coupling agent is added (Figure lb). The reaction mixture is stirred at 40°C under argon atmosphere until the amount of starting riluzole in the reaction mixture no longer decreases. The reaction mixture cooled and 3.00 cm3of hydrochloric acid saturated ethyl acetate (24.0% solution, 18.5 mmol) are added at room temperature, then the suspension stirred for further 1 hour. The crystalline product was filtered, washed with a small amount of acetone, and dried in a vacuum at 50°C. The crude product suspended in 6 cm3of tert-butanol, heated to 50°C, and stirred for 1 hour. Then cooled to room temperature, 2 cm3of acetone added, and the stirring continued for 30 minutes. The crystalline product filtered, washed with a small amount of a 4: 1 tert-butanol: acetone solvent mixture, and dried in a vacuum at 50°C.

[0323] Yield: 0.40 g (75.8%);

[0324] Purity (HPLC): 100%.

[0325] Example 9

[0326] Process for preparation crystalline troriluzole hydrochloride hydrate [(1 :2: 1) salt] from troriluzole base In a device ensuring intensive mixing, 3 cm3of toluene are measured and 0.15 g (0.4 mmol) of troriluzole base are suspended in it. The suspension is stirred and 0.18 cm3of ethyl acetate saturated with hydrochloric acid (23.2% solution, 1.1 mmol) are added at room temperature, then the suspension is stirred for 4 hours. The crystalline product is filtered, washed with a small amount of toluene, and dried in a vacuum at 50°C.

[0327] Yield: 0.15 g (84%).

[0328] Purity (HPLC): 100%.

[0329] Example 10

[0330] Process for preparation troriluzole hydrochloride [(1 : 1) salt] from troriluzole base

[0331] In a device providing intensive mixing 3 cm3of diethyl ether are measured and 0.15 g (0.4 mmol) of base suspended in it. The suspension is stirred and 0.06 cm3of hydrochloric acid- saturated ethyl acetate (22.8% solution, 0.35 mmol) are added at room temperature, then the suspension is stirred for 6 hours. The crystalline product is filtered, washed with a small amount of diethyl ether, and dried in a vacuum at 50°C.

[0332] Yield: 0.14 g (83.3%).

[0333] Purity (HPLC): 100%.

[0334] The X-ray powder diffraction pattern of the obtained product's powder sample is shown in Figure 25.

[0335] Example 11

[0336] Process for preparation crystalline troriluzole hydrochloride hydrate [(1 :2: 1) salt] from troriluzole hydrochloride

[0337] In a device providing intensive mixing 105 cm3of acetic acid are measured and 5.00 g of (10,5 mmol) troriluzole hydrochloride hydrate are suspended in it. The suspension is heated at 80°C and stirred until dissolved, then 1.80 cm3of hydrochloric acid-saturated ethyl acetate (22.8% solution, 10.8 mmol) are added, and the stirring is continued at this temperature for 1 hour. Then, the suspension was allowed to cool slowly to room temperature. The crystalline product was filtered and washed with a small amount of ethyl acetate, and dried in a vacuum at 50°C. Yield: 4.90 g (91.0%).

[0338] Purity (HPLC): 100%. The X-ray powder diffraction pattern of the obtained product's powder sample is shown in Figure 14, its dynamic vapor sorption isotherms are shown in Figure 15, and its thermogravimetric analysis is shown in Figure 16. During dynamic vapor sorption analysis, the material absorbed a significant amount of water without liquefying at high relative humidity, and with the loss of 1 mole of HC1, it is transformed into its troriluzole hydrochloride hydrate [(1: 1 : 1) salt] crystalline form. During thermogravimetric analysis, upon heating, it first loses one mole of water, then one mole of HC1.

[0339] Example 12

[0340] Process for preparation crystalline Form A polymorph of troriluzole hydrochloride [(1: 1) salt] from troriluzole hydrochloride

[0341] In a device providing intensive mixing 200 cm3of toluene are measured and 2.00 g (4.2 mmol) of troriluzole hydrochloride hydrate suspended in it. The suspension is stirred at room temperature for 19 hours. The crystalline product is filtered, washed with a small amount of toluene, and dried in a vacuum at 50°C.

[0342] Yield: 1.90 g (95.0%).

[0343] Purity (HPLC): 99.72%.

[0344] The X-ray powder diffraction pattern of the obtained product's powder sample is shown in Figure 17, its dynamic vapor sorption isotherms are shown in Figure 18, and its thermogravimetric analysis is shown in Figure 19. Based on dynamic vapor sorption analysis, the material is stable between 0 and 75% relative humidity at 25°C; at higher humidity, it transforms into its troriluzole hydrochloride hydrate form.

[0345] Example 13

[0346] Process for preparation crystalline of troriluzole hydrochloride hydrate [(1 : 1 : 1) salt] from troriluzole hydrochloride

[0347] In a suitably sized device 4.8 cm3of tetrahydrofuran and 5.0 cm3of methanol are measured, and 0.20 g (0.4 mmol) of troriluzole hydrochloride are suspended in it, then stirred the mixture until dissolved. If necessary, the solution is filtered, then device is placed in an undisturbed location with the lid open and allowed the solvent to evaporate slowly at room temperature.

[0348] Yield: 0.90 g (98.0%).

[0349] Purity (HPLC): 100%.

[0350] The X-ray powder diffraction pattern corresponds to the pattern shown in Figure 7. Example 14

[0351] Process for preparation crystalline of troriluzole hydrochloride hydrate [(1 : 1 : 1) salt] from troriluzole hydrochloride hydrate [(1 :2:1) salt]

[0352] In a device ensuring intensive mixing 37.5 cm3of isopropyl alcohol are measured and 1.50 g (2.9 mmol) of crystalline of troriluzole hydrochloride hydrate [(1 :2: 1) salt] are suspended and 0.03 g of crystalline of troriluzole hydrochloride hydrate [(1 :1 : 1) salt] as seed crystals. The suspension is heated at 50°C and stirred for 3 hours, then cooled to room temperature and continued stirring for 3 hours. The crystalline product is filtered, washed with a small amount of isopropanol, and dried in a vacuum at 50°C.

[0353] Yield: 1.33 g (95.5%).

[0354] Purity (HPLC): 100%.

[0355] The X-ray powder diffraction pattern corresponds to the pattern shown in Figure 7.

[0356] Example 15

[0357] Process for preparation crystalline of troriluzole hydrochloride hydrate [(1 : 1 : 1) salt] from troriluzole hydrochloride hydrate [(1 :2:1) salt]

[0358] In a drying oven 1.50 g (2.9 mmol) of troriluzole hydrochloride hydrate [(1:2: 1) salt] are placed, then using a mild vacuum at room temperature alternate between passing humid and dry air through the chamber every 1-2 hours. Continue the process until the sample in the drying chamber no longer absorbs a significant amount of moisture. Yield: 1.13 g (93.3%).

[0359] Yield: 1.13 g (93.3%).

[0360] Purity (HPLC): 100%.

[0361] The X-ray powder diffraction pattern corresponds to the pattern shown in Figure 7.

[0362] Example 16

[0363] Process for preparation crystalline Form B polymorph of troriluzole hydrochloride [(1 : 1) salt] from crystalline of troriluzole hydrochloride hydrate [(1 : 1 : 1) salt]

[0364] In a drying oven 1.20 g (2.4 mmol) of troriluzole hydrochloride hydrate [(1 : 1 : 1) salt] are placed and dried at 170°C for 4 hours in inert atmosphere.

[0365] Yield: 1.00 g (93.3%). Purity (HPLC): 99.38%.

[0366] The X-ray powder diffraction pattern of the obtained product is shown in Figure 20, its dynamic vapor sorption isotherms in Figure 21, and its thermogravimetric profile in Figure 22. Based on the dynamic vapor sorption study, the material binds water at 25°C with increasing relative humidity and transforms into its crystalline troriluzole hydrochloride hydrate [(1 : 1 :1) salt] form.

[0367] Example 17

[0368] Process for preparation crystalline troriluzole hydrochloride acetate solvate [(1 : 1 : 1) salt] from troriluzole hydrochloride

[0369] In a device ensuring intensive mixing 21 cm3of acetic acid are measured and 1.00 g (2.1 mmol) of troriluzole salt is suspended in it. The suspension is heated at 80°C and stirred until it is dissolved, then 0.36cm3of ethyl acetate saturated with hydrochloric acid (23.2% solution, 2.1 mmol) are added, and the stirring is continued at this temperature for 30 minutes. Then the suspension is allowed to cool to room temperature slowly. During cooling to room temperature, a gas stream (air, nitrogen, argon) is passed over the solution, and stirring is continued for 1 hour. Then, the gas flow was stopped, and the stirring is continued for 3 days. The crystalline product is filtered, washed with a small amount of ethyl acetate, and dried in a vacuum at 50°C. Yield: 1.00 g (89.1%).

[0370] Purity (HPLC): 100%.

[0371] 'H NMR (DMSO-t / e. 600 MHz): 5 = 12.72 (b. 1H); 9.16 (b); 8.63 / 8.61 (bt. J=5.4 Hz. 1H); 8.26 / 8.24 (b. 3H); 8.14 / 8.16 (d. J=2.0 Hz. 1H); 7.84 / 7.87 (d. J=8.9 Hz. 1H); 7.44 / 7.45 (m. 1H); 4.35 / 4.50 (s. 2H); 4.17 / 4.03 (d. J=5.4 Hz. 2H); 3.62 (q. J=5.8 Hz. 2H); 3.12 / 2.90 (s. 3H); 1.92 (s. 3H) ppm.

[0372] °C NMR (DMSO-t / e. 150 MHz): 5 = 172.25; 169.06 / 168.86; 169.00 / 168.96; 166.36 / 166.27; 159.44 / 159.34; 147.79 / 147.76; 144.33 / 144.39; 132.88 / 132.92; 121.83 / 121.95; 120.44 (q. J=255.9 Hz); 120.17 / 120.21; 115.30; 51.25 / 51.51; 40.80 / 40.35; 40.12; 36.00 / 34.94; 21.35.

[0373] The X-ray powder diffraction pattern of the obtained product is shown in Figure 23.

[0374] Example 18 Process for the preparation of BocGlyGlySarOBn (7; benzyl 2-[2-(2-{[(tert- butoxy)carbonyl]amino}acetamido)-N-methylacetamido]acetate)

[0375] In a device ensuring intensive mixing 65 cm3of ethyl acetate are measured and 2.70 g (12.5 mmol) of SarOBn*HCl (5; benzyl 2-(methylamino)acetate hydrochloride), 2.90 g (12.5 mmol) of BocGlyGlyOH (6; 2-(2-{[(tert-butoxy)carbonyl]amino}acetamido)acetic acid) are suspended and 8 cm3(47,0 mmol) of DIPEA (ethylbis(propan-2-yl)amine) is added. The suspension is stirred at room temperature under an inert atmosphere (argon), and 4.75 g (12.5 mmol) HATU-t ([(dimethylamino)({3H-[ 1,2,3 ]triazolo[4,5-b]pyridin-3- yloxy})methylidene]dimethylazanium; hexafluoro-X5-phosphanuide) are added. The reaction mixture is stirred at room temperature for 2 hours. To the reaction mixture 65 cm3of ethyl acetate and 100 cm3of 5% sodium bicarbonate solution are added, then stirred vigorously the two-phase system for 5-10 minutes. Phases are separated, the aqueous phase was washed with 2 x 50 cm3of ethyl acetate and the combined organic phase was washed with 1 x 100 cm3of water, 3 x 150 cm30.05 M aqueous hydrochloric acid solution, 1 x 100 cm3of water and 1 x 100 cm3with saturated sodium chloride solution. The organic phase is dried over sodium sulfate, filtered, and the solvent is removed under vacuum.

[0376] Yield: 2.08 g (42.23%);

[0377] Purity (HPLC): 95.0%.

[0378] Example 19

[0379] Process for the preparation of BocGlyGlySarOH (3; 2-[2-(2-{[(tert- butoxy)carbonyl]amino}acetamido)-N-methylacetamido]acetic acid)

[0380] In a hydrogenation device ensuring intensive mixing 25 cm3of methanol is measured and 2.00 g (5.1 mmol) of BocGlyGlySarOBn (7; 2 benzyl 2-[2-(2-{[(tert- butoxy)carbonyl]amino}acetamido)-N-methylacetamido]acetate) and 0.20 g of Pd catalyst (Selcat Q, 10% Pd content) are suspended. After inerting, the hydrogenation device is filled to 6 bar with hydrogen, then the reaction mixture is stirred at room temperature for 2 hours. Then the reaction mixture is filtered through a celite layer, then evaporated. If necessary, the product is dissolved in ethyl acetate, dried over sodium sulfate, and then filtered, after which the solvent is evaporated.

[0381] Yield: 1.48 g (96.1%).

Claims

Claims:

1. Process for the preparation of compound of the formula(1) troriluzole or salts, solvates or hydrates thereof, characterized in that the compound of the formula(2) riluzole, or a compound of the general formula of (2 * HnA) acid addition salt wherein A means a mono- or polyvalent anion and the meaning of n (depending on the meaning of A) is 1, 2, or 3 in the presence of a base and a peptide coupling agent reacted with a compound of formula(3) (BocGlyGlySarOH) tripeptide, then, starting from the thus obtained compound of formula(4) intermediate, optionally without isolation the Boc protecting group is cleaved using an acid, and the resulting compound of formula (1) is separated in the form of a base, a salt, a hydrate or a solvate form.

2. Process according to the Claim 1, characterized in that in the procedure, as a peptide coupling agent,- a carbodiimide-type compound is used, preferably dicyclohexylcarbodiimide (DCC), N,N'- diisopropylcarbodiimide (DIC), l-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), 1- cyclohexyl-(2-morpholinoethyl)carbodiimide metho-p-toluenesulfonate (CMCT), preferably carbonyl diimidazole, dicyclohexylcarbodiimide and / or- aza-benzotriazole-type compounds, preferably l-hydroxy-7-azabenzotriazole (HO At), 1- [bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-b]pyridinium-3-oxide- hexafluorophosphate (HATU), [benzotri azol- 1 -yloxy(dimethylamino)methylene]- dimethylazanium hexafluorophosphate (HBTU), HBTU / TBTU, 2-(6-chloro-lH-benzotriazol- 1 -yl)- 1 , 1 ,3 ,3 -tetramethylamin-hexafluorophosphate (HCTU), (benzotri azol- 1 -yloxy)- tripyrrolidinophosphonium-hexafluorophosphate (PyBOP), (7-azabenzotriazol- 1 -yloxy)- tripyrrolidinophosphonium-hexafluorophosphate (PyAOP), preferably 1- [bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-b]pyridinium-3-oxide- hexafluorophosphate (HATU) and / or- most preferably, l-[bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-b]pyridinium-3- oxide-hexafluorophosphate (HATU) is used.

3. Process according to Claim 1 or 2, characterized in that in the procedure as a base, an organic base, preferably tertiary amines, preferably trialkyl-amines, preferably triethylamine (TEA), diisopropylethylamine (DIPEA), most preferably diisopropylethylamine (DIPEA), or as acyclic amine, pyridine, 1,6-dimethylpyridine, most preferably diisopropylethylamine (DIPEA) is used.

4. Process according to any of Claims 1-3, characterized in that the procedure carried out in the present of a solvent, preferably carried out in a- dipolar aprotic solvent wherein the dipolar aprotic solvent is-preferably an ester-type solvent, more preferably an ester formed from Ci-Ce alcohols with Ci-Ce organic acids, even more preferably methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n- or sec-butyl acetate, methyl-, n-propyl- or isopropyl propionate, or methyl- , ethyl-, n-propyl- or isopropyl butyrate, most preferably ethyl acetate, or- preferably a formamide-type solvent, more preferably dimethylformamide, diethylformamide, dimethylacetamide, diethylacetamide, dimethyl or diethyl propionamide, most preferably dimethylformamide, cyclic amides, preferably N-methylpyrrolidone, or- preferably an ether-type solvent, more preferably aliphatic ethers such as diethyl ether, diisopropyl ether, methyl ethyl ether, methyl isopropyl ether, more preferably cyclic ethers, preferably dioxane or tetrahydrofuran, methyl tetrahydrofuran, more preferably tetrahydrofuran, methyl tetrahydrofuran, most preferably tetrahydrofuran, or- ketone-type solvents, preferably symmetric and asymmetric ketones containing C1-C4 aliphatic carbon chains, more preferably acetone, methyl ethyl ketone, methyl isobutyl ketone, most preferably acetone, or cyclic ketones, preferably cyclopentanone, cyclohexanone, cycloheptanone, or cyclooctanone, or- sulfoxide-type solvents, such as dimethyl sulfoxide, diethyl sulfoxide, or dioxolane, most preferably dimethyl sulfoxide, or- nitrile-type solvents, such as acetonitrile, propionitrile, butyronitrile, isobutyronitrile most preferably acetonitrile, or- preferably in a non-polar aprotic solvent, which solvent is saturated or unsaturated, open-chain or cyclic hydrocarbons, preferably Ci-Cs straight or branched chain alkanes, or their mixtures, preferably pentane, hexane, heptane isomers, mixtures, cyclic saturated hydrocarbons with C5- Cs carbon atoms, preferably cyclopentane, cyclohexane, methylcyclohexane, cycloheptane, cyclooctane, or their mixtures, or aromatic solvent, preferably toluene or xylene.

5. Process according to any of Claims 1-4, characterized in that for the cleavage of the Boc protecting group in the procedure an organic or inorganic acid is used, as inorganic acid preferably hydrogen chloride, hydrogen bromide, hydrogen iodide, sulfuric acid, nitric acid, phosphoric acid, more preferably hydrogen chloride, most preferably aqueous hydrogenchloride solution; as organic acid, sulfonic acid, preferably ethane sulfonic acid, methanesulfonic acid, benzenesulfonic acid, para-toluene sulfonic acid, carboxylic acid, preferably Ci-Ce aliphatic carboxylic acid, more preferably chlorinated or fluorinated acetic acid derivative, most preferably trifluoroacetic acid is used.

6. Process according to any of Claims 1-5, characterized in that the meaning of HnA in the general formula (2 * HnA) is an organic or inorganic acid, wherein the inorganic acid is preferably hydrogen chloride, hydrogen bromide, hydrogen iodide, sulfuric acid, nitric acid, phosphoric acid, most preferably hydrogen chloride; or wherein the organic acid is sulfonic acids, preferably ethane sulfonic acid, methanesulfonic acid, benzenesulfonic acid, para-toluene sulfonic acid, or carboxylic acid, preferably C1-C6 aliphatic carboxylic acid, more preferably chlorinated or fluorinated acetic acid derivative, most preferably trifluoroacetic acid.

7. Process according to any of Claims 1-6, characterized in that, after the acidic hydrolysis of the compound of formula (4), the troriluzole salt of formula (1) formed in the reaction mixture is: a.) filtered from the reaction mixture, optionally dried, and recrystallized if necessary, or b.) filtered from the reaction mixture, optionally dried, and if necessary, reacted with an inorganic base in water, organic solvent, or their mixture, and the troriluzole base of formula (1) thus obtained is separated and recrystallized if necessary, or c.) the troriluzole base of formula (1) is liberated from the troriluzole salt of formula (1) formed in the reaction mixture by adding a base to the reaction mixture, the base is separated and recrystallized if necessary or, the base prepared according to b.) or c.) is reacted with an acid in water, an organic solvent, or a mixture thereof, the salt thus obtained is separated and, if necessary, recrystallized.

8. Process according to any of Claims 1-7, characterized in that, the troriluzole salt of formula (1) formed in the reaction mixture after the acidic hydrolysis of the compound of formula (4) is separated.

9. Process according to any of Claims 1-8, characterized in that, the intermediate of formula (4) is not separated, but the Boc protecting group is cleaved by adding acid and, if necessary, additional solvent to the reaction mixture in which it was formed.

10. Troriluzole base.

11. Troriluzole base according to Claim 10 which is crystalline.

12. Crystalline form of troriluzole according to Claim 11 wherein the crystalline form characterized with:- the characteristic X-ray powder diffraction peaks of the Form I polymorph form are as follows: 20 (±0.2 °26): 19.82; 22.42; 23.

38. preferably 20 (±0.2 °26): 19.40; 19.82; 22.42; 23.38; 24.

45. most preferably 26 (±0.2 °26): 3.84; 5.48; 6.43; 7.00; 7.70; 9.05; 9.85; 11.35; 14.03; 15.29; 16.03; 16.69; 17.66; 18.20; 18.94; 19.40; 19.82; 20.43; 20.63; 21.07; 21.45; 21.89; 22.42; 23.38; 24.15; 24.45; 24.92; 25.35; 26.29; 26.48; 27.18; 27.34; 27.77; 28.33; 28.69; 29.39; 29.76; 30.48; 30.96; 31.55; 32.73; 32.93; 33.80; 34.

16. or- the characteristic X-ray powder diffraction peaks of the Form II polymorph form are as follows: 26 (±0.2 °26): 2.51; 16.30; 22.

86. preferably: 26 (±0.2 °26): 2.51; 4.20; 4.96; 16.30; 17.59; 22.

86. more preferably: 26 (±0.2 °26): 2.51; 4.20; 4.96; 16.30; 17.59; 18.41; 20.44; 22.86; 26.29; 27.22; 30.78; 31.

87. or- the characteristic X-ray powder diffraction peaks of the Form III polymorph form are as follows: 26 (±0.2 °26): 14.24; 18.44; 24.

19. preferably: 26 (±0.2 °26): 9.19; 14.24; 18.44; 21.00; 21.96; 24.

19. more preferably: 26 (±0.2 °26): 4.95; 9.19; 9.97; 10.88; 12.84; 14.24; 16.78;17.72; 18.06; 18.44; 18.66; 19.36; 20.05; 21.00; 21.37; 21.96; 22.12; 22.83; 23.31; 24.19;25.01; 25.21; 25.77; 26.40; 26.61; 28.00; 28.52; 28.93; 29.70; 29.90; 31.31; 31.69; 32.13;32.60; 32.98; 33.24; 34.79, or- the characteristic X-ray powder diffraction peaks of the Form IV polymorph form are as follows: 26 (±0.2 °26): 10.27; 18.87; 22.

76. preferably: 26 (±0.2 °26): 4.10; 10.27; 12.50; 18.87; 19.33; 22.76; 22.

92. more preferably: 26 (±0.2 °26): 4.10; 10.27; 12.32; 12.50; 15.54; 16.48; 18.41; 18.87; 19.33; 19.46; 19.55; 20.64; 21.30; 21.67; 22.76; 22.92; 23.34; 23.74; 24.83; 25.63; 28.13; 28.80; 29.88; 30.35; 30.51; 32.11; 32.84; 33.29; 34.08; 34.67, or- the characteristic X-ray powder diffraction peaks of the Form V polymorph form are as follows: 26 (±0.2 °26): 13.02; 17.36; 19.

47. preferably: 26 (±0.2 °26): 4.52; 13.02; 16.99;17.36; 19.47; 20.33; 21.

67. more preferably: 26 (±0.2 °26): 2.38; 4.52; 9.07; 13.02; 14.54;16.46; 16.99; 17.36; 18.43; 19.04; 19.47; 20.07; 20.33; 20.57; 21.14; 21.67; 22.50; 22.69;22.88; 23.25; 24.07; 24.41; 24.84; 25.08; 25.53; 26.46; 27.04; 27.61; 28.34; 28.80; 29.53;31.12; 31.48; 31.88; 32.16; 33.58; 33.89; 34.11; 34.68; 34.93.

12. Crystalline salts of troriluzole with hydrochloric acid, hydrates and acetic acid solvates thereof in which the stoichiometric ratio of troriluzole, hydrochloric acid and water is 1 :1 (monohydrochloride), 1 : 1 : 1 (monohydrochloride monohydrate), or 1 :2: 1 (di-hydrochloride monohydrate), or solvate [(1 : 1 : 1 / HC1 : acetic acid) salt],13. Crystalline troriluzole hydrochloride hydrate [(1: 1 : 1) salt] according to Claim 12, characterized the characteristic X-ray powder diffraction peaks are as follows: 29 (±0.2 °29): 5.63; 15.80; 25.

48. preferably: 29 (±0.2 °29): 5.63; 13.33; 15.80; 16.58; 18.39; 25.48; 25.75; 27.

04. more preferably: 29 (±0.2 °29): 5.63; 7.65; 11.05; 13.33; 14.25; 14.52; 15.80; 16.58;17.96; 18.18; 18.39; 19.25; 20.09; 20.48; 20.62; 21.01; 21.78; 22.00; 22.66; 22.86; 23.08;23.77; 24.27; 24.44; 25.16; 25.48; 25.75; 26.11; 26.53; 27.04; 27.72; 27.90; 28.23; 28.72;29.32; 29.71; 29.99; 30.17; 30.80; 31.05; 31.37; 31.59; 31.91; 32.17; 32.37; 33.11; 33.41;33.54; 34.17; 34.63.

14. Non-hygroscopic form of the crystalline troriluzole hydrochloride hydrate [(1 :1 : 1) salt] according to Claim 13, characterized in that non-hygroscopic form of the crystalline troriluzole hydrochloride hydrate [(1 : 1 : 1) salt] under DVS measurement conditions, absorbs less than 1% by weight of water at 25°C, in the 0-95% relative humidity range.

15. Non-hygroscopic form of the crystalline troriluzole hydrochloride hydrate [(1 :1 : 1) salt] according to Claims 13 or 14, characterized in that non-hygroscopic form of the crystalline troriluzole hydrochloride hydrate [(1 :1 : 1) salt] under DVS measurement conditions, absorbs less than 1% by weight of water at 25°C, in the 0-95% relative humidity range wherein the DSV test is carried out with the conditions as follows:Instrument: TA Q5000SA dynamic vapour sorption analyser (DVS)Atmosphere: NitrogenTotal gas flow: 200 mL / minSolvent: WaterBalance purge flow: 10 mL / minBalance temperature: 35 °CPan type: Platinum 100 pl, unsealedMethod: CustomDrying: NoConditioning: 30 minTemperature: 25 °C, isothermRelative humidity range: 0% to 95% RHInitial humidity: 20% RH or 40% RHHumidity step stages: Desorption - adsorption - desorptionHumidity step size: 5% RHStabilization criteria: < 0.01% for 10 minMaximum dwell time: 360 minData sampling interval: 5 sec / pointNumber of cycles:

216. Crystalline troriluzole hydrochloride hydrate [(1 :2: 1) salt] characterized the characteristic X-ray powder diffraction peaks are as follows:26 (±0.2 °26): 10.79; 14.15; 20.

78. preferably: 29 (±0.2 °29): 9.27; 10.79; 12.06; 14.15; 20.78; 22.80; 23.

26. more preferably: 29 (±0.2 °26): 3.08; 9.27; 10.79; 12.06; 14.15; 14.34; 14.64;15.18; 15.50; 15.73; 16.12; 16.57; 17.33; 18.37; 19.33; 20.51; 20.78; 20.88; 21.32; 21.58;22.02; 22.42; 22.80; 23.07; 23.26; 23.81; 24.62; 25.45; 25.80; 26.18; 27.85; 28.16; 28.57;28.89; 29.56; 29.91; 30.17; 30.36; 30.59; 31.04; 31.27; 31.55; 31.84; 32.31; 32.76; 32.96;33.50; 33.67; 33.88; 34.08; 34.49; 34.69.

17. Crystalline troriluzole hydrochloride [(1 : 1) salt / anhydrate / ] Form A polymorph form according to Claim 12 characterized the characteristic X-ray powder diffraction peaks are as follows: 26 (±0.2 °29): 9.57; 18.13; 20.

89. preferably: 29 (±0.2 °29): 9.57; 13.48; 18.13; 19.28; 20.00; 20.89; 30.

12. more preferably: 29 (±0.2 °29): 9.57; 12.79; 13.48; 14.04; 16.60; 17.59; 18.13; 19.28; 20.00; 20.89; 21.38; 21.98; 23.39; 24.12; 24.63; 25.14; 25.45; 26.22; 28.17; 29.11; 29.76; 30.12; 30.77; 31.58; 32.81; 33.13; 33.44; 34.12; 34.54.

18. Crystalline troriluzole hydrochloride [(1 :1) salt / anhydrate / ] Form B polymorph form according to Claim 12 characterized the characteristic X-ray powder diffraction peaks are asfollows: 26 (±0.2 °29): 3.53; 17.18; 19.

48. preferably: 29 (±0.2 °26): 3.53; 7.06; 14.27; 17.18;19.48; 20.38; 22.31; 25.

03. more preferably: 26 (±0.2 °29): 3.53; 7.06; 10.57; 14.27; 14.61;16.02; 17.18; 17.81; 18.51; 18.89; 19.48; 19.96; 20.38; 20.54; 21.24; 22.31; 22.76; 23.23;23.70; 23.84; 24.47; 25.03; 25.30; 26.20; 27.28; 28.26; 28.79; 29.63; 30.44; 30.54; 30.70;31.06; 31.56; 31.97; 32.39; 32.60; 32.94; 33.32; 33.81; 34.24; 34.61.

19. Crystalline troriluzole hydrochloride acetic acid solvate [(1: 1 : 1) / troriluzole:HCl:acetic acid] according to Claim 12 characterized the characteristic X-ray powder diffraction peaks are as follows: 29 (±0,2 °29): 11,47; 16,44; 27,34, preferably: 29 (±0,2 °29): 8,13; 11,47; 13,11; 16,44; 19,84; 21,93; 22,11; 27,34, more preferably: 29 (±0,2 °29): 8,13; 9,64; 11,47; 11,69;11,82; 13,12; 13,99; 15,97; 16,15; 16,44; 17,33; 18,06; 18,71; 19,84; 20,27; 20,73; 21,31;21,93; 22,11; 22,65; 22,92; 23,84; 24,23; 24,63; 24,86; 25,53; 25,74; 26,26; 26,44; 26,57;26,91; 27,34; 28,16; 28,39; 28,90; 29,17; 29,30; 29,68; 30,32; 30,63; 31,38; 31,58; 32,64;33,02; 33,23; 34,42; 34,93.

20. Troriluzole hydrochloride [(1 : 1) salt] amorphous form.

21. Non-hygroscopic form of the crystalline troriluzole hydrochloride hydrate [(1 :1 : 1) salt] obtainable by process in which crystalline troriluzole hydrochloride hydrate [(1 :2: 1) salt] is transformed into crystalline troriluzole hydrochloride hydrate [(1 : 1 : 1) salt],22. Non-hygroscopic form of the crystalline troriluzole hydrochloride hydrate [(1 :1 : 1) salt] according to Claim 21 obtainable by process in which crystalline troriluzole hydrochloride hydrate [(1 :2: 1) salt] is conditioned at room temperature alternately with high humidity air and dry air (in a drying oven).

23. Non-hygroscopic form of the crystalline troriluzole hydrochloride hydrate [(1 :1 : 1) salt] according to Claim 21 or 22 obtainable by process in which crystalline troriluzole hydrochloride hydrate [(1 :2: 1) salt] is conditioned alternately with high humidity air and dry air (in a drying oven), characterized by the fact that the non-hygroscopic form, during DVS testing at 25°C, does not absorb more than 1% by weight of water even at the stage of the test when the RH is 95%.

24. Non-hygroscopic form of the crystalline troriluzole hydrochloride hydrate [(1 :1 : 1) salt] according to any of Claims 21-23 or obtainable by process in which crystalline troriluzole hydrochloride hydrate [(1 :2:1) salt] is conditioned alternately with high humidity air and dry air (in a drying oven), characterized by the fact that the non-hygroscopic form, during DVS testing at 25°C, does not absorb more than 1% by weight of water even at the stage of the test when the RH is 95%, which crystalline product characterized the characteristic X-ray powder diffraction peaks are as follows: 29 (±0.2 °29): 5.63; 15.80; 25.48; preferably: 29 (±0.2 °29): 5.63; 13.33; 15.80; 16.58; 18.39; 25.48; 25.75; 27.04; more preferably: 29 (±0.2 °29): 5.63; 7.65; 11.05; 13.33; 14.25; 14.52; 15.80; 16.58; 17.96; 18.18; 18.39; 19.25; 20.09; 20.48; 20.62; 21.01; 21.78; 22.00; 22.66; 22.86; 23.08; 23.77; 24.27; 24.44; 25.16; 25.48; 25.75; 26.11; 26.53; 27.04; 27.72; 27.90; 28.23; 28.72; 29.32; 29.71; 29.99; 30.17; 30.80; 31.05; 31.37; 31.59; 31.91; 32.17; 32.37; 33.11; 33.41; 33.54; 34.17; 34.63.

25. Non-hygrscopic form of the crystalline troriluzole hydrochloride hydrate [(1 : 1 : 1) salt] according to any of Claims 21-24 obtainable by process in which crystalline troriluzole hydrochloride hydrate [(1 :2:1) salt] is conditioned alternately with high humidity air and dry air (in a drying oven), characterized by the fact that the non-hygroscopic form, during DVS testing at 25°C, does not absorb more than 1% by weight of water even at the stage of the test when the RH is 95% wherein the DVS test is carried out with parameters as follows:Instrument: TA Q5999SA dynamic vapour sorption analyser (DVS)Atmosphere: NitrogenTotal gas flow: 299 mL / minSolvent: WaterBalance purge flow: 19 mL / minBalance temperature: 35 °CPan type: Platinum 199 pl, unsealedMethod: CustomDrying: NoConditioning: 39 minTemperature: 25 °C, isothermRelative humidity range: 0% to 95% RHInitial humidity: 20% RH or 40% RHHumidity step stages: Desorption - adsorption - desorptionHumidity step size: 5% RHStabilization criteria: < 0.01% for 10 minMaximum dwell time: 360 minData sampling interval: 5 sec / pointNumber of cycles:

226. A troriluzole-containing pharmaceutical composition, which as an active ingredient comprises a therapeutically effective amount of the troriluzole base according to any of claims 10-12, or the crystalline salts, hydrates, and acetic acid solvates of troriluzole with hydrochloric acid according to claims 13-19 or 21-25, wherein the stochiometric ratio of troriluzole, HC1 and water is 1 :1 (monohydrochloride), 1 : 1 : 1 (monohydrochloride monohydrate), or 1 :2: 1 (dihydrochloride monohydrate) or acetic acid solvate [(l : l : l / troriluzole:HCl:acetic acid) salt], amorph troriluzole hydrochloride 1 : 1 salt according to Claim 20.

27. Use of troriluzole base, preferably crystalline base, crystalline base Form I, II, III, IV, V or polymorph form, or troriluzole salt composed with hydrochloric acid, and hydrates and acetic acid solvates thereof in which the stochiometric ratio of troriluzole, HC1 and water is 1 : 1 (monohydrochloride), 1 : 1 : 1 (monohydrochloride monohydrate), or 1 :2: 1 (dihydrochloride monohydrate) or acetic acid solvate [(l :l : l / troriluzole:HCl:acetic acid) salt], amorph troriluzole hydrochloride 1 : 1 salt as a glutamate modulator for the treatment of obsessive- compulsive or generalized anxiety disorder syndrome, atopic dermatitis, Takayasu's arteritis, psoriatic arthritis, temporal arteritis, alopecia areata, rheumatoid arthritis, spondylarthritis, juvenile rheumatoid arthritis, sleep disorders, systemic lupus erythematosus, ulcerative colitis, non-segmental vitiligo, vitiligo, hidradenitis suppurativa, ankylosing spondylitis, juvenile idiopathic arthritis, Crohn's disease, and immune system disorders.

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