Treatment methods for trigeminal neuralgia

Abstract

We offer treatment methods for trigeminal neuralgia. [Solution] A method for treating trigeminal neuralgia in a subject in need is provided herein by administering to the subject a composition comprising an mGlu5 negative allosteric modulator (NAM) having the structure of formula I. TIFF2026090636000021.tif19128

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims priority to U.S. Patent Application No. 63 / 058,630, filed on 30 July 2020, the contents of which are incorporated herein by reference in their entirety.

[0002] field This disclosure relates to the field of medicine and the treatment of trigeminal neuralgia. More specifically, this disclosure relates to the use of compositions comprising 2-chloro-4-[1-(4-fluorophenyl)-2,5-dimethyl-1H-imidazole-4-ylethinyl]pyridine or a pharmaceutically acceptable salt thereof in the treatment or remission of trigeminal neuralgia. [Background technology]

[0003] background Trigeminal neuralgia (TGN or TN) is a chronic pain condition affecting the trigeminal nerve, which transmits sensation from the face to the brain. TGN includes typical and atypical trigeminal neuralgia, as well as classical, secondary, and idiopathic TGN. Typical forms involve the onset of intense, sudden, and jarring pain on one side of the face, lasting from a few seconds to several minutes, while atypical forms involve less intense, constant burning pain. Pain caused by TGN significantly impacts daily living activities and can lead to severe depression and anxiety.

[0004] Medications such as anticonvulsants (e.g., carbamazepine) or antidepressants (e.g., amitriptyline) may help alleviate pain caused by TGN, but their medical use is limited due to the significant side effects of some of these drugs.

[0005] Therefore, there is an unmet medical need to develop novel methods for treating TGN without significant side effects. [Overview of the Initiative]

[0006] overview In one scenario, for the object that needs it, formula I: A step of administering a composition comprising a therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof, which is TIFF2026090636000001.tif28128. Methods for treating trigeminal neuralgia (TGN), including the above, are provided herein.

[0007] In some embodiments, the treatment uses a composition comprising a crystalline anhydrous form (Form A) of the monosulfate of the compound of Formula I, wherein Form A has an X-ray powder diffraction (XRPD) pattern substantially shown in Figure 1. Specifically, Form A has Cu at 2θ (2 theta). Kα The following X-ray powder diffraction peaks obtained by the line are characterized by: 9.8, 13.4, 14.2, 18.1, 18.9, 19.6, 22.6, 22.9, 25.7, 27.1, and 29.9 (±0.2°). Crystalline morphology A was determined by differential scanning calorimetry (DSC) analysis. m This is typically around 180-190°C.

[0008] In some embodiments, the treatment involves using a composition comprising a crystalline monohydrate form (form B) of the compound of formula I, wherein form B has an XRPD pattern substantially shown in Figure 2. Crystalline form B is determined by DSC analysis. m This is typically around 60-70°C.

[0009] In some embodiments, the treatment involves using a composition comprising a crystalline hemihydrate form (form C) of the hemisulfate of the compound of formula I, wherein form C has an XRPD pattern substantially shown in Figure 3. Crystalline form C is determined by DSC analysis. m This is typically around 90-100°C.

[0010] In some embodiments, the composition used is a tablet formulation, such as a controlled-release tablet formulation, or a matrix pellet formulation, such as a controlled-release matrix pellet formulation that can be encapsulated in a capsule, as specified herein.

[0011] In some embodiments, treating involves using a composition comprising a pharmaceutically acceptable salt of a compound of Formula I, wherein the salt is present in the composition at 90% by weight or more (e.g., 95% by weight or more, or 99% by weight or more) in crystalline Form A, based on the total weight of the salts present in the composition.

[0012] This disclosure provides a solid pharmaceutical composition comprising a solid form of a compound of Formula I: TIFF2026090636000002.tif34128, wherein the solid form is a crystalline anhydrous form (Form A) of a monosulfate of the compound of Formula I, characterized by at least three peaks selected from Kα the following XRPD peaks obtained with Cu at 2θ (2-theta): 9.8, 13.4, 14.2, 18.1, 18.9, 19.6, 22.6, 22.9, 25.7, 27.1, and 29.9 (±0.2°), and having a median particle size (Dv50) of about 100 μm or less, and the solid pharmaceutical composition is in the form of a matrix pellet. The solid pharmaceutical composition is also included. In some embodiments, the solid form has a particle size of 47 μm or less (e.g., about 25 μm or less, or about 10 μm or less).

[0013] In some embodiments, the pharmaceutical composition comprises a monosulfate of Form A characterized by the following XRPD peaks obtained with Cu Kα at 2θ (2-theta): 9.8, 13.4, 14.2, 18.1, 18.9, 19.6, 22.6, 22.9, 25.7, 27.1, and 29.9 (±0.2°).

[0014] In some embodiments, the pharmaceutical composition comprises a monosulfate of Form A characterized by the XRPD pattern substantially shown in FIG. 1.

[0015] This disclosure provides a method for preparing a matrix pellet comprising a crystalline anhydrous form (Form A) of a monosulfate of a compound of Formula I: TIFF2026090636000003.tif28128, To form the mixture, a step of granulating the monosulfate in Form A and one or more polymers together with purified water; To obtain a solid, a step of extruding, spheronizing, drying, and sieving the mixture; and To obtain matrix pellets, a step of mixing the solid with another pharmaceutical excipient is also included.

[0016] In some embodiments, the method of preparation further includes a step of filling the matrix pellets into capsules to form matrix pellet capsules. In some embodiments, the one or more polymers are selected from the group consisting of cellulose such as microcrystalline cellulose, methacrylic acid copolymers, and hypromellose. In some embodiments, the remaining pharmaceutical excipient is talc.

[0017] In another aspect, it includes a step of administering to a subject in need thereof a composition containing a therapeutically effective amount of an mGlu5 negative allosteric modulator (NAM) or a pharmaceutically acceptable salt thereof, wherein the mGlu5 NAM is a compound of Formula I: A method for treating TGN is provided herein, wherein the compound is of TIFF2026090636000004.tif34128.

[0018] Details of one or more embodiments of the disclosure are described in the following description. Other features, objects, and advantages of the disclosure will become apparent from the following drawings, description, and appended claims.

Brief Description of the Drawings

[0019] [Figure 1] FIG. 1 shows an exemplary XRPD pattern of the crystalline anhydrous form (Form A) of the monosulfate of the compound of Formula I. [Figure 2] FIG. 2 shows an exemplary XRPD pattern of the crystalline monohydrate form (Form B) of the monosulfate of the compound of Formula I. [Figure 3] FIG. 3 shows an exemplary XRPD pattern of the crystalline hemihydrate form (Form C) of the hemisulfate of the compound of Formula I. [Modes for carrying out the invention]

[0020] Detailed explanation As generally described herein, this disclosure provides a method for treating trigeminal neuralgia (TGN) in subjects where there is a need for such treatment. This disclosure also describes treating TGN by using specific crystalline forms of pharmaceutically acceptable salts of the compound of formula I. Furthermore, this disclosure provides a solid form of the crystalline anhydrous form (Form A) of the sulfate of the compound of formula I having a particle size (Dv50) of about 100 μm or less (e.g., less than 47 μm or less than 10 μm).

[0021] definition To facilitate understanding of the present invention, several terms and expressions are defined below.

[0022] Unless otherwise defined, all technical and scientific terms used herein have the same meanings as those commonly interpreted by those skilled in the art in which this invention pertains. Unless otherwise defined, all abbreviations used herein have their conventional meanings in the fields of chemistry and biology. The chemical structures and formulas described herein are constructed in accordance with the standard rules of chemical valence known in the field of chemistry.

[0023] Throughout this description, where a composition is described as having, including, or comprising a particular component, or where a process and method is described as having, including, or comprising a particular step, it is further intended that there exist compositions of the present invention that are essentially composed of or comprise the described component, and that there exist processes and methods of the present invention that are essentially composed of or comprise the described processing step.

[0024] In an application, when it is said that an element or component is included in and / or selected from the list of elements or components described, it should be understood that the element or component may be any one of the elements or components described, or that the element or component may be selected from a group consisting of two or more of the elements or components described.

[0025] Furthermore, the elements and / or features of the compositions or methods described herein, whether express or implied herein, should be understood to be able to be combined in various ways without departing from the spirit and scope of the invention. For example, where a particular compound is referred to, that compound may be used in various embodiments of the compositions of the invention and / or in the methods of the invention, unless interpreted differently in the context. In other words, while the embodiments are described and illustrated in this application in a manner that allows for the clear and concise description and depiction of the application, it is intended and will be perceived that the embodiments may be combined or separated in various ways without departing from the teachings and invention. For example, it will be perceived that all features described and illustrated herein may be applicable to all aspects of the invention described and illustrated herein.

[0026] As used in this disclosure, the articles "a" and "an" refer to one or more (i.e., at least one) grammatical objects of the article, unless otherwise inappropriate in context. For example, "an element" means one or more elements.

[0027] The term "and / or" is used in this disclosure to mean either "and" or "or" unless otherwise specified.

[0028] The expression "at least one of ~" should be understood to include each of the listed objects following it, and any various combinations of two or more of those listed objects, unless otherwise interpreted from context and usage. The expression "and / or" in relation to three or more listed objects should be understood to have the same meaning unless otherwise interpreted from context.

[0029] The use of the terms “comprise,” “comprises,” “comprising,” “include,” “includes,” “including,” “have,” “has,” “having,” “contain,” “contains,” or “containing,” including their grammatical equivalents, should generally be understood as open-ended and non-restrictive, not excluding, for example, further elements or processes not mentioned, unless specifically stated or interpreted from the context.

[0030] Where the term "approximately" precedes a quantitative value, the present invention also includes that specific quantitative value itself unless otherwise specifically stated. As used herein, the term "approximately" refers to a variation of ±10% from the nominal value unless otherwise specifically indicated or inferred from the context.

[0031] In various places in this specification, variables or parameters are disclosed in groups or ranges. The descriptions are particularly intended to include any individual subcombinations of members of such groups and ranges. For example, the integers in the range of 0 to 40 are 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, and 40, and the integers in the range of 1 to 20 are 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20, which are particularly intended to be disclosed individually.

[0032] Any use of examples or illustrative terms herein, such as “e.g., “e.g., “including” or “including,” is intended solely to better illustrate the invention and does not constitute a limitation of the scope of the invention unless otherwise stated in the appended claims. No language in the specification should be construed as indicating that any element not described in the appended claims is essential to the practice of the invention.

[0033] As a general rule, percentages for compositions are weight-based unless otherwise specified. Furthermore, if a variable is not defined, the previously established definition of the variable takes precedence.

[0034] As used herein, “composition,” “pharmaceutical composition,” or “pharmaceutical preparation” means a combination of an activator with an inert or active excipient or carrier that makes the composition particularly suitable for diagnostic or therapeutic use in vivo or ex vivo.

[0035] "Pharmacologically acceptable" means that, when administered to animals or humans as necessary, it does not produce adverse, allergic, or other unintended reactions, and / or is approved or appropriable by federal or state regulatory agencies or corresponding agencies in countries other than the United States, or is a compound, molecular entity, composition, material and / or dosage form listed for use in animals, more specifically in humans, in the United States Pharmacopeia or any other commonly recognized pharmacopoeia.

[0036] As used herein, “pharmaceutically acceptable salt” means any salt of an acidic or basic group that may be present in the compound of the present invention (e.g., the compound of formula I) that is suitable for pharmaceutically acceptable administration.

[0037] Examples of acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, perchloric acid, fumaric acid, maleic acid, phosphoric acid, glycolic acid, lactic acid, salicylic acid, succinic acid, toluene-p-sulfonic acid, tartaric acid, acetic acid, citric acid, methanesulfonic acid, ethanesulfonic acid, formic acid, benzoic acid, malonic acid, naphthalene-2-sulfonic acid, and benzenesulfonic acid. Other acids, such as oxalic acid, are not pharmaceutically acceptable on their own, but may be used in the preparation of salts that are useful as intermediates in obtaining the compounds described herein and their pharmaceutically acceptable acid addition salts.

[0038] Examples of bases include alkali metal hydroxides (e.g., sodium and potassium), alkaline earth metal hydroxides (e.g., magnesium and calcium), ammonia, and W is C. 1~4 Formula NW4 is an alkyl group. + It includes, in a non-limited manner, compounds such as the following.

[0039] Examples of salts include, without limitation, acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, flucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, monosulfate, 2-naphthalenesulfonate, nicotinate, oxalate, palmoate, pectinate, persulfate, phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate, undecanoate, and the like. Other examples of salts include anions of the compounds of the invention combined with suitable cations such as Na + 、K + 、Ca 2+ 、NH4 + 、and NW4 + (where W can be a C 1~4 alkyl group).

[0040] For therapeutic use, salts of the compounds of the invention are intended to be pharmaceutically acceptable. However, salts of acids and bases that are not pharmaceutically acceptable may also be used, for example, in the preparation or purification of pharmaceutically acceptable compounds.

[0041] As used herein, “pharmaceutically acceptable excipients” means substances that can be included in the compositions of the present invention without causing significant adverse toxic effects to the patient, and which assist in the administration and / or absorption of the activator to the subject. Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, ordinary salines such as phosphate-buffered saline, emulsions (e.g., oil / water or water / oil emulsions), lactoringer's solution, ordinary sucrose, ordinary glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavorings, salt solutions (such as Ringer's solution), alcohols, oils, gelatin, carbohydrates such as lactose, amylose or starch, fatty acid esters, hydroxymethylcellulose, polyvinylpyrrolidine, and dyes. Such preparations may be sterilized and, if desired, mixed with adjuvants such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts affecting osmotic pressure, buffers, colorants, and / or flavorings, which do not react adversely with the compounds of the invention. For examples of excipients, see Martin, Remington's Pharmaceutical Sciences, 15th Ed., Mack Publ. Co., Easton, PA (1975).

[0042] The “subjects” to which the drug is intended to be administered include, but are not limited to, humans (i.e., males or females of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or elderly)) and / or non-human animals, such as primates (e.g., cynomolgus macaques, rhesus macaques), cattle, pigs, horses, sheep, goats, rodents, cats, and / or dogs. In certain embodiments, the subject is human. In certain embodiments, the subject is a non-human animal.

[0043] As used herein, “solid dosage form” means a pharmaceutically acceptable dose in solid form, such as tablets, capsules, granules, powders, pouches, reconstituteable powders, dry powder inhalants, and chewables.

[0044] As used herein, “administering” means oral administration, suppository administration, topical contact, intravenous administration, parenteral administration, intraperitoneal administration, intramuscular administration, intrafocal administration, intrathecal administration, intracranial administration, intranasal administration, transmucosal administration (e.g., buccal, sublingual, nasal, or transdermal), or subcutaneous administration, or implantation of a sustained-release device, such as a mini osmotic pump. Parenteral administration includes, for example, intravenous, intramuscular, intra-arterial, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial. Other modes of delivery include, but are not limited to, the use of liposomal formulations, intravenous injection, transdermal patches, etc.

[0045] "Concurrent administration" means that the compositions described herein are administered concurrently with, immediately before, or immediately after the administration of one or more additional therapeutic agents (e.g., anticancer agents, chemotherapeutic agents, or treatments for neurodegenerative diseases). Compounds of Formula I or pharmaceutically acceptable salts thereof may be administered to a patient alone or concurrently. Concurrent administration means that the compounds may be administered simultaneously or sequentially individually or in combination (multiple compounds or drugs). Thus, if desired, the preparations may be combined with other active substances (e.g., to reduce metabolic degradation).

[0046] As used herein, unless otherwise specified, the terms “treat,” “treating,” and “treatment” include any action taken while a subject is suffering from a specified disease, disorder, or condition that reduces the severity of the disease, disorder, or condition or slows or delays its progression (e.g., “therapeutic action”). As used herein, “treat,” “treating,” and “treatment” may include any effect that results in improvement of a condition, disease, disorder, etc., or one or more of their symptoms, such as reducing, decreasing, regulating, relieving, or eliminating. Treating may mean curing, improving, or at least partially relieving a disorder.

[0047] As used herein, the term “therapeutic effective dose” refers to the amount of a compound (e.g., the compound of formula I) or a pharmaceutically acceptable salt thereof that produces a biological or medical response in a tissue, system, animal, or human, as determined by a researcher, veterinarian, physician, or other clinician. The compounds or pharmaceutically acceptable salts thereof described herein may be administered in therapeutic effective doses to treat a disease. The therapeutic effective dose of a compound or a pharmaceutically acceptable salt thereof may be the amount necessary to achieve a desired therapeutic and / or prophylactic effect, such as an amount that results in the relief of symptoms of a disease such as TGN.

[0048] Trigeminal neuralgia (TGN) is a long-term pain disorder affecting the trigeminal nerve. Typically caused by compression of the trigeminal nerve by a blood vessel, TGN is characterized by the onset of severe facial pain along the trigeminal nerve, a pair of cranial nerves with three main branches: the ophthalmic nerve (V1), the maxillary nerve (V2), and the mandibular nerve (V3). While all three branches of the nerve may be affected, TGN most commonly involves the middle branch (maxillary nerve or V2) and the lower branch (mandibular nerve or V3) of the trigeminal nerve.

[0049] Current treatments for TGN include microvascular decompression surgery in certain cases and the use of medications such as anticonvulsants (e.g., carbamazepine) or antidepressants (e.g., amitriptyline). Existing treatments may have limited benefits due to few observed favorable effects or significant side effects.

[0050] compound Equation I shown below: The compound TIFF2026090636000005.tif28128 is an mGlu5 negative allosteric modulator (NAM), also known as 2-chloro-4-[1-(4-fluorophenyl)-2,5-dimethyl-1H-imidazole-4-ylethynyl]pyridine.

[0051] A method for chemically synthesizing the compound of formula I (including Example 1 provided herein) is described in U.S. Patent No. 7,332,510, which is incorporated by reference in its entirety. In some embodiments, the compound of formula I is called a bathylindrant.

[0052] The compounds of formula I described herein should be understood to include either the free base or a pharmaceutically acceptable salt of the compound of formula I described herein in a crystalline solid form.

[0053] In certain embodiments, pharmaceutically acceptable salts of the compound of formula I may be salts of the compound of formula I with a physiologically compatible mineral acid such as hydrochloric acid, sulfuric acid, sulfite, or phosphoric acid, or with an organic acid such as methanesulfonic acid, p-toluenesulfonic acid, acetic acid, lactic acid, trifluoroacetic acid, citric acid, fumaric acid, maleic acid, tartaric acid, succinic acid, or salicylic acid. Exemplary pharmaceutically acceptable salts of the compound of formula I are monosulfate or hemisulfate.

[0054] In certain embodiments, pharmaceutically acceptable salts of the compound of formula I are monosulfates or hemisulfates, each in hydrate or anhydrous form (e.g., anhydrous, hemihydrate, or monohydrate).

[0055] In certain embodiments, the pharmaceutically acceptable salts of the compound of formula I are in crystalline or amorphous form.

[0056] In some embodiments, the compound is a crystalline anhydride form (Form A) of the sulfate of the compound of Formula I, having the X-ray powder diffraction (XRPD) pattern substantially shown in Figure 1. In some embodiments, Form A is Cu at 2θ (2 theta). Kα The following X-ray powder diffraction peaks obtained by the line are characterized by at least three peaks selected from 9.8, 13.4, 14.2, 18.1, 18.9, 19.6, 22.6, 22.9, 25.7, 27.1, and 29.9 (±0.2°). Crystalline morphology A is determined by DSC analysis. mThe temperature is typically around 180-190°C. In some embodiments, form A is 3068, 2730, 2618, 2236, 2213, 1628, 1587, 1569, 1518, 1384, 1374, 1295, 1236, 1168, 1157, 1116, 1064, 1019, 902, 855, 786, and 674 cm -1 (±3cm -1 It is characterized by an infrared spectrum with a sharp band in ).

[0057] In some embodiments, the compound is the crystalline monohydrate form (form B) of the sulfate of the compound of formula I, having substantially the XRPD pattern shown in Figure 2. Crystalline form B is determined by DSC analysis. m This is typically around 60-70°C.

[0058] In some embodiments, the compound is the crystalline hemihydrate form (form C) of the hemisulfate of the compound of formula I, having the XRPD pattern substantially shown in Figure 3. Crystalline form C is determined by DSC analysis. m This is typically around 90-100°C.

[0059] Pharmaceutical composition In one aspect, the present disclosure relates to compositions such as pharmaceutical compositions comprising a compound of formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient for the treatment of TGN in subjects where such treatment is needed. In various embodiments, the composition is a solid pharmaceutical composition.

[0060] In various embodiments, the amounts of the compound of formula I or its pharmaceutically acceptable salt in the pharmaceutical compositions described herein are approximately 0.01 mg to approximately 30 mg, approximately 0.05 mg to approximately 20 mg, approximately 0.1 mg to approximately 10 mg, approximately 0.5 mg to approximately 10 mg, approximately 1 mg to approximately 10 mg, approximately 2 mg to approximately 10 mg, approximately 3 mg to approximately 10 mg, approximately 4 mg to approximately 10 mg, approximately 5 mg to approximately 10 mg, approximately 6 mg to approximately 10 mg, approximately 7 mg to approximately 10 mg, approximately 8 mg to approximately 10 mg, approximately 9 mg to approximately 10 mg, approximately 1 mg to approximately 9 mg, approximately 1 mg to approximately 8 mg, approximately 1 mg to approximately 7 mg, and approximately 1 mg to approximately 6 mg mg, about 1 mg to about 5 mg, about 1 mg to about 4.5 mg, about 1 mg to about 4 mg, about 1 mg to about 3.5 mg, about 1 mg to about 3 mg, about 1 mg to about 2.5 mg, about 1 mg to about 2 mg, about 1 mg to about 1.5 mg, about 1.5 mg to about 9 mg, about 1.5 mg to about 8 mg, about 1.5 mg ~7mg, 1.5mg~6mg, 1.5mg~5mg, 1.5mg~4.5mg, 1.5mg~4mg, 1.5mg~3.5mg, 1.5mg~3mg, 1.5mg~2.5mg, 1.5mg~2mg, 2mg~9mg, 2mg ~Approx. 8mg, approx. 2mg ~ approx. 7mg, approx. 2mg ~ approx. 6mg, approx. 2mg ~ approx. 5mg, approx. 2mg ~ approx. 4.5mg, approx. 2mg ~ approx. 4mg, approx. 2mg ~ approx. 3.5mg, approx. g ~ about 7mg, about 2.5mg - about 6mg, about 2.5mg - about 5mg, about 2.5mg - about 4.5mg, about 2.5mg - about 4mg, about 2.5mg - about 3.5mg, about 2.5mg - about 3mg, about 3mg - about 9mg, about 3mg - about 8mg, about 3mg - about 7mg, about 3mg - about 6mg , about 3 mg to about 5 mg, about 3 mg to about 4.5 mg, about 3 mg to about 4 mg, about 3 mg to about 3.5 mg, about 3.5 mg to about 9 mg, about 3.5 mg to about 8 mg, about 3.5 mg to about 7 mg, about 3.5 mg to about 6 mg, about 3.5 mg to about 5 mg, about 3.5 mg to about 4.5 mg, about 3. 5mg to about 4mg, about 4mg to about 9mg, about 4mg to about 8mg, about 4mg to about 7mg, about 4mg to about 6mg, about 4mg to about 5mg, about 4mg to about 4.5mg, about 4.5mg to about 9mg, about 4.5mg to about 8mg, about 4.5mg to about 7mg, about 4.5mg to about 6mg, about 4.It could be approximately 5mg to 5mg, approximately 5mg to 9mg, approximately 5mg to 8mg, approximately 5mg to 7mg, approximately 5mg to 6mg, approximately 6mg to 9mg, approximately 6mg to 8mg, approximately 6mg to 7mg, approximately 7mg to 9mg, approximately 7mg to 8mg, or approximately 8mg to 9mg.

[0061] In certain embodiments, the amount of the compound of formula I or a pharmaceutically acceptable salt thereof in the pharmaceutical composition described herein may be about 0.1 mg to about 1.5 mg.

[0062] In certain embodiments, the amount of the compound of formula I or a pharmaceutically acceptable salt in the pharmaceutical composition described herein may be about 0.1 mg to about 4.0 mg, about 0.1 mg to about 3.5 mg, about 0.1 mg to about 3.0 mg, about 1.5 mg to about 3.5 mg, or about 1.0 mg to about 3.0 mg once daily. In certain embodiments, the amount of the compound of formula I or a pharmaceutically acceptable salt in the pharmaceutical composition described herein may be about 4.0 mg, about 3.5 mg, about 3.0 mg, about 2.5 mg, about 2.0 mg, about 1.5 mg, or about 1.0 mg once daily.

[0063] In certain embodiments, the amount of the compound of formula I or its pharmaceutically acceptable salt in the pharmaceutical composition described herein is approximately 4.0 mg. In certain embodiments, the amount of the compound of formula I or its pharmaceutically acceptable salt in the pharmaceutical composition described herein is approximately 3.5 mg. In certain embodiments, the amount of the compound of formula I or its pharmaceutically acceptable salt in the pharmaceutical composition described herein is approximately 3.0 mg. In certain embodiments, the amount of the compound of formula I or its pharmaceutically acceptable salt in the pharmaceutical composition described herein is approximately 2.5 mg. In certain embodiments, the amount of the compound of formula I or its pharmaceutically acceptable salt in the pharmaceutical composition described herein is approximately 2.0 mg. In certain embodiments, the amount of the compound of formula I or its pharmaceutically acceptable salt in the pharmaceutical composition described herein is approximately 1.5 mg. In certain embodiments, the amount of the compound of formula I or its pharmaceutically acceptable salt in the pharmaceutical composition described herein is approximately 1.0 mg.

[0064] In various embodiments, the amount of the compound of formula I or a pharmaceutically acceptable salt thereof in the pharmaceutical composition described herein may be about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 1.0 mg, about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg, about 3.5 mg, about 4 mg, about 4.5 mg, about 5 mg, about 5.5 mg, about 6 mg, about 6.5 mg, about 7 mg, about 7.5 mg, about 8 mg, about 8.5 mg, about 9 mg, about 9.5 mg, or about 10 mg.

[0065] In certain embodiments, the amount of the compound of formula I or a pharmaceutically acceptable salt in the pharmaceutical composition described herein may be about 0.1 mg to about 0.2 mg (e.g., about 0.13 mg).

[0066] In certain embodiments, the amount of compound of formula I or a pharmaceutically acceptable salt in the pharmaceutical composition described herein may be about 0.2 mg to about 0.3 mg (e.g., about 0.26 mg).

[0067] In certain embodiments, the amount of compound of formula I or a pharmaceutically acceptable salt in the pharmaceutical composition described herein may be about 0.6 mg to about 0.7 mg (e.g., about 0.65 mg).

[0068] In certain embodiments, the amount of the compound of formula I or a pharmaceutically acceptable salt in the pharmaceutical composition described herein may be about 1.2 mg to about 1.4 mg (e.g., about 1.3 mg).

[0069] In some embodiments, the compound of formula I or a pharmaceutically acceptable salt thereof is present in the composition in amounts of about 0.01% to about 20% by weight, about 0.05% to about 15% by weight, about 0.1% to about 10% by weight, about 0.1% to about 5% by weight, about 0.1% to about 1% by weight, or about 0.1% to about 0.5% by weight, based on the total weight of the composition.

[0070] In some embodiments, the compound of formula I or a pharmaceutically acceptable salt thereof is present in the composition in an amount of about 0.05% to about 15% by weight.

[0071] In some embodiments, the compound of formula I or a pharmaceutically acceptable salt thereof is present in the composition in an amount of about 0.1% to about 0.5% by weight.

[0072] In various embodiments, the pharmaceutical compositions described herein contain a therapeutically effective amount of a pharmaceutically acceptable salt of the compound of formula I. In some embodiments, the pharmaceutically acceptable salt of the compound of formula I may be a salt of the compound of formula I with a physiologically compatible mineral acid such as hydrochloric acid, sulfuric acid, sulfite, or phosphoric acid, or with an organic acid such as methanesulfonic acid, p-toluenesulfonic acid, acetic acid, lactic acid, trifluoroacetic acid, citric acid, fumaric acid, maleic acid, tartaric acid, succinic acid, or salicylic acid.

[0073] In certain embodiments, pharmaceutically acceptable salts of the compound of formula I are monosulfates or hemisulfates, each in hydrate or anhydrous form (e.g., anhydrous, hemihydrate, or monohydrate).

[0074] In certain embodiments, the pharmaceutically acceptable salts of the compound of formula I are in crystalline or amorphous form.

[0075] In certain embodiments, the pharmaceutical compositions described herein include a crystalline anhydrous form (Form A) of the sulfate of the compound of Formula I having an X-ray powder diffraction (XRPD) pattern substantially shown in Figure 1. Crystalline Form A is determined by DSC analysis. m This is typically around 180-190°C (e.g., 180±1°C, 182±1°C, 184±1°C, 186±1°C, 188±1°C, or 190±1°C).

[0076] In some embodiments, the pharmaceutical compositions described herein include a crystalline monohydrate form (form B) of the compound of formula I having an XRPD pattern substantially shown in Figure 2. Crystalline form B is determined by DSC analysis.m This is typically around 60-70°C (e.g., 60±1°C, 62±1°C, 64±1°C, 66±1°C, 68±1°C, or 70±1°C).

[0077] In some embodiments, the pharmaceutical compositions described herein include a crystalline hemihydrate form (form C) of the hemisulfate of the compound of formula I having the XRPD pattern substantially shown in Figure 3. Crystalline form C is determined by DSC analysis. m This is typically around 90-100°C (e.g., 90±1°C, 92±1°C, 94±1°C, 96±1°C, 98±1°C, or 100±1°C).

[0078] In certain embodiments, the pharmaceutical compositions described herein include 2730, 2592, 2219, 1633, 1586, 1570, 1513, 1375, 1343, 1293, 1226, 1157, 1130, 1084, 1040, 986, 903, 848, 788, 712, and 670 cm. -1 (±3cm -1 This includes an amorphous form of the sulfate of the compound of formula I, characterized by an infrared spectrum having a band in the ) range.

[0079] In some embodiments, the pharmaceutical composition is a tablet formulation, such as a controlled-release tablet formulation, or a matrix pellet formulation, such as a controlled-release matrix pellet formulation that can be encapsulated in a capsule. As used herein, “controlled-release formulation” or “controlled-release administration method” refers to a mechanism that delivers the drug after administration, either delayed (delayed-release administration) or over a long period (long-release administration) (as opposed to immediate-release administration). See Perrie et al., Pharmaceutics: Drug Delivery and Targeting (2nd), 2012, 7-13.

[0080] In certain embodiments, the pharmaceutical composition is a controlled-release matrix pellet formulation encapsulated in a capsule, containing an amount of about 0.05 mg to about 20 mg (e.g., about 0.1 mg to about 0.2 mg, about 0.2 mg to about 0.3 mg, about 0.6 mg to about 0.7 mg, or about 1.2 mg to about 1.4 mg) of the compound of formula I or a pharmaceutically acceptable salt thereof.

[0081] In certain embodiments, the pharmaceutical composition is a controlled-release pellet formulation encapsulated in a capsule, wherein the compound of formula I or a pharmaceutically acceptable salt thereof is present in the composition in an amount of about 0.01% to about 20% by weight (e.g., about 0.05% to about 15% by weight, about 0.1% to about 1% by weight, or about 0.1% to about 0.5% by weight) based on the total weight of the composition.

[0082] In certain embodiments, the pharmaceutical compositions described herein comprise a crystalline anhydrous form (Form A) of a sulfate monosulfate of a compound of Formula I having the XRPD pattern substantially shown in Figure 1; the sulfate monosulfate of Form A is present in the composition in an amount of about 0.05 mg to about 20 mg (e.g., about 0.1 mg to about 0.2 mg, about 0.2 mg to about 0.3 mg, about 0.6 mg to about 0.7 mg, or about 1.2 mg to about 1.4 mg).

[0083] In certain embodiments, the pharmaceutical compositions described herein comprise a crystalline anhydrous form (Form A) of a sulfate monosulfate of a compound of Formula I having the XRPD pattern substantially shown in Figure 1; the sulfate monosulfate of Form A is present in the composition in an amount of about 0.01% to about 20% by weight (e.g., about 0.05% to about 15% by weight, about 0.1% to about 1% by weight, or about 0.1% to about 0.5% by weight) based on the total weight of the composition.

[0084] As described herein, this disclosure includes a solid pharmaceutical composition comprising a solid form of the compound of formula I, i.e., a crystalline anhydride form (form A) of the sulfate of the compound of formula I; the composition is in the form of a matrix pellet, and the solid form has an average particle size (Dv50) of approximately 100 μm or less. Dv50 can be determined by LA-950 laser diffraction. See https: / / static.horiba.com / fileadmin / Horiba / Products / Scientific / Particle_Characterization / Downloads / Technical_Notes / TN159_LA-950_Laser_Diffraction_Technique.pdf.

[0085] In various embodiments, the pharmaceutical composition includes matrix pellets in solid form having particle sizes of less than 47 μm, less than 45 μm, less than 40 μm, less than 35 μm, less than 30 μm, less than 25 μm, less than 20 μm, less than 15 μm, less than 10 μm, or less than 5 μm. In certain embodiments, the solid form has a particle size of about 10 μm or less (e.g., about 10 μm, about 9 μm, about 8 μm, about 7 μm, about 6 μm, about 5 μm, about 4 μm, about 3 μm, about 2 μm, or about 1 μm).

[0086] In certain embodiments, the solid form has a particle size of less than 47 μm, and the sulfate of form A is present in the composition in an amount of 1% by weight or less based on the total weight of the composition.

[0087] In certain embodiments, the solid form has a particle size of about 10 μm or less (e.g., about 3.3 μm), and the sulfate of form A is present in the composition in an amount of 0.5% by weight or less (e.g., 0.1% by weight) based on the total weight of the composition.

[0088] In certain embodiments, the pharmaceutical composition includes a pharmaceutical excipient comprising a polymer, a binder, a disintegrant, a lubricant, or a lubricant.

[0089] In certain embodiments, the polymer is a matrix-forming polymer (e.g., microcrystalline cellulose), a pH-responsive polymer (e.g., methacrylic acid copolymer), or a binder (e.g., hypromellose). In certain embodiments, the polymer is one or more polymers selected from the group consisting of cellulose such as microcrystalline cellulose, methacrylic acid copolymer, and hypromellose. In certain embodiments, the lubricant is talc.

[0090] The pharmaceutical compositions provided herein may be administered by a variety of routes, including, but not limited to, oral administration, suppository administration, topical contact, parenteral administration (e.g., intravenous, intramuscular, intra-arterial, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial), intrafocal administration, intrathecal administration, intranasal administration, transmucosal administration (e.g., buccal, sublingual, nasal, or transdermal), or by implantation of sustained-release devices, such as mini-osmotic pumps. In certain embodiments, the pharmaceutical compositions disclosed herein are administered orally.

[0091] The pharmaceutical compositions provided herein may be administered over a long period of time ("long-term administration"). Long-term administration refers to the administration of the compound or its pharmaceutical composition over a long period, for example, 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc., or may continue indefinitely, for example, throughout the lifetime of the subject. In certain embodiments, long-term administration is intended to maintain a constant concentration of the compound in the blood, for example, within a therapeutic window over a long period of time.

[0092] The pharmaceutical compositions provided herein may be provided in unit dosage forms to facilitate accurate administration. The term “unit dosage form” refers to a physically distinct unit suitable as a single dose for human subjects and other mammals, each unit containing a predetermined amount of active substance calculated to produce a desired therapeutic effect in conjunction with a suitable pharmaceutical excipient. In various embodiments, the pharmaceutical dosage forms described herein may be administered as unit doses. Typical unit dosage forms include ampoules or syringes of liquid compositions that have been pre-measured and pre-filled, or, in the case of solid compositions, pills, tablets, capsules, etc.

[0093] In certain embodiments, the pharmaceutical compositions provided herein are administered to patients in solid dosage form. In certain embodiments, the solid dosage form is a capsule (e.g., a controlled-release pellet formulation enclosed in a capsule). In certain embodiments, the solid dosage form is a tablet (e.g., a controlled-release tablet formulation).

[0094] In certain embodiments, the pharmaceutical compositions provided herein may contain a compound of formula I as the sole activator or in combination with other activators.

[0095] The descriptions of pharmaceutical compositions provided herein are primarily directed toward pharmaceutical compositions suitable for administration to humans, but those skilled in the art will understand that such compositions are generally suitable for administration to all types of animals. Modifications of pharmaceutical compositions suitable for administration to humans to make them suitable for administration to various animals are well understood, and a veterinary pharmacologist with ordinary skill can design and / or carry out such modifications by ordinary experiments alone. General considerations in the formulation and / or manufacture of pharmaceutical compositions can be found, for example, in Remington: The Science and Practice of Pharmacy 21st ed., Lippincott Williams & Wilkins, 2005.

[0096] Methods of use and treatment In one aspect, a method for treating trigeminal neuralgia (TGN) in subjects (e.g., humans) who need it is provided herein.

[0097] In various forms, the necessary formula I applies to the target: A method for treating TGN in a subject in need is provided herein, comprising the step of administering a composition comprising a therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof, which is TIFF2026090636000006.tif28128.

[0098] In certain embodiments, the necessary formula I applies to the target: A method for treating TGN in a subject in need is provided herein, comprising the step of administering a composition comprising a therapeutically effective amount of the compound of formula I or a pharmaceutically acceptable salt thereof, wherein the administering step comprises administering the compound of formula I or a pharmaceutically acceptable salt thereof in an amount of about 1.5 mg to about 3.5 mg once daily. In some embodiments, the subject has a body weight of at least about 71 kg. In some embodiments, the subject has a body weight of less than about 71 kg (e.g., 30, 35, 40, 45, 50, 55, 60, 65, or 70 kg). In some embodiments, the subject has a body weight of at least about 71 kg. In some embodiments, the subject has a body weight of less than about 71 kg (e.g., 30, 35, 40, 45, 50, 55, 60, 65, or 70 kg). In some embodiments, the subject has a body weight of approximately 71 kg to approximately 150 kg (for example, 70, 71, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, or 150 kg).

[0099] In various embodiments, the step of administering a therapeutically effective amount of the compound of formula I or a pharmaceutically acceptable salt thereof includes administering to a subject about 0.05 mg to about 20 mg (for example, about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg, about 3.5 mg, about 4 mg, about 4.5 mg, about 5 mg, about 5.5 mg, about 6 mg, about 6.5 mg, about 7 mg, about 7.5 mg, about 8 mg, about 8.5 mg, about 9 mg, about 9.5 mg, or about 10 mg) of the compound of formula I or a pharmaceutically acceptable salt thereof.

[0100] In various embodiments, the step of administering a therapeutically effective amount of the compound of formula I or a pharmaceutically acceptable salt thereof includes administering to a subject about 0.1 mg to about 4.0 mg, about 0.1 mg to about 3.5 mg, about 0.1 mg to about 3.0 mg, about 1.5 mg to about 3.5 mg, or about 1.0 mg to about 4.0 mg. In specific embodiments, the step of administering a therapeutically effective amount of the compound of formula I or a pharmaceutically acceptable salt thereof includes administering to a subject about 1.5 mg to about 3.5 mg.

[0101] In certain embodiments, the step of administering a therapeutically effective dose of the compound of formula I or a pharmaceutically acceptable salt thereof includes administering approximately 1.0 mg to the subject once daily. In certain embodiments, the step of administering a therapeutically effective dose of the compound of formula I or a pharmaceutically acceptable salt thereof includes administering approximately 1.5 mg to the subject once daily. In certain embodiments, the step of administering a therapeutically effective dose of the compound of formula I or a pharmaceutically acceptable salt thereof includes administering approximately 2.0 mg to the subject once daily. In certain embodiments, the step of administering a therapeutically effective dose of the compound of formula I or a pharmaceutically acceptable salt thereof includes administering approximately 2.5 mg to the subject once daily. In certain embodiments, the step of administering a therapeutically effective dose of the compound of formula I or a pharmaceutically acceptable salt thereof includes administering approximately 3.0 mg to the subject once daily. In certain embodiments, the step of administering a therapeutically effective dose of the compound of formula I or a pharmaceutically acceptable salt thereof includes administering approximately 3.5 mg to the subject once daily. In certain embodiments, the step of administering a therapeutically effective dose of the compound of formula I or a pharmaceutically acceptable salt thereof includes administering approximately 4.0 mg to the subject once daily. In certain embodiments, the step of administering a therapeutically effective dose of the compound of formula I or a pharmaceutically acceptable salt thereof includes administering approximately 0.1 mg to approximately 1.5 mg of the compound of formula I or a pharmaceutically acceptable salt thereof to the subject in need.

[0102] In certain embodiments, a method for administering the free base form of a compound of formula I for the treatment of TGN in subjects requiring such treatment is provided herein.

[0103] In certain embodiments, a method is provided herein for administering a pharmaceutically acceptable salt of a compound of formula I for the treatment of TGN in subjects where such treatment is necessary.

[0104] In certain embodiments, treatment involves administering a compound of formula I or a pharmaceutically acceptable salt thereof once, twice, three, four, or five times daily. In certain embodiments, treatment involves administering a compound of formula I or a pharmaceutically acceptable salt thereof once daily.

[0105] In certain embodiments, treatment involves administering a compound of formula I or a pharmaceutically acceptable salt thereof to a subject by various routes, including, but not limited to, oral administration, suppository administration, topical contact, parenteral administration (e.g., intravenous, intramuscular, intra-arterial, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial), intrafocal administration, intrathecal administration, intranasal administration, transmucosal administration (e.g., buccal, sublingual, nasal, or transdermal), or sustained-release devices, such as the implantation of a mini osmotic pump.

[0106] In certain embodiments, treatment involves administering a compound of formula I or a pharmaceutically acceptable salt thereof by oral administration.

[0107] In certain embodiments, treatment involves administering a compound of formula I or a pharmaceutically acceptable salt thereof as a unit dose.

[0108] In certain embodiments, treatment involves administering the compound of formula I in its free base form.

[0109] In certain embodiments, treatment involves administering a compound of formula I in the form of a pharmaceutically acceptable salt thereof. In some embodiments, a pharmaceutically acceptable salt of a compound of formula I may be a salt of the compound of formula I with a physiologically compatible mineral acid such as hydrochloric acid, sulfuric acid, sulfurous acid or phosphoric acid, or with an organic acid such as methanesulfonic acid, p-toluenesulfonic acid, acetic acid, lactic acid, trifluoroacetic acid, citric acid, fumaric acid, maleic acid, tartaric acid, succinic acid or salicylic acid.

[0110] In certain embodiments, as described above, the treatment involves administering a compound of formula I in sulfate form (e.g., monosulfate or hemisulfate) or in crystalline form (e.g., form A, form B, or form C).

[0111] In various embodiments, the process includes administering to a subject in need a composition comprising a therapeutically effective amount of mGlu5-negative allosteric modulator (NAM) or a pharmaceutically acceptable salt thereof, wherein the mGlu5 NAM is of formula I: A method for treating TGN, which is a compound of TIFF2026090636000008.tif28128, is provided herein.

[0112] In certain embodiments, treatment includes administering a compound of formula I as monotherapy.

[0113] In certain embodiments, the method provided herein further includes the step of administering a therapeutically effective amount of another therapeutic agent to a subject.

[0114] As described herein, the present invention relates to the use of compounds of formula I or pharmaceutically acceptable salts thereof for the treatment of trigeminal neuralgia (TGN). In some embodiments, TGN is typical TGN, which presents with a severe, sudden, shock-like pain on one side of the face lasting from a few seconds to several minutes. In some embodiments, TGN is atypical TGN, which presents with a less severe, steady burning pain. In certain embodiments, TGN is classified according to the International Classification of Headache Disorders (ICHD-3). In certain embodiments, TGN is classical TGN. In some embodiments, TGN is secondary TGN. In certain embodiments, TGN is idiopathic TGN.

[0115] In certain aspects, the therapeutic effect of the treatment is (a) Decreased activity of high-voltage activated calcium channels; (b) Decreased activity of voltage-gated sodium channels; (c) Suppression of ion channel action potential propagation; or (d) Suppression of rapid firing of neurons It is determined by [the following].

[0116] In some embodiments, the effectiveness of the compound is determined by the Brief Pain Inventory-Facial (BPI-F) scale. In some embodiments, the effectiveness of the compound is determined by the change in overall impression. In some embodiments, the effectiveness of the compound is determined by the Sheehan's Disorder Scale (SDS). In some embodiments, the effectiveness of the compound is determined by the patient diary. In some embodiments, the effectiveness of the compound is determined by the number and severity of attacks, or the number of pain-free days. In some embodiments, the effectiveness of the compound is determined by the rating on the Medication Satisfaction Questionnaire (MSQ). In some embodiments, the effectiveness of the compound is determined by the change in patient overall impression (PGI-C). In some embodiments, the effectiveness of the compound is determined by the patient-rated overall impression-severity.

[0117] It is expected that those skilled in the art can make the most of the present invention based on the above description, even without further detailed description. The following specific examples are therefore not intended to limit the remainder of the disclosure and should be construed as mere illustrations. All publications cited herein are incorporated by reference in their entirety. [Examples]

[0118] Examples are provided below to allow for a more detailed understanding of the disclosures described herein. The examples described herein are presented to illustrate the compounds, pharmaceutical compositions, and methods described herein and are not intended to limit their scope in any way.

[0119] Example 1: Synthesis of 2-chloro-4-[1-(4-fluorophenyl)-2,5-dimethyl-1H-imidazole-4-ylethynyl]pyridine (compound of formula I, as described above) [see U.S. Patent No. 7,332,510]. 200 mg, 0.6 mmol of 2-chloro-4-[1-(4-fluorophenyl)-2-methyl-1H-imidazole-4-ylethynyl]-pyridine was dissolved in 10 mL of tetrahydrofuran (THF) and cooled to -75°C. Lithium diisopropylamide (0.45 mL, 0.91 mmol) was added, and the mixture was stirred at -75°C for 15 minutes. Iodomethane (0.05 mL, 0.85 mmol) was added, and stirring was continued at -75°C for 2 hours. The reaction mixture was quenched with saturated NaHCO3 solution and extracted with water and ethyl acetate. The combined organic extract was dried over sodium sulfate, filtered, and evaporated. The crude product was purified by flash chromatography on silica gel (heptane / ethyl acetate 90:10-20:80 gradient) and by recrystallization from ethyl acetate. The title compound was obtained as a white solid. MS: m / z = 326.5 (M+H+).

[0120] Example 2: Preparation of polymorphs of salts of the compound of formula I [see U.S. Patent No. 8,063,076]. Sulfate monosulfate of Form A: 61.0 g of 2-chloro-4-[1-(4-fluorophenyl)-2,5-dimethyl-1H-imidazole-4-ylethynyl]pyridine was dissolved in 610 mL of 2-propanol. The solution was filtered, and the filter was rinsed with 31 mL of 2-propanol. A mixture of 30 mL of water and 18.91 g of sulfuric acid (97%) was added dropwise to the combined solution. The solution was cooled to 0-5°C. Seeding was performed at 58°C if necessary. The solid residue was filtered, washed with 2-propanol (0-5°C), and dried at 50°C and less than 1 mbar for 18 hours to obtain 69.1 g (87.1%) of the sulfate monosulfate of the compound of Formula I in yield. Seed crystals of Form A can be prepared by cooling and crystallizing a hot solution of 250 mg of the sulfate monosulfate in 10 mL of 2-propanol. After cooling to 0°C, the solid residue was filtered and dried under vacuum at 50°C to obtain the sulfate of morphology A, which was confirmed by the XRPD pattern substantially shown in Figure 1.

[0121] Form B sulfate: 300 mg of Form A sulfate of compound I was dissolved in 3 mL of 2-propanol and 1 mL of water at 60°C to produce a clear solution. Form B sulfate was seeded into the clear solution and sealed at room temperature (e.g., about 25°C). After 3 days, a single crystal had formed. Seed crystals can be prepared by forming a saturated slurry of Form A sulfate of compound I in 2-propanol and water (3:1 v / v) at room temperature. The slurry was stirred at room temperature for about 3 weeks. The solid was filtered through a glass 35 filter to obtain crystalline Form B sulfate, which was confirmed by the XRPD pattern substantially shown in Figure 2.

[0122] Hemisulfate of Form C: 128 g of water and 41 g of monosulfate of Form A of compound I were mixed. The slurry was stirred at room temperature for 2 to 16 hours. After all of the monosulfate of Form A had been converted to hemisulfate, the resulting crystals were filtered and rinsed with water. The resulting wet cake was dried in a vacuum oven at 40°C for 48 hours to obtain hemisulfate of Form C in 93% yield. Hemisulfate of Form C was confirmed by the XRPD pattern substantially shown in Figure 3.

[0123] Amorphous sulfate monosulfate: 0.53 g of the sulfate monosulfate of compound I was dissolved in 10 mL of methanol at approximately 65°C. After complete evaporation of the solvent under vacuum, the solid (foam) was further dried at approximately 50°C at 5–20 mbar for 18 hours. Analysis (XRPD and DSC) revealed that the amorphous form of compound I was obtained. The amorphous sulfate monosulfates were found at 2730, 2592, 2219, 1633, 1586, 1570, 1513, 1375, 1343, 1293, 1226, 1157, 1130, 1084, 1040, 986, 903, 848, 788, 712, and 670 cm⁻¹. -1 (±3cm -1 It is characterized by an infrared spectrum having a band in ). The glass transition temperature (T) of the amorphous form is determined by DSC. g The temperature varied significantly depending on the solvent content, being observed at approximately 42°C for wet samples (sealed pans) and approximately 77°C for in-situ dried samples (pans with perforated lids).

[0124] Example 3: Form A: Sulfate-controlled release matrix pellet capsules Two different matrix pellet compositions were prepared according to the formulations shown in Table 1 below. The matrix pellets thus obtained were filled into capsules to obtain matrix pellet capsules. The process involved granulating a mixture of sulfate of form A, microcrystalline cellulose, methacrylic acid copolymer, and hypromellose with purified water using a high-shear wet granulation method; then extruding the mixture, spheroidizing it, fluid-bed drying it, and sieving it to obtain a solid material; and subsequently mixing the solid material with talc, an external pharmaceutical excipient, to obtain matrix pellets; and then filling the matrix pellets into capsules to obtain matrix pellet capsules. More specifically, the granulation, extrusion, spheroidizing, drying, sieving, and mixing steps were carried out as follows. 1. Weigh the sulfate of form A and approximately 15% of the required amount of microcrystalline cellulose, and place them in a suitable container. Mix the contents at 40 ± 10 rpm for 30 minutes using a tubular mixer or equivalent blender. 2. All other excipients: methacrylate copolymer, hypromellose, and the remaining microcrystalline cellulose were weighed. 3. All materials from Step 2 were followed by the mixture from Step 1, which was then transferred to a high-shear granulator. All components were mixed for 2 minutes using the impeller and chopper at the following speeds: impeller: 300±100 rpm and chopper: 1500±500 rpm. 4. The powder mixture from step 3 was granulated by spraying purified water (approximately 83% of the batch size) onto the powder mixture in a high-shear granulator while continuously mixing the contents using an impeller at 300±100 rpm and a chopper at 1500±500 rpm for 20 minutes. Power consumption at the granulation endpoint was recorded. 5. The wet granules were fed at a uniform rate and extruded from the extruder using a screen #1.0 mm and a speed setting of approximately 40 ± 5 rpm. 6. Using a #1 graded plate, approximately 700g of the extruded material from step 5 was transferred to a spheroidizing and granulating machine. The contents were spheroidized for 5 ± 1 minutes at a speed of approximately 0.6 (approximately 1000 rpm). 7. The spheroidized material from step 6 was collected and dried in a fluidized bed dryer with an inlet temperature of 60±10°C until the moisture content of the pellets, as measured using a halogen moisture meter or equivalent instrument set to 90°C, was less than 0.8%. 8. The dried pellets from step 7 were sorted by passing them through size #10 and #40 screens, and the pellet fraction between the #10 and #40 screens was collected. 9. The amount of talc was adjusted and weighed using the weight of the pellets from step 8. 10. Place the pellets from step 9 into a bin blender or equivalent device, add talc, and mix at 20±5 rpm for 5 minutes. 11. The pellets from step 10 were filled into hard gelatin capsules. 12. The filled capsules from step 11 were stored in a sealed fiber drum in a double polyethylene-lined bag with two silica gel bags between polyethylene bags, at a temperature not exceeding 25°C.

[0125] (Table 1) Matrix pellet formulation TIFF2026090636000009.tif71161*In the paragraph below, * represents a dose of 0.5 mg, and # represents a dose of 1.0 mg.

[0126] The uniformity of content in the matrix pellets was found to vary depending on the median particle size (Dv50) and the amount of sulfate monosulfate ("API") of form A. Specifically, three API variants were prepared at two different dosages (API: 0.1 mg and 1.0 mg) by fine grinding with a jet mill and pin mill to median particle sizes (Dv50) of 3.3 μm (jet mill), 10 μm (pin mill), and 47 μm (pin mill), respectively. At a dosage of 1.0 mg API, matrix pellets prepared using APIs with Dv50s of 3.3 μm, 10 μm, and 47 μm showed USP dosage unit uniformity (UDU) tolerance values ​​(AV) of 2.2, 6.3, and 3.4, respectively, all of which met the UDU tolerance criterion (AV < 15). At a dosage of 0.1 mg of API, matrix pellets prepared using API with a Dv50 of 47 μm had an AV of 20.9, failing to meet the UDU acceptance criteria. Unexpectedly, however, matrix pellets prepared using API with Dv50s of 3.3 μm and 10 μm had AVs of 6.0 and 10.3, respectively, meeting the UDU acceptance criteria. This demonstrates that API particle sizes (Dv50) of 10 μm or less (e.g., 3.3 to 10 μm) result in acceptable manufacturing processes and formulation performance (e.g., content uniformity, pellet size distribution, and solubility) for matrix pellet formulations, making them more suitable for drug development.

[0127] Example 4: Study of the compound of formula I for the treatment of subjects with trigeminal neuralgia (TGN) As shown in Table 2 below, a Phase II / III, multicenter, prospective, parallel-group, double-blind, randomized treatment discontinuation, placebo-controlled trial of 12 weeks following an 8-week induction period was conducted in conjunction with a 52-week open-label long-term administration trial to evaluate the efficacy and safety of the compound of formula I (also referred to herein as "basinglant") at doses of 1.5–3.5 mg per day in patients with trigeminal neuralgia-related pain that was not adequately responding to current analgesic therapy. The trial duration was up to 24 weeks, consisting of three periods followed by a 52-week open-label long-term administration trial. 200 patients were enrolled in trial period 1, and 70 patients were randomly assigned to period 2.

[0128] (Table 2) Goals and endpoints TIFF2026090636000010.tif195165TIFF2026090636000011.tif237165

[0129] Other embodiments All features disclosed herein may be combined in any combination. Individual features disclosed herein may be replaced by alternative features that serve the same, equivalent, or similar purposes. Therefore, unless otherwise explicitly stated, individual features disclosed are merely examples of a set of equivalent or similar schematic functions.

[0130] Furthermore, from the above description, those skilled in the art can easily confirm the essential features of the present invention, and can adapt the invention to various uses and conditions by making various changes and modifications without departing from its spirit and scope. Therefore, other embodiments are also within the scope of the claims.

Claims

1. For those who require it, Formula I: A step of administering a composition comprising a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof. Methods for treating trigeminal neuralgia (TGN), including [mention specific treatments here].

2. The method according to claim 1, wherein the administration step includes administering the compound of formula I in its free base form.

3. The method according to claim 1, wherein the administration step includes administering the compound of formula I in the form of a pharmaceutically acceptable salt thereof.

4. The method according to claim 3, wherein the pharmaceutically acceptable salt is a monosulfate or a hemisulfate.

5. The method according to claim 4, wherein the pharmaceutically acceptable salt is in a crystalline or amorphous form.

6. The pharmaceutically acceptable salt includes the crystalline anhydrous form (form A) of the monosulfate of the compound of formula I, where form A is Cu at 2θ (2 theta). Kα The following X-ray powder diffraction peaks are obtained by the line: 9.8, 13.4, 14.2, 18.1, 18.9, 19.6, 22.6, 22.9, 25.7, 27.1, and 29.9 (±0.2°) The method according to claim 5, characterized by at least three more selected peaks.

7. Form A is Cu at 2θ (2 theta) Kα The following X-ray powder diffraction peaks are obtained by the line: 9.8, 13.4, 14.2, 18.1, 18.9, 19.6, 22.6, 22.9, 25.7, 27.1, and 29.9 (±0.2°) The method according to claim 6, characterized by the above.

8. The method according to claim 6 or 7, wherein form A has an X-ray powder diffraction (XRPD) pattern substantially shown in Figure 1.

9. The method according to claim 5, wherein the pharmaceutically acceptable salt comprises a crystalline monohydrate form (form B) of the monosulfate of the compound of formula I, and form B has an XRPD pattern substantially shown in Figure 2.

10. The pharmaceutically acceptable salts are 2730, 2592, 2219, 1633, 1586, 1570, 1513, 1375, 1343, 1293, 1226, 1157, 1130, 1084, 1040, 986, 903, 848, 788, 712, and 670 cm³. -1 (±3cm -1 The method according to claim 5, comprising an amorphous form of a sulfate of the compound of formula I, characterized by an infrared spectrum having a band in ).

11. The method according to claim 5, wherein the pharmaceutically acceptable salt comprises a crystalline hemihydrate form (form C) of the hemisulfate of the compound of formula I, and form C has an XRPD pattern substantially shown in Figure 3.

12. The method according to any one of claims 1 to 11, wherein the composition is an immediate-release formulation encapsulated in a capsule, a controlled-release tablet formulation, or a controlled-release pellet formulation encapsulated in a capsule.

13. The method according to claim 12, wherein the composition is a controlled-release pellet formulation enclosed in a capsule, and contains a compound of formula I or a pharmaceutically acceptable salt thereof in an amount of about 0.05 mg to about 20 mg.

14. The method according to any one of claims 1 to 13, wherein a compound of formula I or a pharmaceutically acceptable salt thereof is present in the composition in an amount of about 0.01% to about 20% by weight based on the total weight of the composition.

15. The method according to claim 14, wherein a compound of formula I or a pharmaceutically acceptable salt thereof is present in the composition in an amount of about 0.05% to about 15% by weight based on the total weight of the composition.

16. The method according to claim 6, wherein the composition is a controlled-release pellet formulation enclosed in a capsule, and the composition contains a sulfate of form A of the compound of formula I in an amount of about 0.05 mg to about 20 mg.

17. The method according to claim 16, wherein the sulfate of form A is present in the composition in an amount of about 0.01% to about 20% by weight based on the total weight of the composition.

18. The method according to claim 17, wherein the sulfate of form A is present in the composition in an amount of about 0.05% to about 15% by weight based on the total weight of the composition.

19. The composition is an immediate-release formulation encapsulated in a capsule, and contains the following: The method according to claim 6, including the method described in claim 6.

20. The composition is an immediate-release formulation encapsulated in a capsule, and contains the following: The method according to claim 6, including the method described in claim 6.

21. The composition is an immediate-release formulation encapsulated in a capsule, and contains the following: The method according to claim 6, including the method described in claim 6.

22. The composition is an immediate-release formulation encapsulated in a capsule, and contains the following: The method according to claim 6, including the method described in claim 6.

23. The composition is a controlled-release pellet formulation enclosed in a capsule, and the composition is as shown in the table below: The method of claim 6, comprising a formulation selected from the group consisting of formulation 1, formulation 2, formulation 3, and formulation 4 shown in [reference].

24. The method according to claim 6, wherein the pharmaceutically acceptable salt is 90% by weight or more of crystalline form A based on the total weight of salts present in the composition.

25. The method according to claim 24, wherein the pharmaceutically acceptable salt is 95% by weight or more of crystalline form A based on the total weight of salts present in the composition.

26. The method according to claim 25, wherein the pharmaceutically acceptable salt is 99% by weight or more of crystalline form A based on the total weight of salt present in the composition.

27. The method according to any one of claims 1 to 26, wherein the administration step comprises administering a compound of formula I or a pharmaceutically acceptable salt thereof once daily.

28. The method according to any one of claims 1 to 27, wherein the administration step comprises administering a compound of formula I or a pharmaceutically acceptable salt thereof in an amount of about 0.1 mg to about 4.0 mg once daily.

29. The method according to any one of claims 1 to 28, wherein the administration step comprises administering a compound of formula I or a pharmaceutically acceptable salt thereof in an amount of about 0.1 mg to about 3.5 mg once daily.

30. The method according to any one of claims 1 to 29, wherein the administration step comprises administering a compound of formula I or a pharmaceutically acceptable salt thereof in an amount of about 0.1 mg to about 3.0 mg once daily.

31. The method according to any one of claims 1 to 30, wherein the administration step comprises administering a compound of formula I or a pharmaceutically acceptable salt thereof in an amount of about 1.0 mg to about 4.0 mg once daily.

32. The method according to any one of claims 1 to 30, wherein the administration step comprises administering a compound of formula I or a pharmaceutically acceptable salt thereof in an amount of about 1.5 mg to about 3.5 mg once daily.

33. The method according to any one of claims 1 to 32, wherein the administration step comprises administering a compound of formula I or a pharmaceutically acceptable salt thereof once daily in an amount of about 4.0 mg, about 3.5 mg, about 3.0 mg, about 2.5 mg, about 2.0 mg, about 1.5 mg, or about 1.0 mg.

34. The method according to any one of claims 1 to 33, wherein the administration step comprises administering a compound of formula I or a pharmaceutically acceptable salt thereof in an amount of about 3.5 mg once daily.

35. The method according to any one of claims 1 to 33, wherein the administration step comprises administering a compound of formula I or a pharmaceutically acceptable salt thereof in an amount of about 1.5 mg once daily.

36. The method according to any one of claims 1 to 35, wherein the administration step comprises orally administering a compound of formula I or a pharmaceutically acceptable salt thereof.

37. The method according to any one of claims 1 to 36, wherein the administration step includes administering a compound of formula I or a pharmaceutically acceptable salt thereof as a unit dose.

38. The method according to any one of claims 1 to 37, wherein TGN is a classical TGN.

39. The method according to any one of claims 1 to 38, wherein TGN is an idiopathic TGN.

40. The therapeutic effect of the treatment, a. Decreased activity of high-voltage activated calcium channels; b. Decreased activity of voltage-gated sodium channels; c. Suppression of ion channel action potential propagation; or d. Suppression of rapid neuronal firing The method according to any one of claims 1 to 39, determined by...

41. The process includes administering a solid pharmaceutical composition to a target that requires it. The solid pharmaceutical composition contains a pharmaceutical excipient and formula I: The compound includes the solid form of the compound, The solid form is Cu at 2θ (2 theta). Kα The following XRPD peaks are obtained from the line: 9.8, 13.4, 14.2, 18.1, 18.9, 19.6, 22.6, 22.9, 25.7, 27.1, and 29.9 (±0.2°) A crystalline anhydrous form (form A) of the sulfate monosulfate of the compound of formula I, characterized by at least three more selected peaks, and having a particle size of about 100 μm or less (Dv50), The solid pharmaceutical composition is in the form of a matrix pellet. Methods for treating trigeminal neuralgia.

42. The method according to claim 41, wherein the solid form has a particle size of less than 47 μm.

43. The method according to claim 41, wherein the solid form has a particle size of approximately 25 μm or less.

44. The method according to claim 41, wherein the solid form has a particle size of approximately 10 μm or less.

45. The method according to any one of claims 41 to 44, wherein the monosulfate of form A is present in the composition in an amount of 1% by weight or less based on the total weight of the composition.

46. The method according to claim 45, wherein the sulfate of form A is present in the composition in an amount of 0.5% by weight or less based on the total weight of the composition.

47. The method according to any one of claims 41 to 46, wherein the pharmaceutical excipient comprises one or more of polymers, binders, disintegrants, lubricants, and lubricants.

48. The method according to claim 47, wherein the polymer is one or more polymers selected from the group consisting of cellulose, methacrylic acid copolymer, and hypromellose.

49. The sulfate of form A is Cu at 2θ (2 theta). Kα The following XRPD peaks are obtained from the line: 9.8, 13.4, 14.2, 18.1, 18.9, 19.6, 22.6, 22.9, 25.7, 27.1, and 29.9 (±0.2°) A method according to any one of claims 41 to 48, characterized by the above.

50. The method according to any one of claims 41 to 49, wherein the monosulfate of form A has an XRPD pattern substantially shown in Figure 1.

51. The procedure includes administering to a subject in need a composition comprising a therapeutically effective amount of mGlu5-negative allosteric modulator (NAM) or a pharmaceutically acceptable salt thereof, wherein the mGlu5 NAM is of formula I: A compound used to treat trigeminal neuralgia.

52. The procedure includes administering to a subject in need a composition comprising a therapeutically effective amount of mGlu5-negative allosteric modulator (NAM) or a pharmaceutically acceptable salt thereof, wherein the mGlu5 NAM is of formula I: A compound of formula I or a pharmaceutically acceptable salt thereof, comprising the step of administering the compound of formula I or a pharmaceutically acceptable salt thereof once daily in an amount of about 1.5 mg to about 3.5 mg.

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