OA21124A

OA21124A - Methods of treatment of trigeminal neuralgia.

Info

Publication number: OA21124A
Application number: OA1202300034
Authority: OA
Inventors: George GARIBALDI
Original assignee: Noema Pharma Ag
Priority date: 2020-07-30
Filing date: 2021-07-30
Publication date: 2023-11-13

Abstract

Provided herein are methods of treating trigeminal neuralgia in a subject in need thereof by administering to the subject compositions comprising an mGlu5 negative allosteric modulator (NAM), having the structure of Formula I :

Description

METHODS OF TREATMENT OF TRIGEMINAL NEURALGIA

CROSS-REFERENCE TO RELATED APPLICATION

This application claims priority to U.S.S.N. 63/058,630 filed on July 30, 2020, the contents of which is incorporated herein by reference in its entirety.

FIELD

The present disclosure relates to the field of medicine and the treatment of trigeminal neuralgia. More specifically, the present disclosure relates to use of compositions comprising 2chloro-4-[ 1 -(4-fl uoiOphenyl)-2,5-dimethyl- l//-imidazol-4-ylethynyl]pyridine, or a phannaceutically acceptable sait thereof, in the treatment or amelioration of trigeminal neuralgia.

BACKGROUND

Trigeminal neuralgia (TGN or TN) is a chronic pain condition that affects the trigeminal nerve, which cames sensation from the face to brain. TGN includes typical and atypical trigeminal neuralgia, as well as classical, secondary and idiopathic TGN. The typical fonn results in épisodes of severe, sudden, shock-like pain in one side of the face that lasts for seconds to a few minutes, while the atypical form results in a constant buming pain that is less severe. The pain resulted from TGN has a significant impact on activities of daily living, which can lead to severe dépréssion and anxiety.

While médications such as anticonvuîsants (e.g., carbamazepine) or antidepressants (e.g., amitriptyline) can help alleviate the pain caused by TGN, some of these médications hâve significant side effects, thereby limiting their medical use.

Therefore, there is an unmet medical need to develop new methods for treating TGN without significant side effects.

SUMMARY

In one aspect, provided herein are methods of treating trigeminal neuralgia (TGN), comprising administering to a subject in need thereof a composition comprising a therapeutically effective amount of a compound or a pharmaceutically acceptable sait thereof, wherein the compound is of Formula I:

Cl

In some embodiments, treating uses a composition comprising a crystalline anhydrate form (Fonn A) of a monosulfate sait of the compound of Fonnula I, wherein Fonn A has an X-ray powder diffraction (XRPD) pattern as substantially shown in FIG. I. Specifically, Form A is characterized by the following X-ray powder diffraction peaks obtained with a Cux« radiation at 2Θ (2 Thêta): 9.8, 13.4, 14.2, I8.l, 18.9, 19.6, 22.6, 22.9, 25.7, 27.1, and 29.9 (±0.2°). The crystalline Fonn A typically has a T_m of about 180-190 °C by differential scanning calorimetry (DSC) analysis.

In some embodiments, treating uses a composition comprising a crystalline monohydrate fonn (Fonn B) of a monosulfate sait of the compound of Fonnula I, wherein Fonn B has an XRPD pattern as substantially shown in FIG. 2. The crystalline Fonn B typically has a T,_n of about 60-70 °C by DSC analysis.

In some embodiments, treating uses a composition comprising a crystalline hemihydrate form (Fonn C) of a hemisulfate sait of the compound of Fonnula I, wherein Fonn C has an XRPD pattern as substantially shown in FIG. 3. The crystalline Form C typically has a T_m ot about 90-100 °C by DSC analysis.

In some embodiments, the composition used is a tabiet formulation such as a modified release tabiet formulation, or a matrix pellet formulation such as a modified release matrix pellet formulation, which can be encapsulated in a capsule, as defined herein.

In some embodiments, treating uses a composition comprising a pharmaceutically acceptable sait of the compound of Formula I, wherein said sait is 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 sait present in the composition.

The present disclosure also includes a solîd pharmaceutical composition comprising a solid form of a compound of Formula I:

Cl

(I), wherein the solid fonn is a crystalline anhydrate form (Form A) of a monosulfate sait ofthe compound of Formula l, characterized by at least three peaks selected from the following XRPD peaks obtained with a Cuxa radiation at 20 (2 Thêta): 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 has a médian particle size (Dv50) of less than or equal to about 100 pm, wherein the solid phannaceutical composition is the fonn of a matrix pellet. In some embodiments, the solid fonn has a particle size of less than 47 pm (e.g,, about 25 pm or less, or about 10 pm or less).

In some embodiments, the phannaceutical composition comprises the Fonn A monosulfate sait characterized by the following XRPD peaks obtained with a Cux« radiation at 20 (2 Thêta): 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°).

In some embodiments, the phannaceutical composition comprises the Fonn A monosulfate sait characterized by an XRPD pattern as substantially shown in FIG. 1.

The present disclosure also includes a method of preparing a matrix pellet comprising a crystalline anhydrate form (Form A) of a monosulfate sait of a compound of Formula I:

F (1), wherein the method comprises: granulating the Form A monosulfate sait and one or more polymers with purified water to form a mixture; extruding, spheronizing, drying, and sieving the mixture to afford a solid material; and blending the solid material with another pharmaceutical excipient to afford a matrix pellet.

In some embodiments, the method of préparation further comprises filling the matrix pellet into a capsule to form a matrix pellet capsule. In some embodiments, the one or more polymers are selected from the group consisting of a cellulose such as microcrystalline cellulose, methacrylic acid copolymer, and hypromellose. In some embodiments, the other pharmaceutical excipient is talc.

In another aspect, provided herein are methods of treating TGN, comprising administering to a subject in need thereof a composition containing a therapeutically efiective amount of an mGlu5 négative allosteric modulator (NAM) or a pharmaceutically acceptable sait thereof, wherein the mGlu5 NAM is a compound of Formula I:

The details of one or more embodiments of the disclosure are set forth in the description below. Other features, objects, and advantages of the disclosure will be apparent from the below drawings, description and from the ciaims.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. I depicts an exemplary XRPD pattern of a crystalline anhydrate form (Form A) of a monosulfate ofthe compound of Formula L

FIG. 2 depicts an exemplary XRPD pattern of a crystalline monohydrate fonn (Form B) of a monosulfate of the compound of Formula l.

FIG. 3 depicts an exemplary XRPD pattern of a crystalline hemihydrate fonn (Fonn C) of a hemisulfate of the compound of Formula I.

DETAILED DESCRIPTION

As generally described herein, the present disclosure provides methods of treating trigeminal neuralgia (TGN) in a subject in need thereof. The present disclosure also describes treating TGN by using certain crystalline forms of pharmaceutically acceptable salts of the compound of Formula I.

In addition, the présent disclosure provides a solid form of a crystalline anhydrate form (Form A) of a monosulfate sait of the compound of Formula I, wherein the solid form has a particle size (Dv50) of less than or equal to about 100 pm (e.g., less than 47 pm, or 10 pm or less).

Définitions

To facilitate an understanding of the présent invention, a number of terms and phrases are defined below.

Unless defined otherwise, ail technical and scient ific terms used herein hâve the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Unless defined otherwise, ail abbreviations used herein bave their conventional meaning w ithin the Chemical and biological arts. The Chemical structures and fonnulae set forth herein are constructed according to the standard rules of Chemical valency known in the Chemical arts.

Throughout the description, where compositions are described as having, includîng, or comprising spécifie components, or where processes and methods are described as having, includîng, or comprising spécifie steps, it is contemplated that, additionally, there are compositions ofthe présent invention that consist essentially of, or consist of, the recited components, and that there are processes and methods according to the présent invention that consist essentially of, or consist of, the recited processing steps.

In the application, where an element or component is said to be included in and/or selected from a list of recited éléments or components, it should be understood that the element or component can be any one of the recited éléments or components, or the element or component can be selected from the group consisting of two or more of the recited éléments or components.

Further, it should be understood that éléments and/or features of a composition or a method described herein can be combined in a variety of ways without departing from the spirit and scope of the présent invention, whether explicit or implicit herein. For example, where reference is made to a particular compound, that compound can be used in various embodiments of compositions ofthe présent invention and/or in methods of the présent invention, unless otherwise understood from the context. In other words, within this application, embodiments hâve been described and depicted in a way that enables a clear and concise application to be written and drawn, but it is intended and will be appreciated that embodiments may be variously combined or separated without parting from the present teachings and invention(s). For example, it will be appreciated that ail features described and depicted herein can be applicable to ali aspects of the iuvention(s) described and depicted herein.

The articles “a” and “an” are used in this disclosure to refer to one or more than one (i.e., at least one) of the grammatical object of the article, unless the context is inappropriate. B y way of example, “an element” means one element or more than one element.

The tenn “and/or” is used in this disclosure to mean either “and” or “or” unless indicated otherwise.

It should be understood that the expression “al least one of ’ includes individually eaeh of the recited objects after the expression and the various combinations of two or more ofthe recited objects unless otherwise understood from the context and use. The expression “and/or” in connection with ihree or more recited objects should be understood to hâve the same meaning unless otherwise understood from the context.

The use of the term “comprise,” “comprises,” “comprising,” “include,” “includes,” “including,” “hâve,” “has,” “having,” “contain,” “contains,” or “containing,” including grammatical équivalents thereof, should be understood generally as open-ended and non-limiling, for example, not excluding additional unrecited éléments or steps, unless otherwise specifically stated or understood from the context.

Where the use ofthe term “about” is before a quantitative value, the present invention also includes the spécifie quantitative value itself, unless specifically stated otherwise. As used herein, the term “about” refers to a ±10% variation from the nominal value unless otherwise indicated or inferred from the context.

At various places in the present spécification, variable or parameters are disclosed in groups or în ranges. It is specifically intended that the description include each and every individual subcombînation of the members of such groups and ranges. For example, an integer in the range of 0 to 40 is specifically intended to individually disclose 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 an integer in the range of 1 to 20 is specifically intended to individually disclose 1, 2, 3, 4, 5,

6, 7,8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20.

The use of any and ail examples, or exemplary language herein, for example, “such as” or “including,” is intended merely to illustrate better the present invention and does not pose a limitation on the scope of the invention unless claimed. No language in the spécification should be construed as indicating any non-claimed element as essentia) to the practice ot the present invention.

As a general matter, compositions specifying a percentage are by weight unless otherwise speciiied. Further, if a variable is not accompanied by a définition, then the previous définition of the variable Controls.

As used herein, “composition” or “pharmaceutical composition” or “pharmaceutical formulation” refers to the combination of an active agent with an excipient or a carrier, inert or active, making the composition especially suitable for diagnostic or therapeutic use in vivo or ex vivo.

“Pharmaceutically acceptable” refers to compounds, molecular entities, compositions, materials and/or dosage forms that do not produce an adverse, allergie or other untoward reaction when adminîstered to an animal, or a human, as appropriate, and/or that are approved or approvable by a regulatory agency of the fédéral or a State government or the corresponding agency in countrîes other than the United States, or that is listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animais, and more particularly, in humans.

As used herein, “pharmaceutically acceptable sait” refers to any sait of an acidic or a basic group that may be present in a compound of the present invention (e.g., the compound of Formula I), which sait is compatible with pharmaceutical administration.

Examples of acids include, but are not limited to, hydrochloric, hydrobromic, sulfuric, nitric, perchloric, fumaric, maleic, phosphoric, glycolic, lactic, salicylic, succinic, toluene-p-sulfonic, tartarîc, acetic, citric, methanesulfouie, ethanesulfonic, formic, benzoic, malonic, naphthalene-2sulfonic and benzenesulfonic acid. Other acids, such as oxalic, while not in themselves phannaceutically acceptable, may be employed in the préparation of salts useful as intermedîates in obtaining the compounds described herein and their phannaceutically acceptable acid addition salts.

Examples of bases include, but are not limited to, alkali métal (e.g., sodium and potassium) hydroxides, alkaline earth métal (e.g., magnésium and calcium) hydroxides, ammonia, and compounds of formula NWV, wherein W is Cm alkyl, and the like.

Examples of salts include, but are not limited, to acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, flucoheptanoate, glycérophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, monosulfate, 2-naphthalenesuIfonate, 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 present invention compounded with a suitable cation such as Na , K’, Ca²⁺, NHL, and NW/ (where W can be a Cm alkyl group), and the like.

For therapeutic use, salts of the compounds of the présent invention are contemplated as being pharmaceutically acceptable, However, salts of acids and bases that are non-pharmaceutically acceptable may also fmd use, for example, in the préparation or purification of a pharmaceutically acceptable compound.

As used herein, “pharmaceutically acceptable excipient” refers to a substance that aids the administration of an active agent to and/or absorption by a subject and can be included in the compositions of the present invention without causing a significant adverse toxicological effect on the patient. Non-limiting examples of pharmaceutically acceptable excipients include water, NaCi, normal saline solutions, such as a phosphate buffered saline solution, émulsions (e.g., such as an oil/water or water/oil émulsions), lactated Ringer’s, normal sucrose, normal glucose, binders, fillers, dis intégrants, lubricants, coatings, sweeteners, flavors, sait solutions (such as Ringer’s solution), alcohols, oils, gelatins, carbohydrates such as lactose, amylose or starch, fatty acid esters, hydroxymethycellulose, polyvinyl pyrrolidine, and colors, and the like. Such préparations can be sterilized and, if desired, mixed with auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and/or aromatic substances and the like that do not deleteriously react with the compounds of the invention. For examples of excipients, see Martin, Remington’s Phannaceutical Sciences, 15th Ed., Mack Publ. Co., Easton, PA (l 975).

A “subject” to which administration is contemplated includes, but îs not limited to, humans (i.e., a male or female of any âge group, e.g., a pédiatrie subject (e.g., infant, child, adolescent) or adult subject (e.g., young adult, middle-aged adult or senior adult)) and/or a non-human animal.

e.g., a mammal such as primates (e.g., cynomolgus monkeys, rhésus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats, and/or dogs. In certain embodiments, the subject is a human. In certain embodiments, the subject is a non-human animal.

As used herein, “solid dosage fonn” means a pharmaceutical dose(s) în solid form, e.g., tablets, capsules, granules, powders, sachets, reconstitutable powders, dry powder inhalers and chewables.

As used herein, “administering means oral administration, administration as a suppository, topîcal contact, intravenous administration, parentéral administration, intraperitoneal administration, intramuscular administration, intralesional administration, intrathecal administration, intracranial administration, intranasal administration, transmucosal administration (e.g., buccal, sublingual, nasal, or transdermal), or subcutaneous administration, or the implantation of a slow-release device, e.g., a mini-osmotic pump, to a subject. Parentéral administration includes, e.g,, 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 infusion, transdermal patches, etc.

By “co-administer,” it is meant that a composition described herein is administered at the same time, just prior to, or just after the administration of one or more additional thérapies (e.g., anti-cancer agent, chemotherapeutic, or treatment for a neurodegenerative disease), The compound of formula I, or a phannaceutically acceptable sait thereof, can be administered alone or can be coadministered to the patient. Co-administration is meant to include simultaneous or sequential administration of the compound îndividually or in combination (more than one compound or agent), Thus, the préparations can also be combined, when desired, with other active substances (e.g., to reduce metabolic dégradation).

As used herein, and unless otherwise specifïed, the terms “treat,” “treating” and “treatment” include an action that occurs while a subject is suffering from the specifïed disease, disorder or condition, which reduces the severity of the disease, disorder or condition, or retards or slows the progression of the disease, disorder or condition (e.g., “therapeutîc treatment”), “Treat,” “treating” and “treatment”, as used herein, can include any effect, for example, lessening, reducing, modulating, ameliorating, or eliminating, that results in the improvement of the condition, disease, disorder, and the like, including one or more symptoms thereof. Treating can be curing, improving, or at least partially ameliorating the disorder.

The phrase “therapeutically effective amount,” as used herein, refers to the amount of a compound (e.g., a compound of Formula I), or a pharmaceutically acceptable sait thereoi, that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician. The compound, or a pharmaceutically acceptable sait thereof, described in the présent disclosure can be administered in therapeutically effective amounts to treat a disease. A therapeutically effective amount of a compound, or a pharmaceutically acceptable sait thereof, can be the quantity required to achieve a desired therapeutic and/or prophylactic effect, such as an amount which results in lessening of a symptom of a disease such as TGN.

Trigeminal neuralgia (TGN) is a long-tenu pain disorder that affects the trigeminal nerve. TGN, typically caused by a blood vessel compressing the trigeminal nerve, is characterized by épisodes of severe facial pain along the trigeminal nerve, which is a paired cranial nerve that has three major branches: the ophthalmic nerve (Vi), the maxillary nerve (V2), and the mandibular nerve (V3). Although ail three branches of the nerve may be affected, TGN most commonly involves the middle branch (the maxillary nerve or V2) and lower branch (mandibular nerve or V3) of the trigeminal nerve.

Current treatment of TGN includes microvascular décompression surgery in certain cases and use of médications such as anticonvulsants (e.g., carbamazepine) or antidepressants (e.g., amitriptyline). The existing treatment may either exhibit less favorable effectiveness or provide limited benefïts due to significant side effects.

Compound

The compound of Formula I, as depicted below, is an mGlu5 négative allosteric modulator (NAM), also known as 2-chloro-4-[l-(4-fluorophenyl)-2,5-dimethyl-l//-imidazol-4ylethynyl]pyridine:

Cl

(DA method of chemicalîy 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 referred to as Basimglurant.

It should be understood that the compound of Fonnula I as described herein includes crystalline solid fonns of either the free base or phannaceutically acceptable salts of the compound of Fonnula I as described herein.

In certain embodiments, the phannaceutically acceptable sait of the compound of Fonnula I can be a sait ofthe compound of Formula 1 with physiologically compatible minerai acids, such as hydrochloric acid, sulfuric (or sulphuric) acid, sulphurous acid or phosphoric acid; or with organic acids, such as methanesulphonîc acid, p-toluenesulphonic acid, acetic acid, lactic acid, trifluoroacetic acid, citric acid, fumaric acid, maleic acid, tartaric acid, succinic acid or salicylic acid. An exemplary phannaceutically acceptable sait of the compound of Formula I is a monosulfate sait or a hemisulfate sait.

In certain embodiments, the pharmaceutically acceptable sait of the compound of Fonnula I is a monosulfate sait or a hemisulfate sait, each being in hydrate or anhydrate form (e.g., anhydrate, hemihydrate, or monohydrate).

In certain embodiments, the pharmaceutically acceptable sait of the compound of Formula I is in a crystalline fonn or an amorphous fonn.

1η some embodiments, the compound is in a crystalline anhydrate fonn (Form A) of a monosulfate sait of the compound of Fonnula I, wherein Fonn A has an X-ray powder diffraction (XRPD) pattern as substantially shown in FIG. 1. In some embodiments, Form A îs characterized by at least three peaks selected from the following X-ray powder diffraction peaks obtained with a Cujî« radiation at 2Θ (2 Thêta): 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 crystalline Fonn A typically has a T_m of about 180-190 °C by DSC analysis. In some embodiments, Form A is characterized by an infrared spectrum having sharp bands at 3068, 2730,

261S, 2236, 2213,1628, 1587,1569, 1518, 1384,1374, 1295,1236, 1168, 1157, 1116, 1064, 1019, 902, 855, 786, and 674 cm¹ (±3 cm'¹).

In some embodiments, the compound is in a crystalline monohydrate form (Form B) of a monosulfate sait of the compound of Formula I, wherein Form B has an XRPD pattern as substantially shown in FIG. 2. The crystalline Form B typically has a T_m of about 60-70 C by DSC analysis.

In some embodiments, the compound is in a crystalline hemihydrate fonn (Fonn C) of a hemisulfate sait ofthe compound of Formula I, wherein Fonn C has an XRPD pattern as substantially shown in FIG. 3. The crystalline Form C typically has a Tm of about 90-100 °C by 10 DSC analysis.

Pharmaceutical Compositions

In one aspect, the present disclosure relates to a composition such as a pharmaceutical composition comprising the compound of Formula I, or a pharmaceutically acceptable sait thereof, ] 5 and a pharmaceutically acceptable excipient, for the treatment of TGN in a subject in need thereof.

In various embodiments, the composition is a solid pharmaceutical composition.

In various embodiments, the amount of the compound of Fonnula I, or a pharmaceutically acceptable sait thereof, in the pharmaceutical compositions described herein can be from about 0.01 mg to about 30 mg, about 0.05 mg to about 20 mg, about 0.1 mg to about 10 mg, about 0.5 mg to 20 about 10 mg, about 1 mg to about 10 mg, about 2 mg to about 10 mg, about 3 mg to about 10 mg, about 4 mg to about 10 mg, about 5 mg to about 10 mg, about 6 mg to about 10 mg, about 7 mg to about 10 mg, about 8 mg to about 10 mg, about 9 mg to about 10 mg, about 1 mg to about 9 mg, about 1 mg to about 8 mg, about I mg to about 7 mg, about 1 mg to about 6 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 25 mg to about 3 mg, about 1 mg to about 2.5 mg, about I 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 to about 7 mg, about 1.5 mg to about 6 mg, about 1.5 mg to about 5 mg, about 1.5 mg to about 4.5 mg, about 1.5 mg to about 4 mg, about 1.5 mg to about 3.5 mg, about 1.5 mg to about 3 mg, about 1.5 mg to about 2.5 mg, about 1.5 mg to about 2 mg, about 2 mg to about 9 mg, about 2 mg to about 8 mg, about 2 mg to about 7 mg, about 2 mg to about 6 mg, about 2 mg to about 5 mg, about 2 mg to about 4.5 mg. about 2 mg to about 4 mg, about 2 mg to about 3.5 mg, about 2 mg to about 3 mg, about 2 mg to about 2.5 mg. about 2.5 mg to about 9 mg, about 2.5 mg to about 8 mg, about 2.5 mg to about 7 mg. about 2.0 mg lo about 6 mg, about 2.5 mg to about 5 mg, about 2.5 mg to about 4.5 mg, about 2.5 mg to about 4 mg, about 2.5 mg to about 3.5 mg, about 2.5 mg to about 3 mg, about 3 mg to about 9 mg, about 3 mg to about 8 mg, about 3 mg to about 7 mg, about 3 mg to about 6 mg, 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 3.5 mg to about 4 mg, about 4 mg to about 9 mg, about 4 mg to about 8 mg, about 4 mg to about 7 mg, about 4 mg to about 6 mg, about 4 mg to about 5 mg, about 4 mg to about 4.5 mg, about 4.5 mg to about 9 mg, about 4.5 mg to about 8 mg, about 4.5 mg to about 7 mg, about 4.5 mg to about 6 mg, about 4.5 mg to about 5 mg, about 5 mg to about 9 mg, about 5 mg to about 8 mg, about 5 mg to about 7 mg, about 5 mg to about 6 mg, about 6 mg to about 9 mg, about 6 mg to about 8 mg, about 6 mg to about 7 mg, about 7 mg to about 9 mg, about 7 mg to about 8 mg, or about 8 mg to about 9 mg.

In certain, embodiments, the amount of the compound of Formula 1, or a pharmaceutically acceptable sait thereof, in the pharmaceutical compositions described herein can be from about 0.1 mg to about 1.5 mg.

In certain embodiments, the amount of the compound of Fonnula I, or a pharmaceutically acceptable sait thereof, in the pharmaceutical compositions described herein can be from about 0.1 mg to about 4.0 mg, from about 0.1 mg to about 3.5 mg, from about 0.1 mg to about 3.0 mg, from about 1.5 mg to about 3.5 mg, or from about 1.0 mg to about 3.0 mg once daily. In certain embodiments, the amount ofthe compound of Formula I, or a pharmaceutically acceptable sait thereof, in the phannaceutical compositions described herein can be 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 once daily.

In certain embodiments, the amount of the compound of Fonnula I, or a phannaceutically acceptable sait thereof, in the pharmaceutical compositions described herein is about 4.0 mg. In certain embodiments, the amount ofthe compound of Fonnula I, or a phannaceutically acceptable sait thereof, in the pharmaceutical compositions described herein is about 3.5 mg. In certain embodiments, the amount ofthe compound of Formula I, or a phannaceutically acceptable sait thereof, in the pharmaceutical compositions described herein is about 3.0 mg. In certain embodiments, the amount of the compound of Fonnula I, or a phannaceutically acceptable sait thereof, in the phannaceuticai compositions described herein is about 2.5 mg. In certain embodiments, the amount of the compound oi Formula I, or a pharmaceutically acceptable sait thereof, in the pharmaceutical compositions described herein is about 2.0 mg. In certain embodiments, the amount of the compound of Formula I, or a phannaceutically acceptable sait thereof, in the pharmaceutical compositions described herein is about 1.5 mg. In certain embodiments, the amount of the compound of Fonnula I, or a pharmaceutically acceptable sait thereof, in the pharmaceutical compositions described herein is about 1.0 mg.

In various embodiments, the amount of the compound of Formula I, or a pharmaceutically acceptable sait thereof, in the phannaceuticai compositions described herein can 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.

In certain embodiments, the amount ofthe compound of Formula I, or a pharmaceutically acceptable sait thereof, in the pharmaceutical compositions described herein can be about 0.1 mg to about 0.2 mg (e.g., about 0.13 mg).

In certain embodiments, the amount of the compound of Fonnula I, or a pharmaceutically acceptable sait thereof, in the pharmaceutical compositions described herein can be about 0.2 mg to about 0.3 mg (e.g., about 0.26 mg).

In certain embodiments, the amount ofthe compound of Fonnula 1, or a phannaceutically acceptable sait thereof, in the phannaceuticai compositions described herein can be about 0.6 mg to about 0.7 mg (e.g., about 0.65 mg).

In certain embodiments, the amount of the compound of Formula I, or a pharmaceutically acceptable sait thereof, in the pharmaceutical compositions described herein can be about 1.2 mg to about 1.4 mg (e.g., about 1.3 mg).

In some embodiments, the compound of Formula I, or a pharmaceutically acceptable sait thereof, is present in the composition in an amount from 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 l% by weight, or about 0.l% to about 0.5% by weight, based on the total weight ofthe composition.

In some embodiments, the compound of Fonnula I, or a phannaceutically acceptable sait thereof, is present in the composition in an amount from about 0.05% to about 15% by weight.

In some embodiments, the compound of Formula I, or a phannaceutically acceptable sait thereof, is present in the composition in an amount from about 0. l% to about 0.5% by weight.

In various embodiments, the pharmaceutical compositions described herein comprise a therapeutically effective amount of a pharmaceutically acceptable sait oi the compound of Formula l. In some embodiments, the phannaceutically acceptable sait of the compound of Fonnula I can be a sait ofthe compound of Fonnula I with physiologically compatible minerai acids, such as hydrochloric acid, sulfuric acid, sulphurous acid or phosphoric acid; or with organic acids, such as mcthanesul phonie acid, p-toluenesulphonic acid, acetic acid, lactic acid, tri fluoroacetic acid, ci trie acid, fumaric acid, maleic acid, tartaric acid, succinic acid or salicylic acid.

In certain embodiments, the pharmaceutically acceptable sait of the compound of Fonnula I is a monosulfate sait or a hemisulfate sait, each being in hydrate or anhydrate form (e.g,, anhydrate, hemihydrate, or monohydrate).

In certain embodiments, the pharmaceutically acceptable sait of the compound of Formula I is in a crystalline form or an amorphous form.

In certain embodiments, the pharmaceutical compositions described herein comprise a crystalline anhydrate form (Form A) of a monosulfate sait of the compound of Formula I, wherein Fonn A has an X-ray powder diffraction (XRPD) pattern as substantially shown in FIG. I. The crystalline Fonn A typically has a T_m of about 180-190 °C by DSC analysis (e.g., l80±l °C, 182± I °C, I84±l °C, I86±l °C, I88±l °C, or 190±l °C).

In some embodiments, the pharmaceutical compositions described herein comprise a crystalline monohydrate form (Form B) of a monosulfate sait of the compound of Formula I, wherein Form B has an XRPD pattern as substantially shown in FIG. 2. The crystalline Fonn B typically has a T_m of about 60-70 °C by DSC analysis (e.g., 60±l °C, 62±l °C, 64±l °C, 66±l °C, 68±l °C, or70±l °C).

In some embodiments, the pharmaceutical compositions described herein comprise a crystalline hemihydrate fonn (Form C) of a hemisulfate sait of the compound of Formula I, wherein

Fonn C has an XRPD pattern as substantially shown in FIG. 3. The crystalline Fonn C typically has a Tm of about 90-100 °C by DSC analysis (e.g., 90± l °C, 92± l °C, 94± l °C, 96± l °C, 98± l °C, or l00±l °C).

In certain embodiments, the pharmaceutical compositions described herein comprise an amorphous fonn of a monosulfate sait oi lhe compound oi Fonnula I, wherein said amorphous fonn is characterized b y an infrared spectrum having bands at 2730, 2592, 2219, 1633, 1586, 1570, 151 j, 1375, 1343, 1293, 1226, 1157, 1 130, 1084, 1040, 986, 903, 848, 788, 712 and 670 cm’¹ (±3 cm' ')

In some embodiments, the pharmaceutical composition is a tablet formulation such as a modîfied release tablet fonnulation, or a matrix pellet formulation such as a modîfied release matrix pellet fonnulation, which can be encapsulated in a capsule. A “modîfied release fonnulation,” or a “modified-release dosage,” as used herein, refers to a mechanism that (in contrast to immediaterelease dosage) delivers a drug with a delay after its administration (delayed-release dosage), or for a prolonged period of time (extended-release dosage). See, Peme et al., Pharmaceutics: Drug Delivery and Targetîng (2^nd), 2012, 7-13.

In certain embodiments, the pharmaceutical composition is a modîfied release matrix pellet fonnulation encapsulated in a capsule, wherein the compound of Fonnula I, or a pharmaceutically acceptable sait thereof, is present in an amount from 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).

In certain embodiments, the pharmaceutical composition is a modîfied release pellet formulation encapsulated in a capsule, wherein the compound of Formula I, or a pharmaceutically acceptable sait thereof, is present in the composition in an amount from 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.

In certain embodiments, the pharmaceutical composition described herein comprises a crystalline anhydrate form (Fonn A) of a monosulfate sait of the compound of Fonnula I, wherein Fonn A has an XRPD pattern as substantially shown in FIG. 1; and the Fonn A monosulfate sait is present in the composition in an amount from 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).

In certain embodiments, the pharmaceutical composition described herein comprises a crystalline anhydrate fonn (Form A) of a monosulfate sait of the compound of Formula I, wherein 5 Fonn A has an XRPD pattern as substantially shown in FIG. 1; and the Fonn A monosulfate sait is present in the composition in an amount from 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.

As described herein, the present disclosure includes a solid pharmaceutical composition 10 comprising a solid form of a compound of Fonnula 1, namely, a crystalline anhydrate fonn (Fonn A) of a monosulfate sait of the compound of Formula I; where the composition is in the fonn of a matrix pellet and the solid form has a mean particle size (Dv50) of less than or equal to about 100 pm. The Dv50 can be determined by a LA-950 laser diffraction method. See, e.g., https://static.horiba.com/fileadmin/Horiba/Products/Scientific/Particle_Characterization/Downloails/ 15 Technical_Notes/TN 159_LA-950_Laser_Diffraction_Technique.pdf

In various embodiments, the pharmaceutical composition comprises a matrix pellet of the solid fonn having a particle size of less than 47 pm, less than 45 pm, less than 40 pm, less than 35 pm, less than 30 pm, less than 25 pm, less than 20 pm, less than 15 pm, less than 10 pm, or less than 5 pm. In certain embodiments, the solid fonn has a particle size of about 10 pm or less (e.g., 20 about 10 pm, about 9 pm, about 8 pm, about 7 pm, about 6 pm, about 5 pm, about 4 pm, about 3 pm, about 2 pm, or about 1 pm).

In certain embodiments, the solid form has a particle size of less than 47 pm and the Fonn A monosulfate sait is present in the composrtion in an amount of i % by weight or less, based on the total weight of the composition.

In certain embodiments, the solid fonn has a particle size of about 10 pm or less (e.g., about

3.3 pm), and the Form A monosulfate sait 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.

In certain embodiments, the pharmaceutical composition comprises a pharmaceutical excipient comprising a polymer, a binder, a disintegrant, a lubricant, or a glidant.

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

The pharmaceutical compositions provided herein can be administered by a variety of routes including, but not limited to, oral administration, administration as a suppository, topical contact, parentéral administration (e.g., intravenous, intramuscular, intra-arterial, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial), intralestonal administration, intrathecal administration, intranasal administration, transmucosal administration (e.g., buccal, sublingual, nasal, or transdermal), or the implantation of a slow-release device, e.g., a mini-osmotic pump, to a subject. In certain embodiments, the pharmaceutical compositions disclosed herein are administered orally.

The pharmaceutical compositions provided herein may also be administered chronically (“chronic administration”). Chronic administration refers to administration of a compound or pharmaceutical composition thereof over an extended period of time, e.g., for example, over 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc., or may be continued indéfinitely, for example, for the rest of the subject’s life. In certain embodiments, the chronic administration is întended to provide a constant level of the compound in the blood, e.g., within the therapeutic window over the extended period of lime.

The pharmaceutical compositions provided herein may be presented in unit dosage forms to facilitate accurate dosing. The term “unit dosage forms” refers to physically discrète units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active materiai calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient. In various embodiments, the pharmaceutical dosage forms described herein can be administered as a unit dose. Typical unit dosage forms include prefilled, premeasured ampules or syringes of the liquid compositions or pills, tablets, capsules or the like in the case of solid compositions.

In certain embodiments, the pharmaceutical compositions provided herein are administered to the patient as a solid dosage form. In certain embodiments, the solid dosage form is a capsule (e.g., a modified release pellet formulation encapsulated in a capsule). In certain embodiments, the solid dosage fonn is a tablet (e.g., a modified release tablet fonnulation).

In certain embodiments, the pharmaceutical compositions provided herein comprise the compound of Formula I as the sole active agent, or in combination with other active agents.

Although the descriptions of pharmaceutical compositions provided herein are principally directed to pharmaceutical compositions which are suitable for administration to humans, it will be understood by the skilled artisan that such compositions are generally suitable for administration to animais of ail sorts. Modification of pharmaceutical compositions suitable for administration to humans in order to render lhe compositions suitable for administration to various animais is well understood, and the ordinarily skilled veterinary pharmacologist can design and/or perform such modification with ordinary expérimentation. General considérations in the formulation and/or manufacture of pharmaceutical compositions can be found, for example, in Remington: The Science and Practice ofPharmacy 2 l^st ed., Lippincott Williams & Wilkins, 2005.

Methods of Use and Treatment

In one aspect, provided herein are methods of treating trigeminal neuralgia (TGN) in a subject (e.g., a human) in need thereof.

In various embodiments, provided herein are methods for treating TGN in a subject in need thereof, comprising administering to a subject in need thereof a composition comprising a therapeutically effective amount of a compound or a phannaceuticaily acceptable sait thereof, wherein lhe compound is of Formula L

In certain embodiments, provided herein are methods of treating TGN in a subject in need thereof, comprising administering to a subject in need thereof a composition comprising a therapeutically effective amount of a compound or a pharmaceutically acceptable sait thereof, wherein the compound is of Formula I:

Cl

F (I), wherein administering comprises administering the compound of Formula I, or a pharmaceutically acceptable sait thereof, in an amount of about i .5 mg to about 3.5 mg once daily. In some embodiments, the subject has a weight of al least about 71 kg. In some embodiments, the subject has a weight 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 weight of at least about 71 kg. In some embodiments, the subject has a weight 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 weight from about 71 kg to about 150 kg (e.g., 70, 71, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, or 150 kg).

In various embodiments, administering a therapeutically effective amount of the compound of Fonnula I, or a phannaceutically acceptable sait thereof, comprises administering to a subject from about 0.05 mg to about 20 mg (e.g., 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 S mg, about 8.5 mg, about 9 mg, about 9.5 mg, or about 10 mg) ofthe compound of Fonnula I, or a phannaceutically acceptable sait thereof.

In various embodiments, administering a therapeutically effective amount of the compound of Fonnula I, or a phannaceutically acceptable sait thereof, comprises administering to a subject from about 0.1 mg to about 4.0 mg, from about 0.1 mg to about 3.5 mg, from about 0.1 mg to about 3.0 mg, from about 1.5 mg to about 3.5 mg, or from about 1.0 mg to about 4.0 mg. Incertain embodiments, administering a therapeutically effective amount of the compound of Formula I, or a phannaceutically acceptable sait thereof, comprises administering to a subject from about 1.5 mg to about 3.5 mg.

In certain embodiments, administering a therapeutically effective amount of the compound of Fonnula I, or a pharmaceutically acceptable sait thereof, comprises administering to a subject about 1.0 mg once daily. In certain embodiments, administering a therapeutically effective amount of the compound of Fonnula I, or a pharmaceutically acceptable sait thereof, comprises administering to a subject about 1.5 mg once daily. In certain embodiments, administering a therapeutically effective amount of the compound of Fonnula 1, or a phannaceutically acceptable sait thereof, comprises administering to a subject about 2.0 mg once daily. In certain embodiments, administering a therapeutically effective amount ofthe compound of Formula I, or a phannaceutically acceptable sait thereof, comprises administering to a subject about 2.5 mg once daily. In certain embodiments, administering a therapeutically effective amount of the compound of Fonnula I, or a pharmaceutically acceptable sait thereof, comprises administering to a subject about 3.0 mg once daily. In certain embodiments, administering a therapeutically effective amount of the compound of Fonnula I, or a phannaceutically acceptable sait thereof, comprises administering to a subject about 3.5 mg once daily. In certain embodiments, administering a therapeutically effective amount of the compound of Formula I, or a pharmaceutically acceptable sait thereof, comprises administering to a subject about 4.0 mg once daily. In certain embodiments, administering a therapeutically effective amount of the compound of Fonnula I, or a pharmaceutically acceptable sait thereof, comprises administering from about 0.1 mg to about 1.5 mg ofthe compound of Fonnula I, or a phannaceutically acceptable sait thereof, to a subject in need thereof.

in certain embodiments, provided herein is a method of administering the free base form of the compound of Fonnula I for the treatment of TGN in a subject in need thereof.

In certain embodiments, provided herein is a method of administering a pharmaceutically acceptable sait of the compound of Formula I for the treatment of TGN in a subject in need thereof.

In certain embodiments, treating comprises administering the compound of Fonnula I, or a pharmaceutically acceptable sait thereof, once, twice, three, four, or five times daily. In certain embodiments, treating comprises administering the compound of Formula 1, or a pharmaceutically acceptable sait thereof, once daily.

In certain embodiments, treating comprises administering the compound of Fonnula I, or a phannaceutically acceptable sait thereof, by a variety of routes including, but not limited to, oral administration, administration as a suppository, topicai contact, parentéral administration (e.g., intravenous, intramuscular, intra-arterial, intradcrmal, subeutaneous, intraperitoneal, intraventricular, and intracranial), intralesional administration, intrathecal administration, intranasal administration, transmucosal administration (e.g., buccal, sublingual, nasal, or transdermal), or the implantation of a sîow-release device, e.g., a mini-osmotic pump, to a subject.

In certain embodiments, treating comprises administering the compound of Formula I, or a pharmaceutically acceptable sait thereof, by oral administration.

In certain embodiments, treating comprises administering the compound of Formula I, or a phannaceutically acceptable sait thereof, as a unit dose.

In certain embodiments, treating comprises administering the compound of Formula I as the free base fonn.

In certain embodiments, treating comprises administering the compound of Formula I in the fonn of a phannaceutically acceptable sait thereof. In some embodiments, the phannaceutically acceptable sait of the compound of Formula I can be a sait of the compound of Formula 1 with physiologically compatible minerai acids, such as hydrochloric acid, sulfuric (or sulphuric) acid, sulphurous acid or phosphoric acid; or with organic acids, such as methanesulphonie acid, ptoluenesulphonic acid, acetic acid, lactic acid, trifluoroacetic acid, citric acid, fumaric acid, maleic acid, tartaric acid, succinic acid or salicylic acid.

In certain embodiments, as described above, treating comprises administering the compound of Formula I in a crystalline form (e.g., Fonn A, Form B, or Fonn C) in a sulfate sait form (e.g., a monosulfate sait or a hemisulfate sait).

In various embodiments, provided herein are methods of treating TGN, comprising administering to a subject in need thereof a composition comprising a therapeutically effective amount of an mGhi5 négative allosteric modulator (NAM), or a pharmaceutically acceptable sait thereof, wherein the mGiu5 NAM îs a compound of Formula I:

H₃C _n

In certain embodiments, treating comprises administering the compound of Formula I as a monotherapy.

In certain embodiments, the methods provided herein further comprise administering a therapeutically effective amount of another therapeutîc agent to the subject.

As described herein, the present invention relates lo use of the compound of Formula I, or a phannaceutically acceptable sait thereof, for treating trigeminal neuralgia (TGN). In some embodiments, the TGN îs typical TGN, which results in épisodes of severe, sudden, shock-like pain in one side of the face that lasts for seconds to a few minutes. In some embodiments, the TGN is atypical TGN, which results in a constant buming pain that îs less severe. In certain embodiments, the TGN is classified by the International Classification of Headache (ICHD-3). In certain embodiments, the TGN is a classical TGN. In some embodiments, the TGN is a secondary TGN. In certain embodiments, the TGN is a idiopathic TGN.

10011 In certain embodiments, the therapeutic effect of the treatment is determined by:

a) réduction of the activity of high-voltage activated calcium channels;

b) réduction of the activity of voltage-gated sodium channels;

c) suppression of the propagation of an ion channel action potential; or

d) suppression of the rapid firing of neurons.

In some embodiments, the efficacy of the compound is determined by Brief Pain InventoryFacial (BPI-F) scale. In some embodiments, the efficacy ofthe compound is determined by Global Impression of change. In some embodiments, the efficacy of the compound is determined by Sheehan Disability Scale (SDS). In some embodiments, the efficacy of the compound is determined by patient diary cards. In some embodiments, the efficacy of the compound is determined by number and severity of attacks (paroxysms) or number of pain free days. In some embodiments, the efficacy of the compound is determined by rating ofthe Médication Satisfaction Questionnaire (MSQ). In some embodiments, the efficacy of the compound is determined by Patient Global Impression of Change (PGI-C). In some embodiments, the efficacy ofthe compound is determined by patient-rated Global Impression - severity.

Without further élaboration, it is believed that one skilied in the art can, based on the above description, utilize the present invention to its fui lest extent. The foilowing spécifie ex amp les are therefore to be construed as merely illustrative, and not limitative ofthe remainder ofthe disclosure in any way whatsoever. Ail publications cited herein are incorporated by reference in their entirety.

EXAMPLES

In order that the disclosure described herein may be more fully understood, the following ex amp les are set forth. The ex amp les described in this application are offered to illustrate the compound, pharmaceutical compositions, and methods described herein and are not to be construed in any way as limiting their scope.

Example 1: Synthesis of 2-chloro-4-[l-(4-fluorophenyl)-2,5-dimethyl-l//-imidazol-4ylethynyl]pyridine (Compound of Formula I, supra) [See U.S. Patent No. 7,332,510].

2-Chloro-4-[l-(4-fluorophenyl)-2-methyl-i//-imidazol-4-ylethynyl]-pyridine (200 mg, 0.6 mmol) was dissolved in 10 mL tetrahydrofuran (THF) and cooled to -75 °C. Lithiumdiisopropylamide (0.45 mL, 0.91 mmol) was added and the mixture stirred for 15 min at -75 °C. lodomethane (0.05 mL, 0.85 mmol) was added and stirring was continued at -75 °C for 2 hrs. The reaction mixture was quenched with saturated NaHCOî solution and extracted with water and ethyl acetate. The combined organic extracts were dried with sodium sulfate, filtered and evaporated. The crude product was purified b y flash chromatography on silica gel (heptane/ethyl acetate 90:10 to 20:80 gradient) and by recrystallization from ethyl acetate. The tille compound was obtained as a white solid. MS: m/z = 326.5 (M+H+).

Example 2: Préparation of Polymorphs of Salts of Compound of Formula I [See U.S. Patent No. 8,063,076].

Form A monosulfate sait: 61.0 g of 2-chloro-4-[l-( 4-fluoro-pheny 1)-2,5-dimethyl-\Himîdazol-4-ylethynyl]-pyridine was dissolved in 610 mL of 2-propanol. The solution was filtered and the filter rinsed with 31 mL of 2-propanol. To the combined solutions a mixture of 30 mL of water and 18.91 g of sulfuric acid (97%) was added drop-wise. The solution was cooled to 0-5 °C. Seeding was performed at 58 °C as needed. The solid residues were filtered, washed with 2propanol (0-5 °C) and dried at 50 °C and less than 1 mbar for 18 hrs to provide the monosulfate sait ofthe compound of Formula I in a yield of 69.1 g (87.1 %). Form A seeding crystals can be prepared upon cooling crystallization of a hot solution of 250 mg of the monosulfate sait in 10 mL of 2-propanol. After cooling to 0 °C, the solid residues can be filtered and dried at 50 °C under vacuum to afford Form A monosulfate sait, which was confimied by the XRPD pattern as substantially shown in FIG. 1.

Form B monosulfate sait: 300 mg of Fonn A monosulfate sait of the compound of Formula 1 was dissolved in 3 mL 2-propanol and 1 mL water at 60 °C to produce a clear solution. The clear solution was seeded with Fonn B monosulfate sait and sealed at room temperature (e.g., about 25 °C). Single crystals were fonned after 3 days. Seeding crystals can be prepared by formation of a saturated sluny of Form A monosulfate sait of the compound of Fonnula I in 2-propanol and water (3:1 v/v) at room temperature, The slurry was stined at room temperature for approximately 3 weeks. The solids were filtered via a glass 35 fdter to afford crystalline Form B monosulfate sait, which was confirmed by the XRPD pattern as substantially shown in FIG. 2.

Form C hemisulfate sait: 41 g of Form A monosulfate of the compound of Formula I was mixed with 128 g of water. The slurry was stirred at room temperature for 2-16 hrs. After ail the Form A monosulfate sait had been converted to the hemisulfate sait, the resulting crystals were collected by filtration and rinsed with water. The wet cake thus obtained was dried at 40 °C in a vacuum oven for 48 hrs to afford Form C hemisulfate sait in a yield of 93%. Form C hemisulfate sait was confirmed by the XRPD pattern as substantially shown în FIG. 3.

Amorphous monosulfate sait: 0.53 g of a monosulfate of the compound of Formula I was dissolved in 10 mL of methanol at approximately 65 °C. After complété évaporation of the solvent under vacuum, the solid (foam) was further dried at about 50 °C under 5-20 mbar for 18 hrs. Analysis (XRPD and DSC) revealed amorphous form of the compound of Formula I was obtained. The amorphous monosulfate sait was characterized by an infrared spectrum having bands 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 (±3 cm'¹). The glass transition temperature (T_g) of the amorphous form determined by DSC was largely dépendent on the solvent content and was observed for the wet sample (closed pan) at about 42 °C and for the in-sïtu dried sample (pan with perforation lid) at about 77 °C.

Example 3: Modified Release Matrix Pellet Capsules of Form A Monosulfate Sait

Two different matrix pellet compositions were prepared according to the formulations shown în Table 1 below. The matrix pellets thus obtained were fi lied into capsules to afford matrix pellet capsules. The process included: high shear wet granulating Form A monosulfate sait, microcrystalline cellulose, methacrylic acid copolymer, and hypromellose, with purified water to form a mixture; followed by extruding, spheronizing, fluid bed drying, and sîeving the mixture to provide a solid material; and subsequently blending the solid material with an extemal pharmaceutical excipient, talc, to afford matrix pellets; and then filling the matrix pcllets into capsules to provide matrix pellet capsules. More specifically, each of the granulating, extruding, spheronizing, drying, sîeving, and blending steps was carried out as follows.

I. Weighed lhe Fonn A monosulfate and about 15% of the required amount of microcrystalline cellulose and place them into a suitabie container. Mixed the contents using a turbula mixer or an équivalent blender for 30 minutes at 40 + 10 rpm.

2. Weighed ail the other excipients; methacrylic acîd copolymer, hypromellose, and the remaining microcrystalline cellulose.

3. Transfered ail the materials from Step 2 into a high shear granulator followed by the mixture from Step l. Mix ail the components for two minutes using the impeller and chopper at the following speeds: Impeller: 300 + 100 rpm and Chopper: 1500 + 500 ipm.

4. Granulated the powder mixture from Step 3 by spraying purified water (approximately 83% ofthe batch size) onto the powder mixture in the high shear granulator while contînualiy mixing the contents using the impeller at 300 + 100 rpm and Chopper at 1500 + 500 rpm for 20 minutes. Recorded the power consumption at the granulation end point.

5. Fed the wet granules at a uniform rate and extruded the wet granules through the extrader using screen # l .0 mm and speed setting of about 40 + 5 rpm.

6. Transferred about 700 g of the extruded material from Step 5 into a spheronizer using #l graded plate. Spheronized the contents for 5 + i minutes at a speed of about 0.6 ( approximately 1000 rpm).

7. Collected the spheronized material from Step 6 and dried in a fluid bed dryer with inlet température of 60 + 10 °C, until the water content of the pellets was less than 0.8% measured using a Halogen Moisture Analyzer or an équivalent set at 90 °C.

8. Screened the dried pellets from Step 7 through size #10 and #40 screens and collected the pellet fraction between #10 and #40 screen.

9. Used the weight of the pellets from Step 8 to weigh the adjusted amount of talc.

10. Placed the pellets from Step 9 in a b in blender or an équivalent, added talc and mixed for 5 minutes at 20 + 5 rpm.

11. Filled the pellets from Step 10 into hard gelatin capsules.

12. Stored the filled capsules from Step 11 in double polyethylene-lined bags with two silica gel bags between the polyethylene bags in a closed fiber drum at a température not above 25 °C.

Table 1. Matrix Pellet Formulations

Ingrédient	Quantity (mg/capsule)	Function
Fonn A monosulfate	0.13*	1.30^#	Active ingrédient
Microcrystalline cellulose	64.62	12S.20	Matrix forming polymer
Methacrylic acid copolymer	30.00	60.00	pH-responding polymer
Hypromellose	5.00	10.00	Binder
Talc	0.25	0.50	Glidant
Total	100.00	200.00

*Represents 0.5 mg dosage and # represents 1.0 mg dosage described in the paragraph below.

The content uniformity of the matrix pellets was found to be dépendent on the médian particle size (Dv50) and amount of the Form A monosulfate sait (“API”). Specifically, three API variants achieved by size réduction with jet mill and pin mill to a respective médian particle size (Dv50) of 3.3 μιη (jet-miiled), 10 pm (pin-milled), and 47 μιη (ρίη-milled) were manufactured at two different dosages (API: 0.1 mg and 1.0 mg). At the dosage of 1.0 mg of API, matrix pellets prepared using API with Dv50 of 3.3 pm, 10 pm, and 47 pm exhibited USP uniformity of dosage units (UDU) acceptance value (AV) of 2.2, 6.3, 3.4, respectively, ail meeting the UDU acceptance criteria (AV < 15). At the dosage of 0.1 mg of API, matrix pellets prepared using API with Dv50 of 47 pm failed to meet the UDU acceptance criteria with an AV of 20.9; unexpectedly, matrix pellets prepared using API with Dv50 of 3,3 pm and 10 pm met the UDU acceptance criteria with an AV of 6.0 and 10.3, respectively. API particle size (Dv50) of 10 pm or less (e.g., between 3.3 - 10 pm) was shown to provide matrix pellets drug product with acceptable manufacturing process and drug product performance (e.g., content uniformity, pellet size distribution, and dissolution), thus more suitable for pharmaceutical drug development.

Example 4: A Study ofthe Compound of Formula I for Treatment of Subjects with Trigeminal Neuralgia (TGN)

A Phase Π/III, mukicenter, S-week run-in phase followed by a 12- week, prospective, 5 parallel-group, double-blind, randomized withdrawal, placebo-controlled study, with a 52 week open label extension, was carried oui, as shown in Table 2 below, to evaluate the efficacy and safety of daily 1.5 to 3.5 mg the compound of Formula I (also referred to herein as “Basimglurant”) in patients with pain associated with trigeminal neuralgia with suboptimal response to their current anti-pain therapy. The study duration was up to 24 weeks and consists of 3 periods followed by a 52 1Ü week open label extension. 200 patients were enrolled in study Period 1 to randomize 70 patients in Period 2.

Table 2. Objectives and endpoînts

PERIOD 1. RUN-IN
Objectives	Endpoînts
Primary
To evaluate the safety of basimglurant daily dosingl.5-3.5 mg.	Incidence and severity of adverse events, laboratory, vital signs and cardiovascular safety will also be evaluated.
Exploratory
To evaluate the efficacy of 8-week once daily treatment with basimglurant on pain associated withtrigeminal neuralgia on the following disease aspects: • Impact on Facial Pain	Mean change from Period 1 baseline (BL 1 ) to Week 8 in the total patient-ratcd Brief Pain Inventory-Facial (BPI-F) scale.

• Patient perceived change of the pain	Measure Global Impression of change from Period 1 baseline (BL1) to Week 8,
• Quantitative and qualitative pain assessments	Number and severity of attacks (paroxysms) as well as duration and severity of continuous pain compared with BL1. Number of pain free days.
• Pain freedom • Patient médication satisfaction	Patient reported rating of the Médication Satisfaction Questionnaire (MSQ).

PERIOD 2. DOUBLE BLIND

Objectives

Endpoints

Primary

To assess the maintenance of effect on pain of double-blind 12-week once daily dosing of basimglurant 1.5-3.5 mg compared with placebo in patients with TGN.

Time to Loss of Efficacy or pain récurrence defined as the confirmed increase in the number of weekly paroxysms or reemergence of continuous pain and/or the need for rescue médication

Secondary

To evaluate the effect of double-blind treatment of once daily dose of basimglurant versus placebo on the following disease aspects: • Impact on facial pain	Mean change in the total patient-rated Brief Pain Inventa ry-Facial (BPI-F) scale compared with Period 2 baseline (BL2) Frequency and severity of attacks
• Pain frequency and severity	(paroxysms) as well as severity and duration of continuous paincaptured in patient diary cards.
• Patient perceived perception of change in pain	Measure Global Impression of change as compared with Period 2 baseline (BL2)
• Patient médication satisfaction.	Patient reported rating of the Médication Satisfaction Questionnaire (MSQ)
• Safety of basimglurant once daily dosing 1.5-3.5mg compared with placebo.	Incidence and severity of adverse events. Laboratoryand cardiovascular safety will also be evaluated.
Exploratory
• The impact of pain on general activities of dailyliving.	Recorded ratings of interférence of pain with

	patient’s activities captured in patient diary cards.
OPEN-LABEL EXTENSION
Objectives	Endpoints
Primary
• To evaluate the long-term safety of basimglurant daily dosing 1.5-3.5 mg.	Incidence and severity of adverse events. Laboratory, vital signs and cardiovascular safety willalso be evaluated.
Secondary
To evaluate the continued efficacy of basimglurant with once daily dosing 1.5-3.5 mg on the following disease aspects: • Impact on facial pain • Pain frequency and severity • Patient perceived severity of pain	Mean scores in the total patient-rated Brief Pain Inventory-Facial (BPI-F) scale. Frequency and severity of attacks (paroxysms) as well as severity and duration of continuous paincaptured in patient diary cards. Measure Global Impression of severity as captured by PGÏ-S.

OTHER EMBODIMENTS

All of the features disclosed in this spécification may be combined in any combination.

Each feature disclosed in this spécification may be replaced by an alternative feature serving the same, équivalent, or similar purpose. Thus, unless expressly stated otherwise, each feature disclosed is only an example of a generic sériés of équivalent or similar features.

Further, from the above description, one skilled in the art can easily ascertain the essential characteristics of the présent invention, and without departing from the spirit and scope thereof, can 10 make various changes and modifications of the invention to adapt it to various usages and conditions. Thus, other embodiments are also within the claims.

Claims

L A method of treating trigeminal neuralgia (TGN), comprising administering to a subject in need thereof a composition comprising a therapeutically effective amount of a compound or a

5 phannaceutically acceptable sait thereof, wherein the compound is of Fonnula I:
2. The method of claim l, wherein administering comprises administering the compound of Formula I in îts free base fonn.
3. The method of claim l, wherein administering comprises administering the compound of Formula 10 l in the fonn of a phannaceutically acceptable sali thereof.
4. The method of claim 3, wherein the phannaceutically acceptable sait is a monosuifate sait or a hemi sulfate sait.
5. The method of claim 4, wherein the phannaceutically acceptable sait is in a crystalline form or an amorphous form.

15
6. The method of claim 5, wherein the pharmaceutically acceptable sait comprises a crystalline an hydrate form (Fonn A) of a monosulfate sait of the compound of Fonnula I, wherein Form A is characterized by at least three peaks selected from the following X-ray powder diffraction peaks obtained with a Cua_h radiation at 20 (2 Thêta): 9.8, 13.4, 14.2, I8.l, 18.9, 19.6, 22.6, 22.9, 25.7, 27.1, and 29.9 (±0.2°).
7. The method of claim 6, wherein Form A is characterized by the following X-ray powder diffraction peaks obtained with a Cua« radiation at 20 (2 Thêta): 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°).
8. The method of claim 6 or 7, wherein Fonn A has an X-ray powder diffraction (XRPD) pattern as substantially shown in Figure l.
9. Fhe method of claim 5, wherein the pharmaceutically acceptable sait comprises a crystalline monohydrate form (Fonn B) of a monosulfate sait of the compound of Formula l, wherein Form B has an XRPD pattern as substantially shown in Figure 2.
10. The method of claim 5, wherein the pharmaceutically acceptable sait comprises an amorphous form of a monosuIfate sait of the compound of Formula I, characterized by an infrared spectrum having bands 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 (±3 cm ¹ ).
1 1. The method of claim 5, wherein the pharmaceutically acceptable sait comprises a crystalline hemihydrate fonn (Fonn C) of a hemisulfate sait of the compound of Formula I, wherein Fonn C has an XRPD pattern as substantially shown în Figure 3.
12. The method of any one of daims 1-11, wherein the composition is an immédiate release fonnulation encapsulâted in a capsule, a modified release tablet formulation, or a modified release pellet fonnulation encapsulated in a capsule.
13. The method of claim 12, wherein the composition is a modified release pellet fonnulation encapsulated in a capsule, and the compound of Formula I, or a pharmaceutically acceptable sait thereof, îs present in an amount from about 0.05 mg to about 20 mg,
14. The method of any one of daims 1-13, wherein the compound of Fonnula I, or a pharmaceutically acceptable sait thereof, is present in the composition în an amount from about 0.01% to about 20% by weight, based on the total weight of the composition.
15. The method of claim 14, wherein the compound of Formula I, or a pharmaceutically acceptable sait thereof, is present in the composition in an amount from about 0.05% to about 15% by weight, based on the total weight ofthe composition.
16. The method of claim 6, wherein the composition is a modified release pellel formulation

5 encapsulated in a capsule, and a Form A monosulfate sait of the compound of Formula I is present in the composition in an amount from about 0.05 mg to about 20 mg.
17. The method of claim 16, wherein the Fonn A monosulfate sait is present in the composition in an amount from about 0.01% to about 20% by weight, based on the total weight ofthe composition.
18. The method of claim 17, wherein the Fonn A monosulfate sait is present in the composition in 10 an amount from about 0.05% to about 15% by weight, based on the total weight of the composition.
19. The method of claim 6, wherein the composition is an immédiate release formulation encapsulated in a capsule, comprising the foilowing formulation:

mg capsule form Λ ofmonosn liait sali îj j

I actusc Monohydratc 1W.9U

Siarch Mu/t Parti.tJly Ptvgelalini/cd 60.01 (type ! Soi) < Toscan uellosc Sodium K.dO

Povidonc 3<i ! 5,io

Sodium l.uiry 1 sulfate t.uo fait 6.o>

Magnésium Stéarate l .Ou total 2uti.no
20. The method of claim 6, wherein the composition is an immédiate release formulation

15 encapsulated in a capsule, comprising the foilowing fonnulation:

mg eapsuic

Ι οππ \ ol moiiosiiHate sait ! jcU'w Mo ne Indra te

Starch Maize i' if üly Prvgei.ttHiizcd (type l ( roseamici!ose Sodium posidone U* Sixiium lauryl sulfate Tak Magnésium Stéarate

i).6$i > lô9.34y w.ù ।

X.O !

I ÿoo

6.t*i

1.00

Total
21. The method of claim 6, wherein the composition is an immédiate release formulation encapsulated in a capsule, comprising the following formulation:

mg capsule

Fonn A of monosiiliate sait 2.602

1 actoxe Mono hydrate 107.39«

Starch Maize Partially Prcgclatmizcd (type 15«J) 6o.œ

Croscannellose Sodium s.co

Povidcute 30 Sodium iatirvl suit aie 1 s .at

Talc 6.U)

Mamtcsium Stéarate 1 .W

Total

2( «).(*»

5
22. The method of claim 6, wherein the composition is an immédiate release formulation encapsulated in a capsule, comprising the following formulation:

ITlfi capsule

Font; Λ of mcmosullate sait 26.U2 ! jdos.· Merioliviiratc K v>8

Starvh Maize t'ainai k l’regcl.ititu7cd 51 U ’¹ (K [x- 1 > t t rpsc.inncUûsc Xx\iiinn xjK* ii Une ?t> 1 γόο

Scditrm lAiiryl si il fa: e

J île 6.10

Maenestrun Sk-arak· l.oii

Total
23. The method of daim 6, wherein the composition is a modified release pellet formulation encapsulated in a capsule, and the composition comprises a formulation selected from the group consisting of Formulation 1, Fonnulation 2, Formulation 3, and Formulation 4, as shown in the table 5 below.

Group Fonnulation 1 Fut mutation 2 Foiinulation 3 | Formulation 4

Ingrédient Quantity (mg/capsule)

Fonn A imnioMilt’iiïe 0 13 o 2e (> os ; 1 30

M i croc rx sial line cellulose t>4 62 120 24 t>4 to : 128 20

Methacnlic acid copolymer 30 OU 6Û 00 30.00 t>0 00

Hypromellose 5 00 10 00 i ? <M> ίο üû 'î aie 0 25 i) so 0 2S j 0 50

Total 100,00 200 00 100 00 ; 1 200 00
24. The method of claim 6, wherein the pharmaceutically acceptable sait îs 90% by weight or more of the crystalline Form A based on the total weight ofthe sait present in the composition.
25. The method of claim 24, wherein the pharmaceutically acceptable sait is 95% by weight or more ofthe crystalline Form A based on the total weight ofthe sait present în the composition.
26. The method of claim 25, wherein the pharmaceutically acceptable sait is 99% by weight or more ofthe crystalline Form A based on the total weight ofthe sait present in the composition.

5
27. The method of any one of claims 1-26, wherein administering comprises administering once daily the compound of Fonnula I, or a pharmaceutically acceptable sait thereof.
28. The method of any one of claims 1-27, wherein administering comprises administering the compound of Formula 1, or a phannaceutically acceptable sait thereof, in an amount of about 0.1 mg to about 4.0 mg once daily.

10
29. The method of any one of claims 1-28, wherein administering comprises administering the compound of Fonnula I, or a pharmaceutically acceptable sait thereof, in an amount of about 0. l mg to about 3.5 mg once daily.
30. The method of any one of claims 1-29, wherein administering comprises administering the compound of Fonnula 1, or a pharmaceutically acceptable sait thereof, in an amount of about 0.1 mg 15 to about 3.0 mg once daily.
3 1. The method of any one of claims 1 -30, wherein administering comprises administering the compound of Fonnula i, or a pharmaceutically acceptable sait thereof, in an amount of about 1.0 mg to about 4.0 mg once daily.
32. The method of any one of claims 1-30, wherein administering comprises administering the 20 compound of Formula I, or a phannaceutically acceptable sait thereof, in an amount of about 1.5 mg to about 3.5 mg once daily.
33. The method of any one of claims 1-32, wherein administering comprises administering the compound of Formula I, or a pharmaceutically acceptable sait thereof, 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 i .0 mg once 25 daily.
34. The method of any one of claims l -33. wherein administering comprises administering the compound of Formula I, or a pharmaceutically acceptable sait thereof, in an amount of about 3.5 mg once daily.
35. The method of any one of claims i -33, wherein administering comprises administering the compound of Formula I, or a phannaceutically acceptable sait thereof, in an amount of about l .5 mg once daily.
36. The method of any one of claims l-35. wherein administering comprises administering orally the compound of Formula L or a phannaceutically acceptable sait thereof.
37. The method of any one of claims l -36, wherein administering comprises administering the compound of Formula I, or a phannaceutically acceptable sait thereof, as a unit dose.
38. The method of any one of claims l -37, wherein the TGN is classical TGN.
39. The method of any one of claims l-38, wherein the TGN is idiopathîc TGN.
40. The method of any one of claims l-39, wherein the therapeutic effect of the treatment is detemiined by:

a. réduction of the activity of high-voltage activated calcium channels;

b. réduction of the activity of voltage-gated sodium channels;

c. suppression ofthe propagation of an ion channel action potential; or

d. suppression of the rapid firing of neurons.
41. A method of treating trigeminal neuralgia, comprising administering to a subject in need thereof a solid pharmaceutical composition, wherein the solid pharmaceutical composition comprises a pharmaceutical excipient and a solid fonn of a compound of Formula I:

Cl

F (B, wherein the solid form is a crystalline anhydrate fonn (Fonn A) of a monosulfate sait ofthe compound of Formula I, characterized by at least three peaks selected from the following XRPD peaks obtained with a Cua_o radiation at 2Θ (2 Thêta); 9.8, 13.4, 14.2, i 8.1, 18.9, 19.6, 22.6. 22.9, 25.7. 27.1, and 29.9 (±0.2°); and has a particle size (Dv50) of less than or equal to about 100 μιη; and wherein the solid pharmaceutical composition is the fonn of a matrix pellet.
42. The method of claim 41, wherein the solid form has a particle size of less than 47 pm.
43. The method of claim 41, wherein the solid form has a particle size of less than or equal to about 25 pm.
44. The method of claim 41, wherein the solid fonn has a particle size of less than or equal to about 10 μιη.
45. The method ofany one of claims 41-44, wherein the Form A monosulfate sait is present în the composition in an amount of l% by weight or less, based on the total weight of the composition.
46. The method of claim 45, wherein the Fonn A monosulfate sait is present in the composition in an amount of 0.5% by weight or less, based on the total weight ofthe composition.
47. The method ofany one of claims 41 -46, wherein the phannaceutical excipient comprises one or more of a polymer, a binder, a disintegrant, a lubricant, and a glidant.
48. The method of claim 47, the polymer is one or more polymers selected from the group consistîng of a cellulose, methacrylic acid copolymer, and hypramellose.
49. The method ofany one of claims 41 -48, wherein the Fonn A monosulfate sait is characterized by the following XRPD peaks obtained with a Cua_h radiation at 2Θ (2 Thêta): 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°).
50. The method of any one of claims 41-49, wherein the Form A monosulfate sait has an XRPD pattern as substantially shown in Figure 1.
51. A method of treating trigeminal neuralgia, comprising administering to a subject in need thereof a composition comprising a therapeutically effective amount of an rnGluô négative allosteric modulator (NAM), or a pharmaceutically acceptable sait thereof, wherein the mGlu5 NAM is a compound of Formula I:

ci

(b
52. A method of treating trigeminal neuralgia, comprising administering to a subject in need thereof a composition comprising a therapeutically effective amount of an mGlu5 négative allosteric modulator (NAM), or a pharmaceutically acceptable sait thereof, wherein the mGlu5 NAM îs a compound of Formula I:

ci

(II.

wherein administering comprises administering the compound of Formula I, or a phannaceutically acceptable sait thereof, in an amount of about 1.5 mg to about 3.5 mg once daily.