Use of phosphodiesterase 10 inhibitors for the treatment of tourette's syndrome

Abstract

Provided herein are methods of treating Tourette Syndrome in a subject in need thereof by administering to the subject a composition comprising a PDE10 inhibitor of Formula (I). Also disclosed are crystalline solid forms of the compounds of Formula (I) and uses thereof.

Description

[0001] Cross-reference to related applications

[0002] This application claims priority to USSN 63 / 035,310, filed June 5, 2020, and USSN 63 / 160,302, filed March 12, 2021, the contents of each of which are incorporated herein by reference in their entirety. Background Technology

[0003] Tourette syndrome (TS) is a neurological disorder characterized by tics, which are involuntary vocalizations or repetitive, purposeless movements. It is estimated that up to 200,000 Americans have the most severe form of TS, and at least one in 100 Americans present with milder, less complex TS symptoms, which may include chronic motor or vocal tics (NIH Handbook on Tourette Syndrome (2012)). The prevalence of TS in American children aged 6–17 years is estimated at 0.3%, although there are indications that this may underestimate its prevalence (Cohen S et al. Neurosci Biobehav Rev. 37(6):997–1007 (2013)).

[0004] Currently, there are no medications that are helpful for all patients with TS. Although neuroleptic drugs (i.e., antipsychotics) are effective in treating tics in some patients, these drugs are associated with significant side effects, and they do not completely eliminate tic symptoms. In addition, the treatment of neurobehavioral disorders associated with TS (such as ADHD) can be complicated because some medications used to treat ADHD are contraindicated in patients with TS (see Prescribing Information for Ritalin) (2013).

[0005] Therefore, there is an unmet need to develop new treatments for the spectrum of TS symptoms, including tics and neurobehavioral disorders. Summary of the Invention

[0006] In one respect, this article provides a method for treating Durrell syndrome, comprising administering to a subject in need of it a composition containing a therapeutically effective amount of a therapeutic agent or a pharmaceutically acceptable salt thereof, wherein the therapeutic agent is a compound of formula I:

[0007]

[0008] In some implementations, subjects have a total tic score of at least 22 based on the Yale Global Tic Severity Scale.

[0009] In another aspect, provided herein are methods of treating Tourette's syndrome, the methods comprising administering to a subject in need thereof a composition containing a therapeutically effective amount of a therapeutic agent or a pharmaceutically acceptable salt thereof, wherein the subject has a total tic score of at least 22 based on the Yale Global Tic Severity Scale, and the therapeutic agent is a compound of Formula I:

[0010]

[0011] In certain embodiments, the subject has been previously administered an additional Tourette's syndrome therapy. In certain embodiments, the previously administered additional Tourette's syndrome therapy is administration of pimozide, haloperidol, or aripiprazole. In certain embodiments, the previously administered additional Tourette's syndrome therapy is administration of a psychostimulant (e.g., methylphenidate, dextroamphetamine, or lisdexamfetamine) or an alpha2 adrenergic receptor antagonist (e.g., atipamezole, efaroxan, or fluparoxan).

[0012] In certain embodiments, the therapeutically effective amount of the compound of Formula I or a pharmaceutically acceptable salt thereof is administered comprises administration of about 2.5 mg to about 5 mg of the compound of Formula I or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of Formula I or a pharmaceutically acceptable salt thereof is administered once per day. In certain embodiments, the compound of Formula I or a pharmaceutically acceptable salt thereof is administered orally. In certain embodiments, the compound of Formula I or a pharmaceutically acceptable salt thereof is administered as a unit dose.

[0013] In certain embodiments, the compound of Formula I is administered as the free base. In certain embodiments, the compound of Formula I is administered as a pharmaceutically acceptable salt.

[0014] In another aspect, provided herein are methods of treating Tourette's syndrome, the methods comprising administering to a subject in need thereof a composition containing a therapeutically effective amount of a phosphodiesterase 10 (PDE10) inhibitor or a pharmaceutically acceptable salt thereof, wherein the PDE10 inhibitor is a compound of Formula I:

[0015]

[0016] In certain embodiments, the subject has attention deficit hyperactivity disorder (ADHD). In certain embodiments, the subject does not have ADHD. In certain embodiments, the subject has obsessive compulsive disorder (OCD). In certain embodiments, the subject does not have OCD.

[0017] Also within the scope of the application are solid forms of the compound of Formula I:

[0018]

[0019] The solid form is a crystalline solid of the free base of the compound of formula I, and the melting point of the crystalline solid is about 210-214 °C (e.g., about 210 °C, about 211 °C, about 212 °C, about 213 °C or about 214 °C) by differential scanning calorimetry (DSC).

[0020] In some embodiments, the above-mentioned solid form is substantially as follows Figure 1 The X-ray powder diffraction (XRPD) pattern shown is of formula I, representing a free alkali crystalline solid.

[0021] In some embodiments, the above-mentioned solid form is substantially as follows Figure 2 The DSC diagram shown is of formula I, representing a free basal crystalline solid.

[0022] This invention also covers a method for treating Durrell syndrome, the method comprising administering to a subject in need a composition containing a therapeutically effective amount of a crystalline solid of a free base of formula I:

[0023]

[0024] The melting point of the solid obtained by DSC crystallization is approximately 210-214℃.

[0025] In some implementations, the above method includes having substantially as Figure 1 The X-ray powder diffraction (XRPD) pattern shown is of formula I, representing a free alkali crystalline solid.

[0026] In some implementations, the above method includes having substantially as Figure 2 The DSC diagram shown is of formula I, representing a free basal crystalline solid. Attached Figure Description

[0027] Figure 1 An exemplary XRPD plot depicting the crystalline solid of the free base of compound I.

[0028] Figure 2 An exemplary DSC plot depicting the crystalline solid of the free base of compound I. Detailed Implementation

[0029] As generally described herein, this disclosure provides a method for treating Durrell syndrome in subjects who require it. This disclosure also describes the crystalline form of the free base of compound I and its uses.

[0030] definition

[0031] To facilitate understanding of this invention, some terms and phrases are defined below.

[0032] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. Abbreviations used herein are in accordance with the standard abbreviations accepted by the chemical and biochemical arts. The chemical structures and formulas set forth herein are constructed according to the standard rules of chemical valence known in the chemical arts.

[0033] Throughout this specification, unless otherwise indicated, the compositions described are described as having, including, or comprising specific components, or as having, including, or comprising specific steps, it is contemplated that, additionally, the compositions of the present application can, optionally, consist essentially of, or consist of, the specific components, and that the processes and methods of the present application can, optionally, consist essentially of, or consist of, the specific steps.

[0034] In this application, when an element or component is said to be included in the list of elements and / or components and / or selected from the group of elements and / or components, it should be understood that the element or component can be any one of the elements or components in the list, or the element or component can be selected from two or more of the elements or components in the list.

[0035] Further, it should be understood that elements and / or features of a composition or method described herein can be combined in a variety of ways without departing from the spirit and scope of the present teachings, whether explicit or implicit. For example, where reference is made to a particular compound, that compound can be used in various embodiments of the compositions of the present teachings and / or in the methods of the present teachings, unless otherwise understood from the context. In other words, the disclosure is, in part, directed to all combinations of particular implementations of the present teachings, whether explicit or implicit. For example, it should be understood that all features described and depicted herein are applicable to all aspects of the present teachings described and depicted herein.

[0036] The articles "a" and "an" are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article unless otherwise indicated by context. By way of example, "an element" means one element or more than one element.

[0037] The term "and / or" used in the disclosure is used to mean "and" or "or", unless otherwise indicated by context.

[0038] It should be understood that the expression "at least one of' includes each of the individual recited objects and various combinations of two or more of the recited objects unless otherwise indicated by context and usage. The expression "and / or" associated with three or more recited objects should be understood to have the same meaning, unless otherwise indicated by context.

[0039] The use of the terms “include,” “includes,” “including,” “have,” “has,” “having,” “contains,” “contains,” or “containing,” including their grammatical equivalents, should generally be understood as open-ended and non-restrictive, e.g., not excluding additional undescribed elements or steps unless the context otherwise specifies or understands.

[0040] When the term "about" is used before a quantitative value, the invention also includes the specific quantitative value itself, unless otherwise specifically stated. As used herein, the term "about" refers to ±10% variation of the index value, unless the context otherwise indicates or infers.

[0041] Throughout this specification, variables or parameters are disclosed in groups or ranges. Specifically, the description is intended to include individual and individual sub-combinations of the members of such groups and ranges. For example, integers in the range 0-40 are specifically intended to be disclosed individually as 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 integers in the range 1-20 are specifically intended to be disclosed individually as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20.

[0042] The use of any and all instances or exemplary language in this document, such as "for example" or "including," is intended only to better illustrate the invention and, unless claimed, does not constitute a limitation on the scope of the invention. None of the language in the specification should be construed as indicating that any non-claimed element is essential to the practice of the invention.

[0043] Generally, unless otherwise specified, percentages are defined as being by weight. Furthermore, if a variable has no accompanying definition, its prior definition prevails.

[0044] As used herein, “pharmaceutical composition” or “pharmaceutical preparation” refers to a combination of an active agent and an excipient or carrier (inert or active) that makes the composition particularly suitable for in vivo or in vitro diagnostic or therapeutic purposes.

[0045] "Pharmaceutical acceptable" means approved or permitted by a federal or state regulatory agency or a corresponding agency in a country other than the United States, or listed in the United States Pharmacopeia or other generally recognized pharmacopoeia for use in animals, and more particularly for use in humans.

[0046] As used herein, “pharmaceutically acceptable salt” means a salt of any acidic or basic group that may be present in the compounds of the present invention (e.g., compounds of formula (I)) and that is compatible with drug administration.

[0047] As is known to those skilled in the art, the “salt” of a compound can be derived from inorganic or organic acids and bases. 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, p-toluenesulfonic 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, although not pharmaceutically acceptable on their own, can be used to prepare salts as intermediates for obtaining the compounds described herein and their pharmaceutically acceptable acid addition salts.

[0048] Examples of bases include, but are not limited to, alkali metal (e.g., sodium and potassium) hydroxides, alkaline earth metal (e.g., magnesium and calcium) hydroxides, ammonia, and NW4. + Compounds in which W is C 1-4 Alkyl groups, etc.

[0049] Examples of salts include, but are not limited to, acetates, adipates, alginates, aspartates, benzoates, benzenesulfonates, hydrogen sulfates, butates, citrates, camphorates, camphorsulfonates, cyclopentanepropionates, disaccharides, dodecyl sulfates, ethanesulfonates, fumarates, fluoroheptates, glycerophosphates, hemisulfates, heptanates, hexanoates, hydrochlorides, hydrobromide, hydroiodates, 2-hydroxyethanesulfonate, lactates, maleates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, oxalates, palmitates, pectates, persulfates, phenylpropionates, picrates, neopentanoates, propionates, succinates, tartrates, thiocyanates, toluenesulfonates, undecanoates, etc. Other examples of salts include anions of the compounds of this invention combined with suitable cations such as Na. + K + Ca 2+ NH4 + and NW4 + (where W can be C) 1-4 Alkyl groups and other complexes.

[0050] For therapeutic purposes, salts of the compounds of the present invention are considered pharmaceutically acceptable. However, salts of non-pharmaceutically acceptable acids and bases may also be found for, for example, the preparation or purification of pharmaceutically acceptable compounds.

[0051] As used herein, "pharmaceutically acceptable excipient" refers to a substance that aids in administration of an active agent to a subject and / or absorption by the subject, and that can be included in the compositions of the present application without posing a significant toxicity problem to the patient. Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, solutions of physiological salts such as phosphate buffered saline solution, emulsions (e.g. oil / water or water / oil emulsions), lactated Ringer's solution, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavorants, salt solutions (e.g. Ringer's solution), alcohols, oils, gelatins, carbohydrates such as lactose, amylose or starch, fatty acids esters, hydroxymethyl cellulose, polyvinyl pyrrolidine and colors, and the like. Such preparations can be sterilized and, if desired, mixed with auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, colorings and / or aromatics and the like which do not deleteriously react with the compounds of the present application. For examples of excipients, see Martin, Remington's Pharmaceutical Sciences, 15th Ed., Mack Publ. Co., Easton, PA (1975).

[0052] "Subject" for purposes of consideration of administration includes, but is not limited to, humans (i.e., male or female of any age group, such as pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adult, middle-aged adult, or senior adult)) and / or non-human animals, such as mammals, such as primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, swine, 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.

[0053] "Solid dosage form" as used herein means a pharmaceutical dosage in solid form such as tablets, capsules, granules, powders, sachets, reconstitutable powders, dry powder inhalers, and chewable tablets.

[0054] "Administering" as used herein means oral administration, administration as a suppository, topical contact, intravenous administration, parenteral administration, intraperitoneal administration, intramuscular administration, intralesional administration, intrathecal administration, intracranial administration, intranasal administration, or subcutaneous administration, transmucosal (e.g., buccal, sublingual, intranasal, or transdermal) administration, or implanting a slow-release device, such as a microosmotic pump, into a subject. Parenteral administration includes, e.g., intravenous, intramuscular, intraarterial, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial. Other modes of delivery include, but are not limited to, use of liposomal formulations, intravenous infusion, transdermal patches, and the like.

[0055] "Co-administration" means administration of a composition described herein at the same time, immediately before, or immediately after administration of one or more additional therapies, such as an anti-cancer agent, a chemotherapeutic, or a treatment for a neurodegenerative disease. A compound of Formula I, or a pharmaceutically acceptable salt thereof, can be administered to a subject alone or can be co-administered. Co-administration is intended to include concurrent or sequential administration, either separately or in combination.

[0056] As used herein, and unless otherwise specified, the terms "treat," "treating," and "treatment" contemplate an action that occurs when a subject is suffering from a particular disease, disorder, or condition, that reduces the severity of the disease, disorder, or condition, or retards or slows the progression of the disease, disorder, or condition (e.g., "therapeutic treatment").

[0057] The phrase "therapeutically effective amount" as used herein means an amount of a composition (e.g., a composition described herein) or a compound of Formula I, or a pharmaceutically acceptable salt thereof, effective to produce some desired therapeutic effect in a subject.

[0058] Tourette Syndrome is described in the Diagnostic and Statistical Manual of Mental Disorders, 5thEdition (DSM-5, 2013) as a disorder characterized by the presence of both multiple motor and one or more vocal tics, with symptoms lasting more than one year. Tics are sudden, rapid, repetitive, purposeless motor movements or vocalizations. Symptoms generally appear before the age of 18. The term "Tourette Syndrome" as used herein includes "persistent (chronic) motor or vocal tic disorder," "persistent (chronic) vocal or motor tic disorder," "transient tic disorder," and "tic disorder." A Tourette Syndrome patient can have both motor and vocal tic symptoms that have been present for at least one year. However, a "tic disorder" patient can have only motor or vocal tics. A "persistent (chronic) motor tic disorder" patient can have only motor tics. A "persistent (chronic) vocal tic disorder" patient can have only vocal tics. A "transient tic disorder" patient can have symptoms for less than one year.

[0059] TS patients can also have symptoms of inattention, hyperactivity, anxiety, mood, and sleep disorders. Currently, TS can be diagnosed using one or more rating scales. One exemplary rating scale is the Yale Global Tic Severity Scale as described in Storch et al., Psychol Assess., 2005, 17(4):486-91.

[0060] Compound

[0061] The compound of Formula I, depicted below, is a phosphodiesterase 10 (PDE10) inhibitor, also known as 1 -methyl-4-(morpholine-4-carbonyl)-N-(2-phenyl[l,2,4]triazolo[l,5- a]pyridin-7-yl)-lH-pyrazole-5-carboxamide.

[0062]

[0063] A method of chemically synthesizing the compound of Formula I (including Example 1 provided below) is described in U.S. Patent No. 8,349,824, which is incorporated by reference in its entirety.

[0064] In various embodiments, the pharmaceutically acceptable salt of the compound of Formula I can 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.

[0065] The present application also encompasses solid forms of the compound of Formula I:

[0066]

[0067] wherein the solid form is a crystalline solid of the free base of the compound of Formula I, and the melting point of the crystalline solid is about 210-214 °C (e.g., about 210 °C, about 211 °C, about 212 °C, about 213 °C, or about 214 °C) by differential scanning calorimetry (DSC).

[0068] In some embodiments, the solid form described above is a crystalline solid of the free base of Formula I having an X-ray powder diffraction (XRPD) pattern substantially as shown in Figure 1

[0069] In some embodiments, the solid form described above is a crystalline solid of the free base of Formula I having a DSC pattern substantially as shown in Figure 2

[0070] Pharmaceutical Compositions

[0071] In one aspect, provided herein is a pharmaceutical composition for treating Tourette Syndrome in a subject in need thereof, comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. It should be understood that the compound of Formula I as described herein includes the crystalline solid of the free base of the compound of Formula I as described herein.

[0072] ​​In various embodiments, the amount of the compound of Formula I, or a pharmaceutically acceptable salt thereof, in the pharmaceutical compositions described herein can be about 1 mg to about 10 mg, about 1.5 mg to about 10 mg, about 2 mg to about 10 mg, about 2.5 mg to about 10 mg, about 3 mg to about 10 mg, about 3.5 mg to about 10 mg, about 4 mg to about 10 mg, about 4.5 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 1 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 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 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 2.5 mg to 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, about 8 mg to about 9 mg, or about 9 mg.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 I, or a pharmaceutically acceptable salt thereof, in the pharmaceutical composition described herein can be about 2.5 mg to about 5 mg.

[0073] In various embodiments, the amount of the compound of Formula I, or a pharmaceutically acceptable salt thereof, in the pharmaceutical composition described herein can be 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. In certain embodiments, the amount of the compound of Formula I, or a pharmaceutically acceptable salt thereof, in the pharmaceutical composition described herein can be about 2.5 mg. In certain embodiments, the amount of the compound of Formula I, or a pharmaceutically acceptable salt thereof, in the pharmaceutical composition described herein can be about 5 mg.

[0074] In another aspect, provided herein is a pharmaceutical composition for treating Tourette Syndrome in a subject in need thereof, comprising about 2.5 mg to about 5 mg of a compound of Formula I, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient. In another aspect, provided herein is a pharmaceutical composition for treating Tourette Syndrome in a subject in need thereof, comprising about 5 mg to about 15 mg of a compound of Formula I, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient.

[0075] In another aspect, provided herein is a pharmaceutical composition for treating Tourette Syndrome in a subject in need thereof, comprising about 2.5 mg to about 5 mg of a compound of Formula I, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient, wherein the subject has a total tic score of at least 22 based on the Yale Global Tic Severity Scale.

[0076] In various embodiments, to effectively treat Tourette's Syndrome in a subject in need thereof, wherein the subject has a total tics score of at least 22 based on the Yale Global Tics Severity Scale, the compound of Formula I, or a pharmaceutically acceptable salt thereof, in a pharmaceutical composition can be administered at a daily dose of about 1 mg to about 20 mg, about 2 mg to about 19 mg, about 3 mg to about 18 mg, about 4 mg to about 17 mg, about 5 mg to about 16 mg, about 5 mg to about 15 mg, about 6 mg to about 14 mg, about 7 mg to about 13 mg, about 8 mg to about 12 mg, about 9 mg to about 11 mg, or about 9 mg to about 10 mg. In certain embodiments, the amount administered per day can be about 2.5 mg to about 5 mg. In certain embodiments, the amount administered per day can be about 5 mg to about 15 mg.

[0077] In various embodiments, to effectively treat Tourette's Syndrome in a subject in need thereof, wherein the subject has a total tics score of at least 22 based on the Yale Global Tics Severity Scale, the compound of Formula I, or a pharmaceutically acceptable salt thereof, in a pharmaceutical composition can be administered at a daily dose of 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, about 10 mg, about 10.5 mg, about 11 mg, about 11.5 mg, about 12 mg, about 12.5 mg, about 13 mg, about 13.5 mg, about 14 mg, about 14.5 mg, about 15 mg, about 15.5 mg, about 16 mg, about 16.5 mg, about 17 mg, about 17.5 mg, about 18 mg, about 18.5 mg, about 19 mg, about 19.5 mg, about 20 mg, about 20.5 mg. In certain embodiments, the amount administered per day can be about 2.5 mg, about 3 mg, about 3.5 mg, about 4 mg, about 4.5 mg, or about 5 mg. In certain embodiments, the amount administered per day can be about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, or about 15 mg.

[0078] In various embodiments, the pharmaceutical compositions described herein comprise a therapeutically effective amount of the free base form of the compound of Formula I.

[0079] In various embodiments, the pharmaceutical compositions described herein comprise a therapeutically effective amount of a pharmaceutically acceptable salt of a compound of Formula I. In some embodiments, the pharmaceutically acceptable salt of a compound of Formula I can be a salt of a 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.

[0080] The pharmaceutical compositions provided herein can be administered by a variety of routes, including, but not limited to, oral (enteral) administration, parenteral (by injection) administration, rectal administration, transdermal administration, intradermal administration, intrathecal administration, subcutaneous (SC) administration, intravenous (IV) administration, intramuscular (IM) administration, and intranasal administration. In certain embodiments, the pharmaceutical compositions disclosed herein are administered orally.

[0081] The pharmaceutical compositions provided herein can also be administered chronically (“chronic administration”). Chronic administration refers to administration of a compound or a pharmaceutical composition thereof over an extended period of time, e.g., for more than 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc., or can continue indefinitely, e.g., for the remainder of the subject’s life. In certain embodiments, chronic administration is intended to provide a constant level of the compound in the blood, e.g., within a therapeutic window, over an extended period of time.

[0082] The pharmaceutical compositions provided herein can be presented in unit dosage form to facilitate accurate dosing. The term “unit dosage form” refers to physically discrete units suitable for unitary dosing to human subjects and other mammals, each unit containing a predetermined quantity of active material 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 unit doses. Typical unit dosage forms include liquid compositions pre-filled, pre-measured ampules or syringes, or, in the case of solid compositions, pills, tablets, capsules, etc.

[0083] In various embodiments, the pharmaceutical compositions provided herein are administered to a patient as a solid dosage form. In certain embodiments, the solid dosage form is a capsule. In certain embodiments, the solid dosage form is a tablet.

[0084] In various embodiments, the pharmaceutical compositions provided herein comprise a compound of Formula I as the only active agent, or in combination with other active agents.

[0085] While the description of the pharmaceutical compositions provided herein is primarily concerned with pharmaceutical compositions suitable for administration to humans, it is understood that such compositions are also suitable for administration to animals of all sorts. Modifications can be made in the pharmaceutical compositions described herein to adapt them to the circumstances of the animal, as is understood by those of skill in the art. General considerations in formulating and / or manufacturing pharmaceutical compositions can be found, e.g., in Remington: The Science and Practice of Pharmacy 21st Ed., Lippincott Williams & Wilkins, 2005.

[0086] Methods of use and treatment

[0087] In one aspect, provided herein are methods of treating Tourette Syndrome in a subject in need thereof.

[0088] In various embodiments, provided herein are methods for treating Tourette Syndrome in a subject in need thereof, the method comprising administering to the subject in need thereof a composition containing a therapeutically effective amount of a therapeutic agent, or a pharmaceutically acceptable salt thereof, wherein the therapeutic agent is a compound of Formula I:

[0089]

[0090] In certain embodiments, the subject has a total tics score of at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, or at least 25 based on the Yale Global Tic Severity Scale. In certain embodiments, the subject has a total tics score of at least 22 based on the Yale Global Tic Severity Scale.

[0091] In some embodiments, provided herein are methods of treating Tourette Syndrome in a subject in need thereof, the method comprising administering to the subject in need thereof a composition containing a therapeutically effective amount of a therapeutic agent, or a pharmaceutically acceptable salt thereof, wherein the subject has a total tics score of at least 22 based on the Yale Global Tic Severity Scale, and the therapeutic agent is a compound of Formula I:

[0092]

[0093] In various embodiments, the subject has been previously administered an additional treatment for Tourette's syndrome. In certain embodiments, the previously administered additional treatment for Tourette's syndrome is administration of pimozide, haloperidol, or aripiprazole. In certain embodiments, the previously administered additional treatment for Tourette's syndrome is administration of a psychostimulant (e.g., methylphenidate, dextroamphetamine, or lisdexamfetamine) or an alpha2 adrenergic receptor antagonist (e.g., atipamezole, efaroxan, or fluparoxan). In certain embodiments, the previously administered additional treatment for Tourette's syndrome is administration of pimozide, haloperidol, aripiprazole, methylphenidate, dextroamphetamine, or lisdexamfetamine, atipamezole, efaroxan, or fluparoxan.

[0094] In various embodiments, administering a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, comprises administering a composition having a compound amount as described above.

[0095] In various embodiments, the composition comprises a compound of Formula I, or a pharmaceutically acceptable salt thereof, as the only active agent.

[0096] In various embodiments, the composition comprises a compound of Formula I, or a pharmaceutically acceptable salt thereof, in combination with an additional active agent. In certain embodiments, the additional active agent is olanzapine or risperidone.

[0097] In various embodiments, the composition comprises a non-active agent selected from the group consisting of mannitol, microcrystalline cellulose, sodium starch glycolate, sucrose monopalmitate, hydroxypropyl methylcellulose, colloidal silicon dioxide, and sodium stearyl fumarate.

[0098] In various embodiments, administering comprises administering a compound of Formula I, or a pharmaceutically acceptable salt thereof, in a capsule.

[0099] In various embodiments, the capsule shell consists of gelatin, titanium dioxide, iron oxide red, and iron oxide yellow.

[0100] In various embodiments, the capsule described above comprises about 1 mg to about 10 mg of a compound of Formula I, or a pharmaceutically acceptable salt thereof.

[0101] In various embodiments, the capsule comprises about 2.5 mg to about 5 mg of a compound of Formula I, or a pharmaceutically acceptable salt thereof.

[0102] In various embodiments, administering comprises administering a compound of Formula I, or a pharmaceutically acceptable salt thereof, in an amount of about 2.5 mg to about 5 mg once a day.

[0103] In various embodiments, administering comprises administering a compound of Formula I, or a pharmaceutically acceptable salt thereof, in an amount of about 5 mg to about 15 mg once a day.

[0104] In various embodiments, administration includes administration of the compound of Formula I, or a pharmaceutically acceptable salt thereof, in an amount of about 1 mg to about 20 mg once a day.

[0105] In various embodiments, administration includes administration of the compound of Formula I, or a pharmaceutically acceptable salt thereof, in an amount of about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, or about 15 mg once a day.

[0106] In various embodiments, administration includes administration of the compound of Formula I, or a pharmaceutically acceptable salt thereof, in an amount of 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, about 10 mg, about 10.5 mg, about 11 mg, about 11.5 mg, about 12 mg, about 12.5 mg, about 13 mg, about 13.5 mg, about 14 mg, about 14.5 mg, about 15 mg, about 15.5 mg, about 16 mg, about 16.5 mg, about 17 mg, about 17.5 mg, about 18 mg, about 18.5 mg, about 19 mg, about 19.5 mg, or about 20 mg once a day. In embodiments, administration includes administration of the compound of Formula I, or a pharmaceutically acceptable salt thereof, in an amount of about 2.5 mg once a day. In embodiments, administration includes administration of the compound of Formula I, or a pharmaceutically acceptable salt thereof, in an amount of about 5 mg once a day. In various embodiments, administration includes administration of the compound of Formula I, or a pharmaceutically acceptable salt thereof, in an immediate release formulation.

[0107] In various embodiments, administration includes administration of the compound of Formula I, or a pharmaceutically acceptable salt thereof, in an extended release formulation.

[0108] In various embodiments, administration maintains therapeutic efficacy throughout the day.

[0109] In various embodiments, the compound of Formula I, or a pharmaceutically acceptable salt thereof, is administered once, twice, three times, four times, or five times a day. In certain embodiments, the compound of Formula I, or a pharmaceutically acceptable salt thereof, is administered once a day.

[0110] In various embodiments, the compound of Formula I, or a pharmaceutically acceptable salt thereof, is administered orally.

[0111] In various embodiments, the compound of Formula I, or a pharmaceutically acceptable salt thereof, is administered as a unit dose.

[0112] In various embodiments, the compound of Formula I is administered as a free base.

[0113] In various embodiments, the compound of Formula I is administered as a pharmaceutically acceptable salt. In certain embodiments, the pharmaceutically acceptable salt of the compound of Formula I can be a salt of a 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. In certain embodiments, the compound of Formula I is administered in crystalline form.

[0114] In various embodiments, provided herein are methods of treating Tourette Syndrome in a subject in need thereof, the methods comprising administering to the subject in need thereof a composition containing a therapeutically effective amount of a phosphodiesterase 10 (PDE10) inhibitor, or a pharmaceutically acceptable salt thereof, wherein the PDE10 inhibitor is a compound of Formula I:

[0115]

[0116] In various embodiments, the TS subject is also diagnosed with one or more diseases, disorders, or conditions selected from the group consisting of attention deficit hyperactivity disorder (ADHD), obsessive compulsive disorder (OCD), oppositional defiant disorder (ODD), conduct disorder, anxiety disorder, autism, mood disorder, phobia, and depression. In various embodiments, the TS subject does not have ADHD, OCD, ODD, conduct disorder, anxiety disorder, autism, mood disorder, phobia, and depression. In certain embodiments, the subject has ADHD. In certain embodiments, the subject does not have ADHD. In certain embodiments, the subject has OCD. In certain embodiments, the subject does not have OCD.

[0117] In various embodiments, the compound of Formula I is administered as a monotherapy.

[0118] In various embodiments, the methods provided herein further comprise administering to the subject a therapeutically effective amount of a second therapeutic agent.

[0119] Without further elaboration, it is believed that one skilled in the art can, based on the description herein, utilize the present application to its fullest extent. The following specific examples are, therefore, to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever.

[0120] Examples

[0121] In order that the disclosure herein described can be more fully understood, the following examples are set forth. The examples described in the present application are provided to illustrate the compounds, pharmaceutical compositions, and methods provided herein, and should not be construed to limit the scope of the disclosure in any way.

[0122] Example 1: Synthesis of 1 -methyl-4-(morpholine-4-carbonyl)-N-(2-phenyl[1,2,4]triazolo[1,5- a]pyridin-7-yl)-1 H-pyrazole-5-carboxamide (compound of Formula I) [see U.S. Patent No. 8,349,824].

[0123] 1 -Methyl-5-(2-phenyl-[ 1,2,4]triazolo[ 1,5-a]pyridin-7-ylcarbamoyl)- 1 H-pyrazole-4- carboxylic acid methyl ester 1 -Methyl-5-(2-phenyl-[ 1,2,4]triazolo[ 1,5-a]pyridin-7-ylcarbamoyl)- 1 H-pyrazole-4- carboxylic acid

[0124] Step A - 1,2-Diamino-4-bromo-pyridinium 2,4,6-trimethyl-benzenesulfonate: To a cooled suspension of O-(mesitylenesulfonyl)hydroxylamine (11.22 g, 52.1 mmol, 1 eq) in dichloromethane (130 ml) was added 4-bromo-pyridin-2-amine (9.3 g, 52.1 mmol, 1 eq.) in portions (exothermic reaction, some cooling was required) to give a white suspension. After 1 h, the white suspension was diluted with diethyl ether (120 ml). The white solid was collected by filtration, washed with diethyl ether and dried to give 1,2-diamino-4-bromo-pyridinium 2,4,6-trimethyl-benzenesulfonate as white crystals (16.74 g, 82.7%). mp.: 176-180 °C. MS: m / z = 188.2, 190.2 (M+H + ).

[0125] Step B - 7-Bromo-2-phenyl-[1,2,4]triazolo[1,5-a]pyridine: 1,2-Diamino-4-bromo-pyridinium 2,4,6-trimethyl-benzenesulfonate (15.6 g, 40.2 mmole) in pyridine (106 ml) was heated at 100 °C overnight with benzoyl chloride (9.4 ml, 80 mmole) to give a brownish red solution and a brown suspension after 2 hrs. The reaction mixture was concentrated in vacuo and the residue was triturated in saturated aqueous ammonium chloride (300 ml) for 2.5 hr while neutralizing to pH 6-7 with saturated aqueous sodium bicarbonate. The solid was collected by filtration, washed with water (40 ml) and dried to give 7-bromo-2-phenyl-[1,2,4]triazolo[1,5-a]pyridine as off-white solid (6.78 g, 61.6%). mp.: 189-191 °C. MS: m / z = 276.1, 274.2 (M+H + ).

[0126] Step C - (2-phenyl-[l,2,4]triazolo[l,5-a]pyridin-7-yl)-carbamic acid tert-butyl ester: To a nitrogen purged suspension of 7-bromo-2-phenyl-[l,2,4]triazolo[l,5- a]pyridine (9 g, 32.8 mmol) in dioxane (180 ml) was added successively tert- butyl carbamate (4.71 g, 39.4 mmol), tris(dibenzylideneacetone)dipalladium(0) (601 mg, 657 μmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (760 mg, 1.31 mmol) and cesium carbonate (15 g, 46 mmol). The brown mixture was then stirred at 100 °C under a nitrogen atmosphere for 22 h. The solvent was removed in vacuo and the brown residue was partitioned between ethyl acetate and water. The aqueous layer was extracted twice with ethyl acetate and the combined organic layers were washed with water (3 x 120 ml) and brine and dried over magnesium sulfate. The solution was concentrated in vacuo to ca. 80 ml: crystallization. The suspension was stirred in an ice bath for 10 min and the solid was collected by filtration, washed with a small amount of cold ethyl acetate and dried to give (2-phenyl-[l,2,4]triazolo[l,5-a]pyridin-7-yl)-carbamic acid tert-butyl ester (7.09 g) as an off-white solid. The mother liquor was evaporated and the residue was loaded onto silica gel (16 g). The product was isolated by chromatography on a 120 g silica gel cartridge (eluent heptane / ethyl acetate 10-50%, 45 min) to give a second crop of 1.748 g of white solid. mp.: 200-201 °C. Decomposition. MS: m / z = 311.3 (M+H + ). Overall yield: 86.7%.

[0127] Step D - 2-phenyl-[l,2,4]triazolo[l,5-a]pyridin-7-ylamine: A suspension of (2-phenyl-[l,2,4]triazolo[l,5-a]pyridin-7-yl)-carbamic acid tert-butyl ester (8.5 g, 27.4 mmol) in hydrochloric acid (6 N in diethyl ether, 175 ml) was stirred at room temperature overnight. The suspension was diluted with water (ca. 2 1) and ethyl acetate under cooling, the aqueous layer was washed once with ethyl acetate, made basic with 32% aqueous sodium hydroxide and extracted twice with ethyl acetate. The combined organic layers were dried over magnesium sulfate and the solvent was removed in vacuo to give 2-phenyl-[l,2,4]triazolo[l,5-a]pyridin-7-ylamine (5.52 g, 95.9%) as a light pink solid. mp.: 212-213 °C. MS: m / z = 211.2 (M+H + ).

[0128] Step E - 1 -Methyl-5-(2-phenyl-[ 1,2,4]triazolo[ 1,5-a]pyridin-7- ylcarbamoyl)-lH-pyrazole-4-carboxylic acid methyl ester: A solution of 2-phenyl- [l,2,4]triazolo[l,5-a]pyridin-7-ylamine (1.534 g, 7.3 mmol), 4-(methoxycarbonyl)- 1 -methyl- 1 H-pyrazole-5-carboxylic acid (1.61 g, 8.76 mmol), propylphosphonic anhydride (50% in ethyl acetate, 10.7 ml, 18.2 mmol) and diisopropylethylamine (5.1 ml, 29.2 mmol) in tetrahydrofuran (54 ml) was stirred at 70 °C for 1.25 hr to give a white suspension. The cooled suspension was poured into saturated aqueous sodium bicarbonate (200 ml), stirred at room temperature for 15 min and the solid collected by filtration, washed with water and dried to give 1 -methyl-5-(2-phenyl- [l,2,4]triazolo[l,5-a]pyridin-7-ylcarbamoyl)-lH-pyrazole-4-carboxylic acid methyl ester as a white solid (2.596 g, 94.5%). mp.: 243-7 °C. MS: m / z = 377.2 (M+H + ).

[0129] 1 -Methyl-4-(morpholine-4-carbonyl)-N-(2-phenyl[ 1,2,4]triazolo[ 1,5-a]pyridin-7-yl)- 1 H- pyrazole-5-carboxamide Study Purpose

[0130] A white suspension of 1 -methyl-5-(2-phenyl-[ 1,2,4]triazolo[ 1,5-a]pyridin-7- ylcarbamoyl)-lH-pyrazole-4-carboxylic acid methyl ester (2.37 g, 6.3 mmol) and lithium hydroxide monohydrate (291 mg, 6.93 mmol) in methanol (100 ml) and water (20 ml) was stirred at 70 °C for 1.25 hr, after 20 min a colourless solution was obtained. The methanol was removed in vacuo, the residue was diluted with water and the cooled aqueous solution neutralised with 2N aqueous hydrochloric acid (3.46 ml, 6.03 mmol). The solid was collected by filtration and dried to give 1 -methyl-5-(2-phenyl- [l,2,4]triazolo[l,5-a]pyridin-7-ylcarbamoyl)-lH-pyrazole-4-carboxylic acid as a white solid (2.21 g, 97%). mp.:

[0131] >300 °C. MS: m / z = 361.1 (M+H + ).

[0132] Study Design Study Phases

[0133] A mixture of 1 -methyl-5-(2-phenyl-[1,2,4]-triazolo[1,5-a]pyridin-7- ylcarbamoyl)-1 H-pyrazole-4-carboxylic acid (100 mg, 276 μmol), morpholine (240 μl, 2.76 mmol) and propylphosphonic anhydride (50% in ethyl acetate, 407 μl, 690 umol) in tetrahydrofuran (7 ml) was stirred at 70°C for 3 hours. The mixture was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate solution and brine. The organic layer was separated, dried over magnesium sulfate and the solvent was evaporated. The residue (76 mg white foam) was triturated with diethyl ether and ethyl acetate to give 1 -methyl-4-(morpholine-4-carbonyl)-N-(2-phenyl- [1,2,4]triazolo[1,5-a]pyridin-7-yl)-1 H-pyrazole-5-carboxamide as a white solid (53 mg, 44.5%). mp.: 203-207°C. MS: m / Z = 432.4 (M+H ).

[0134] Example 2: Efficacy study of a compound of formula I for the treatment of subjects with Tourette syndrome

[0135] Number of Patients

[0136] Primary efficacy objective: To evaluate the efficacy of a double-blind, 12-week, once-daily dose of a compound of formula I (2.5 mg - 5 mg) compared to placebo in adolescent and adult patients with Tourette syndrome (TS). The primary outcome is the change from baseline to Week 12 (or endpoint) in the Yale Global Tic Severity Scale (YGTTS).

[0137] Secondary objectives:

[0138] 1. Percent change from baseline to Week 12 (or endpoint) in YGTSS total tic score (TTS); efficacy is evaluated by the percent change in TTS subjects from randomization to last visit (Week 12) based on YGTSS.

[0139] 2. Remission rate based on the Clinician Global Impression of Tourette Syndrome (TS-CGI) change scale; remission rate (percentage of patients with a score of 1 or 2) is evaluated by the TS-CGI change scale at Week 12 (or endpoint) versus baseline.

[0140] 3. Remission rate based on the Patient Global Change Impression (PGIC); patient-reported remission (percentage of patients with a score of 1 or 2) is reported at Week 12 (or endpoint) of the study.

[0141] 4. Partial remission rate based on the investigator-assessed TS-CGI Improvement Scale; the partial remission rate (percentage of patients with a score of 3) is assessed by the TS-CGI Improvement Scale from baseline to Week 12 (or endpoint).

[0142] 5. Change in TS-CGI Severity Scale score from baseline to Week 12 (or endpoint); this is assessed by the change in TS-CGI Severity Scale score from baseline to Week 12 (or endpoint).

[0143] Target Population

[0144] This is a multicenter, randomized, double-blind, placebo-controlled study in patients who show the least evidence of benefit from their current treatment.

[0145] Patients diagnosed with TS who sign the informed consent, meet the study eligibility criteria, and agree to participate in the study enter a screening period of up to 30 days.

[0146] Eligible patients are randomized to receive one of two treatments via an interactive voice / web response system:

[0147] 1. Treatment A: 2.5 mg or 5 mg dose of the compound of Formula I

[0148] 2. Treatment B: Placebo

[0149] At the end of the screening period, patients who continue to meet all inclusion criteria are randomized to receive double-blind treatment.

[0150] Efficacy Outcome Measures

[0151] The total study duration is up to 16 weeks.

[0152] 1. Screening and stabilization phase: 4 weeks

[0153] 2. Randomization phase: 12 weeks

[0154] Safety Outcome Measures

[0155] A total of 90 patients are randomized to treatment groups. It is estimated that 120 patients will be screened and 90 eligible patients will be randomized.

[0156] Evaluation Schedule

[0157] Patients meet the following study inclusion criteria:

[0158] 1. Ability and willingness to provide written informed consent and to comply with the study procedures;

[0159] 2. Fluency in the language of the investigator, study staff, and informed consent.

[0160] 3. Age between 11-50 years;

[0161] 4. Subject meets TS diagnostic criteria of the current Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) and is in need of pharmacotherapy;

[0162] 5. Subject has a TTS > 22 based on YGTSS at baseline visit; and

[0163] 6. For female patients, agree to use two appropriate methods of contraception, including at least one barrier method and at least one method with an annual failure rate of <1%, from the start of screening until 90 days after the last dose of study drug.

[0164] Patients meeting any of the following criteria are excluded from study participation:

[0165] 1. Females with a positive pregnancy test result or who are pregnant or breastfeeding;

[0166] 2. Subjects with secondary tic symptoms of Tourette’s Disorder with co-occurring tics, Huntington’s Chorea, neuroacanthocytosis, mental retardation, or autism;

[0167] 3. Subjects with comorbidities that are in need of pharmacotherapy, such as attention deficit / hyperactivity disorder, obsessive-compulsive disorder, or oppositional defiant disorder (if the Investigator judges that the case is not in need of pharmacotherapy for any of the above disorders during the study, the patient is eligible for participation in the trial);

[0168] 4. Mentally retarded subjects;

[0169] 5. Subjects with a current diagnosis of bipolar disorder, psychotic disorder, schizophrenia, or depressive disorder;

[0170] 6. Subjects who have experienced a seizure in the past year;

[0171] 7. Subjects with a history of severe traumatic brain injury or stroke;

[0172] 8. Subjects with any unstable medical condition or current illness (e.g., congenital heart disease, arrhythmia, or cancer) that, in the Investigator’s judgment, would place them at risk for a major adverse event during the trial or would interfere with safety and efficacy assessments;

[0173] 9. Subjects who require both pharmacotherapy and cognitive behavioral therapy (CBT, including habit reversal therapy, cognitive therapy, relaxation training, etc.) during the trial period; or

[0174] 10. Subjects who have participated in any clinical trial of an investigational therapy within the past month.

[0175] Table 1 : Evaluation Schedule

[0176] The primary outcome was change from baseline to Week 12 (or endpoint) in the Yale Global Tics Severity Scale (YGTSS).

[0177] The secondary efficacy outcome measures for this study were as follows:

[0178] 1. Percent change from baseline to Week 12 (or endpoint) in YGTSS TTS; efficacy was evaluated by percent subject change in total tics score (TTS) based on the Yale Global Tics Severity Scale (YGTSS) from randomization to last visit (Week 12).

[0179] 2. Remission rate based on TS-CGI Improvement Scale; remission rate (percent of patients with a score of 1 or 2) was evaluated by TS-CGI Improvement Scale from baseline to Week 12 (or endpoint).

[0180] 3. Remission rate based on Patient Global Change Impression (PGIC); patient-reported remission (percent of patients with a score of 1 or 2) was reported at study Week 12 (or endpoint).

[0181] 4. Partial remission rate based on TS-CGI Improvement; partial remission rate (percent of patients with a score of 3) was evaluated by TS-CGI Improvement Scale from baseline to Week 12 (or endpoint).

[0182] 5. Change from baseline to Week 12 (or endpoint) in TS-CGI Severity Scale score; efficacy was evaluated by change from baseline to Week 12 (or endpoint) in TS-CGI Severity Scale score.

[0183] Objectives and Endpoints

[0184] The safety outcome measures for the study were:

[0185] 1. Incidence, nature, and severity of adverse events

[0186] 2. Laboratory test results, vital sign assessments, and ECG parameters

[0187] Study Design

[0188] Schedule

[0189]

[0190] Example 3: Safety and efficacy study of a compound of Formula I for the treatment of subjects with Tourette Syndrome

[0191] An open-label, phase Ila, multicenter, 12-week, prospective study is provided below to assess the safety and efficacy of a compound of Formula I at doses ranging from 5 mg to 15 mg per day in adult male patients with Tourette Syndrome (TS).

[0192] Study Treatments

[0193] Primary and secondary objectives and endpoints are listed in Table 2 below:

[0194] Table 2: Primary and secondary objectives and endpoints

[0195]

[0196] Treatment Name

[0197] This is an open-label, multicenter, phase Ila study to determine the optimal dose of a compound of Formula I in adult male patients with TS that will induce antitwitching relief as assessed by the Clinical Global Impression of Change in Tourette Syndrome (TS-CGI-C) at Week 12 or post-treatment. Relief is defined as ratings of "minimal improvement," "much improved," and "very much improved."

[0198] A total of 10 patients were enrolled in the study. Male adult patients exhibiting the least evidence of benefit from their current treatment were enrolled in the study.

[0199] Potential patients were subjected to a screening evaluation. Patients who qualified were assigned a starting dose of 5 mg once daily. Treatment continued for up to 12 weeks, or until unacceptable intolerance or patient withdrawal of consent. Dose escalation was permitted at the discretion of the investigator in increments of 2.5 mg up to a maximum of 15 mg once daily. During the study, the daily dose of the compound was reduced by 2.5 mg if intolerance occurred at any given dose.

[0200] According to activities Compound of Formula I (SoA) a screening evaluation, clinical efficacy and safety evaluations, and patient-reported outcomes (Table 3 below) were performed.

[0201]

[0202] At Week 12 or at the end of treatment, remission of treatment was assessed by the Tourette Syndrome Clinical Global Impression of Change (TS-CGI-C). Remission was defined as ratings of "minimal improvement," "much improved," and "very much improved." Secondary efficacy assessments included the total tic score (TTS) of the Yale Global Tic Severity Scale (YGTSS) and severity of illness assessed by the TS-CGI Severity (TS-CGI-S). Safety was assessed by physical examinations, vital signs, ECGs, laboratory evaluations, adverse events, and serious adverse events. Patient-reported outcomes were assessed by the Clinical Global Impression (PGI-C) and Medication Satisfaction Questionnaire (MSQ).

[0203] Type

[0204] Study treatment was defined as any study intervention, marketed product, placebo, or medical device intended to be administered to a patient according to the study protocol.

[0205] The study treatment administered was as shown in Table 4 below:

[0206] Table 4. Study Treatment

[0207] Drug Dosage Form Capsule Unit Dose Strength 2.5 mg, 5.0 mg Dose Levels Once a day Route of Administration Oral Figure 1 Storage Conditions UPLC Analysis (Area % Main Peak)

[0208] Manufacture / Handling / Storage / Duties: The clinical formulation of the compound of Formula I is a brownish red hard gelatin capsule for oral administration. The capsule fill consists of the compound of Formula I and inactive ingredients mannitol, microcrystalline cellulose, sodium starch glycolate, sucrose monopalmitate, hydroxypropyl methylcellulose, colloidal silicon dioxide, and sodium stearyl fumarate.

[0209] The capsule shell consists of gelatin, titanium dioxide, iron oxide red, and iron oxide yellow. All excipients used in the formulation are of pharmacopoeial (Ph. Eur. and / or USP / NF) grade.

[0210] Hard gelatin capsules containing 2.5 mg and 5 mg of the compound of Formula I are available. The capsules of the compound are stored under recommended storage conditions, "store at 15-25 °C," "protect from moisture and light."

[0211] Example 4: Crystalline Form of the Compound of Formula I

[0212] Preparation of the crystalline form: The amorphous form of the compound of Formula I was stirred in water or a mixture of 50% water in methanol at 65 °C for 3 days to give a crystalline form of the free base of the compound of Formula I. The crystalline form is at least thermodynamically stable between 20 °C and 60 °C. The XRPD and DSC patterns are substantially as shown in 4 w, 40 °C, 75 % RH and 2 The XRPD pattern can be obtained by the following protocol known in the art.

[0213] Melting point: The maximum melting point peak (Tm) of the crystalline form was determined using DSC, which was performed using a Mettler Toledo DSC 821e with a sample robot TSO801 RO. 2-5 mg of sample was placed in a 40 uL AL crucible with an AL lid pierced, and the sample was heated from 25 °C to 300 °C at a rate of 10 °C / min. The temperatures at the onset of the crystalline melting peak, the peak onset, the peak maximum, and the peak end were collected. The DSC indicated that the Tm of this crystalline form was 213.16 °C. m m

[0214] Solubility: The above crystalline form showed very low solubility in aqueous solutions at pH > 3 (<0.004 mg / mL). The solubility in simulated gastric fluid (SGF), fasted state simulated intestinal fluid (FaSSIF), and fed state simulated intestinal fluid (FeSSIF) was 0.019 mg / ml, 0.006 mg / ml, and 0.022 mg / ml, respectively. The solubility increased 50-100 fold in the presence of surfactants (e.g., Tween-80, sodium dodecyl sulfate, dioctyl sulfosuccinate, or Pluronic F68) and cyclodextrins; however, it was still quite low. Overall, the crystalline form exhibited poor solubility in not only aqueous systems, but also in most of the organic solvents tested (<50 mg / mL) at ambient temperature (22 °C).

[0215] Stability: Preliminary forced degradation studies were performed on the crystalline form of the free base of the compound of Formula I under acidic, basic, oxidative, and photolytic stress conditions to study the survivability of the crystalline form under various stress conditions. Due to the low solubility of the compound of Formula I in the standard solvent, ethanol, ethanol was replaced by N-methyl-2-pyrrolidone (NMP).

[0216] A defined amount of the crystalline form of the free base of the compound of Formula I (0.2-0.8 mg) was weighed into 1.8 mL HPLC vials and stored open (75% RH) or closed (ambient) at the indicated temperature and time. Following incubation, the compound was dissolved in 1-1.5 mL NMP to a final concentration of 0.2-0.5 mg / mL and subjected to UPLC analysis (254 nm). The results are essentially as shown in Table 5 below. The data indicate that the crystalline form was stable in the solid state (degradation products <0.5%) at various temperatures, for example, at 40-60 °C for at least 4 weeks.

[0217] Table 5. Preliminary solid state stability

[0218] 4 w, RT ​ 4w，40℃ 100 4w60℃ 100 ​ 100 ​ 100 4w，4℃ 100 1h，80℃ 100 1d，80℃ 100 8d，80℃ 100

[0219] ​​The crystalline form of the free base of the compound of Formula I is stable up to 8 days in the solid state at 80 °C and in solution at pH 3 - pH 7 and RT. At higher or lower pH, degradation is observed. The crystalline form is stable after exposure to light in the solid state. In solution, it is stable to unstable in a time dependent manner in the sun test, moderate to unstable. It is also stable to oxidation for 1 day, but shows some sensitivity after long time exposure. The crystalline form is compatible with almost all excipients; however, drug recovery in the CompaS assay is strongly dependent on the solvent used for extraction.

[0220] In the suspension vehicle used for PK, PD and Tox studies (0.5% HPC / 1% Tween 80), the crystalline form is also stable up to 5 weeks at RT with only a small amount of particle growth and no hydrate formation. For parenteral administration, a 30% Kleptose formulation (1.5 mg / ml, physiological osmotic pressure, pH 6.2) was developed which is stable at 40 °C for at least 4 weeks.

[0221] incorporated by reference

[0222] The present application makes reference to a variety of published patents, published patent applications, journal articles and other publications, all of which are hereby incorporated by reference into this document. To the extent that any incorporated reference conflicts with the specification, the specification will control. In addition, any particular embodiment of the present disclosure that falls within the scope of the prior art can be expressly excluded from any one or more of the claims. Because such embodiments are deemed obvious, even if not explicitly set forth in the description, they may be excluded from the claims by implication or deduction. Any particular embodiment of the present disclosure may, for any reason, be excluded from any claim, whether or not related to the existence of prior art.

[0223] equivalents

[0224] The application can be embodied in other specific forms without departing from the spirit or essential characteristics thereof. The foregoing embodiments are therefore to be considered in all respects as illustrative only and not restrictive of the application described herein. The scope of the application is therefore indicated by the appended claims rather than by the description, and all changes that come within the meaning and range of equivalents are intended to be embraced therein.

Claims

1. Use of a composition in the manufacture of a medicament for the treatment of Tourette Syndrome, wherein the treatment comprises administering to a subject in need thereof a composition containing a therapeutically effective amount of a therapeutic agent or a pharmaceutically acceptable salt thereof, wherein the therapeutic agent is a compound of Formula I: (I)。 2. The use of claim 1, wherein the subject has a total tics score of at least 22 based on the Yale Global Tic Severity Scale at the start of treatment.

3. Use of a composition in the manufacture of a medicament for the treatment of Tourette Syndrome, wherein the treatment comprises administering to a subject in need thereof a composition containing a therapeutically effective amount of a therapeutic agent or a pharmaceutically acceptable salt thereof, wherein the subject has a total tics score of at least 22 based on the Yale Global Tic Severity Scale at the start of treatment and the therapeutic agent is a compound of Formula I: (I)。 4. The use of any one of claims 1-3, wherein the subject has previously been administered an additional Tourette Syndrome therapy.

5. The use of claim 4, wherein the previously administered additional Tourette Syndrome therapy is administration of pimozide, haloperidol, aripiprazole, methylphenidate, dextroamphetamine, dexmethylphenidate, atiprimazole, efaproxiral, or imidrex.

6. The use of claim 5, wherein the administration comprises administration of the compound of Formula I or a pharmaceutically acceptable salt thereof once a day.

7. The use of claim 5, wherein the administration comprises oral administration of the compound of Formula I or a pharmaceutically acceptable salt thereof.

8. The use of claim 5, wherein the administration comprises administration of the compound of Formula I or a pharmaceutically acceptable salt thereof as a unit dose.

9. The use of claim 1, wherein the administration comprises administration of the compound of Formula I as its free base.

10. The use of claim 1, wherein the administration comprises administration of the compound of Formula I as a pharmaceutically acceptable salt thereof.

11. The use of any one of claims 1-3, 9, 10, wherein the composition comprises the compound of Formula I or a pharmaceutically acceptable salt thereof as the only active agent.

12. The use of any one of claims 1-3, 9, 10, wherein the composition comprises the compound of Formula I or a pharmaceutically acceptable salt thereof in combination with an additional active agent.

13. The use of claim 12, wherein the other active agent is olanzapine or risperidone.

14. The use of any one of claims 1-3, 9, 10, wherein the composition comprises a non-active agent selected from the group consisting of mannitol, microcrystalline cellulose, sodium starch glycolate, sucrose monopalmitate, hydroxypropyl methylcellulose, colloidal silicon dioxide, and sodium stearyl fumarate.

15. The use of any one of claims 1-3, 9, 10, wherein the administration comprises administration of the compound of Formula I or a pharmaceutically acceptable salt thereof as a capsule.

16. The use of claim 15, wherein the capsule shell consists of gelatin, titanium dioxide, iron oxide red, and iron oxide yellow.

17. The use of claim 15, wherein the capsule contains 1 mg-10 mg of the compound of Formula I or a pharmaceutically acceptable salt thereof.

18. The use of claim 17, wherein the capsule comprises 2.5 mg - 5 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof.

19. The use of any one of claims 1-3, 9, 10, wherein the administration comprises administering the compound of Formula I, or a pharmaceutically acceptable salt thereof, in an amount of 2.5 mg - 5 mg once a day.

20. The use of any one of claims 1-3, 9, 10, wherein the administration comprises administering the compound of Formula I, or a pharmaceutically acceptable salt thereof, in an amount of 5 mg - 15 mg once a day.

21. The use of any one of claims 1-3, 9, 10, wherein the administration comprises administering the compound of Formula I, or a pharmaceutically acceptable salt thereof, in an amount of 1.0 mg, 1.5 mg, 2.0 mg, 2.5 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg, 17.5 mg, or 20 mg once a day.

22. The use of any one of claims 1-3, 9, 10, wherein the administration comprises administering the compound of Formula I, or a pharmaceutically acceptable salt thereof, as an immediate release formulation.

23. The use of any one of claims 1-3, 9, 10, wherein the administration comprises administering the compound of Formula I, or a pharmaceutically acceptable salt thereof, as an extended release formulation.

24. The use of any one of claims 1-3, 9, 10, wherein the administration maintains therapeutic effect throughout the day.

25. The use of any one of claims 1-3, 9, 10, wherein the subject has attention deficit hyperactivity disorder (ADHD).

26. The use of any one of claims 1-3, 9, 10, wherein the subject does not have ADHD.

27. The use of any one of claims 1-3, 9, 10, wherein the subject has obsessive compulsive disorder (OCD).

28. The use of any one of claims 1-3, 9, 10, wherein the subject does not have OCD.

29. Use of a composition in the manufacture of a medicament for the treatment of Tourette’s syndrome, wherein the treatment comprises administering to a subject in need thereof a composition containing a therapeutically effective amount of a therapeutic agent, or a pharmaceutically acceptable salt thereof, wherein the subject has a total tics score of at least 22 on the Yale Global Tic Severity Scale at the start of treatment, and the therapeutic agent is a compound of Formula I: Formula I wherein the administration comprises administering the compound of Formula I, or a pharmaceutically acceptable salt thereof, in an amount of 5 mg - 15 mg once a day. (I), 30. Use of a composition in the manufacture of a medicament for the treatment of Tourette’s syndrome, wherein the treatment comprises administering to a subject in need thereof a composition containing a therapeutically effective amount of a crystalline solid of the free base of the compound of Formula I: Formula I wherein the crystalline solid has a melting point onset of 210-214 °C as determined by DSC.

31. The use of claim 30, wherein the crystalline solid has an XRPD pattern as shown in Figure 1. (I), 32. The use of claim 30, wherein the crystalline solid has a DSC plot as shown in Figure 2. ​ ​ 33. The use of any of claims 1-3, 9, 10, wherein the administration comprises administering the compound of Formula I or a pharmaceutically acceptable salt thereof in an amount of 1.0 mg to 20 mg once a day.

34. The use of any of claims 1-3, 9, 10, wherein the administration comprises administering the compound of Formula I or a pharmaceutically acceptable salt thereof in an amount of 2.5 mg once a day.

35. The use of any of claims 1-3, 9, 10, wherein the administration comprises administering the compound of Formula I or a pharmaceutically acceptable salt thereof in an amount of 5.0 mg once a day.

36. The use of any of claims 1-3, 9, 10, wherein the administration comprises administering the compound of Formula I or a pharmaceutically acceptable salt thereof in an amount of 7.5 mg once a day.

37. The use of any of claims 1-3, 9, 10, wherein the administration comprises administering the compound of Formula I or a pharmaceutically acceptable salt thereof in an amount of 10 mg once a day.

38. The use of any of claims 1-3, 9, 10, wherein the administration comprises administering the compound of Formula I or a pharmaceutically acceptable salt thereof in an amount of 12.5 mg once a day.

39. The use of any of claims 1-3, 9, 10, wherein the administration comprises administering the compound of Formula I or a pharmaceutically acceptable salt thereof in an amount of 15 mg once a day.

40. The use of any of claims 1-3, 9, 10, wherein the administration comprises administering the compound of Formula I or a pharmaceutically acceptable salt thereof in an amount of 17.5 mg once a day.

41. The use of any of claims 1-3, 9, 10, wherein the administration comprises administering the compound of Formula I or a pharmaceutically acceptable salt thereof in an amount of 20 mg once a day.

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