Use of phosphodiesterase 10 inhibitors for treatment of durres syndrome

Abstract

The present invention relates to the use of a phosphodiesterase 10 inhibitor for the treatment of Dulres Syndrome. Provided herein are methods of treating a Tourre 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 compound of formula (I) and uses thereof. (I)

Description

[0001] This invention is a divisional application. The original application was filed on June 4, 2021, with application number 202180057821.7, and the invention title was "Use of a phosphodiesterase 10 inhibitor for the treatment of Durex syndrome".

[0002] Cross-references to related applications 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 estimated prevalence of TS in U.S. children aged 6–17 years is 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: (I).

[0007] In some implementations, subjects have a total tic score of at least 22 based on the Yale Global Tic Severity Scale.

[0008] On the other hand, 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 subject has a total tic score of at least 22 based on the Yale Comprehensive Tic Severity Scale, and the therapeutic agent is a compound of formula I: (I).

[0009] In some embodiments, the subject has previously received additional treatment for Durex syndrome. In some embodiments, the prior administration of additional Durex syndrome treatment is pimozide, haloperidol, or aripiprazole. In some embodiments, the prior administration of additional Durex syndrome treatment is a psychostimulant (e.g., methylphenidate, dextroamphetamine, or lidextroamphetamine) or an α2-adrenergic receptor antagonist (e.g., atemexazole, efavirenzine, or mizocrisin).

[0010] In some embodiments, a therapeutically effective amount of the compound of formula I or a pharmaceutically acceptable salt thereof is administered, including about 2.5 mg to about 5 mg of the compound of formula I or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of formula I or a pharmaceutically acceptable salt thereof is administered once daily. In some embodiments, the compound of formula I or a pharmaceutically acceptable salt thereof is administered orally. In some embodiments, the compound of formula I or a pharmaceutically acceptable salt thereof is administered as a unit dose.

[0011] In some embodiments, the Formula I compound is administered as a free base. In some embodiments, the Formula I compound is administered as a pharmaceutically acceptable salt.

[0012] On the other hand, this article provides a method for treating Durrell syndrome, comprising administering to a subject in need 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: (I).

[0013] In some implementations, the subject has attention deficit hyperactivity disorder (ADHD). In some implementations, the subject does not have ADHD. In some implementations, the subject has obsessive-compulsive disorder (OCD). In some implementations, the subject does not have OCD.

[0014] Still within the scope of this invention are the solid forms of compounds of formula I: (I), 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).

[0015] 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.

[0016] 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.

[0017] 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: (I), The melting point of the solid obtained by DSC crystallization is approximately 210-214℃.

[0018] 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.

[0019] 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

[0020] Figure 1 An exemplary XRPD plot depicting the crystalline solid of the free base of compound I.

[0021] Figure 2 An exemplary DSC plot depicting the crystalline solid of the free base of compound I. Detailed Implementation

[0022] 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.

[0023] definition To facilitate understanding of this invention, some terms and phrases are defined below.

[0024] Unless otherwise defined, 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 invention pertains. Abbreviations used herein have their conventional meanings in the fields of chemistry and biology. The chemical structures and formulas described herein are constructed according to the standard rules of chemical valence known in the field of chemistry.

[0025] Throughout this specification, when a composition is described as having, including, or comprising a specific component, or when a process or method is described as having, including, or comprising a specific step, it is taken into consideration that, in addition, there are compositions of the invention that are substantially composed of or comprised of said components, and there are processes and methods of the invention that are substantially composed of or comprised of said processing steps.

[0026] In this application, when an element or component is referred to as being included in and / or selected from the list of elements or components, it should be understood that the element or component may be any one of the elements or components, or the element or component may be selected from two or more of the elements or components.

[0027] Furthermore, it should be understood that the elements and / or features of the compositions or methods described herein can be combined in various ways without departing from the spirit and scope of the invention, whether explicitly stated or implied herein. For example, when reference is made to a particular compound, that compound can be used in various embodiments of the compositions of the invention and / or the methods of the invention, unless otherwise understood from the context. In other words, in this application, embodiments have been described and depicted in a manner that makes the application clear and concise to write and draw, but it is intended and will be appreciated that embodiments can be combined or separated differently without departing from the teaching and invention. For example, it should be appreciated that all features described and depicted herein are applicable to all aspects of the invention described and depicted herein.

[0028] As used herein, the articles “a” and “an” refer to one or more (i.e., at least one) grammatical object of the article, unless the context is inappropriate. For example, “one element” means one or more elements.

[0029] As used in this disclosure, the term “and / or” means “and” or “or”, unless otherwise specified.

[0030] It should be understood that the expression "at least one" includes each of the individual objects following the expression, as well as various combinations of two or more of the objects, unless otherwise understood from the context and use. The expression "and / or" associated with three or more of the objects should be understood to have the same meaning, unless otherwise understood from the context.

[0031] 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.

[0032] 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.

[0033] 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.

[0034] 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.

[0035] Generally, unless otherwise specified, percentages are defined as being by weight. Furthermore, if a variable has no accompanying definition, its prior definition prevails.

[0036] 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.

[0037] "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.

[0038] 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.

[0039] 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.

[0040] 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.

[0041] 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.

[0042] 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.

[0043] As used herein, "pharmaceuticalally acceptable excipient" refers to a substance that facilitates administration to a subject of an active agent and / or absorption by the subject, and may be included in the compositions of the present invention without causing significant adverse toxicological effects on the patient. Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, physiological saline solutions (e.g., phosphate-buffered saline solutions), emulsions (e.g., oil / water or water / oil emulsions), lactated Ringer's solution, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavoring agents, salt solutions (e.g., Ringer's solution), alcohols, oils, gelatin, carbohydrates (e.g., lactose, amylose, or starch), fatty acid esters, hydroxymethyl cellulose, polyvinylpyrrolidone, and pigments, etc. Such formulations are sterilizable and, if desired, can be mixed with adjuvants such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring and / or aromatic substances, etc., which do not react adversely with the compounds of the present invention. For examples of excipients, see Martin, Remington's Pharmaceutical Sciences, 15th edition, Mack Publ. Co., Easton, PA (1975).

[0044] The term "subject" considered for administration includes, but is not limited to, humans (i.e., men or women of any age group, such as pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or elderly adults)) and / or non-human animals, such as mammals, like primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats, and / or dogs. In some embodiments, the subject is a human. In some embodiments, the subject is a non-human animal.

[0045] As used in this article, "solid dosage form" refers to a drug dosage in solid form, such as tablets, capsules, granules, powders, sachets, reconstitutable powders, dry powder inhalers, and chewable tablets.

[0046] As used herein, “administration” means oral administration, administration as a suppository, local contact, intravenous administration, parenteral administration, intraperitoneal administration, intramuscular administration, intralesional administration, intrathecal administration, intrathecal administration, intranasal or subcutaneous administration, transmucosal administration (e.g., buccal, sublingual, nasal, or percutaneous), or implantation of a sustained-release device, such as a microosmotic pump, into the subject. Parenteral administration includes, for example, intravenous, intramuscular, intraarterial, intradermal, subcutaneous, intraperitoneal, intravenous, and intracranial administration. Other delivery modalities include, but are not limited to, the use of liposomal formulations, intravenous infusion, and percutaneous patches.

[0047] "Co-administration" means that the composition described herein is administered simultaneously, immediately before, or immediately after the administration of one or more other therapies (e.g., anticancer agents, chemotherapy, or treatment of neurodegenerative diseases). Compounds of Formula I or pharmaceutically acceptable salts thereof may be administered to the subject alone or in combination. Co-administration means the simultaneous or sequential, single or combined administration of compounds (more than one compound or agent). Therefore, the formulation may also be combined with other active substances (e.g., to reduce metabolic degradation) when necessary.

[0048] As used herein, and unless otherwise specified, the terms “treat,” “treating,” and “treatment” refer to actions that, when a subject has a particular disease, disorder, or condition, reduce the severity of the disease, disorder, or condition, or delay or slow the progression of the disease, disorder, or condition (e.g., “therapeutic intervention”).

[0049] As used herein, the phrase “therapeutic effective amount” means an amount of a composition (such as the composition described herein) or a compound of formula I or a pharmaceutically acceptable salt thereof that is effective in producing some desired therapeutic effect in a subject.

[0050] Durrell syndrome is described in the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5, 2013) as a disorder characterized by the presence of both polymotor and one or more vocal tics, with symptoms lasting for more than one year. Tics are sudden, rapid, repetitive, arrhythmic motor movements or vocalizations. Symptoms typically appear before the age of 18. As used herein, the term “Durrell syndrome” includes “persistent (chronic) motor tic disorder,” “persistent (chronic) vocal tic disorder,” “transient tic disorder,” and “tic disorder.” Patients with Durrell syndrome may have both motor and vocal tic symptoms that have been present for at least one year. However, patients with “tic disorder” may have only motor or vocal tics. Patients with “persistent (chronic) motor tic disorder” may have only motor tics. Patients with “persistent (chronic) vocal tic disorder” may have only vocal tics. Patients with “transient tic disorder” may have symptoms for less than one year.

[0051] Patients with TS may also experience inattention, hyperactivity, anxiety, mood disorders, and sleep disturbances. Currently, TS can be diagnosed using one or more rating scales. One exemplary rating scale is the Yale Comprehensive Tic Severity Scale, as described in Storch et al., Psychol Assess., 2005, 17(4):486-91.

[0052] compound The compound of formula I described below is a phosphodiesterase 10 (PDE10) inhibitor, also known as 1-methyl-4-(morpholino-4-carbonyl)-N-(2-phenyl[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide.

[0053] (I). A method for chemically synthesizing a compound of formula I (including Example 1 provided below) is described in U.S. Patent No. 8,349,824, which is incorporated herein by reference in its entirety.

[0054] In various embodiments, a pharmaceutically acceptable salt of Formula I compound may be a salt of Formula I compound 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.

[0055] This invention also covers the solid form of compounds of formula I: (I), 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).

[0056] 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.

[0057] 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.

[0058] Pharmaceutical Composition In one respect, this document provides a pharmaceutical composition for treating Durrell syndrome in subjects who require it, 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 comprises a crystalline solid of a free base of the compound of formula I as described herein.

[0059] In various embodiments, the amount of the compound of formula I or a pharmaceutically acceptable salt thereof in the pharmaceutical composition described herein may be about 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 ... mg - approximately 1.5 mg, approximately 1.5 mg - approximately 9 mg, approximately 1.5 mg - approximately 8 mg, approximately 1.5 mg - approximately 7 mg, approximately 1.5 mg - approximately 6 mg, approximately 1.5 mg - approximately 5 mg, approximately 1.5 mg - approximately 4.5 mg, approximately 1.5 mg - approximately 4 mg, approximately 1.5 mg - approximately 3.5 mg, approximately 1.5 mg - approximately 3 mg, approximately 1.5 mg - approximately 2.5 mg, approximately 1.5 mg - approximately 2 mg, approximately 2 mg - approximately 9 mg, approximately 2 mg - approximately 8 mg, approximately 2 mg - approximately 7 mg, approximately 2 mg - approximately 6 mg, approximately 2 mg - approximately 5 mg, approximately 2 mg - approximately 4.5 mg, approximately 2 mg - approximately 4 mg, approximately 2 mg - approximately 3.5 mg, approximately 2 mg - approximately 3 mg, approximately 2 mg - approximately 2.5 mg, approximately 2.5 mg - approximately 9 mg, approximately 2.5 mg - approximately 8 mg, approximately 2.5 mg - approximately 7 mg mg, approximately 2.5 mg - approximately 6 mg, approximately 2.5 mg - approximately 5 mg, approximately 2.5 mg - approximately 4.5 mg, approximately 2.5 mg - approximately 4 mg, approximately 2.5 mg - approximately 3.5 mg, approximately 2.5 mg - approximately 3 mg, approximately 3 mg - approximately 9 mg, approximately 3 mg - approximately 8 mg, approximately 3 mg - approximately 7 mg, approximately 3 mg - approximately 6 mg, approximately 3 mg - approximately 5 mg, approximately 3 mg - approximately 4.5 mg, approximately 3 mg - approximately 4 mg, approximately 3 mg - approximately 3.5 mg, approximately 3.5 mg - approximately 9 mg, approximately 3.5 mg - approximately 8 mg, approximately 3.5 mg - approximately 7 mg, approximately 3.5 mg - approximately 6 mg, approximately 3.5 mg - approximately 5 mg, approximately 3.5 mg - approximately 4.5 mg, approximately 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 some embodiments, the amount of the compound of formula I or a pharmaceutically acceptable salt thereof in the pharmaceutical composition described herein may be about 2.5 mg to about 5 mg.

[0060] In various embodiments, the amount of the Formula I compound or a pharmaceutically acceptable salt thereof in the pharmaceutical compositions described herein may 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 some embodiments, the amount of the Formula I compound or a pharmaceutically acceptable salt thereof in the pharmaceutical compositions described herein may be about 2.5 mg. In some embodiments, the amount of the Formula I compound or a pharmaceutically acceptable salt thereof in the pharmaceutical compositions described herein may be about 5 mg.

[0061] In another aspect, this article provides a pharmaceutical composition for treating Durex syndrome in subjects who require it, 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, this article provides a pharmaceutical composition for treating Durex syndrome in subjects who require it, 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.

[0062] On the other hand, this article provides a pharmaceutical composition for treating Durrell syndrome in subjects who require it, 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 Comprehensive Tic Severity Scale.

[0063] In various embodiments, for effective treatment of Durrell syndrome in subjects who require it, wherein the subjects have a total tic score of at least 22 based on the Yale Comprehensive Tic Severity Scale, the compound of Formula I or a pharmaceutically acceptable salt thereof in the pharmaceutical composition may 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 some embodiments, the daily dose may be about 2.5 mg to about 5 mg. In some embodiments, the daily dose may be about 5 mg to about 15 mg.

[0064] In various embodiments, for effective treatment of Durrell syndrome in subjects requiring it, wherein the subjects have a total tic score of at least 22 based on the Yale Comprehensive Tic Severity Scale, the compound of formula I or a pharmaceutically acceptable salt thereof in the pharmaceutical composition may be in the form 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 ... The daily dose may be approximately 18.5 mg, 19 mg, 19.5 mg, 20 mg, or 20.5 mg. In some embodiments, the daily dose may be approximately 2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, or 5 mg. In some embodiments, the daily dose may be approximately 5 mg, 7.5 mg, 10 mg, 12.5 mg, or 15 mg.

[0065] In various embodiments, the pharmaceutical composition described herein comprises a therapeutically effective amount of the free base form of a compound of formula I.

[0066] In various embodiments, the pharmaceutical compositions described herein comprise a pharmaceutically acceptable salt of a compound of formula I in a therapeutically effective amount. In some embodiments, the pharmaceutically acceptable salt of the compound of formula I may be a salt of the compound of formula (I) with a physiologically compatible mineral acid such as hydrochloric acid, sulfuric acid, 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.

[0067] The pharmaceutical compositions provided herein can be administered via a variety of routes, including but not limited to oral (enteral), parenteral (by injection), rectal, transdermal, intradermal, intrathecal, subcutaneous (SC), intravenous (IV), intramuscular (IM), and intranasal administration. In some embodiments, the pharmaceutical compositions disclosed herein are for oral administration.

[0068] The pharmaceutical compositions described herein can also be administered chronically (“chronic administration”). Chronic administration means administering the compound or a pharmaceutical composition thereof for an extended period of time, such as more than 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc., or it may continue indefinitely, such as for the remainder of the subject's life. In some embodiments, chronic administration is intended to provide a constant level of the compound in the blood, for example, within the therapeutic window for an extended period of time.

[0069] The pharmaceutical compositions described herein can be presented in unit dosage forms for precise dosing. The term "unit dosage form" refers to a physically discrete unit suitable for human subjects and other mammals as a unit dose, each unit containing a predetermined amount of active material calculated to produce the desired therapeutic effect, in combination with suitable pharmaceutical excipients. In various embodiments, the pharmaceutical dosage forms described herein can be administered as unit doses. Typical unit dosage forms include liquid compositions in the case of pre-filled, pre-filled ampoules or syringes, or, in the case of solid compositions, pills, tablets, capsules, etc.

[0070] In various embodiments, the pharmaceutical compositions provided herein are administered to patients as solid dosage forms. In some embodiments, the solid dosage form is a capsule. In some embodiments, the solid dosage form is a tablet.

[0071] In various embodiments, the pharmaceutical compositions provided herein comprise a compound of formula I, either as the sole active agent or in combination with other active agents.

[0072] Although the description of the pharmaceutical compositions provided herein is primarily directed toward those suitable for administration to humans, those skilled in the art will understand that such compositions are generally suitable for administration to all species of animals. Modifications to make a composition suitable for administration to a variety of animals are fully understood, and such modifications can generally be designed and / or performed by a skilled veterinary pharmacologist using routine experiments. General considerations in the formulation and / or manufacture of pharmaceutical compositions can be found, for example, in Remington: The Science and Practice of Pharmacy, 21st edition, Lippincott Williams & Wilkins, 2005.

[0073] Use and treatment methods On the one hand, this article provides a method for treating Durrell syndrome in subjects who require it.

[0074] In various embodiments, this document provides a method for treating Durrell syndrome in a subject who requires it, the method comprising administering to the subject who requires it a composition containing a therapeutically effective amount of the therapeutic agent or a pharmaceutically acceptable salt thereof, wherein the therapeutic agent is a compound of formula I: (I).

[0075] In some implementations, the subjects have a total tic 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 Comprehensive Tic Severity Scale. In some implementations, the subjects have a total tic score of at least 22 based on the Yale Comprehensive Tic Severity Scale.

[0076] In some embodiments, this document provides a method for treating Durrell syndrome in a subject who requires it, the method comprising administering to the subject who requires it a composition containing a therapeutically effective amount of the therapeutic agent or a pharmaceutically acceptable salt thereof, wherein the subject has a total tic score of at least 22 based on the Yale Comprehensive Tic Severity Scale, and the therapeutic agent is a compound of formula I: (I).

[0077] In various embodiments, the subject has previously received additional treatment for Durex syndrome. In some embodiments, the prior administration of additional Durex syndrome treatment is pimozide, haloperidol, or aripiprazole. In some embodiments, the prior administration of additional Durex syndrome treatment is a psychostimulant (e.g., methylphenidate, dextroamphetamine, or lidxepin) or an α2-adrenergic receptor antagonist (e.g., atemexazole, efavirenzine, or mizocrisin). In some embodiments, the prior administration of additional Durex syndrome treatment is pimozide, haloperidol, aripiprazole, methylphenidate, dextroamphetamine, or lidxepin, atemexazole, efavirenzine, or mizocrisin.

[0078] 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 the amount of the compound as described above.

[0079] In various embodiments, the composition comprises a compound of formula I or a pharmaceutically acceptable salt thereof as the sole active agent.

[0080] In various embodiments, the composition comprises a Formula I compound or a pharmaceutically acceptable salt thereof in combination with an additional active agent. In some embodiments, the additional active agent is olanzapine or risperidone.

[0081] In various embodiments, the composition comprises an inactive agent selected from mannitol, microcrystalline cellulose, sodium starch glycolate, sucrose monopalmitate, hydroxypropyl methylcellulose, colloidal silica, and sodium stearoyl fumarate.

[0082] In various implementation schemes, administration includes administering a Formula I compound or a pharmaceutically acceptable salt thereof in a capsule form.

[0083] In various implementations, the capsule shell is composed of gelatin, titanium dioxide, iron oxide red, and iron oxide yellow.

[0084] In various embodiments, the capsules described above contain about 1 mg to about 10 mg of a compound of formula I or a pharmaceutically acceptable salt thereof.

[0085] In various embodiments, the capsule contains about 2.5 mg to about 5 mg of a compound of formula I or a pharmaceutically acceptable salt thereof.

[0086] In various implementation methods, administration includes administering a Formula I compound or a pharmaceutically acceptable salt thereof once daily in an amount of about 2.5 mg to about 5 mg.

[0087] In various implementation methods, administration includes administering a Formula I compound or a pharmaceutically acceptable salt thereof once daily in an amount of about 5 mg to about 15 mg.

[0088] In various implementation methods, administration includes administering a Formula I compound or a pharmaceutically acceptable salt thereof once daily in an amount of about 1 mg to about 20 mg.

[0089] In various implementation schemes, administration includes once daily administration of a compound of formula I or a pharmaceutically acceptable salt thereof in amounts of about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, or about 15 mg.

[0090] In various embodiments, administration includes once daily in amounts 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 of a compound of formula I or a pharmaceutically acceptable salt thereof. In some embodiments, administration comprises administering a compound of formula I or a pharmaceutically acceptable salt thereof once daily in an amount of about 2.5 mg. In other embodiments, administration comprises administering a compound of formula I or a pharmaceutically acceptable salt thereof once daily in an amount of about 5 mg. In various embodiments, administration comprises administering a compound of formula I or a pharmaceutically acceptable salt thereof in an immediately released formulation.

[0091] In various implementation schemes, administration includes administering a Formula I compound or a pharmaceutically acceptable salt thereof as a prolonged-release formulation.

[0092] In all implementation schemes, the treatment is maintained throughout the day.

[0093] In various embodiments, the Formula I compound or a pharmaceutically acceptable salt thereof is administered once, twice, three times, four times, or five times daily. In some embodiments, the Formula I compound or a pharmaceutically acceptable salt thereof is administered once daily.

[0094] In various implementation schemes, the Formula I compound or its pharmaceutically acceptable salt is administered orally.

[0095] In various implementation schemes, the Formula I compound or a pharmaceutically acceptable salt thereof is administered as a unit dose.

[0096] In various implementation schemes, the Formula I compound is applied in the form of a free base.

[0097] In various embodiments, the Formula I compound is administered in the form of a pharmaceutically acceptable salt. In some embodiments, a pharmaceutically acceptable salt of the Formula I compound may be a salt of the Formula I compound 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 some embodiments, the Formula I compound is administered in crystalline form.

[0098] In various embodiments, this document provides a method for treating Durrell syndrome in a subject who requires it, the method comprising administering to the subject who requires it 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: (I).

[0099] In various implementation schemes, TS subjects are also diagnosed with one or more diseases, disorders, or conditions selected from: Attention Deficit Hyperactivity Disorder (ADHD), Obsessive-Compulsive Disorder (OCD), Oppositional Defiance Disorder (ODD), Conduct Disorder, Anxiety Disorder, Autism, Mood Disorder, Phobia, and Depression. In various implementation schemes, TS subjects do not have ADHD, OCD, ODD, Conduct Disorder, Anxiety Disorder, Autism, Mood Disorder, Phobia, or Depression. In some implementation schemes, subjects have ADHD. In some implementation schemes, subjects do not have ADHD. In some implementation schemes, subjects have OCD. In some implementation schemes, subjects do not have OCD.

[0100] In various implementation schemes, the Formula I compound is administered as a single therapy.

[0101] In various implementations, the method provided herein further includes administering a therapeutically effective amount of a second therapeutic agent to the subject.

[0102] Without further elaboration, it is believed that those skilled in the art can make full use of the invention based on the above description. Therefore, the specific examples below are merely illustrative and in no way limit the remainder of this disclosure. Example

[0103] To provide a fuller understanding of the disclosure described herein, the following examples are presented. The examples described in this application are provided to illustrate the compounds, pharmaceutical compositions, and methods provided herein, and should not be construed as limiting their scope in any way.

[0104] Example 1: Synthesis of 1-methyl-4-(morpholino-4-carbonyl)-N-(2-phenyl[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide (compound of formula I) [see U.S. Patent No. 8,349,824]. 1-Methyl-5-(2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1H-pyrazole-4- Methyl carboxylate Step A - 1,2-Diamino-4-bromopyridinium 2,4,6-trimethylbenzenesulfonate: 4-bromopyridinium-2-amine (9.3 g, 52.1 mmol, 1 eq.) was added fractionally to a cooled suspension of O-(trimethylbenzenesulfonyl)hydroxyamine (11.22 g, 52.1 mmol, 1 eq.) in dichloromethane (130 ml) (exothermic reaction, requiring some cooling) to give a white suspension. After 1 hour, 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-bromopyridinium 2,4,6-trimethylbenzenesulfonate (16.74 g, 82.7%) as white crystals. mp.: 176–180 °C. MS: m / z = 188.2, 190.2 (M+H + ).

[0105] Step B - 7-Bromo-2-phenyl-[1,2,4]triazolo[1,5-a]pyridine: 1,2-diamino-4-bromopyridinium 2,4,6-trimethylbenzenesulfonate (15.6 g, 40.2 mmole) in pyridine (106 ml) was heated overnight at 100 °C with benzoyl chloride (9.4 ml, 80 mmole) to give a reddish-brown solution, and after 2 hrs, a brown suspension was obtained. The reaction mixture was concentrated under vacuum, and the residue was milled in a saturated aqueous ammonium chloride solution (300 ml) for 2.5 hr, while neutralizing to pH 6-7 with a saturated aqueous sodium bicarbonate solution. 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 (6.78 g, 61.6%) as a grayish-white solid. mp.: 189-191 °C. MS: m / z = 276.1, 274.2 (M+H + ).

[0106] Step C - (2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-tert-butyl carbamate: Tert-butyl carbamate (4.71 g, 39.4 mmol), tris(dibenzylacetone)dipalladium(0) (601 mg, 657 µmol), 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene (760 mg, 1.31 mmol), and cesium carbonate (15 g, 46 mmol) were successively added to a suspension of 7-bromo-2-phenyl-[1,2,4]triazolo[1,5-a]pyridine (9 g, 32.8 mmol) purged with nitrogen in dioxane (180 ml). The brown mixture was then stirred at 100 °C for 22 hours under a nitrogen atmosphere. The solvent was removed under vacuum, 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 × 120 ml) and brine, and dried over magnesium sulfate. The solution was concentrated under vacuum to approximately 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 7.09 g of tert-butyl 2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-carbamate as a grayish-white solid. The mother liquor was evaporated, and the residue was loaded onto silica gel (16 g). The product was separated by chromatography on a 120 g silica gel cylinder (eluent: heptane / ethyl acetate 10-50%, 45 min) to give a second batch of 1.748 g of white solid. mp.: 200-201 °C. Decomposition. MS: m / z = 311.3 (M+H + Total yield: 86.7%.

[0107] Step D - 2-Phenylon-[1,2,4]triazolo[1,5-a]pyridin-7-ylamine: A suspension of (2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-tert-butyl carbamate (8.5 g, 27.4 mmol) in hydrochloric acid (6 N in diethyl ether, 175 ml) was stirred overnight at room temperature. The suspension was diluted with water (about 2 l) and ethyl acetate under cooling. The aqueous layer was washed once with ethyl acetate, made alkaline 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 under vacuum to give 2-phenyl-[1,2,4]triazolo[1,5-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 + ).

[0108] Step E-1-Methyl-5-(2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid methyl ester: A solution of 2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-ylamine (1.534 g, 7.3 mmol), 4-(methoxycarbonyl)-1-methyl-1H-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 obtain a white suspension. The cooled suspension was poured into a saturated sodium bicarbonate aqueous solution (200 ml), stirred at room temperature for 15 min, and the solid was collected by filtration. The solid was washed with water and dried to give methyl 1-methyl-5-(2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid (2.596 g, 94.5%) as a white solid. mp.: 243-7℃. MS: m / z = 377.2 (M+H) + ).

[0109] 1-Methyl-5-(2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1H-pyrazole-4- carboxylic acid A white suspension of methyl 1-methyl-5-(2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid (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 colorless solution was obtained. Methanol was removed under vacuum, the residue was diluted with water, and the cooled aqueous solution was neutralized with 2N hydrochloric acid (3.46 ml, 6.03 mmol). The solid was collected by filtration and dried to give 2.21 g, 97%, of 1-methyl-5-(2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid as a white solid. mp.: >300 °C. MS: m / z = 361.1 (M+H + ).

[0110] 1-Methyl-4-(morpholino-4-carbonyl)-N-(2-phenyl[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyridine 5-oxazolium-5-carboxamide A mixture of 1-methyl-5-(2-phenyl-[1,2,4]-triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid (100 mg, 276 µmol), morpholine (240 µl, 2.76 mmol), and propylphosphonic anhydride (50% in ethyl acetate, 407 µl, 690 μmol) in tetrahydrofuran (7 mL) was stirred at 70 °C for 3 hours. The mixture was diluted with ethyl acetate and washed with saturated sodium bicarbonate aqueous solution and brine. The organic layer was separated, dried over magnesium sulfate, and the solvent was evaporated. The residue was ground with diethyl ether and ethyl acetate (76 mg white foam) to give 1-methyl-4-(morpholino-4-carbonyl)-N-(2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide (53 mg, 44.5%) as a white solid. mp.: 203–207 °C. MS: m / Z = 432.4 (M+H).

[0111] Example 2: Efficacy study of compound I in treating subjects with Durrell syndrome Research Objective Primary efficacy objective: To evaluate the efficacy of a double-blind, 12-week, once-daily dose of Formula I compound (2.5 mg–5 mg) compared with placebo in adolescent and adult patients with Durrell syndrome (TS). The primary outcome was the change from baseline to week 12 (or the endpoint) on the Yale Comprehensive Tic Severity Scale (YGTTS).

[0112] Secondary objective: 1. Percentage change in YGTSS total tic score (TTS) from baseline to week 12 (or endpoint); efficacy was evaluated by the percentage change in subjects’ TTS based on YGTSS from randomization to their last visit (week 12).

[0113] 2. Response rate based on investigator-assessed Durrell syndrome-clinical global impression (TS-CGI) change scale; response rate was assessed at week 12 (or endpoint) using the TS-CGI change scale as reference baseline (percentage of patients with a score of 1 or 2).

[0114] 3. Response rate based on Patient Global Impression of Change (PGIC); patient-reported response (percentage of patients with a score of 1 or 2) is reported at week 12 (or the endpoint of the study).

[0115] 4. Partial response rate based on investigator-assessed TS-CGI Improvement Scale; partial response rate (percentage of patients with a score of 3) was assessed using the TS-CGI Improvement Scale from baseline to week 12 (or the endpoint).

[0116] 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).

[0117] Research Design This is a multicenter, randomized, double-blind, placebo-controlled study in patients who showed the second-best evidence of benefit from their current treatment.

[0118] Patients diagnosed with TS signed informed consent, met the study eligibility criteria, and agreed to participate in the study, entering a 30-day screening period.

[0119] Eligible patients are randomized via an interactive voice / network response system to receive one of two treatments: 1. Treatment A: Compound of Formula I at doses of 2.5 mg or 5 mg. 2. Treatment B: Placebo At the end of the screening period, patients who met all inclusion criteria were randomized to receive double-blind treatment.

[0120] Research phase The entire study lasted 16 weeks.

[0121] 1. Screening and stabilization phase: 4 weeks 2. Stochastic phase: 12 weeks Number of patients A total of 90 patients were randomized to the treatment group. It was estimated that 120 patients were screened, and 90 eligible patients were randomized.

[0122] Target audience The patient met the following study inclusion criteria: 1. The ability and willingness to provide written informed consent and comply with research procedures; 2. Fluent in the language of researchers, educators, and informed consent.

[0123] 3. Age between 11 and 50 years old; 4. Subjects meet the diagnostic criteria for TS according to the current Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) and require medication. 5. Subjects at baseline had a TTS ≥ 22 based on YGTSS at their initial medical visit; and 6. For female patients, from the start of screening until 90 days after the last dose of study drug, consent should be given to the use of two appropriate methods of contraception, including at least one barrier method of contraception and at least one method of contraception with an annual failure rate of <1%.

[0124] Patients meeting any of the following criteria were excluded from study participation: 1. Women who have a positive pregnancy test result, are currently pregnant, or are breastfeeding; 2. Subjects with secondary tic symptoms accompanied by delayed tic, Huntington's disease, neuroacanthocytosis, intellectual disability or autism; 3. Subjects with comorbidities requiring medication, such as attention deficit / attention deficit hyperactivity disorder, obsessive-compulsive disorder, or oppositional defiant disorder (the patient is eligible to participate in this trial if the investigator determines that the patient does not require medication for any of the above conditions during the study period). 4. Subjects with lower intelligence; 5. Subjects currently diagnosed with bipolar disorder, mental disorder, schizophrenia, or depressive disorder; 6. Subjects who have experienced an epileptic seizure in the past year; 7. Subjects with a history of severe traumatic brain injury or stroke; 8. Subjects with any unstable medical condition or current illness (e.g., congenital heart disease, arrhythmia, or cancer) will, in the investigator's judgment, be at risk of major adverse events during this trial or that may interfere with the evaluation of safety and efficacy. 9. Subjects who require both medication and cognitive behavioral therapy (CBT, including habit reversal therapy, cognitive therapy, relaxation training, etc.) during the trial; or 10. Subjects who have participated in any clinical trial of any investigational therapy within the past month.

[0125] Therapeutic outcome measurement The primary outcome was the change in the Yale Comprehensive Tic Severity Scale (YGTTS) from baseline to week 12 (or the endpoint).

[0126] The secondary efficacy outcomes of this study are measured as follows: 1. Percentage change in YGTSS TTS from baseline to week 12 (or endpoint); efficacy was assessed by percentage change in total tic score (TTS) in subjects from randomization to their last visit (week 12) based on the Yale Comprehensive Tic Severity Scale (YGTSS).

[0127] 2. Response rate based on the TS-CGI Improvement Scale; Response rate (percentage of patients with a score of 1 or 2) was assessed from baseline to week 12 (or the endpoint) using the TS-CGI Improvement Scale.

[0128] 3. Response rate based on Patient Global Impression of Change (PGIC); patient-reported response (percentage of patients with a score of 1 or 2) is reported at week 12 (or the endpoint of the study).

[0129] 4. Partial response rate based on TS-CGI improvement; partial response rate (percentage of patients with a score of 3) was assessed using the TS-CGI improvement scale from baseline to week 12 (or the endpoint).

[0130] 5. Changes in TS-CGI severity scale scores from baseline to week 12 (or endpoint); efficacy was assessed by changes in TS-CGI severity scale scores from baseline to week 12 (or endpoint).

[0131] Safety outcome measurement The safety outcome measures of the study are: 1. Incidence, nature, and severity of adverse events 2. Laboratory test results, vital sign assessment, and ECG parameters Evaluation Details Table 1: Evaluation Details Example 3: Safety and efficacy study of compound I in treating subjects with Durrell syndrome The following is an open-label, phase IIa, multicenter, 12-week prospective study to evaluate the safety and efficacy of Formula I compounds at daily doses ranging from 5 mg to 15 mg in adult male patients with Durrell syndrome (TS).

[0132] Purpose and End Point The primary and secondary objectives and endpoints are listed in Table 2 below: Table 2: Primary and Secondary Objectives and Endpoints Research Design This is an open-label, multicenter, phase IIa study to determine the optimal dose of compound I in adult male patients with TS that will induce an antitic remission as assessed by the Clinical Global Change Impression of Durrell Syndrome (TS-CGI-C) at week 12 or post-treatment. Remission is defined as “minimum improvement,” “significant improvement,” and “gross improvement.”

[0133] A total of 10 patients were enrolled in this study. Male adult patients who demonstrated the second-best evidence of benefit from their current treatment were included in this study.

[0134] Potential patients underwent screening and evaluation. Eligible patients 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 investigator's discretion in increments of 2.5 mg, up to a maximum of 15 mg once daily. If intolerance occurred at any given dose during the study period, the daily dose of the compound was reduced by 2.5 mg.

[0135] According to the activity list (SoA) is used for screening evaluation, clinical efficacy and safety evaluation, and patient-reported results (Table 3 below).

[0136] Treatment response was assessed using the Clinical Global Impression of Change in Durrell's Syndrome (TS-CGI-C) at week 12 or at the end of treatment. Response was defined as "minimum improvement," "significant improvement," or "gross improvement." Secondary efficacy assessments included the total tic score (TTS) on the Yale Comprehensive Tic Severity Scale (YGTSS) and disease severity based on the TS-CGI Severity Score (TS-CGI-S). Safety was assessed through physical examination, vital signs, ECG, laboratory evaluations, and surveillance for adverse and serious adverse events. Patient-reported outcomes were evaluated using the Clinical Global Impression of Change in Change (PGI-C) and the Medication Satisfaction Questionnaire (MSQ).

[0137] Research on treatment Research treatment is defined as any research intervention, product on the market, placebo, or medical device intended to be administered to a patient according to a research protocol.

[0138] The treatments administered are shown in Table 4 below: Table 4. Study Treatment Treatment Name Formula I compound type drug Dosage form Capsules Unit dose intensity 2.5 mg, 5.0 mg dose level Once a day Application route oral Preparation / Handling / Storage / Responsibilities: The clinical formulation of Formula I compound is a brownish-red hard gelatin capsule for oral administration. The capsule filler consists of Formula I compound and the inactive ingredients mannitol, microcrystalline cellulose, sodium starch glycolate, sucrose monopalmitate, hydroxypropyl methylcellulose, colloidal silica, and sodium stearoyl fumarate.

[0139] The capsule shell is composed of gelatin, titanium dioxide, iron oxide red, and iron oxide yellow. All excipients used in the formulation are pharmacopoeia (Ph. Eur. and / or USP / NF) grade.

[0140] Hard gelatin capsules containing 2.5 mg and 5 mg of compound I are available. The capsules of the compound should be stored under the recommended storage conditions: "store at 15-25°C" and "protected from light and moisture".

[0141] Example 4: Crystalline form of compound I Preparation of the crystalline form: The amorphous form of compound I was stirred in water or a mixture of 50% water and methanol at 65°C for 3 days to obtain the crystalline form of the free base of compound I. The crystalline form is thermodynamically stable at least between 20°C and 60°C. XRPD and DSC plots are essentially as follows. Figure 1 and 2 As shown. The XRPD diagram can be obtained through the following methods known in the art.

[0142] Melting point: The maximum melting point peak (T) of the crystalline form was determined using DSC. m The sample was analyzed using a Mettler Toledo DSC 821e equipped with a sample robot, TSO801RO. 2–5 mg of sample was placed in a 40 μL AL crucible with a perforated AL cap, and the sample was heated from 25 °C to 300 °C at a rate of 10 °C / min. The temperatures at the start, initial, maximum, and end of the crystallization melting peak were collected. DSC analysis showed that the Tc of this crystalline form… m It is 213.16℃.

[0143] Solubility: The above crystalline form exhibits very low solubility in aqueous solutions with pH > 3 (< 0.004 mg / mL). Solubility in simulated gastric juice (SGF), fasting-state simulated intestinal juice (FaSSIF), and feeding-state simulated intestinal juice (FeSSIF) is 0.019 mg / mL, 0.006 mg / mL, and 0.022 mg / mL, respectively. Solubility increases 50-100 times in the presence of surfactants (e.g., Tween-80, sodium dodecyl sulfate, dioctyl sulfosuccinate, or Pluronic F68) and cyclodextrin; however, it remains quite low. Overall, this crystal exhibits poor solubility at ambient temperature (22°C) not only in aqueous systems but also in most tested organic solvents (< 50 mg / mL).

[0144] Stability: Preliminary forced degradation studies were conducted on the crystalline form of the free base of Formula I under acidic, alkaline, oxidizing, and photodegrading stress conditions to investigate the survivability of the crystalline form under various stress conditions. Due to the low solubility of Formula I in the standard solvent ethanol, ethanol was substituted with N-methyl-2-pyrrolidone (NMP).

[0145] A defined amount (0.2–0.8 mg) of the free base of Formula I compound was weighed into a 1.8 mL HPLC vial and stored open (75% RH) or closed (ambient) at the specified temperature and time. After incubation, the compound was dissolved in 1–1.5 mL of NMP to a final concentration of 0.2–0.5 mg / mL and analyzed by UPLC (254 nm). The results are essentially as shown in Table 5 below. The data indicate that the crystalline form is stable in the solid state at various temperatures (degradation products <0.5%), for example, stable for at least 4 weeks at 40–60 °C.

[0146] Table 5. Preliminary solid-state stability The crystalline form of the free base of Formula I compound is stable in solution at 80 °C as a solid and at pH 3–7 and RT for up to 8 days. Degradation was observed at higher or lower pH values. The crystalline form is stable after exposure to light in a solid state. In solution, it is stable to sunlight and, in a sunlight exposure test, is moderately stable to unstable in a time-dependent manner. It is also stable to oxidation for 1 day but shows some sensitivity after prolonged exposure. The crystalline form is compatible with almost all excipients; however, drug recovery in CompaS assays is strongly dependent on the solvent used for extraction.

[0147] In the suspension medium (0.5% HPC / 1% Tween 80) used in PK, PD, and Tox studies, the crystalline form was also stable at RT for up to 5 weeks, with only a small amount of particle growth and no hydrate formation. For parenteral administration, a 30% Kleptose formulation (1.5 mg / ml, physiological osmolarity, pH 6.2) was developed with stability at 40°C for at least 4 weeks.

[0148] By combining citations This application references various published patents, published patent applications, journal articles, and other publications, all of which are incorporated herein by reference. In the event of any conflict between any incorporated reference and this specification, the specification shall prevail. Furthermore, any particular embodiment of this disclosure that falls within the scope of the prior art is expressly excluded from any one or more of the claims. Because such embodiments are considered to be known to one of ordinary skill in the art, they may be excluded even if not expressly stated herein. For any reason, whether or not related to the existence of the prior art, any particular embodiment of this disclosure is excluded from any claim.

[0149] equivalent This invention may be embodied in other specific forms without departing from its spirit or essential characteristics. Therefore, the above embodiments are to be considered illustrative in all respects and not limiting of the invention described herein. Accordingly, the scope of the invention is defined by the appended claims rather than by the foregoing description, and all variations falling within the equivalent meaning and scope of the claims are intended to be included therein.

Claims

1. A compound of formula I in solid form: (I), 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, as determined by differential scanning calorimetry (DSC), is 210-214 °C.

2. A compound of formula I in solid form: (I), The solid form is a crystalline solid of the free base of the compound of formula I, and the crystalline solid has an X-ray powder diffraction (XRPD) pattern as shown in Figure 1.

3. The solid form according to claim 1, wherein the crystalline solid has an X-ray powder diffraction (XRPD) pattern as shown in FIG1.

4. The solid form according to any one of claims 1-3, wherein the crystalline solid has a DSC curve as shown in FIG2.

5. The solid form according to any one of claims 1-3, wherein the crystalline solid is present in the capsule.

6. The solid form according to claim 5, wherein the capsule shell is composed of gelatin, titanium dioxide, iron oxide red, and iron oxide yellow.

7. The solid form according to claim 5, wherein the capsule further comprises one or more inactive agents selected from mannitol, microcrystalline cellulose, sodium starch glycolate, sucrose monopalmitate, hydroxypropyl methylcellulose, colloidal silica, and sodium stearoyl fumarate.

8. The solid form according to any one of claims 1-3, wherein the crystalline solid is an immediate-release formulation.

9. The solid form according to any one of claims 1-3, wherein the crystalline solid is a prolonged-release formulation.

10. The solid form according to any one of claims 1-3, wherein the crystalline solid is present in the capsule in an amount of 1-10 mg.

11. The solid form according to any one of claims 1-3, wherein the crystalline solid is present in the capsule in an amount of 2.5-5 mg.

12. The solid form according to any one of claims 1-3, wherein the crystalline solid is present in the capsule in an amount of 1 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg, 10 mg, 10.5 mg, 11 mg, 11.5 mg, 12 mg, 12.5 mg, 13 mg, 13.5 mg, 14 mg, 14.5 mg, 15 mg, 15.5 mg, 16 mg, 16.5 mg, 17 mg, 17.5 mg, 18 mg, 18.5 mg, 19 mg, 19.5 mg, or 20 mg.

13. The solid form according to any one of claims 1-3, wherein the crystalline solid is present in the capsule in an amount of 2.5 mg.

14. The solid form according to any one of claims 1-3, wherein the crystalline solid is present in the capsule in an amount of 5 mg.

15. The solid form according to any one of claims 1-3, wherein the crystalline solid is present in the capsule in an amount of 7.5 mg.

16. The solid form according to any one of claims 1-3, wherein the crystalline solid is present in the capsule in an amount of 10 mg.

17. The solid form according to any one of claims 1-3, wherein the crystalline solid is present in the capsule in an amount of 12.5 mg.

18. The solid form according to any one of claims 1-3, wherein the crystalline solid is present in the capsule in an amount of 15 mg.

19. The solid form according to any one of claims 1-3, wherein the crystalline solid is present in the capsule in an amount of 17.5 mg.

20. The solid form according to any one of claims 1-3, wherein the crystalline solid is present in the capsule in an amount of 20 mg.

21. The solid form according to any one of claims 1-3, wherein the melting point of the crystalline solid, as determined by differential scanning calorimetry (DSC), is 210°C.

22. The solid form according to any one of claims 1-3, wherein the melting point of the crystalline solid, as determined by differential scanning calorimetry (DSC), is 211°C.

23. The solid form according to any one of claims 1-3, wherein the melting point of the crystalline solid, as determined by differential scanning calorimetry (DSC), is 212°C.

24. The solid form according to any one of claims 1-3, wherein the melting point of the crystalline solid, as determined by differential scanning calorimetry (DSC), is 213°C.

25. The solid form according to any one of claims 1-3, wherein the melting point of the crystalline solid, as determined by differential scanning calorimetry (DSC), is 214°C.

26. A capsule comprising a compound of formula I in solid form: (I), 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, as determined by differential scanning calorimetry (DSC), is 210-214 °C.

27. A capsule comprising a compound of formula I in solid form: (I), The solid form is a crystalline solid of the free base of the compound of formula I, and the crystalline solid has an X-ray powder diffraction (XRPD) pattern as shown in Figure 1.

28. The capsule according to claim 26 or 27, wherein the capsule shell is composed of gelatin, titanium dioxide, iron oxide red, and iron oxide yellow.

29. The capsule according to claim 26 or 27 further comprises one or more inactive agents selected from mannitol, microcrystalline cellulose, sodium starch glycolate, sucrose monopalmitate, hydroxypropyl methylcellulose, colloidal silica and sodium stearoyl fumarate.

30. The capsule according to claim 26 or 27, wherein the crystalline solid is an immediate-release formulation.

31. The capsule according to claim 26 or 27, wherein the crystalline solid is a prolonged-release formulation.

32. The capsule according to claim 26 or 27, wherein the crystalline solid is present in the capsule in an amount of 1-10 mg.

33. The capsule according to claim 26 or 27, wherein the crystalline solid is present in the capsule in an amount of 2.5-5 mg.

34. The capsule according to claim 26 or 27, wherein the crystalline solid is present in the capsule in an amount of 1 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg, 10 mg, 10.5 mg, 11 mg, 11.5 mg, 12 mg, 12.5 mg, 13 mg, 13.5 mg, 14 mg, 14.5 mg, 15 mg, 15.5 mg, 16 mg, 16.5 mg, 17 mg, 17.5 mg, 18 mg, 18.5 mg, 19 mg, 19.5 mg, or 20 mg.

35. The capsule according to claim 26 or 27, wherein the crystalline solid is present in the capsule in an amount of 2.5 mg.

36. The capsule according to claim 26 or 27, wherein the crystalline solid is present in the capsule in an amount of 5 mg.

37. The capsule according to claim 26 or 27, wherein the crystalline solid is present in the capsule in an amount of 7.5 mg.

38. The capsule according to claim 26 or 27, wherein the crystalline solid is present in the capsule in an amount of 10 mg.

39. The capsule according to claim 26 or 27, wherein the crystalline solid is present in the capsule in an amount of 12.5 mg.

40. The capsule according to claim 26 or 27, wherein the crystalline solid is present in the capsule in an amount of 15 mg.

41. The capsule according to claim 26 or 27, wherein the crystalline solid is present in the capsule in an amount of 17.5 mg.

42. The capsule according to claim 26 or 27, wherein the crystalline solid is present in the capsule in an amount of 20 mg.

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