Treatments for pathological repetitive behaviours

Abstract

The present invention provides an effective pharmacological therapy for pathological repetitive behaviours.

Description

[0001] TREATMENTS FOR PATHOLOGICAL REPETITIVE BEHAVIOURS

[0001] The present invention relates to the treatment of pathological repetitive behaviours. BACKGROUND OF THE INVENTION

[0002] Many neuropsychiatric disorders are characterised by pathological repetitive behaviours such as compulsions, tics, stereotypies, or mannerisms (Lamothe et al, Translational Psychiatry 2023, 13, 26).

[0003] Two neuropsychiatric disorders with high comorbidity include Tourette Syndrome, a childhood-onset neurodevelopmental disorder characterised by tics, and obsessive- compulsive disorder (OCD), a heterogeneous disorder, of which the most typical form is characterised by obsessions and obsession-dependent compulsions. Tics are defined as sudden, rapid, recurrent, non-rhythmic, stereotyped motor events or vocalisations. Compulsions are clinically described as pathological repetitive behaviours that individuals feel driven to perform in response to an obsession or according to rules that must be rigidly applied. A third category of disorder with pathological repetitive behaviours, which includes trichotillomania and dermatillomania (or skin-picking disorder), can be categorised according to its symptoms being either of a tic-like or a compulsive-like nature. A fourth category of disorder with pathological repetitive behaviours is Body dysmorphic disorder (BDD), a psychiatric condition defined in the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition Text Revision (DSM-5-TR) as a preoccupation with a perceived defect or flaw in one’s physical appearance when, in fact, they appear normal. To meet diagnostic criteria for BDD, patients must engage in repetitive behaviours, such as excessive mirror checking, camouflaging (ie, covering up the defect with makeup or clothing), skin picking, excessive grooming, excessive weight lifting, or pervasive mental acts such as comparing one’s appearance to others. These behaviours are time-consuming, difficult to control, and distressing to the individual.

[0004] OCD is a chronic and debilitating neuropsychiatric condition where a patient has intrusive thoughts or images (obsessions) and / or repetitive or ritualistic actions (compulsions). These repetitive or ritualistic actions are performed in an attempt to alleviate stress resulting from the intrusive thoughts or images. Whilst most people may have some obsessions and compulsions, those with OCD have no control of their obsessions and compulsions to the point that that they are unable to carry out everyday tasks and their lives are negatively impacted.

[0005] The obsessions are not simply excessive worries about real life issues. The thoughts and images are intrusive, inappropriate and cause anxiety or distress (Stein, The Lancet, 360, 3 August 2002). The compulsions result from the patient trying to suppress such thoughts through another thought or action. Such compulsions are aimed at reducing distress or preventing a dreaded situation from occurring but are not connected in a realistic way with what they are intended to neutralise or are clearly excessive. The compulsions are time-consuming and interfere with the patient’s social and occupational activities. Typically, those with OCD are aware that their obsessions are unreasonable and this causes further distress. One manifestation of OCD involves patients engaging in excessive checking behaviour, such as checking if doors are locked or appliances are switched off. Checking behaviour itself can be useful, but in OCD the excessive checking shown by patients becomes maladaptive and are performed at the expense of other activities. The compulsive checking may be due to obsessions about safety (such as fears about being responsible for a fire, flood or some sort of fatal accident), health, mistakes, or inappropriate behaviour concerns.

[0006] OCD is common. The worldwide prevalence is estimated to be between 1-3% of the adult population and thus OCD represents a major health-economic burden. Despite this high prevalence, the causes of OCD are unknown. There has been some evidence to suggest that genetics play a role, but work in this field has not yielded any definitive molecular targets for therapeutic intervention (Robbins et al., Neuron 102, 3 April 2019). Accordingly, current therapeutic approaches to treating OCD involves psychological therapy and limited pharmacotherapy. Selective serotonin reuptake inhibitors (SSRIs) are the first line pharmacological treatment of OCD.

[0007] SSRIs work by increasing the amount of the neurotransmitter serotonin in the synapse. Serotonin is released by the presynaptic cell and then diffuses across the synapse to the postsynaptic cell, where it binds to serotonin receptors to stimulate neuronal signalling in that cell. Once the serotonin is released and the message transmitted, the serotonin is taken back up by the presynaptic cell to be reused. SSRIs increase the amount of serotonin in the synapse by inhibiting serotonin reuptake by the presynaptic cell. This increases the amount of serotonin in the synapse and thus increases stimulation of the serotonin receptors on the postsynaptic cell.

[0008] SSRIs are usually used to treat major depressive disorders, but they exhibit utility in treating OCD when used at high doses, typically above the dose range included in the approved label by their manufacturers. Consequently, the risk of side effects is increased. For example, the Food and Drug Administration has issued a warning against the use of the SSRI citalopram in doses in excess of 40 mg / day due to an increased risk of heart complications, and high levels of patient dropout due to negative side-effects was observed in a clinical trial investigating SSRIs for the treatment of OCD (Bloch et al., Mol. Psychiatry, 2010, 15(8), 850-855). Furthermore, the efficacy of SSRIs in treating OCD is low, meaning that approximately half of OCD patients do not respond sufficiently to SSRIs (Kellner, Dialogues in Clinical Neuroscience, 12, 2, 2010).

[0009] Accordingly, there exists a need for effective pharmacological therapies for OCD. SUMMARY OF THE INVENTION

[0010] In a first aspect the invention provides a compound comprising the structure: wherein: X and X′ are each independently absent or are each independently O; y is 1; q is independently an integer selected from 0, 1, 2, 3, and 4; m is an integer selected from 0, 1, 2, and 3; W is independently selected from CH2, O, S, and NCH3; R1is independently selected from halogen, cyano, nitro, unsubstituted C1-C6alkyl, perfluoroalkyl, —OR5, —C(O)OR5, and C(O)NR6R7; R3is independently selected from hydrogen, branched or unbranched C1-C6alkyl, C3-C8- cycloalkyl, phenyl, benzyl and C1-C6alkylC3-C8cycloalkyl, wherein benzyl is optionally substituted with perfluoroalkyl and R5, R6, and R7are each independently selected from hydrogen, and branched or unbranched alkyl, for use in the treatment of pathological repetitive behaviours or OCD in a patient.

[0011] Preferably, the compound is 4-Chloro-3′-((2-cyclopentyl-1-oxoisoindolin-5-yloxy)- methyl)biphenyl-3-carboxylic acid, or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof.

[0012] The compound or the pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof may be administered at a dose of 0.01 mg / kg to 100 mg / kg, 0.05 mg / kg to 50 mg / kg, 0.1 mg / kg to 30 mg / kg, 0.3 mg / kg to 10 mg / kg, or preferably 3 mg / kg to 30 mg / kg. The compound the pharmaceutically acceptable salt, hydrate, solvate, optical isomer, or polymorph thereof may be administered at a dose of at least 1 mg / kg, at least 2 mg / kg, at least 3 mg / kg, at least 4 mg / kg, at least 5 mg / kg, at least 6 mg / kg, at least 7 mg / kg, at least 8 mg / kg, at least 9 mg / kg, at least 10 mg / kg, at least 11 mg / kg, at least 12 mg / kg, at least 13 mg / kg, at least 14 mg / kg, at least 15 mg / kg, at least 16 mg / kg, at least 17 mg / kg, at least 18 mg / kg, at least 19 mg / kg, at least 20 mg / kg, at least 25 mg / kg, at least 30 mg / kg, at least 35 mg / kg, at least 40 mg / kg, at least 45 mg / kg, or at least 50 mg / kg. The compound the pharmaceutically acceptable salt, hydrate, solvate, optical isomer, or polymorph thereof may be administered at a dose of at most 1 mg / kg, at most 2 mg / kg, at most 3 mg / kg, at most 4 mg / kg, at most 5 mg / kg, at most 6 mg / kg, at most 7 mg / kg, at most 8 mg / kg, at most 9 mg / kg, at most 10 mg / kg, at most 11 mg / kg at most 12 mg / kg, at most 13 mg / kg, at most 14 mg / kg, at most 15 mg / kg, at most 16 mg / kg, at most 17 mg / kg, at most 18 mg / kg, at most 19 mg / kg, at most 20 mg / kg, at most 25 mg / kg, at most 30 mg / kg, at most 35 mg / kg, at most 40 mg / kg, at most 45 mg / kg, or at most 50 mg / kg.

[0013] The compound or the pharmaceutically acceptable salt, hydrate, solvate, optical isomer, or polymorph thereof may be administered orally, parenterally, subcutaneously, intravenously, intramuscularly, intrathecally, intradermally, intraarterially, intraarticularly, intraperitoneally, via cutaneous administration, via transcutaneous administration, via intra-osseus administration or by inhalation (both nasal and pulmonary). Oral administration is preferred.

[0014] The patient’s OCD may be characterised by a score according to the Yale-Brown Obsessive Compulsive scale of at least 8, at least 16, a least 24 or optionally at least 32. The patient’s OCD may be characterised by a Yale-Brown Obsessive Compulsive scale score of 16-40, 24-40 or optionally 32-40.

[0015] Alternatively, or additionally, the patient’s OCD may be characterised a score according to the Obsessive-Compulsive Inventory (OCI) or Obsessive-Compulsive Inventory - Revised (OCI-R) of at least 21, at least 30, at least 40, at least 50, or at least 60. The patient’s OCD may be characterised a score according to the Obsessive-Compulsive Inventory (OCI) or Obsessive-Compulsive Inventory - Revised (OCI-R) of 21-72, 30-72, 40- 72, 50-72 or 60-72.

[0016] The patient may have checking compulsions.

[0017] In a second aspect the invention provides a pharmaceutical composition for use in the treatment of pathological repetitive behaviour in a patient, wherein said pharmaceutical composition comprises the aforementioned compound or a pharmaceutically acceptable salt, hydrate, solvate, optical isomer, or polymorph thereof.

[0018] The pharmaceutical composition may comprise the compound or the pharmaceutically acceptable salt, hydrate, solvate, optical isomer, polymorph thereof in an amount of 0.7 mg to 7000 mg, 3.5 mg to 3500 mg, 7 mg to 2100 mg, 21 mg to 700 mg, preferably 210 mg to 2100 mg.

[0019] The pharmaceutical composition may be administered orally, parenterally, subcutaneously, intravenously, intramuscularly, intrathecally, intradermally, intraarterially, intraarticularly, intraperitoneally, via cutaneous administration, via transcutaneous administration, via intra-osseus administration or by inhalation (both nasal and pulmonary). Oral administration is preferred.

[0020] The patient’s OCD may be characterised by a score according to the Yale-Brown Obsessive Compulsive scale of at least 8, at least 16, a least 24 or optionally at least 32. The patient’s OCD may be characterised by a Yale-Brown Obsessive Compulsive scale score of 16-40, 24-40 or 32-40, preferably 16-40.

[0021] Alternatively, or additionally, the patient’s OCD may be characterised a score according to the Obsessive-Compulsive Inventory (OCI) or Obsessive-Compulsive Inventory - Revised (OCI-R) of at least 21, at least 30, at least 40, at least 50 or at least 60, preferably at least 40. The patient’s OCD may be characterised a score according to the Obsessive-Compulsive Inventory (OCI) or Obsessive-Compulsive Inventory - Revised (OCI- R) of 21-72, 30-72, 40-72, 50-72 or 60-72, preferably 40-72.

[0022] The patient may have checking compulsions.

[0023] The pharmaceutical composition may comprise a pharmaceutically acceptable excipient. The pharmaceutically acceptable excipient may be selected from the group consisting of a solvent, a co-solvent, a buffer, a stabiliser, an antioxidant, a preservative, a chelating agent, an emulsifier, a flavouring, a lubricant, a suspending agent, a tonicity- adjusting agent, a surfactant, a solubilising agent, a suspending aid, a dispersion agent, a humectant, a thickener, a colouring agent, a wetting agent, an anti-foaming agent, a viscosity modifier, a sweetener, and any combination thereof. The pharmaceutical formulation may comprise the compound or the pharmaceutically acceptable salt, hydrate, solvate, optical isomer, or polymorph thereof and phosphate buffered saline.

[0024] The pharmaceutical composition may comprise a second active agent. The second active agent may comprise an atypical neuroleptic, a neuroleptic, an anticonvulsant or an antidepressant. The atypical neuroleptic may comprise amisulpride, aripiprazole, asenapine, blonanserin, clozapine, lurasidone, melperone, olanzapine, paliperidone, perospirone, risperidone, sertindole or sulpiride. The neuroleptic may comprise chlorpromazine, chlorprothixene, levomepromazine, mesoridazine, periciazine, promazine, loxapine, molindone, perphenazine, thiothixene, droperidol, flupentixol, fluphenazine, pimozide, prochlorperazine, thioproperazine or zuclopenthixol. The anticonvulsant may comprise paraldehyde, phenobarbital, clobazam, clonazepam, clorazepate, diazepam, midazolam, a valproate, vigabatrin, progabide, tiagabine, ethadione, brivaracetam or zonisamine. The antidepressant may comprise fluoxetine, paroxetine, sertraline, citalopram, escitalopram, duloxetine, venlafaxine, desvenlafaxine, trazodone, vortioxetine, bupropion, imipramine, nortriptyline, amitriptyline, tranylcypromine or phenelzine.

[0025] In a third aspect the invention provides a kit comprising the aforementioned compound or a pharmaceutically acceptable salt, hydrate, solvate, optical isomer, or polymorph thereof. The kit may comprise instructions (for providing information to the patient, such as safety information or information on how to correctly administer the compound or pharmaceutical composition) or the aforementioned second active agent. The second active agent may be for simultaneous, separate or sequential use with the aforementioned compound or a pharmaceutically acceptable salt, hydrate, solvate, optical isomer, or polymorph thereof.

[0026] In a fourth aspect the invention provides a method of treating pathological repetitive behaviour in a patient, comprising administering to the patient a therapeutically effective amount of the aforementioned compound or a pharmaceutically acceptable salt, hydrate, solvate, optical isomer, or polymorph thereof, or the aforementioned pharmaceutical composition.

[0027] In a fifth aspect, the invention provides a use of the aforementioned compound or a pharmaceutically acceptable salt, hydrate, solvate, optical isomer, or polymorph thereof in the preparation of a medicament for the treatment of pathological repetitive behaviour. BRIEF DESCRIPTION OF THE FIGURES Figure 1 shows the effect of Compound A on excessive grooming duration. Figure 2 shows the effect of fluoxetine on excessive grooming duration. Figure 3 shows the effect of Compound A in combination with fluoxetine on excessive grooming duration. DETAILED DESCRIPTION OF THE INVENTION

[0028] Throughout this specification, one or more aspects of the invention may be combined with one or more features described in the specification to define distinct embodiments of the invention.

[0029] In the discussion herein, reference is made to a number of terms, which are to be understood to have the meanings accepted in the art, unless explicitly defined below.

[0030] Throughout this specification the word "comprise" will be understood to mean the inclusion of a stated element or integer, or group of elements or integers, but not the exclusion of any other element or integer, or group of elements or integers. References to “comprising” or “comprise” also encompass providing basis for “consisting” or “consist”.

[0031] The term “consisting” is to be understood to mean the inclusion of a stated element or integer, or group of elements or integers, and the exclusion of any other element or integer or group of elements or integers.

[0032] The term “consisting essentially of” is to be understood to mean the inclusion of a stated element or integer, or group of elements or integers, and that further components may be present, provided that those further components do not materially affect the essential characteristics of the formulation, composition, or compound.

[0033] The term “about” herein, when qualifying a number or value, is used to refer to values that lie within ±1%, ± 5%, or ±10% of the value specified.

[0034] The terms "treatment" and “therapy” define the therapeutic treatment of a patient, but also include within their meanings the reduction or halting of the rate of progression of a disorder or condition, or the amelioration or cure the disorder or condition. Prophylaxis of a disorder or condition as a result of treatment or therapy is also included. The term “treatment” also includes the reduction in severity of the pathological repetitive behaviours, prevention of an increase in their severity, or prevention of relapse of such behaviours after a period of relative quiescence.

[0035] “Pathological repetitive behaviours” include compulsions, tics, stereotypies, or mannerisms (Lamothe et al, Translational Psychiatry 2023, 13, 26). Compulsions are clinically described as pathological repetitive behaviours that individuals feel driven to perform in response to an obsession or according to rules that must be rigidly applied. Tics are defined as sudden, rapid, recurrent, non-rhythmic, stereotyped motor events or vocalisations. Stereotypies are repetitive, seemingly purposeless movements or vocalizations. Stereotypies can manifest as simple actions like hand-flapping or body rocking, or more complex behaviours like pacing or self-caressing, these movements are often involuntary and may occur in response to stress, excitement, or boredom. For the purposes of this specification, "Pathological repetitive behaviours", are uncontrolled behaviours within a subject that are driven by an urge to relieve a strong impulse, not primarily for pleasure (unlike addictions).

[0036] Obsessive-compulsive disorder (OCD) OCD is a chronic and debilitating neuropsychiatric condition where a patient has intrusive thoughts or images (obsessions) and / or repetitive or ritualistic actions (compulsions).

[0037] Trichotillomania, also known as trich or TTM, is when someone cannot resist the urge to pull out their hair. They may pull out the hair on their head or in other places, such as their eyebrows or eyelashes.

[0038] Dermatillomania, also known as skin picking disorder or excoriation disorder, is a mental health condition where individuals compulsively pick at their skin, causing tissue damage and potential scarring.

[0039] Tourette Syndrome is a childhood-onset neurodevelopmental disorder characterised by tics, and obsessive-compulsive disorder (OCD), a heterogeneous disorder, of which the most typical form is characterised by obsessions and obsession- dependent compulsions.

[0040] Body dysmorphic disorder (BDD) is a psychiatric condition defined in the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition Text Revision (DSM-5-TR) as a preoccupation with a perceived defect or flaw in one’s physical appearance when, in fact, they appear normal.

[0041] As used herein, the term “patient” preferably refers to a mammal. Typically, the mammal is a human.

[0042] The term “C1-C6alkyl” and “alkyl” means a straight or branched chain or cyclic hydrocarbon having one to six carbon atoms. Preferably “C1-C6alkyl” is “C1-C3alkyl” and includes methyl, ethyl, propyl, and isopropyl.

[0043] The term “C3-C8cycloalkyl” means an aliphatic carbocyclic ring containing 3 to 8 ring members with optional branching and containing 3 to 8 carbon atoms in total. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylcyclohexyl, cycloheptyl and cyclooctyl.

[0044] The term “C1-C6alkylC3-C8cycloalkyl” means an aliphatic carbocyclic ring containing 3 to 8 carbon atom ring members with a C1-C6alkyl substitution. Preferably the C1-C6alkyl substitution is a straight chain.

[0045] The term “perfluoroalkyl” means a straight or branched group comprising one or more carbon-fluorine bonds and is meant to include but not be limited to, trifluoromethyl, 2,2,2-trifluoroethyl and the like.

[0046] The term “halogen” includes fluorine, chlorine, bromine, iodine, in both radioactive and non-radioactive forms. Preferably the halogen is fluorine or chlorine, preferably chlorine.

[0047] The term “pharmaceutically acceptable” refers to any non-toxic composition of matter that is suitable for administration to a patient. For example, the term “pharmaceutically acceptable salt” is preferably any non-toxic addition salt that includes a cationic counterion. Illustrative examples include sodium, lithium, potassium, calcium, magnesium, ammonium, and quaternary ammonium (substituted with at least one organic moiety) cations.

[0048] The term “therapeutically effective amount” means an amount of the compound that is effective in treating the named disorder or condition.

[0049] A dose measured in “mg / kg” refers to a dose of an active agent in milligrams calculated based on the body weight of a patient to be treated. For example, a dose of 1 mg / kg would result in a 100 kg subject being administered a dose of 100 mg. Compounds

[0050] The compounds of the present invention are described in PCT publication number US Pat.8,748,632B, where they are referred to as “compounds of Formula (IV)”. US Pat. 8,748,632B describes the synthesis of the compounds of the present invention. The skilled person will understand that deuterium-analogues and metabolites of the claimed compounds are expected to have the benefits of the claimed compounds too.

[0051] The term “compound” or “compound or a pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof” refers to a compound comprising the general structure (I): wherein X and X′ are each independently absent or are each independently O; y is 1; q is independently an integer selected from 0, 1, 2, 3, and 4; m is an integer selected from 0, 1, 2, and 3; W is independently selected from CH2, O, S, and NCH3; R1is independently selected from halogen, cyano, nitro, unsubstituted C1-C6alkyl, perfluoroalkyl, —OR5, —C(O)OR5, and C(O)NR6R7; R3is independently selected from hydrogen, branched or unbranched C1-C6alkyl, C3-C8- cycloalkyl, phenyl, benzyl and C1-C6alkylC3-C8cycloalkyl, wherein benzyl is optionally substituted with perfluoroalkyl; and R5, R6, and R7are each independently selected from hydrogen, branched or unbranched alkyl. Preferably X is absent and / or X’ is O. Preferably q is 0, 1 or 2, preferably 1 or 2, preferably 1. Preferably m is 1, 2 or 3, preferably 2. Preferably W is CH2. Preferably each R1is independently selected from halogen, perfluoroalkyl and —C(O)OR5, preferably halogen and —C(O)OR5. Preferably m is 2 and one R1is halogen and one R1is —C(O)OR5. Preferably R3is branched or unbranched C1-C6alkyl, C3-C8-cycloalkyl or C1-C6alkylC3-C8- cycloalkyl, preferably C3-C8-cycloalkyl, most preferably cyclopentyl. Preferably R5is hydrogen.

[0052] The compound is preferably 4-Chloro-3′-((2-cyclopentyl-1-oxoisoindolin-5-yloxy)- methyl)biphenyl-3-carboxylic acid (Compound A). Preferably, the compound comprises or is the structure: or a pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof.

[0053] The salt of 4-Chloro-3′-((2-cyclopentyl-1-oxoisoindolin-5-yloxy)-methyl)biphenyl- 3-carboxylic acid may be the sodium salt. Obsessive compulsive disorder

[0054] In the Diagnostic and Statistical Manual of Mental Disorders, 5thedition (DSM-V), OCD is recognised as a disorder distinct from anxiety. OCD is grouped with several other disorders with common features, which group is defined as “Obsessive-Compulsive and Related Disorders”. The group includes Body Dysmorphic Disorder, Hoarding Disorder and others in addition to OCD. Accordingly, a preferred embodiment of the invention provides a compound, a pharmaceutical composition, a kit, a method of treating a patient, or use according to any aspect of the present disclosure for use in treating a disorder which is defined the DSM-5 under the section defined as "Obsessive-Compulsive and Related Disorders", the contents of which are hereby incorporated by reference in their entirety. The DSM-V provides the following diagnostic criteria for OCD: A. Presence of obsessions, compulsions, or both. − Obsessions are defined by (1) and (2): (1) Recurrent and persistent thoughts, urges, or images that are experienced, at some time during the disturbance, as intrusive and unwanted, and that in most individuals cause marked anxiety or distress. (2) The individual attempts to ignore or suppress such thoughts, urges, or images, or to neutralise them with some other thought or action. − Compulsions are defined by (1) and (2): (1) Repetitive behaviours (e.g. hand washing, ordering, checking) or mental acts (e.g. praying, counting, repeating words silently) that the individual feels driven to perform in response to an obsession or according to rules that must be applied rigidly. (2) The behaviours or mental acts are aimed at preventing or reducing anxiety or distress, or preventing some dreaded event or situation; however, these behaviours or mental acts are not connected in a realistic way with what they are designed to neutralise or prevent, or are clearly excessive. B. The obsessions or compulsions are time-consuming or cause clinically significant distress or impairment in social, occupational, or other important areas of functioning. C. The obsessive-compulsive symptoms are not attributable to the physiological effects of a substance (e.g. a drug of abuse, a medication) or another medical condition. D. The disturbance is not better explained by the symptoms of another mental disorder (e.g. generalised anxiety disorder).

[0055] OCD is typically diagnosed by a healthcare provider following a discussion with a patient about their symptoms. An improvement in OCD may result in a reduction in the number or time spent on obsessions and / or compulsions. The patient may generally feel less anxious as the OCD symptoms are reduced.

[0056] The severity of OCD may be measured by the Yale-Brown Obsessive Compulsive Scale. This scale is a clinician-rated, 10-item scale, each item rated from 0 (no symptoms) to 4 (extreme symptoms) (total range, 0 to 40), with separate subtotals for severity of obsessions and compulsions. The Yale-Brown Obsessive Compulsive Scale is described in Goodman et al., Arch. Gen. Psychiatry 1989; 46: 1006–1011 and Goodman et al., Arch. Gen. Psychiatry 1989; 46: 1012–1016. The patient’s OCD may be characterised by a score of at least about 8, at least about 12, at least about 16, at least about 20, at least about 24, at least about 28 or at least about 32, preferably at least 16, according to the Yale Brown Obsessive Compulsive Scale. Following treatment with the aforementioned compound or a pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof, a patient may exhibit a reduction in their Yale Brown Obsessive Compulsive score.

[0057] Alternatively, or additionally, the severity of OCD may be measured according to the Obsessive Compulsive Inventory (or its updated form: Obsessive Compulsive Inventory – Revised). The Obsessive-Compulsive Inventory consists of 42 items composing 7 subscales: Washing, Checking, Doubting, Ordering, Obsessing (i.e., having obsessional thoughts). Hoarding, and Mental Neutralizing. Each item is rated on a 5-point (0-4) Likert scale of symptom frequency and associated distress. The Obsessive-Compulsive Inventory is described in Foa et al., Psychological Assessment, 1998, 10, 3, 206-214. The patient’s OCD may be characterised by a score according to the Obsessive Compulsive Inventory of at least 21, at least 30, at least 35, at least 40, at least 45, at least 50, at least 55, at least 60, at least 65 or at least 70, preferably at least 40; or a score of 21-72, 30-72, 40-72, 50- 72 or 60-72, preferably 40-72. Following treatment with the aforementioned compound or a pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof, the patient may have a reduction in their Obsessive Compulsive Inventory score.

[0058] OCD is heterogenous. Those with OCD may have a variety of obsessions and compulsions. The obsessions may be fear of harming themselves or others through their own actions, the fear of harming themselves or others through a mistake such as leaving a light on, the fear of contamination or disease, or the need for symmetry and orderliness. The compulsions may include cleaning and hand-washing, checking, counting, ordering and arranging, hoarding, asking for reassurance, or repeating words in their head.

[0059] Optionally, the patient to be treated with the aforementioned compound or a pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof exhibits checking compulsions. Typically, checking compulsions arise when a person experiences intrusive thoughts, fears of or concerns about, for example, items not being where they are supposed to be, lights or appliances being left on, and doors not being locked. As a result of these obsessions, patients with OCD feel the compulsion to “check” and make sure the items they are concerned with have been put in the right place, the lights or appliances are turned off, and the doors are locked. The presence of checking compulsions can be determined through conversations with the patient by a healthcare provider.

[0060] OCD may be studied using animal models and such models may be used to evaluate compounds of the present invention. One rodent model of compulsive behaviour is the SAP90 / PSD95-associated protein 3 (SAPAP3) knock-out (KO) mouse, which has a prominent compulsive grooming phenotype that is reduced by SSRI treatment (Davis et al., Nat Commun. 2021; 12: 6040). Mice lacking SAPAP3 also demonstrate impaired cognitive flexibility, aberrant habit formation, and altered glutamatergic signalling in the dorsal striatum, a region implicated in OCD pathology. A recent analysis of post-mortem brains demonstrated reduced expression of the SAPAP3 protein in the striatum of OCD patients, and variants of the Sapap3 gene have been associated with early-onset OCD and trichotillomania, another compulsive disorder. Other studies have implied involvement of dorsal striatal circuits in the generation of several types of pathological repetitive behaviours, including a strong comorbidity of tic- and compulsive-like symptoms in patients with Tourette’s syndrome. It is noted that whilst the SAPAP3 knockout (KO) mouse is a model of compulsive-like behaviour in OCD, this model is also predictive of other compulsive behaviour found in Tourette’s syndrome and trichotillomania. Dose

[0061] The aforementioned compound or the pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof may be administered at a dose of at least 0.1 mg / kg, at least 0.3 mg / kg, at least 0.5 mg / kg, at least 1 mg / kg, at least 2 mg / kg, at least 3 mg / kg, at least 4 mg / kg, at least 5 mg / kg, at least 6 mg / kg, at least 7 mg / kg, at least 8 mg / kg, at least 9 mg / kg, or at least 10 mg / kg, at least 11 mg / kg, at least 12 mg / kg, at least 13 mg / kg, at least 14 mg / kg, at least 15 mg / kg, at least 16 mg / kg, at least 17 mg / kg, at least 18 mg / kg, at least 19 mg / kg, at least 20 mg / kg, at least 25 mg / kg, at least 30 mg / kg, at least 35 mg / kg, at least 40 mg / kg, at least 45 mg / kg, or at least 50 mg / kg. The aforementioned compound or the pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof may be administered at a dose of at most 1 mg / kg, at most 2 mg / kg, at most 3 mg / kg, at most 4 mg / kg, at most 5 mg / kg, at most 6 mg / kg, at most 7 mg / kg, at most 8 mg / kg, at most 9 mg / kg, at most 10 mg / kg, at most 11 mg / kg at most 12 mg / kg, at most 13 mg / kg, at most 14 mg / kg, at most 15 mg / kg, at most 16 mg / kg, at most 17 mg / kg, at most 18 mg / kg, at most 19 mg / kg, at most 20 mg / kg, at most 25 mg / kg, at most 30 mg / kg, at most 35 mg / kg, at most 40 mg / kg, at most 45 mg / kg, or at most 50 mg / kg. Any of the aforementioned upper and lower limits may be combined to form a range. Preferably, the compound comprises or is 4-Chloro-3′-((2-cyclopentyl-1-oxoisoindolin-5-yloxy)- methyl)biphenyl-3-carboxylic acid.

[0062] The aforementioned compound or the pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof may be administered at a dose of 0.01 mg / kg to 100 mg / kg, 0.1 mg / kg to 50 mg / kg, 0.3 mg / kg to 45 mg / kg, 0.5 mg / kg to 40 mg / kg, 1 mg / kg to 30 mg / kg or 2 mg / kg to 20 mg / kg, 0.3 mg / kg to 10 mg / kg, 0.3 mg / kg to 3 mg / kg, 0.3 mg / kg to 1 mg / kg, or preferably 3 mg / kg to 10 mg / kg. The aforementioned compound or the pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof may be administered at a dose of 0.01 mg / kg to 100 mg / kg, 0.05 mg / kg to 50 mg / kg, 0.1 mg / kg to 30 mg / kg, 0.3 mg / kg to 10 mg / kg, or preferably 1 mg / kg to 3 mg / kg.4-Chloro-3′-((2- cyclopentyl-1-oxoisoindolin-5-yloxy)-methyl)biphenyl-3-carboxylic acid.

[0063] The dose may be administered over a period of time. The period of time may be from 1 month to 12 months, for example from 2 months to 11 months, from 3 months to 10 months, from 4 months to 9 months, from 5 months to 8 months, from 6 months to 7 months. The dose may be administered for at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months or at least 12 months. The dose may be administered for 1 year, 2 years, 3 years, 4 years or at least 5 years. The dose may be administered for a suitable amount of time such that the symptoms of OCD decrease. The dose may be administered for an indefinite period of time (e.g. for the duration of the patient’s life). Preferably, the aforementioned compound or the pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof is administered for at least 3 months and even more preferably for at least one year. Preferably, the compound comprises 4-Chloro-3′-((2-cyclopentyl-1-oxoisoindolin-5-yloxy)- methyl)biphenyl-3-carboxylic acid.

[0064] The dose may be administered once a day, twice a day, three times a day or four times a day. The dose may be administered once a week, twice a week, three times a week, four times a week, five times a week, six times a week, or 7 times a week. Preferably, a dose of 3 mg / kg to 10 mg / kg is administered once a day, twice a day, three times a day or four times a day. Preferably, the aforementioned compound is 4-Chloro-3′-((2- cyclopentyl-1-oxoisoindolin-5-yloxy)-methyl)biphenyl-3-carboxylic acid. Preferably, the aforementioned compound is 4-Chloro-3′-((2-cyclopentyl-1-oxoisoindolin-5-yloxy)- methyl)biphenyl-3-carboxylic acid and is administered once a day. More preferably, the aforementioned compound is 4-Chloro-3′-((2-cyclopentyl-1-oxoisoindolin-5-yloxy)- methyl)biphenyl-3-carboxylic acid and is administered once a day at a dose of 3 mg / kg – 30 mg / kg.

[0065] The aforementioned compound or the pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof may be administered parenterally, subcutaneously, subcutaneously, intravenously, intramuscularly, intrathecally, intradermally, intraarterially, intraarticularly, intraperitoneally, via cutaneous administration, via transcutaneous administration, via intra-osseus administration or by inhalation. Preferably, the aforementioned compound or the pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof is administered orally. Preferably, the aforementioned compound is 4-Chloro-3′-((2-cyclopentyl-1-oxoisoindolin-5-yloxy)- methyl)biphenyl-3-carboxylic acid. A dose of 3 mg / kg to 10 mg / kg of 4-Chloro-3′-((2- cyclopentyl-1-oxoisoindolin-5-yloxy)-methyl)biphenyl-3-carboxylic acid may be administered orally. A dose of 3 mg / kg to 30 mg / kg of 4-Chloro-3′-((2-cyclopentyl-1- oxoisoindolin-5-yloxy)-methyl)biphenyl-3-carboxylic acid may be administered orally and once a day, twice a day, three times a day or four times a day. A dose of 3 mg / kg to 30 mg / kg of 4-Chloro-3′-((2-cyclopentyl-1-oxoisoindolin-5-yloxy)-methyl)biphenyl-3- carboxylic acid may be administered orally and once a day, twice a day, three times a day or four times a day, for at least 3 months. Pharmaceutical composition

[0001] A pharmaceutical composition is any composition that is suitable for administration to a patient. The patient is typically a human. The pharmaceutical composition may comprise the aforementioned compound or the pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof and preferably a pharmaceutically acceptable excipient. Preferably, the aforementioned compound is 4-Chloro-3′-((2- cyclopentyl-1-oxoisoindolin-5-yloxy)-methyl)biphenyl-3-carboxylic acid. The pharmaceutically acceptable excipient may comprise a solvent, a co-solvent, a buffer, a stabiliser, an antioxidant, a preservative, a chelating agent, an emulsifier, a flavouring, a lubricant, a suspending agent, a tonicity adjusting agent, a surfactant, a solubilising agent, a suspending aid, a dispersion agent, a humectant, a thickener, a colouring agent, a wetting agent, an anti-foaming agent, a viscosity modifier, a sweetener or any combination thereof. The pharmaceutically acceptable excipient may comprise glucose. The pharmaceutically acceptable excipient may comprise sodium chloride. The pharmaceutically acceptable excipient may comprise phosphate buffered saline.

[0066] The pharmaceutical composition may comprise the aforementioned compound or the pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof in an amount of 7 mg, 10 mg, 15 mg, 20 mg, 21 mg, 25 mg, 30 mg, 40 mg, 50 mg, 60 mg, 80 mg, 100 mg, 150 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 300 mg, 350 mg, 400mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, or 800 mg. The pharmaceutical composition may comprise the aforementioned compound or the pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof in an amount of 0.7 mg to 7000 mg, 3.5 mg to 3500 mg, 7 mg to 2100 mg, 21 mg to 700 mg, preferably 210 mg to 2100 mg. Preferably, the aforementioned compound is 4-Chloro-3′-((2-cyclopentyl-1- oxoisoindolin-5-yloxy)-methyl)biphenyl-3-carboxylic acid. Preferably, the dose is about 210 mg or about 2100 mg, or 210 mg to 2100 mg. Such quantities are useful for a unit dosage form.

[0067] The pharmaceutical composition may be either in liquid or solid form. A solid form pharmaceutical composition may comprise a powder, a tablet, a dispersible granule, a capsule, a cachet or a suppository. The solid excipient may comprise a diluent, a flavouring agent, solubilising agent, lubricant, a suspending agent, a binder or a tablet disintegrating agent. The solid excipient may comprise magnesium carbonate, magnesium stearate, talc, lactose, sugar, pectin, dextrin, starch, methyl cellulose, sodium carboxymethyl cellulose, wax or the like. The solid form pharmaceutical composition may be suitable for oral administration in the form of a tablet, powder or capsule. A liquid form pharmaceutical composition may comprise a solution, a suspension or an emulsion. For example, the aforementioned compound or the pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof may be prepared in sterile water or a water / propylene glycol solution. An aqueous solution may be prepared by dissolving the aforementioned compound or the pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof in water and adding an excipient comprising a diluent, a flavouring agent, a solubilising agent, a lubricant or a suspending agent. The aqueous solution may be suitable for oral administration or for injection. The aqueous solution may comprise phosphate buffered saline.

[0068] The pharmaceutical composition may comprise an additional active agent. The additional active agent may comprise an atypical neuroleptic, a neuroleptic, an anticonvulsant or an antidepressant.

[0069] The atypical neuroleptic may comprise amisulpride, aripiprazole, asenapine, blonanserin, clozapine, lurasidone, melperone, olanzapine, paliperidone, perospirone, risperidone, sertindole or sulpiride.

[0070] The neuroleptic may comprise chlorpromazine, chlorprothixene, levomepromazine, mesoridazine, periciazine, promazine, loxapine, molindone, perphenazine, thiothixene, droperidol, flupentixol, fluphenazine, pimozide, prochlorperazine, thioproperazine or zuclopenthixol.

[0071] The anticonvulsant may comprise paraldehyde, phenobarbital, clobazam, clonazepam, clorazepate, diazepam, midazolam, a valproate, vigabatrin, progabide, tiagabine, ethadione, brivaracetam or zonisamine.

[0072] The antidepressant may comprise fluoxetine, paroxetine, sertraline, citalopram, escitalopram, duloxetine, venlafaxine, desvenlafaxine, trazodone, vortioxetine, bupropion, imipramine, nortriptyline, amitriptyline, tranylcypromine or phenelzine.

[0073] The invention will now be illustrated by the following Examples which are in no way meant to be limiting. EXAMPLES Example 1 Synthesis of 4-Chloro-3′-((2-cyclopentyl-1-oxoisoindolin-5-yloxy)- methyl)biphenyl-3-carboxylic acid (“Compound A”)

[0074] 4-Chloro-3′-((2-cyclopentyl-1-oxoisoindolin-5-yloxy)-methyl)biphenyl-3-carboxylic acid (Compound A) was synthesised according to the methods described in Dhanya RP. J Med Chem.2011;54:342–53. Example 2 4-Chloro-3′-((2-cyclopentyl-1-oxoisoindolin-5-yloxy)-methyl)biphenyl-3- carboxylic acid (“Compound A”) reduces grooming behaviour the SAPAP3 mouse model of OCD

[0075] SAPAP3 KO mice were generated by homologous recombination in R1 embryonic stem cells using standard procedures. Adult mice, age 4 months, were used for behavioural analyses. Mice were housed in groups of the same genotype in a temperature and humidity-controlled room with a 12h light-dark cycle (lights on 7 am to 7 pm). Food and water were available ad libitum. Genotyping was conducted using TransnetXY Automated Genotyping. All experiments were conducted with the experimenter blind to genotype and drug treatment. Separate investigators prepared and coded the dosing solutions, allocated the mice to the study treatment groups, dosed the animals, and collected the behavioural data.

[0076] Grooming behaviour for SAPAP3 KO and wild-type (WT) mice were recorded for 10-min sessions. The experiment comprised the following groups of 10 animals: (a) WT mice treated daily with vehicle (sterile water). (b) SAPAP3 KO mice treated daily with vehicle (sterile water). (c) SAPAP3 KO mice treated daily with Compound A (10 mg / kg i.p.). (d) SAPAP3 KO mice treated daily with Compound A (20 mg / kg i.p.). (e) SAPAP3 KO mice treated daily with fluoxetine (5 mg / kg i.p.). (f) SAPAP3 KO mice treated daily with Compound A (10 mg / kg) plus fluoxetine (5 mg / kg i.p.).

[0077] The next day mice were injected intraperitoneally with either saline or drug treatment and immediately placed in the behavioural rig. Grooming was quantitated as time spent in seconds grooming during each 10-minute session at time points of 1 h, 1, 3 and 7 days after first treatment with drug or vehicle. Excessive grooming was quantitated as the difference between grooming in the SAPAP3 KO mice relative to the WT.

[0078] Results In Figures 1-3, ‘D0’ refers to results 1h after first administration of drug or vehicle; ‘D1’ refers to results 1 day after such first administration; ‘D3’ refers to results 3 days after such first administration; ‘D7’ refers to results 7 days after such first administration. Levels of significance are marked as follows: * p<0.05 ** p<0.01 *** p<0.001 **** p<0.0001 The Figures clearly show that Compound A produces strong effects to reduce excessive grooming (a pathological repetitive behaviour) in SAPAP3 KO mice, and that at a dose of 10 mg / kg, when combined with fluoxetine (5 mg / kg), a significant effect is observed within 1h after administration that is more pronounced than with either agent alone. The effect is to render the grooming behaviour in SAPAP3 KO mice statistically no different from WT mice.

Claims

Claims 1. A compound comprising the structure:wherein: X and X′ are each independently absent or are each independently O; y is 1; q is independently an integer selected from 0, 1, 2, 3, and 4; m is an integer selected from 0, 1, 2, and 3; W is independently selected from CH2, O, S, and NCH3; R1is independently selected from halogen, cyano, nitro, unsubstituted C1-C6alkyl, perfluoroalkyl, —OR5, —C(O)OR5, and C(O)NR6R7; R3is independently selected from hydrogen, branched or unbranched C1-C6alkyl, C3-C8- cycloalkyl, phenyl, benzyl and C1-C6alkylC3-C8cycloalkyl, wherein benzyl is optionally substituted with perfluoroalkyl and R5, R6, and R7are each independently selected from hydrogen, branched or unbranched alkyl, for use in the treatment of pathological repetitive behaviours in a patient.

2. The compound or the pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof for use according to claim 1, wherein the compound comprises 4-Chloro-3′-((2- cyclopentyl-1-oxoisoindolin-5-yloxy)-methyl)biphenyl-3-carboxylic acid.

3. The compound or the pharmaceutically acceptable salt, hydrate, solvate, optical isomer, polymorph thereof for use according to any one of the preceding claims, wherein the compound or the pharmaceutically acceptable salt, hydrate, solvate, optical isomer, polymorph thereof is administered at a dose of 0.01 mg / kg to 100 mg / kg, 0.3 mg / kg to 45mg / kg, 0.05 mg / kg to 50 mg / kg, 0.1 mg / kg to 30 mg / kg, 0.3 mg / kg to 10 mg / kg or 1 mg / kg to 3 mg / kg, preferably 3 mg / kg to 30 mg / kg.

4. A pharmaceutical composition for use in the treatment of pathological repetitive behaviours in a patient, wherein the pharmaceutical composition comprises a compound according to any previous claim or a pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof.

5. A pharmaceutical composition comprising a compound of the structure (I) shown in claim 1 or a pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof, together with a selective serotonin reuptake inhibitor (SSRI).

6. A pharmaceutical composition according to claim 5 where the SSRI is drawn from the group of fluoxetine, paroxetine, sertraline, citalopram or escitalopram.

7. The compound or the pharmaceutically acceptable salt, hydrate, solvate, optical isomer, polymorph thereof for use according to any one of claims 1-3, or the pharmaceutical composition for use according to any one of claims 4-6, administered orally, parenterally, subcutaneously, intravenously, intramuscularly, intrathecally, intradermally, intraarterially, intraarticularly, intraperitoneally, via cutaneous administration, via transcutaneous administration, via intra-osseus administration or by inhalation (either nasal or pulmonary), preferably orally.

8. The compound or the pharmaceutically acceptable salt, hydrate, solvate, optical isomer, polymorph thereof as described in any one of claims 1-3, or the pharmaceutical composition as described in any one of claims 4-7, for use in the treatment of OCD in a patient.

9. The compound or the pharmaceutically acceptable salt, hydrate, solvate, optical isomer, polymorph thereof as described in any one of claims 1-3, or the pharmaceutical composition as described in any one of claims 4-7, for use in the treatment of Tourette Syndrome in a patient.

10. The compound or the pharmaceutically acceptable salt, hydrate, solvate, optical isomer, polymorph thereof as described in any one of claims 1-3, or the pharmaceutical composition as described in any one of claims 4-7, for use in the treatment of trichotillomania or dermatillomania in a patient.

11. The compound or the pharmaceutically acceptable salt, hydrate, solvate, optical isomer, polymorph thereof as described in any one of claims 1-3, or the pharmaceutical composition as described in any one of claims 4-7, for use in the treatment of Body Dysmorphic Disorder in a patient.

12. The compound or the pharmaceutically acceptable salt, hydrate, solvate, optical isomer, polymorph thereof or the pharmaceutical composition for use according to claim 8, wherein the patient’s OCD is characterised by: (i) a score on the Yale-Brown Obsessive Compulsive scale of at least 8, at least 16, a least 24 or at least 32, preferably at least 16; (ii) a score on the Yale-Brown Obsessive Compulsive scale of 16-40, 24-40 or 32-40, preferably 16-40; (iii) a score on the Obsessive-Compulsive Inventory (OCI) or Obsessive-Compulsive Inventory - Revised (OCI-R) scale of at least 21, at least 30, at least 40, at least 50 or at least 60, preferably at least 40; or (iv) a score on the Obsessive-Compulsive Inventory (OCI) or Obsessive-Compulsive Inventory - Revised (OCI-R) scale of 21-72, 32-72, 40-72, 50-72 or 60-72, preferably 40-72.

13. The pharmaceutical composition for use according to any one of claims 4-11, further comprising a pharmaceutically acceptable excipient.

14. The pharmaceutical composition for use according to claim 13, wherein the pharmaceutically acceptable excipient comprises a solvent, a co-solvent, a buffer, a stabiliser, an antioxidant, a preservative, a chelating agent, an emulsifier, a flavouring, a lubricant, a suspending agent, a tonicity-adjusting agent, a surfactant, a solubilising agent, a suspending aid, a dispersion agent, a humectant, a thickener, a colouring agent, awetting agent, an anti-foaming agent, a viscosity modifier, a sweetener and any combination thereof; preferably wherein the pharmaceutically acceptable excipient comprises phosphate buffered saline.

15. A method of treating pathological repetitive behaviours, or OCD, or Tourette Syndrome or trichotillomania or dermatillomania or Body Dysmorphic Disorder in a patient, comprising administering to the patient a therapeutically effective amount of the pharmaceutical composition, compound or the pharmaceutically acceptable salt, hydrate, solvate, optical isomer, polymorph thereof according to any one of the preceding claims.

16. Use of a pharmaceutical composition, compound or a pharmaceutically acceptable salt, hydrate, solvate, optical isomer, polymorph thereof according to any one of the preceding claims in the preparation of a medicament for the treatment of pathological repetitive behaviours, or OCD, or Tourette Syndrome or trichotillomania or dermatillomania or Body Dysmorphic Disorder .

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