Compounds for use in the treatment or prevention of attention-deficit / hyperactivity disorder

Abstract

The present invention provides aceclofenac, amlodipine, or doxazosin, or a pharma- ceutically acceptable salt or solvate thereof, for use in the treatment or prevention of attention-deficit hyperactivity disorder (ADHD). The present invention also provides a kit and a method for the treatment or prevention of ADHD.

Description

[Technical field]

[0001] The present invention relates to the treatment and / or prevention of Attention Deficit / Hyperactivity Disorder (ADHD). The present invention also relates to dosing regimens and kits that find utility in the treatment and / or prevention of ADHD. [Background technology]

[0002] Attention-Deficit / Hyperactivity Disorder (ADHD) is characterized by impairments in the level of attention, hyperactivity, or impulsivity, or a combination thereof. The condition affects approximately 5% of individuals under the age of 18 worldwide, and approximately 65% ​​of cases persist into adulthood. The prevalence of ADHD in adults is estimated to be approximately 2.5% worldwide (Non-Patent Document 1).

[0003] The pathogenesis of ADHD is complex and not fully understood. However, impaired dopaminergic neurotransmission is thought to be a common feature of ADHD patients. Recent studies have also found that genetic mutations in the Latrophilin 3 (LPHN3, also called ADGRL3) gene are strongly associated with ADHD (Non-Patent Document 2). Further studies in zebrafish have shown that downregulation of the zebrafish LPHN3 homolog, latrophilin3.1 (lphn3.1), causes hyperactivity (Non-Patent Document 3 and Non-Patent Document 4). These studies also suggest that downregulation of lphn3.1 is associated with abnormal dopaminergic neurotransmission.

[0004] Established treatments for ADHD include pharmacological treatments such as psychostimulants (e.g., methylphenidate, dexamphetamine and lisdexamphetamine), norepinephrine reuptake inhibitors (e.g., atomoxetine), and α2-adrenergic agonists (e.g., guanfacine and clonidine). Treatments for ADHD can also include the use of non-pharmacological therapies, either as monotherapy or in combination with pharmacological treatments. Examples of non-pharmacological treatments that may benefit patients with ADHD include cognitive behavioral therapy (CBT), dietary treatments (e.g., elimination of supplemental fatty acids and artificial food dyes), and exercise programs.

[0005] Clinical guidelines such as the UK National Institute for Health and Care Excellence (NICE) guidelines recommend the use of methylphenidate, atomoxetine and dexamphetamine for the treatment of ADHD in children or adolescents, and lisdexamphetamine or methylphenidate for the treatment of ADHD in adults. However, despite the approved use of such treatments for ADHD, they remain controversial due to their limited efficacy and / or adverse effects (Non-Patent Document 5). [Prior art documents] [Non-patent literature]

[0006] [Non-Patent Document 1] Thapar & Cooper,The Lancet,2016,387(10024),1240-1250 [Non-Patent Document 2] Arcos-Burgos et al.,2010,Molecular Psychiatry,15,1053-1066 [Non-Patent Document 3] Lange et al.Mol Psychiatry 2012,17,946-954 [Non-Patent Document 4] Lange et al.,2018,Prog Neuropsychopharm Biol Psych,84,181-189 [Non-Patent Document 5] Cortese et al.,2018,The Lancet,Psychiatry,5(9),727-738 Summary of the Invention [Problem to be solved by the invention]

[0007] Thus, there remains a need for additional treatments for ADHD that provide clinical benefit while being well clinically tolerated. [Means for solving the problem]

[0008] The present invention relates to a compound according to formula (I) for use in the treatment or prevention of attention deficit / hyperactivity disorder (ADHD).

[0009] [ka] or a pharma- ceutically acceptable salt or solvate thereof, for use in the treatment or prevention of attention-deficit / hyperactivity disorder (ADHD).

[0010] The present invention relates to a compound according to formula (II) for use in the treatment or prevention of attention deficit / hyperactivity disorder (ADHD)

[0011] [ka] or a pharma- ceutically acceptable salt, or solvate thereof, for use in the treatment or prevention of attention-deficit / hyperactivity disorder (ADHD).

[0012] The present invention relates to a compound according to formula (III) for use in the treatment or prevention of Attention Deficit / Hyperactivity Disorder (ADHD)

[0013] [ka] or a pharma- ceutically acceptable salt, or solvate thereof, for use in the treatment or prevention of attention-deficit / hyperactivity disorder (ADHD).

[0014] The present invention further provides a method for the treatment and / or prevention of ADHD, comprising the step of administering a dose of a compound of formula (I), (II) or (III) to a patient known to have or suspected of having ADHD or at risk of developing ADHD.

[0015] The present inventors have found that in a zebrafish (Danio rerio) model of ADHD, compounds of formula (I), (II) or (III) are surprisingly effective in reducing ADHD symptoms such as hyperactivity and motor impulsivity in Lphn3.1 knockout zebrafish larvae.

[0016] The present invention also provides the use of a compound according to formula (I), (II) or (III) for the manufacture of a medicament for the treatment and / or prevention of ADHD. The present invention further provides a kit comprising a compound according to formula (I), (II) or (III) and one or more further pharmacological interventions, instructions for dietary intervention and / or instructions for psychological intervention. The kit of the present invention finds use in the treatment or prevention of ADHD. [Brief description of the drawings]

[0017] [Figure 1]Spectrograms of 24-hour recordings of velocity (mm / sec) of zebrafish larvae with homozygous knockout of the Lphn3.1 gene (referred to herein as "Lphn3.1 HOM") and wild-type Lphn3.1 gene (referred to herein as "Lphn3.1 WT"). Both groups of larvae were administered vehicle control (i.e., DMSO only). The grey area shown in the spectrogram indicates the light-off phase of the experiment (five 30-minute phases, the first phase starting at 1:30 pm, followed by a 10-hour light-off night period starting at 10 pm and ending at 8 am the next morning). [Diagram 2] Bar graphs showing the difference in the mean distance traveled by Lphn3.1 HOM and Lphn3.1 WT larvae during the five 30-min light phases are shown. No significant interaction between genotype and vehicle (i.e., DMSO) was observed (f=1,003, df=1, p=0.317). A significant effect of genotype on the distance traveled was observed between Lphn3.1 HOM and Lphn3.1 WT larvae (f=117.67, df=1, p<0.001). No significant effect of vehicle was observed between naive (i.e., larvae that received neither the test compound nor the vehicle control) and DMSO-treated larvae (f=0,222 df=1, p=0.638). [Diagram 3]A comparison of the distance traveled by Lphn3.1 HOM larvae receiving aceclofenac, atomoxetine (referred to as tomoxetine hydrochloride in FIG. 3), or vehicle control (i.e., DMSO only) is shown. The dashed line on the plot indicates the average distance traveled by Lphn3.1 HOM larvae over five light phases after treatment with vehicle control (n=189). The dotted line indicates the average distance traveled by Lphn3.1 HOM larvae over five light phases after treatment with 1 μM atomoxetine hydrochloride (n=24). The dots indicate the effect of aceclofenac at dosages of 1 μM, 10 μM, or 30 μM on the average distance traveled by Lphn3.1 HOM larvae over five light phases (n=24) (all data presented ± SEM). A statistically significant difference was observed between larvae treated with aceclofenac and those receiving the vehicle control (f=3,479, df=3, p=0.017; time 2: f=7,035, df=3, p<0.001). [Figure 4] A comparison of the distance traveled by Lphn3.1 HOM larvae receiving amlodipine, atomoxetine (referred to as tomoxetine hydrochloride in FIG. 4), or vehicle control (i.e., DMSO only) is shown. The dashed line on the plot indicates the average distance traveled by Lphn3.1 HOM larvae over five light phases after treatment with vehicle control (n=189). The dotted line indicates the average distance traveled by Lphn3.1 HOM larvae over five light phases after treatment with 1 μM atomoxetine hydrochloride (n=24). The dots indicate the effect of amlodipine at dosages of 1 μM, 10 μM, or 30 μM on the average distance traveled by Lphn3.1 HOM larvae over five light phases (n=24) (all data presented ± SEM). A statistically significant difference was observed between amlodipine-treated larvae and those receiving the vehicle control (f=23,684, df=3, p<0.001; time 2: f=31,699, df=3, p<0.001). [Diagram 5]A comparison of the distance traveled by Lphn3.1 HOM larvae receiving doxazosin, atomoxetine (referred to as tomoxetine hydrochloride in FIG. 5), or vehicle control (i.e., DMSO only) is shown. The dashed line on the plot indicates the average distance traveled by Lphn3.1 HOM larvae over five light phases after treatment with vehicle control (n=189). The dotted line indicates the average distance traveled by Lphn3.1 HOM larvae over five light phases after treatment with 1 μM atomoxetine hydrochloride (n=24). The dots indicate the effect of doxazosin at dosages of 1 μM, 10 μM, or 30 μM on the average distance traveled by Lphn3.1 HOM larvae over five light phases (n=24) (all data presented ± SEM). A statistically significant difference was observed between larvae treated with doxazosin and those receiving the vehicle control (f=14,642, df=3, p<0.001; 2nd time: f=29,29, df=3, p<0.001). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0018] The inventors of the present invention have found that compounds according to formula (I), (II) and (III) are surprisingly effective in treating or preventing ADHD.

[0019] As discussed in more detail below, the inventors have found that aceclofenac, amlodipine, and doxazosin are surprisingly effective in reducing activity in zebrafish larvae in a model of ADHD. The ADHD model used by the inventors uses zebrafish carrying a homozygous knockout of the Latrophilin 3 (lphn.3.1) gene. Mutations in the corresponding lphn.3.1 gene in humans (i.e., LPHN3) have been strongly implicated as a risk factor for ADHD in humans (Arcos-Burgos et al., 2010, Mol Psychiatry 15, 1053-1066, and Lange et al., Prog Neuropsychopharmacol Biol Psychiatry, 2018, 84(A), 181-189). The function of the lphn.3.1 gene in zebrafish has been found to correlate with that observed in humans. In the zebrafish model used by the inventors, ADHD-like behavioral phenotypes (e.g., hyperactivity and motor impulsivity) are observed in zebrafish larvae carrying homozygous knockouts of the lphn3.1 gene. Using the zebrafish model of ADHD, the inventors have discovered that aceclofenac, a nonsteroidal anti-inflammatory drug (NSAID) commonly used to treat osteoarthritis, rheumatoid arthritis, and ankylosing spondylitis, is surprisingly effective in reducing ADHD behaviors such as hyperactivity and motor impulsivity. Also, using the zebrafish model of ADHD, the inventors have discovered that amlodipine, a dihydropyridine calcium channel blocker commonly used to treat hypertension and angina pectoris, and doxazosin, an alpha 1 receptor blocker commonly used to treat hypertension and benign prostatic hyperplasia symptoms, are surprisingly effective in reducing ADHD behaviors such as hyperactivity and motor impulsivity.

[0020] Thus, the present invention provides a compound of formula (I), (II) or (III) (i.e. aceclofenac, amlodipine or doxazosin, respectively), or a pharma- ceutically acceptable salt or solvate thereof, for use in the treatment or prevention of ADHD.

[0021] For the avoidance of doubt, in this document, references to compounds of formula (I), (II) or (III) are intended to include all salts thereof, and solvates thereof, unless otherwise stated.

[0022] Compounds of formula (I), (II) or (III) can be prepared using methods well known to those skilled in the art of organic chemistry. Pharmaceutical preparations of compounds of formula (I), (II) or (III) suitable for use in the present invention are available from commercial sources. For example, pharmaceutical preparations of compounds of formula (I) are commercially available under the name PRESERVEX®, pharmaceutical preparations of compounds of formula (II) are commercially available under the name ISTIN®, and pharmaceutical preparations of compounds of formula (III) are commercially available under the name CARDURA®. Generic pharmaceutical preparations of compounds of formula (I), (II) or (III) are also available.

[0023] For the avoidance of doubt, references herein to compounds of formula (II) and (III) are intended to include all enantiomers thereof, unless otherwise indicated. Also, for the avoidance of doubt, references herein to compounds of formula (I), (II) and (III) are intended to include compounds that differ by minor, structural differences, and are envisioned to exhibit similar properties to aceclofenac, amlodipine and doxazosin in the ADHD models described herein.

[0024] Compounds of formula (I), (II) or (III) may form salts or solvates. Salts of compounds of formula (I), (II) or (III) suitable for use in the present invention are those in which the counterion is pharma- ceutically acceptable. However, the use of salts having pharma-ceutically unacceptable counterions is within the scope of the present invention, for example, for use as intermediates in the preparation of compounds of formula (I), (II) or (III) and their pharma-ceutically acceptable salts and physiologically functional derivatives. Suitable salts for use in accordance with the present invention include those formed with organic or inorganic acids. In particular, suitable salts formed with acids for use in accordance with the present invention include salts formed with mineral acids, strong organic carboxylic acids such as alkane carboxylic acids of 1 to 4 carbon atoms that are unsubstituted or substituted (e.g., by halogen), e.g., saturated or unsaturated dicarboxylic acids, e.g., hydroxy carboxylic acids, e.g., amino acids, or organic sulfonic acids, e.g., (C1-C4)-alkyl- or aryl-sulfonic acids that are unsubstituted or substituted (e.g., by halogen). Pharmaceutically acceptable acid addition salts include those formed from hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, citric acid, tartaric acid, acetic acid, phosphoric acid, lactic acid, pyruvic acid, acetic acid, trifluoroacetic acid, succinic acid, perchloric acid, fumaric acid, maleic acid, glycolic acid, lactic acid, salicylic acid, oxalic acid, oxaloacetic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, formic acid, benzoic acid, malonic acid, naphthalene-2-sulfonic acid, benzenesulfonic acid, isethionic acid, ascorbic acid, malic acid, phthalic acid, aspartic acid, and glutamic acid, lysine, and arginic acid. Suitable cations that may be present in the salt include alkali metal cations, particularly sodium, potassium, and calcium, as well as ammonium or amino cations.

[0025] Those skilled in the art of organic chemistry will understand that many organic compounds form complexes with solvents from which they may react or precipitate or crystallize. These complexes are known as "solvates". For example, complexes with water are known as "hydrates". Complexes may incorporate the solvent in stoichiometric or non-stoichiometric amounts. Solvates are described in Water-Insoluble Drug Formulation, 2nd ed R. Lui CRC Press, page 553, and Byrn et al Pharm Res 12(7), 1995, 945-954. Prior to being constituted in solution, the compounds of formula (I), (II) or (III) may be in the form of a solvate. Solvates of compounds of formula (I), (II) or (III) suitable for use as pharmaceuticals according to the present invention are solvates in which the associated solvent is pharma- ceutically acceptable. For example, hydrates are pharma-ceutically acceptable solvates.

[0026] Compounds that can be converted to a compound of formula (I), (II) or (III) or its active metabolite or residue upon administration to a recipient are known as "prodrugs". Thus, in certain embodiments, compounds of formula (I), (II) or (III) can be provided in the form of a prodrug. A prodrug can be converted to its active form having a medical effect, for example, by hydrolysis in the body, for example, in the blood. Pharmaceutically acceptable prodrugs are described in T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, Vol. 14 of the ACHiguchi and V. Stella, Prodrugs as Novel Delivery Systems, Vol. 14 of the ACHiguchi and V. Stella, Prodrugs as Novel Delivery Systems, Vol. 14 of the AC. "Design of Prodrugs" ed. H. Bundgaard, Elsevier, 1985 and Edward B Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press 1987, which are incorporated herein by reference.

[0027] Pharmaceutical Compositions While it is possible for a compound of formula (I), (II) or (III) to be administered alone, it is preferred that it be present in a composition, particularly a pharmaceutical composition. The pharmaceutical compositions of the present invention comprise a compound of formula (I), (II) or (III) and one or more pharma- ceutically acceptable excipients.

[0028] Pharmaceutical compositions include those suitable for oral, parenteral (including subcutaneous, intradermal, intraosseous injection, intramuscular, intravascular (bolus or infusion), and intramedullary), intraperitoneal, transmucosal, transdermal, rectal and topical (including cutaneous, buccal, sublingual and ocular) administration, although the most suitable route may depend on the characteristics of the subject being treated, such as race, age, weight, sex, medical condition, the particular type of ADHD (e.g., "impulsive / hyperactive", "inattentive" and "combined" ADHD) and its severity, and other relevant medical and physical factors.

[0029] Preparations for parenteral administration include aqueous and non-aqueous sterile injection solutions that may contain antioxidants, buffers, bacteriol, and solutes that render the preparation isotonic with the blood of the intended recipient, as well as aqueous and non-aqueous sterile suspensions that may contain suspending agents and thickening agents.The preparations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a lyophilised condition requiring only the addition of a sterile liquid carrier (e.g. saline or water for injection) immediately prior to use.Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind described herein. Exemplary compositions for parenteral administration include injectable solutions or suspensions, which may contain, for example, a suitable non-toxic parenterally acceptable diluent or solvent (e.g., mannitol, 1,3-butanediol, water, Ringer's solution, isotonic sodium chloride solution) or other suitable dispersing or wetting agents and suspending agents, including synthetic mono- or diglycerides, and fatty acids, including oleic acid, or Cremaphor.

[0030] Compositions for nasal, aerosol or inhalation administration include solutions in saline, which may contain, for example, benzyl alcohol or other suitable preservatives, absorption enhancers to enhance bioavailability, and / or other solubilizing or dispersing agents such as those known in the art.

[0031] Formulations for rectal administration may be presented as a suppository with a carrier such as cocoa butter, synthetic glyceride esters, or polyethylene glycols. Such carriers are typically solid at ordinary temperatures, but liquefy and / or melt in the rectal cavity to release the drug.

[0032] Formulations for topical administration in the mouth (e.g., buccal or sublingual administration) include, for example, lozenges (containing the active ingredient in a flavored base such as sucrose or acacia or tragacanth) and pastilles (containing the active ingredient in a base such as gelatin and glycerin or sucrose and acacia).Exemplary compositions for topical administration include a topical carrier such as Plastibase (mineral oil gelled with polyethylene).

[0033] Pharmaceutical compositions suitable for oral administration can be presented as discrete units, such as capsules, cachets or tablets, each containing a predetermined amount of active ingredient, as powder or granules, as a solution or suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion. The compound of formula (I), (II) or (III) can also be presented as a bolus, electuary, or paste. The pharmaceutical composition can optionally be in a form that provides a slow or controlled release of the compound of formula (I), (II) or (III) when administered to a subject. Various pharma-ceutical acceptable carriers and their formulations are described in standard formulation treatises, such as Remington's Pharmaceutical Sciences by EW Martin. See also Wang, YJ and Hanson, MA, Journal of Parenteral Science and Technology, Technical Report No. 10, Supp. 42: 2S, 1988.

[0034] Preferred unit dosage compositions are those containing a probing or therapeutic dose, or an appropriate fraction thereof, of a compound of Formula (I), (II) or (III). In a preferred embodiment, the compositions for use according to the present invention consist essentially of a compound of Formula (I), (II) or (III) and at least one pharma- ceutically acceptable excipient.

[0035] Exemplary compositions comprising a compound of formula (I) for use in accordance with the present invention include one or more of the following pharma- ceutically acceptable carriers: microcrystalline cellulose, croscarmellose sodium, copovidone, glyceryl palmitostearate, polyvinylpyrrolidone (e.g., povidone K30), hypromellose, polyethylene glycol, anhydrous colloidal silica, glycerol distearate, talc, titanium dioxide.A further exemplary composition comprising a compound of formula (I) for use in accordance with the present invention is a tablet having a core and a coating, the core comprising microcrystalline cellulose, croscarmellose sodium, povidone, and glyceryl palmitostearate, and the coating comprising hypromellose, polyethylene glycol, and titanium dioxide.

[0036] An exemplary composition comprising a compound of formula (II) for use according to the invention comprises one or more of the following pharma- ceutically acceptable carriers: calcium hydrogen phosphate, microcrystalline cellulose, sodium starch glycolate, magnesium stearate, sodium citrate, croscarmellose sodium, crospovidone, calcium hydrogen phosphate anhydrous, anhydrous colloidal silica. A further exemplary composition comprising a compound of formula (II) for use according to the invention is a tablet comprising sodium starch glycolate, calcium hydrogen phosphate anhydrous, microcrystalline cellulose, magnesium stearate. A further exemplary composition comprising a compound of formula (II) for use according to the invention is an oral liquid comprising methyl paraben, propylene glycol, disodium hydrogen phosphate anhydrous, sodium dihydrogen phosphate dihydrate, purified water, glycerol, and liquid maltitol.

[0037] Exemplary compositions comprising a compound of formula (III) for use in accordance with the invention include one or more of the following pharma- ceutically acceptable carriers: lactose, magnesium stearate, polyvinylpyrrolidone (e.g., K29-32), sodium stearyl fumarate, microcrystalline cellulose, sodium lauryl sulfate, sodium starch glycolate, butylated hydroxytoluene, tocopherol, colloidal anhydrous silica, polyethylene oxide, sodium chloride, hypromellose, iron oxide, titanium dioxide, cellulose acetate, macrogol, ammonium hydroxide, propylene glycol, methacrylic acid-ethyl acetate copolymer. A further exemplary composition comprising a compound of formula (III) for use in accordance with the invention is a tablet having a core and a coating, the core comprising polyethylene oxide, microcrystalline cellulose, povidone, butylated hydroxytoluene, α-tocopherol, colloidal anhydrous silica, and sodium stearyl fumarate, and the coating comprising methacrylic acid-ethyl acetate copolymer, colloidal anhydrous silica, macrogol, and titanium dioxide.

[0038] It should be understood that in addition to the ingredients particularly mentioned above, formulations for use in the present invention may include other agents conventional in the art having regard to the type of formulation in question.

[0039] The composition for use according to the present invention may contain one or more additional therapeutic agents.The examples of additional therapeutic agents that can be present in the composition for use according to the present invention include, but are not limited to, methylphenidate, amphetamine (e.g., dexamphetamine), lisdexamphetamine, atomoxetine, viloxazine, clonidine and guanfacine.Typically, the one or more additional therapeutic agents are psychostimulants such as amphetamine, methylphenidate and lisdexamphetamine.

[0040] Attention-Deficit / Hyperactivity Disorder (ADHD) The inventors have found that compounds of formula (I), (II) and (III), and pharmaceutical compositions thereof, are particularly effective in reducing the symptoms of, or delaying the onset of, ADHD in subjects known to have, or suspected of having, ADHD, and in preventing ADHD in subjects known to be at risk of, or suspected of developing ADHD.

[0041] Thus, a compound of formula (I), (II) or (III) for use according to the present invention, or a pharmaceutical composition thereof, may be administered to a subject known or suspected to have ADHD, or known or suspected to be at risk for developing ADHD. The subject may be a human subject, e.g., a human patient. The human subject may be a child (e.g., less than about 10 years of age), an adolescent (e.g., between about 10 and 19 years of age), or an adult (e.g., greater than about 18 to 21 years of age).

[0042] A subject known or suspected of having ADHD may have ADHD characterized by impulsive and hyperactive behavior without impairment in levels of attention (i.e., "impulsive / hyperactive" ADHD). Alternatively, a subject known or suspected of having ADHD may have ADHD characterized by impairment in levels of attention without hyperactivity or impulsivity (i.e., "inattentive" ADHD). Alternatively, a subject known or suspected of having ADHD may have ADHD characterized by a combination of hyperactive and impulsive behavior and reduced levels of attention (i.e., "combined" ADHD).

[0043] A subject who is known or suspected to be at risk of developing ADHD may be a subject who has a known or suspected genetic predisposition to developing ADHD, for example, the subject may have a mutation in the Latrophilin 3 (LPHN3) gene. Additional examples of genetic mutations involved in ADHD have been reported (see, for example, Faraone and Larsson, Molecular Psychiatry, 2019, 24, 562-575, which is incorporated herein by reference), including, for example, mutations in one or more of the following genes: serotonin transporter (5HTT) gene, dopamine transporter (DAT1) gene, D4 ​​dopamine receptor (DRD4) gene, D5 dopamine receptor (DRD5) gene, serotonin 1B receptor gene (HTR1B), and synaptosome-associated protein (SNAP25) gene. Additionally, or alternatively, a subject known to have or suspected to be at risk for developing ADHD may be a subject who has been exposed to one or more potential environmental risk factors associated with ADHD, such as maternal pre-pregnancy obesity, pre-eclampsia, hypertension, acetaminophen exposure, and smoking during pregnancy, and childhood atopic disease.

[0044] In addition, subjects known or suspected to have ADHD or known or suspected to be at risk for developing ADHD may also have signs or symptoms of other conditions, such as depression, anxiety disorder, oppositional defiant disorder (ODD), conduct disorder, sleep problems (e.g., insomnia sleep onset disorder), autism spectrum disorder (ASD), bipolar disorder, epilepsy, Tourette's syndrome, and / or learning disorders such as dyslexia. Typically, the subject meets the diagnostic criteria for ADHD as set forth in the Diagnostic and Statistical Manual of Mental Disorders (DSM) or the International Classification of Diseases (ICD).

[0045] In addition, subjects known or suspected to have ADHD, or known or suspected to be at risk for developing ADHD, may also suffer from a substance abuse disorder, e.g., addiction to and / or abuse of psychostimulants such as amphetamines.

[0046] For example, a compound of formula (I), (II) or (III), or composition thereof, for use according to the present invention may be administered when one or more established psychostimulant-based ADHD treatments (e.g., methylphenidate, dexamphetamine, and lisdexamphetamine) are deemed inappropriate because the subject is at risk for, has a history of, or currently suffers from a substance abuse disorder.

[0047] The present inventors have demonstrated, using a zebrafish model of ADHD, that compounds of formula (I), (II) or (III) are surprisingly effective in reducing hyperactivity and motor impulsivity. The efficacy of compounds of formula (I), (II) or (III) in reducing hyperactivity and motor impulsivity in a zebrafish model of ADHD makes compounds of formula (I), (II) or (III) particularly attractive treatments for ADHD characterized by hyperactive and / or impulsive behavior (i.e., "impulsive / hyperactive" ADHD or "combined" ADHD). Thus, in certain embodiments, compounds of formula (I), (II) or (III) for use according to the present invention, or pharmaceutical compositions thereof, may be administered to subjects known or suspected to have ADHD characterized by impulsive and hyperactive behavior without impaired levels of attention (i.e., "impulsive / hyperactive" ADHD), or ADHD characterized by a combination of hyperactive and impulsive behavior and reduced levels of attention (i.e., "combined" ADHD).

[0048] The compound of formula (I), (II) or (III) or composition thereof for use according to the present invention may be administered to a subject in whom one or more established ADHD treatments (e.g., methylphenidate, dexamphetamine, lisdexamphetamine, atomoxetine, viloxazine, guanfacine, and clonidine) have not been effective in reducing one or more of the symptoms of ADHD and / or intolerable adverse effects induced. Examples of adverse effects known or suspected to be caused by established ADHD treatments include sleep disorders, loss of appetite, elevated blood pressure, growth retardation, disruption of circadian rhythm, and neurotoxicity.

[0049] The compounds of formula (I), (II) or (III), and compositions thereof, described herein find utility in methods of treating or preventing ADHD, comprising administering a compound of formula (I), (II) or (III), or a composition thereof, to a patient known to have or suspected of having ADHD, or known to be at risk of developing ADHD, or suspected of having ADHD. The compounds of formula (I), (II) or (III) also find use in the manufacture of a medicament for the treatment or prevention of ADHD.

[0050] Medication Regimen The amount of a compound of formula (I), (II), or (III) required to achieve a therapeutic effect will vary depending on the particular route of administration and the characteristics of the subject being treated, such as race, age, weight, sex, medical condition, the particular type of ADHD (e.g., "impulsive / hyperactive," "inattentive," and "combined" ADHD) and its severity, and other relevant medical and physical factors. A physician of ordinary skill can readily determine and administer the effective amount of a compound of formula (I), (II), or (III) required to treat or prevent ADHD.

[0051] Compounds of Formula (I), (II), or (III) may be administered daily (including several times daily), every other or third day, every week, every two weeks, every three weeks, or every four weeks, or even as a single dose, depending on the subject and the characteristics of ADHD being treated.

[0052] The compound of formula (I) (excluding the mass of any counterion or solvent) may be administered in an amount of about 1 mg to 1000 mg per dose. For example, a subject may be administered at least 1 mg, at least 5 mg, at least 10 mg, at least 15 mg, at least 20 mg, at least 25 mg, at least 40 mg, at least 50 mg, at least 60 mg, at least 70 mg, at least 80 mg, at least 90 mg, at least 100 mg, at least 150 mg, at least 200 mg, at least 300 mg, at least 400 mg, at least 500 mg, at least 600 mg, at least 700 mg, at least 800 mg, at least 900 mg, or 1000 mg.

[0053] Typically, the compound of formula (I) is administered as a single daily dose of about 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, or 600 mg (excluding the mass of any counterion or solvent). Alternatively, the compound of formula (I) is administered as a dose of 100 mg, 150 mg, 200 mg, 250 mg, or 300 mg (excluding the mass of any counterion or solvent), two, three, or four times a day. For example, a daily dose of 100 mg per day may be administered as two separate doses of 50 mg, the first dose being administered in the morning and the second dose being administered in the evening (e.g., after 6 p.m.). Or, for example, a daily dose of 200 mg per day may be administered as two separate doses of 100 mg, the first dose being administered in the morning and the second dose being administered in the evening.

[0054] The compound of formula (II) (excluding the mass of any counterion or solvent) may be administered in an amount of about 0.1 mg to 10 mg per dose. For example, a subject may be administered at least 0.1 mg, at least 0.5 mg, at least 1 mg, at least 1.5 mg, at least 2 mg, at least 2.5 mg, at least 3 mg, at least 4 mg, at least 5 mg, at least 6 mg, at least 7 mg, at least 8 mg, at least 9 mg, or at least 10 mg.

[0055] Typically, the compound of formula (II) is administered as a single daily dose of about 1 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, 5 mg, or 10 mg (excluding the mass of any counterion or solvent). For example, a single daily dose of 2 mg, 2.5 mg, 5 mg, 7.5 mg, or 10 mg. Alternatively, the compound of formula (II) is administered as a double, triple, or four doses per day of about 1 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, or 5 mg (excluding the mass of any counterion or solvent). For example, a daily dose of 5 mg per day can be administered as two separate doses of 2.5 mg, for example, a first dose is administered in the morning and a second dose is administered in the evening (e.g., after 6 pm). Alternatively, for example, a daily dose of 10 mg per day may be administered as two separate doses, for example, a first dose of 5 mg administered in the morning and a second dose of 5 mg administered in the evening.

[0056] The compound of formula (III) (excluding the mass of any counterion or solvent) may be administered in an amount of about 0.1 mg to 16 mg per dose. For example, the subject may be administered at least 0.5 mg, at least 1 mg, at least 2 mg, at least 3 mg, at least 4 mg, at least 5 mg, at least 6 mg, at least 7 mg, at least 8 mg, at least 9 mg, at least 10 mg, at least 11 mg, at least 12 mg, at least 13 mg, at least 14 mg, at least 15 mg, at least 16 mg. Typically, the compound of formula (III) is administered as a single daily dose of about 1 mg, 2 mg, 4 mg, 8 mg, or 16 mg (excluding the mass of any counterion or solvent). Alternatively, the compound of formula (III) is administered as two, three, or four daily doses of 1 mg, 2 mg, 4 mg, 8 mg, or 16 mg (excluding the mass of any counterion or solvent).

[0057] In certain embodiments, a compound of formula (I), (II), or (III) is administered as a composition. Preferably, the composition is a pharmaceutical composition for use in accordance with the present invention.

[0058] Although the compound of formula (I), (II) or (III) may be used as the sole active ingredient in the present invention, it may also be used in combination with one or more additional therapeutic interventions, the use of such combinations providing an embodiment of the present invention. Examples of additional therapeutic interventions include pharmacological interventions, dietary interventions, and psychological interventions.

[0059] The additional pharmacological intervention can be a therapeutic agent useful for treating or preventing ADHD, or other pharmacologically active substances. Such agents are known in the art. Examples of additional therapeutic agents for use in the present invention include those described herein. Typically, additional therapeutic agents are psychostimulants such as amphetamine, methylphenidate, and lisdexamfetamine. Examples of suitable dietary intervention include, for example, supplemental fatty acids, and elimination of artificial food dyes from diet. Examples of suitable psychological intervention include, for example, cognitive behavioral therapy (CBT).

[0060] One or more additional therapeutic interventions may be used simultaneously, sequentially, or separately with the administration of the compound of formula (I), (II), or (III). The individual components of such combinations may be administered separately at different times during the course of therapy, or simultaneously in divided or single combination forms. A physician of ordinary skill can easily determine and administer the effective amount of one or more therapeutic interventions required to have the desired therapeutic effect.

[0061] Preferred unit dosage compositions for use in accordance with the present invention are those containing an effective dose, or an appropriate fraction thereof, of a compound of Formula (I), (II), or (III). Release of a compound of Formula (I), (II), or (III) from a particular composition may also be sustained, for example, when the composition contains suitable controlled-release excipients.

[0062] kit The present invention provides kits comprising a compound of Formula (I), (II), or (III), one or more pharma- ceutically acceptable excipients, and, optionally, one or more additional therapeutic agents useful for the treatment or prevention of ADHD. Examples of such additional therapeutic agents include those suitable for use in the present invention and optionally present in the pharmaceutical compositions of the present invention as additional therapeutic agents.

[0063] The kits of the invention may also contain instructions for a suitable dietary intervention and / or instructions for a suitable psychological intervention for ADHD. For example, the kit may contain instructions for a suitable nutritional plan for the subject to be treated and / or the kit may contain instructions / guidance for cognitive behavioral therapy (CBT).

[0064] The kits of the present invention find use in the treatment and prevention of ADHD.

[0065] For the avoidance of doubt, the compounds of formula (I), (II), or (III) present in the kits according to the invention are in forms and amounts suitable for use according to the invention. Suitable pharmaceutical compositions and formulations are described herein. Those skilled in the art can readily determine the amounts of compounds of formula (I), (II), or (III) suitable for inclusion in the kits of the invention and for use according to the invention.

[0066] metabolite The active metabolites of the compounds of formula (I), (II), or (III) may be used for the treatment or prevention of Attention Deficit / Hyperactivity Disorder (ADHD). In embodiments where the compound is an active metabolite of a compound of formula (I), (II), or (III), the compound may be isolated from cells treated with a compound of formula (I), (II), or (III) or may be prepared using standard organic chemistry techniques. For the avoidance of doubt, when the compound used in accordance with the present invention is an active metabolite of a compound of formula (I), (II), or (III), the compound may be used in the form of a composition and / or as a medicament in the same manner as described herein for the compounds of formula (I), (II), or (III).

[0067] In certain embodiments, the compound used according to the invention is an active metabolite of the compound of formula (I), which is known to be metabolized in humans to the active metabolites 4-hydroxy-aceclofenac, diclofenac, and 4-hydroxy-diclofenac. Thus, in certain embodiments, the present invention also provides a metabolite of the compound of formula (I) for use in the treatment or prevention of Attention Deficit / Hyperactivity Disorder (ADHD), wherein the metabolite is a compound according to formula (IV):

[0068] [ka] Here, R 1 is hydrogen or OH, and R 1 If is hydrogen, R 2 is hydrogen, and R 1 If is OH, then R 2 is hydrogen or —CHCOOH, or a pharma- ceutically acceptable salt or solvate thereof.

[0069] In certain embodiments, in the compound of formula (IV), R1 and R2 are each hydrogen. That is, the compound of formula (IV) is diclofenac. When the compound of formula (IV) is diclofenac, the compound can be obtained from a commercial source. For example, when the compound of formula (IV) is diclofenac, the compound can be a product marketed under the name VOLTAREN®, or its generic drug.

[0070] Equivalent The present invention has been described broadly and comprehensively herein. Those skilled in the art will readily appreciate that all parameters, dimensions, materials, and configurations described herein are intended to be exemplary, and that the actual parameters, dimensions, materials, and / or configurations will depend on the particular application or applications in which the teachings of the present invention are used. Those skilled in the art will recognize or be able to ascertain, using no more than routine experimentation, many equivalents to certain embodiments of the invention described herein. Accordingly, the foregoing embodiments are presented by way of example only, and it is to be understood that, within the scope of the appended claims and equivalents thereto, the invention may be practiced otherwise than as specifically described or claimed. The present invention relates to each individual feature, system, article, material, kit, and / or method described herein. In addition, any combination of two or more such features, systems, articles, materials, kits, and / or methods is included within the scope of the present invention, if such features, systems, articles, materials, kits, and / or methods are not mutually inconsistent. Furthermore, each of the narrower species and subgeneric groupings included in the generic disclosure also form part of the present invention. This includes the generic specification of the invention with a provisos or negative limitation removing any subject matter from the genus, regardless of whether the removed material is specifically described herein.

[0071] Incorporation by Reference The contents of the publications, patents, and patent applications, and all other documents and electronically available information mentioned or cited in this specification are incorporated herein by reference in their entirety to the same extent as if each individual publication was specifically and individually indicated to be incorporated by reference. Applicants reserve the right to physically incorporate into this application any and all materials and information from any such publications, patents, patent applications, or other physical and electronic documents. The following examples illustrate the invention. EXAMPLES

[0072] Danio rerio has gained popularity in biological psychiatry. Its rich behavioral repertoire, well-established behavioral assays, and the availability of automated behavioral assays make zebrafish a useful model for a variety of human brain disorders. The neural pathways involved in brain physiology are highly conserved, including all major neurotransmitter systems and high genetic homology. Gene editing techniques allow for accurate modeling of human disorders. The lphn3.1 knockout model of ADHD described herein robustly exhibits characteristics of human ADHD, namely hyperactivity, hypersensitivity to known dopamine agonists, and phenotypic rescue following administration of known anti-ADHD compounds.

[0073] Materials and Methods: Zebrafish larvae carrying a knockout of the Latrophilin 3 (Lphn3.1) gene were generated by CRISPR-Cas9. Zebrafish were maintained in a 3L or 10L multi-tank constant-flow system (Aquatic Habitats, Apopka, FL, USA) with a 14:10 light:dark cycle. For behavioral analysis, a total of 881 6-day post-fertilization (dpf) embryos carrying a homozygous knockout of the Lphn3.1 gene were used in the study. Adult zebrafish carrying a homozygous knockout of the Lphn3.1 gene and those with wild-type Lphn3.1 gene were fed with various diets, such as TetraMin flakes (Tetra Holding GmbH, Melle, Germany) and live Artemia, three times a day. Water temperature was kept constant at 28.5°C and changed at a rate of 10% per day. Eggs were collected between 10:00 AM and 12:00 PM and placed in 2 L tanks. The following day, dead eggs were removed and the tanks were cleaned. Eggs were incubated for 4 days at 28.5 °C in system water mixed with methylene blue. All procedures in this study were performed in strict compliance with and approved by the National Bioethics Committee of Iceland regulations (Regulation 460 / 2017).

[0074] Genotyping Strains were verified for knockdown of the Lphn3.1 gene using Western blot.

[0075] Behavior Recording At 5 dpf, larvae were placed in individual wells of a 96-microwell plate (Nunc, Roskilde, Denmark) in the water system. The microwell plate was transferred to a custom-made activity monitoring system equipped with 24 infrared cameras (Ikegami, ICD-49E; Ikegami Tsushinki Co, Japan), which was thermostated at 28.5°C, shielded from sunlight, and illuminated from below with white light (255 lx; light phase) and infrared light (0 lx; ​​dark phase). Larvae behavior was tracked in two dimensions at 5 Hz. Larvae were left to acclimate in the activity monitoring system for 24 h before recording. Exclusion criteria were based on the proportion of samples in the recording in which larvae were not tracked. A threshold was set at 10%, so that larvae that were tracked for less than 90% of the total recording time were excluded from the study.

[0076] Motility assay Behavioral recordings were performed after a 24-h acclimation period. Locomotor activity was recorded between 1:00 PM and 6:00 PM at 6 dpf during alternating light and dark conditions presented at 30-min intervals. The mean distance traveled by larvae during this period (mm) was calculated as the average of the total swimming distance during five separate 30-min intervals immediately following the shift to light conditions.

[0077] Example 1: Efficacy of Aceclofenac, Amlodipine or Doxazosin Compared to Atomoxetine in a Zebrafish Model of ADHD Zebrafish larvae carrying a homozygous knockout of the Lphn3.1 gene (referred to herein as "Lphn3.1 HOM") and wild-type Lphn3.1 gene (referred to herein as "Lphn3.1 WT") were exposed to commercially available ADHD medications atomoxetine hydrochloride (tomoxetine hydrochloride), aceclofenac (Prestwick, 67400 Illkirch, France), amlodipine (Prestwick, 67400 Illkirch, France), doxazosin (Prestwick, 67400 Illkirch, France), or vehicle control prior to the start of behavioral recordings.

[0078] On the day of recording, drugs were prepared. Drugs were diluted from stock solutions using distilled water (Invitrogen, Paisley, PA4 9RF, UK). Three different concentrations of each drug were used: 1 μM, 10 μM and 30 μM. In addition, a 0.03% DMSO (Sigma-Aldrich, St. Louis, USA) solution was prepared for the vehicle control group. Drugs and vehicle controls were added to the microwells between 11:30 am and 12:30 pm on the day of recording.

[0079] Data were acquired using EthoVision XT (Version 11.5.2016, Noldus) and exported to Microsoft Excel for analysis. Statistical analysis was performed using IBM SPSS Statistics for Windows, Version 26 (IBM corp., Armonk, NY, USA). Figures were produced using Microsoft Excel and GraphPad Prism Software (Version 5.01, GraphPad Software Inc.). Data are presented as mean ± standard error of the mean (sem). For the analysis of Lphn3.1 naive (i.e., untreated larvae that did not receive test compound or vehicle control) and DMSO larvae (i.e., larvae that received only DMSO vehicle control), statistical differences were evaluated using two-way ANOVA. For the analysis of Lphn3.1 larvae treated with aceclofenac, statistical differences were evaluated using one-way ANOVA with Dunnett's two-tailed post hoc analysis. P<0.05 was considered statistically significant.

[0080] result: After 24 hours of recording, it became clear that Lphn3.1 HOM larvae exhibited a pronounced hyperactivity phenotype. For Lphn3.1 HOM larvae, a higher peak velocity after lights-off (which causes a typical short increase in zebrafish activity) and a higher grand average velocity during the light-on period were observed (Figure 1). In Figure 1, the activity of Lphn3.1 HOM larvae is shown in the upper line, and that of Lphn3.1 WT larvae is shown in the lower line. The overall activity pattern of the larvae suggested that any period could be selected for statistical analysis.

[0081] Using the average distance traveled during the light-on period, we demonstrated that, first, homozygous larvae were indeed statistically significantly hyperlocomotive compared to wild-types, and, second, the vehicle (DMSO) had no effect on behavior (Figure 2).

[0082] Atomoxetine, aceclofenac, amlodipine, and doxazosin were each found to increase the rate in wild-type larvae. The effects of aceclofenac, amlodipine, and doxazosin were compared to the optimal dose of atomoxetine (see Figures 3, 4, and 5, respectively). Comparison with Lphn3.1 HOM larvae administered vehicle control revealed that all doses of aceclofenac, amlodipine, and doxazosin were significantly (dose-dependently) different from the vehicle control and untreated larvae. These data indicate that aceclofenac, amlodipine, and doxazosin are effective in reducing ADHD-like phenotypes in Lphn3.1 HOM larvae.

Claims

1. A compound represented by the following formula (II) for use in the treatment or prevention of attention deficit / hyperactivity disorder (ADHD), 【Chemical 1】 or a compound comprising a pharmaceutically acceptable salt or solvate thereof.

2. The compound according to claim 1, for administration to a patient who is known to have ADHD, suspected of having ADHD, known to be at risk of developing ADHD, or suspected of being at risk of developing ADHD, the compound being represented by the above formula (II), or a pharmaceutically acceptable salt or solvate thereof.

3. The compound according to claim 2, wherein the patient who is known to have ADHD, suspected of having ADHD, known to be at risk of developing ADHD, or suspected of being at risk of developing ADHD also has signs or symptoms of depression, anxiety disorder, oppositional defiant disorder (ODD), conduct disorder, sleep problems, autism spectrum disorder (ASD), bipolar disorder, epilepsy, Tourette syndrome, and / or a learning disorder such as dyslexia.

4. The compound according to any one of claims 1 to 3, for administration to a patient in whom one or more established ADHD treatments with methylphenidate, dextroamphetamine, lisdexamfetamine, atomoxetine, viloxazine, guanfacine, and / or clonidine have not been effective in reducing one or more of the symptoms of ADHD and / or the induced intolerable adverse effects.

5. The compound according to claim 4, wherein the adverse effects include sleep disorders, loss of appetite, increased blood pressure, growth disorders, disruption of the circadian rhythm, and neurotoxicity.

6. The compound according to any one of claims 1 to 5, wherein the compound is administered at a dose of about 0.1 mg to 10 mg (excluding the mass of any counterion or solvent).

7. The compound according to either claim 5 or 6, wherein the dose of the compound is administered once daily at a dose of 2 mg, 2.5 mg, 5.0 mg, 7.5 mg or 10 mg (excluding the mass of any counterion or solvent).

8. The compound according to any one of claims 5 to 7, wherein the dosage of the compound is administered at a dosage of 1 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg or 5 mg (excluding the mass of any counterion or solvent) two, three or four times a day.

9. The compound according to any one of claims 1 to 5, wherein the compound is administered as a pharmaceutical composition.

10. The compound according to any one of claims 1 to 4, wherein the compound is administered simultaneously, continuously or separately with one or more further therapeutic interventions selected from dietary therapy intervention, psychological intervention and pharmacological intervention.

11. The compound according to claim 5, wherein the compound is administered simultaneously, continuously or separately with one or more further pharmacological interventions selected from methylphenidate, dextroamphetamine, lisdexamfetamine, atomoxetine and guanfacine.

12. The compound according to any one of claims 1 to 11, wherein the ADHD is selected from impulsive / hyperactive ADHD, inattentive ADHD, and combined ADHD.

13. A kit comprising the compound according to claim 1 and one or more further pharmacological interventions, wherein the one or more further pharmacological interventions are selected from methylphenidate, amphetamine, lisdexamfetamine, atomoxetine, viloxazine, clonidine, and / or guanfacine.

14. The kit according to claim 13, for use in the treatment or prevention of ADHD.

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