Use of a calcium channel blocker in the treatment of adhd

Abstract

The present invention provides cilnidipine, nilvadipine, isradipine, felodipine, verapamil, nimodipine or nifedipine, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment or prophylaxis of Attention Deficit / Hyperactivity Disorder (ADHD). The invention also provides kits and methods for the treatment or prophylaxis of ADHD.

Description

[0001] USE OF A CALCIUM CHANNEL BLOCKER IN THE TREATMENT OF ADHD

[0002] Field of the Invention

[0003] The present invention relates to the treatment and / or prophylaxis of Attention Deficit / Hyperactivity Disorder (ADHD). The present invention also relates to dosage regimens and kits that find utility in the treatment and / or prophylaxis of ADHD.

[0004] Background of the Invention

[0005] Attention Deficit / Hyperactivity Disorder (ADHD) is characterised by impaired levels of attention, hyperactivity or impulsivity, or a combination thereof. It is estimated that the condition affects approximately 5% of individuals under the age of 18 years worldwide with persistence of symptoms into adulthood in approximately 65% of cases. The prevalence of ADHD in adults is estimated to be approximately 2.5% worldwide (Thapar & Cooper, The Lancet, 2016, 387(10024), 1240-1250).

[0006] The aetiology of ADHD is complex and not fully understood. However, impairment of dopaminergic neurotransmission is considered to be a common feature in ADHD patients. Recent studies have also found that genetic mutations in the Latrophilin 3 (LPHN3, also referred to as ADGRL3 gene are strongly associated with ADHD (Arcos-Burgos et al., 2010, Molecular Psychiatry, 15, 1053-1066). Further studies in zebrafish have shown that down regulation of latrophilin3.1 (lphn3.1 the zebrafish LPHN3 homologue, results in hyperactivity (Lange et al. Mol Psychiatry 2012, 17, 946-954 and Lange et al., 2018, Prog Neuropsychopharm Biol Psych, 84, 181-189). These studies also suggest that down regulation of lphn3.1 is linked to aberrant dopaminergic neurotransmission.

[0007] Established treatments for ADHD include pharmacological treatments such as stimulants (for example, methylphenidate, dexamphetamine and lisdexamfetamine), norepinephrine reuptake inhibitors (for example, atomoxetine) and a2-adrenergic agonists (for example, guanfacine and clonidine). Treatment of ADHD may also include the use of non-pharmacological therapies either as a monotherapy or in combination with pharmacological treatments. Examples of non-pharmacological treatments that may benefit patients with ADHD include cognitive behavioural therapy (CBT), dietary treatments (for example, supplementary fatty acids and the exclusion of artificial food colour), and exercise programs. 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 lisdexamfetamine or methylphenidate for the treatment of ADHD in adults. However, despite the approved use of such treatments for ADHD, their use remains controversial due to their limited efficacy and / or adverse effects (Cortese et al., 2018, The Lancet, Psychiatry, 5(9), 727-738).

[0008] Thus, there remains a need for further treatments for ADHD that provide clinical benefits whilst also displaying good clinical tolerability.

[0009] Summary of the Invention

[0010] The present invention provides a compound according to formula (I) or a pharmaceutically acceptable salt, pro-drug or solvate thereof; for use in the treatment or prophylaxis of Attention Deficit / Hyperactivity Disorder (ADHD).

[0011] In a further embodiment, the invention provides cilnidipine, or a pharmaceutically acceptable salt, pro-drug or solvate thereof; for use in the treatment or prophylaxis of Attention Deficit / Hyperactivity Disorder (ADHD).

[0012] In a further embodiment the invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt, pro-drug or solvate thereof; in the manufacture of a medicament for use in the treatment or prophylaxis of Attention Deficit / Hyperactivity Disorder (ADHD).

[0013] In a further embodiment, the invention provides a method for the treatment or prophylaxis of Attention Deficit / Hyperactivity Disorder (ADHD) comprising administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, pro-drug or solvate thereof;. The present invention also provides a compound according to formula (II) or a pharmaceutically acceptable salt, pro-drug or solvate thereof; for use in the treatment or prophylaxis of Attention Deficit / Hyperactivity Disorder (ADHD).

[0014] In a further embodiment, the invention provides nilvadipine, or a pharmaceutically acceptable salt, pro-drug or solvate thereof; for use in the treatment or prophylaxis of Attention Deficit / Hyperactivity Disorder (ADHD).

[0015] In a further embodiment the invention provides the use of a compound of formula (II) or a pharmaceutically acceptable salt, pro-drug or solvate thereof; in the manufacture of a medicament for use in the treatment or prophylaxis of Attention Deficit / Hyperactivity Disorder (ADHD).

[0016] In a further embodiment, the invention provides a method for the treatment or prophylaxis of Attention Deficit / Hyperactivity Disorder (ADHD) comprising administering an effective amount of a compound of formula (II) or a pharmaceutically acceptable salt, pro-drug or solvate thereof.

[0017] The present invention also provides a compound according to formula (III) or a pharmaceutically acceptable salt, pro-drug or solvate thereof; for use in the treatment or prophylaxis of Attention Deficit / Hyperactivity Disorder (ADHD). In a further embodiment, the invention provides isradipine, or a pharmaceutically acceptable salt, pro-drug or solvate thereof; for use in the treatment or prophylaxis of Attention Deficit / Hyperactivity Disorder (ADHD).

[0018] In a further embodiment the invention provides the use of a compound of formula (III) or a pharmaceutically acceptable salt, pro-drug or solvate thereof; in the manufacture of a medicament for use in the treatment or prophylaxis of Attention Deficit / Hyperactivity Disorder (ADHD).

[0019] In a further embodiment, the invention provides a method for the treatment or prophylaxis of Attention Deficit / Hyperactivity Disorder (ADHD) comprising administering an effective amount of a compound of formula (III) or a pharmaceutically acceptable salt, pro-drug or solvate thereof;.

[0020] The present invention also provides a compound according to formula (IV) or a pharmaceutically acceptable salt, pro-drug or solvate thereof; for use in the treatment or prophylaxis of Attention Deficit / Hyperactivity Disorder (ADHD).

[0021] In a further embodiment, the invention provides felodipine, or a pharmaceutically acceptable salt, pro-drug or solvate thereof; for use in the treatment or prophylaxis of Attention Deficit / Hyperactivity Disorder (ADHD).

[0022] In a further embodiment the invention provides the use of a compound of formula (IV) or a pharmaceutically acceptable salt, pro-drug or solvate thereof; in the manufacture of a medicament for use in the treatment or prophylaxis of Attention Deficit / Hyperactivity Disorder (ADHD).

[0023] In a further embodiment, the invention provides a method for the treatment or prophylaxis of Attention Deficit / Hyperactivity Disorder (ADHD) comprising administering an effective amount of a compound of formula (IV) or a pharmaceutically acceptable salt, pro-drug or solvate thereof. The present invention also provides a compound according to formula (V) or a pharmaceutically acceptable salt, pro-drug or solvate thereof; for use in the treatment or prophylaxis of Attention Deficit / Hyperactivity Disorder (ADHD).

[0024] In a further embodiment, the invention provides verapamil, or a pharmaceutically acceptable salt, pro-drug or solvate thereof; for use in the treatment or prophylaxis of Attention Deficit / Hyperactivity Disorder (ADHD).

[0025] In a further embodiment the invention provides the use of a compound of formula (V) or a pharmaceutically acceptable salt, pro-drug or solvate thereof; in the manufacture of a medicament for use in the treatment or prophylaxis of Attention Deficit / Hyperactivity Disorder (ADHD).

[0026] In a further embodiment, the invention provides a method for the treatment or prophylaxis of Attention Deficit / Hyperactivity Disorder (ADHD) comprising administering an effective amount of a compound of formula (V) or a pharmaceutically acceptable salt, pro-drug or solvate thereof;.

[0027] The present invention also provides a compound according to formula (VI) or a pharmaceutically acceptable salt, pro-drug or solvate thereof; for use in the treatment or prophylaxis of Attention Deficit / Hyperactivity Disorder (ADHD).

[0028] In a further embodiment, the invention provides nimodipine, or a pharmaceutically acceptable salt, pro-drug or solvate thereof; for use in the treatment or prophylaxis of Attention Deficit / Hyperactivity Disorder (ADHD). In a further embodiment the invention provides the use of a compound of formula (VI) or a pharmaceutically acceptable salt, pro-drug or solvate thereof; in the manufacture of a medicament for use in the treatment or prophylaxis of Attention Deficit / Hyperactivity Disorder (ADHD).

[0029] In a further embodiment, the invention provides a method for the treatment or prophylaxis of Attention Deficit / Hyperactivity Disorder (ADHD) comprising administering an effective amount of a compound of formula (VI) or a pharmaceutically acceptable salt, pro-drug or solvate thereof.

[0030] The present invention also provides a compound according to formula (VII) or a pharmaceutically acceptable salt, pro-drug or solvate thereof; for use in the treatment or prophylaxis of Attention Deficit / Hyperactivity Disorder (ADHD).

[0031] In a further embodiment, the invention provides nifedipine, or a pharmaceutically acceptable salt, pro-drug or solvate thereof; for use in the treatment or prophylaxis of Attention Deficit / Hyperactivity Disorder (ADHD).

[0032] In a further embodiment the invention provides the use of a compound of formula (VII) or a pharmaceutically acceptable salt, pro-drug or solvate thereof; in the manufacture of a medicament for use in the treatment or prophylaxis of Attention Deficit / Hyperactivity Disorder (ADHD).

[0033] In a further embodiment, the invention provides a method for the treatment or prophylaxis of Attention Deficit / Hyperactivity Disorder (ADHD) comprising administering an effective amount of a compound of formula (VII) or a pharmaceutically acceptable salt, pro-drug or solvate thereof.

[0034] The present invention further provides a compound of formula (I), (II), (III), (IV), (V), (VI) or (VII) or pharmaceutically acceptable salts, pro-drugs or solvates thereof; for use in a method for the treatment and / or prophylaxis of ADHD, in a patient known to have, suspected of having, or at risk of developing ADHD.

[0035] The present invention further provides a compound of formula (I), (II), (III), (IV), (V), (VI) or (VII) or pharmaceutically acceptable salts, pro-drug or solvates thereof; for use in the manufacture of a medicament for use in a method for the treatment and / or prophylaxis of ADHD, in a patient known to have, suspected of having, or at risk of developing ADHD.

[0036] The present invention further provides a method for the treatment and / or prophylaxis of ADHD, comprising a step of administering a dose of the compound of formula (I), (II), (III), (IV), (V), (VI) or (VII) or pharmaceutically acceptable salts, pro-drug or solvates thereof; to a patient known to have, suspected of having, or at risk of developing ADHD.

[0037] The present inventors have found that in a zebrafish (Danio rerio) model of ADHD, the compounds of formula (I), (II), (III), (IV), (V), (VI) or (VII) were surprisingly effective at reducing ADHD symptoms such as hyperactivity and motor impulsivity n I.phn3.1 knock-out zebrafish larvae.

[0038] The invention also provides the use of the compound according to formula (I), (II), (III), (IV), (V), (VI) or (VII) or pharmaceutically acceptable salts, pro-drug or solvates thereof; for the manufacture of a medicament for the treatment and / or prophylaxis of ADHD.

[0039] The present invention further provides a kit comprising the compound according to formula (I), (II), (III), (IV), (V), (VI) or (VII) or pharmaceutically acceptable salts, pro-drug or solvates thereof; and one or more further pharmacological interventions, instructions for a dietetic intervention and / or instructions for a psychological intervention. The kit of the present invention finds use in the treatment or prophylaxis of ADHD.

[0040] Description of the Drawings

[0041] Figure 1 shows a spectrogram of a 24 hour recording of the velocity (mm / s) of zebrafish larvae with a homozygous knock-out of the Lphn3.1 gene (herein referred to as “Lphn3.1 HOM”) and zebrafish larvae with a wild-type Lphn3.1 gene (herein referred to as “Lphn3.1 WT”). Both groups of larvae were administered a vehicle control (i.e. DMSO only). The grey area shown on the spectrogram indicates the lights-off phases of the experiment (five 30 minute phases, the first phases starting at 1.30 pm and followed by a 10 hour night period wherein lights were off, starting at 10:00 p.m. and ending at 8:00 a.m. the morning after).

[0042] Figure 2 shows a bar graph that depicts the differences in average distance moved by Lphn3.1 HOM and Lphn3.1 WT larvae during the five 30 minute lights-on phases. Both groups of larvae were administered a vehicle control (i.e. DMSO only). A significant effect of genotype on distance moved, between Lphn3.1 HOM DMSO and Lphn3.1 WT DMSO larvae, was observed (t=2.947, df=205, p<.01).

[0043] Figure 3 (a) shows a bar graph that depicts the differences in average distance moved over the five lights-on phases by Lphn3.1 HOM larvae that received cilni dipine at a dosage of 1 pM, 10 pM or 30 pM (n=24) or a vehicle control (i.e. DMSO only) (n=102) and Lphn3.1 WT vehicle control (i.e. DMSO only)(n=105) (all data presented with + / - SEM). Figure 3 (b) shows a comparison of the distance moved by Lphn3.1 HOM larvae that received cilnidipine, atomoxetine (tomoxetin hydrochloride) or a vehicle control (i.e. DMSO). The dashed line on the plot indicates the average distance moved by Lphn3.1 HOM larvae over five lights-on phases following treatment with the vehicle control (n=102). The dotted line indicates the average distance moved by Lphn3.1 HOM larvae over the five lights-on phases following treatment with 1 pM atomoxetine hydrochloride (n=24). The dots indicate the effect of cilnidipine at a dosage of 1 pM, 10 pM or 30 pM on the average distance moved by Lphn3.1 HOM larvae over the five lights-on phases (n=24) (all data presented with + / - SEM). Statistically significant differences were found between larvae treated with cilnidipine and larvae that received the vehicle control (f=32.57, df=21, p<0.0001).

[0044] Figure 4 (a) shows a bar graph that depicts the differences in average distance moved over the five lights-on phases by Lphn3.1 HOM larvae that received nilvadipine at a dosage of 1 pM, 10 pM or 30 pM (n=24) or a vehicle control (i.e. DMSO only) (n=102) and Lphn3.1 WT vehicle control (i.e. DMSO only)(n=105) (all data presented with + / - SEM). Figure 4 (b) shows a comparison of the distance moved by Lphn3.1 HOM larvae that received nilvadipine, atomoxetine (tomoxetin hydrochloride) or a vehicle control (i.e. DMSO). The dashed line on the plot indicates the average distance moved by Lphn3.1 HOM larvae over five lights-on phases following treatment with the vehicle control (n=102). The dotted line indicates the average distance moved by Lphn3.1 HOM larvae over the five lights-on phases following treatment with 1 pM atomoxetine hydrochloride (n=24). The dots indicate the effect of nilvadipine at a dosage of 1 pM, 10 pM or 30 pM on the average distance moved by Lphn3.1 HOM larvae over the five lights-on phases (n=24) (all data presented with + / - SEM). Statistically significant differences were found between larvae treated with nilvadipine and larvae that received the vehicle control (f=32.57, df=21, p<0.0001).

[0045] Figure 5 (a) shows a bar graph that depicts the differences in average distance moved over the five lights-on phases by Lphn3.1 HOM larvae that received isradipine at a dosage of 1 pM, 10 pM or 30 pM (n=24) or a vehicle control (i.e. DMSO only) (n=102) and Lphn3.1 WT vehicle control (i.e. DMSO only)(n=105) (all data presented with + / - SEM). Figure 5 (b) shows a comparison of the distance moved by Lphn3.1 HOM larvae that received isradipine, atomoxetine (tomoxetin hydrochloride) or a vehicle control (i.e. DMSO). The dashed line on the plot indicates the average distance moved by Lphn3.1 HOM larvae over five lights-on phases following treatment with the vehicle control (n=102). The dotted line indicates the average distance moved by Lphn3.1 HOM larvae over the five lights-on phases following treatment with 1 pM atomoxetine hydrochloride (n=24). The dots indicate the effect of isradipine at a dosage of 1 pM, 10 pM or 30 pM on the average distance moved by Lphn3.1 HOM larvae over the five lights-on phases (n=24) (all data presented with + / - SEM). Statistically significant differences were found between larvae treated with isradipine and larvae that received the vehicle control (f=32.57, df=21, p<0.0001).

[0046] Figure 6 (a) shows a bar graph that depicts the differences in average distance moved over the five lights-on phases by Lphn3.1 HOM larvae that received felodipine at a dosage of 1 pM, 10 pM or 30 pM (n=24) or a vehicle control (i.e. DMSO only) (n=102) and Lphn3.1 WT vehicle control (i.e. DMSO only)(n=105) (all data presented with + / - SEM). Figure 6 (b) shows a comparison of the distance moved by Lphn3.1 HOM larvae that received felodipine, atomoxetine (tomoxetin hydrochloride) or a vehicle control (i.e. DMSO). The dashed line on the plot indicates the average distance moved by Lphn3.1 HOM larvae over five lights-on phases following treatment with the vehicle control (n=102). The dotted line indicates the average distance moved by Lphn3.1 HOM larvae over the five lights-on phases following treatment with 1 pM atomoxetine hydrochloride (n=24). The dots indicate the effect of felodipine at a dosage of 1 pM, 10 pM or 30 pM on the average distance moved by Lphn3.1 HOM larvae over the five lights-on phases (n=24) (all data presented with + / - SEM). Statistically significant differences were found between larvae treated with felodipine and larvae that received the vehicle control (f=32.57, df=21, p<0.0001).

[0047] Figure 7 (a) shows a bar graph that depicts the differences in average distance moved over the five lights-on phases by Lphn3.1 HOM larvae that received verapamil at a dosage of 1 pM, 10 pM or 30 pM (n=24) or a vehicle control (i.e. DMSO only) (n=102) and Lphn3.1 WT vehicle control (i.e. DMSO only)(n=105) (all data presented with + / - SEM). Figure 7 (b) shows a comparison of the distance moved by Lphn3.1 HOM larvae that received verapamil, atomoxetine (tomoxetin hydrochloride) or a vehicle control (i.e. DMSO). The dashed line on the plot indicates the average distance moved by Lphn3.1 HOM larvae over five lights-on phases following treatment with the vehicle control (n=102). The dotted line indicates the average distance moved by Lphn3.1 HOM larvae over the five lights-on phases following treatment with 1 pM atomoxetine hydrochloride (n=24). The dots indicate the effect of verapamil at a dosage of 1 pM, 10 pM or 30 pM on the average distance moved by Lphn3.1 HOM larvae over the five lights-on phases (n=24) (all data presented with + / - SEM). Statistically significant differences were found between larvae treated with verapamil and larvae that received the vehicle control (f=32.57, df=21, p<0.0001).

[0048] Figure 8 (a) shows a bar graph that depicts the differences in average distance moved over the five lights-on phases by Lphn3.1 HOM larvae that received nimodipine at a dosage of 1 pM, 10 pM or 30 pM (n=24) or a vehicle control (i.e. DMSO only) (n=102) and Lphn3.1 WT vehicle control (i.e. DMSO only)(n=105) (all data presented with + / - SEM). Figure 8 (b) shows a comparison of the distance moved by Lphn3.1 HOM larvae that received nimodipine, atomoxetine (tomoxetin hydrochloride) or a vehicle control (i.e. DMSO). The dashed line on the plot indicates the average distance moved by Lphn3.1 HOM larvae over five lights-on phases following treatment with the vehicle control (n=102). The dotted line indicates the average distance moved by Lphn3.1 HOM larvae over the five lights-on phases following treatment with 1 pM atomoxetine hydrochloride (n=24). The dots indicate the effect of nimodipine at a dosage of 1 pM, 10 pM or 30 pM on the average distance moved by Lphn3.1 HOM larvae over the five lights-on phases (n=24) (all data presented with + / - SEM). Statistically significant differences were found between larvae treated with nimodipine and larvae that received the vehicle control (f=32.57, df=21, p<0.0001).

[0049] Figure 9 (a) shows a bar graph that depicts the differences in average distance moved over the five lights-on phases by Lphn3.1 HOM larvae that received nifedipine at a dosage of 1 pM, 10 pM or 30 pM (n=24) or a vehicle control (i.e. DMSO only) (n=102) and Lphn3.1 WT vehicle control (i.e. DMSO only)(n=105) (all data presented with + / - SEM). Figure 9 (b) shows a comparison of the distance moved by Lphn3.1 HOM larvae that received nifedipine, atomoxetine (tomoxetin hydrochloride) or a vehicle control (i.e. DMSO). The dashed line on the plot indicates the average distance moved by Lphn3.1 HOM larvae over five lights-on phases following treatment with the vehicle control (n=102). The dotted line indicates the average distance moved by Lphn3.1 HOM larvae over the five lights-on phases following treatment with 1 pM atomoxetine hydrochloride (n=24). The dots indicate the effect of nifedipine at a dosage of 1 pM, 10 pM or 30 pM on the average distance moved by Lphn3.1 HOM larvae over the five lights-on phases (n=24) (all data presented with + / - SEM). Statistically significant differences were found between larvae treated with nifedipine and larvae that received the vehicle control (f=32.57, df=21, p<0.0001).

[0050] Detailed Description

[0051] The inventors of the present invention have found that the compounds according to formula (I), (II), (III), (IV), (V), (VI) or (VII) are surprisingly effective for the treatment or prophylaxis of ADHD.

[0052] As discussed in more detail below, the present inventors have found that cilnidipine, nilvadipine, isradipine, felodipine, verapamil, nimodipine and nifedipine are surprisingly effective at reducing the activity of zebrafish larvae in a model of ADHD. The ADHD model used by the present inventors uses zebrafish carrying a homozygous knock-out of the Latrophilin 3 (lphn.3.1) gene. Mutations in the corresponding lphn.3.1 gene in humans (i.e. I. HN3) 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 the function observed in humans. In the zebrafish model used by the present inventors, ADHD-like behavioural phenotypes, such as hyperactivity and motor impulsivity, are observed in zebrafish larvae carrying a homozygous knock-out of the lphn3.1 gene.

[0053] Using the zebrafish model of ADHD, the present inventors have identified cilnidipine, a calcium antagonist accompanied with L-type and N-type calcium channel blocking activity typically used to treat hypertension, as being surprisingly effective at reducing ADHD behaviours such as hyperactivity and motor impulsivity.

[0054] The present inventors have also identified, using the zebrafish model of ADHD, nilvadipine, a calcium antagonist accompanied with L-type calcium channel blocking activity typically used to treat hypertension, as being surprisingly effective at reducing ADHD behaviours such as hyperactivity and motor impulsivity.

[0055] The present inventors have also identified, using the zebrafish model of ADHD, isradipine, a calcium antagonist accompanied with L-type calcium channel blocking activity typically used to treat hypertension, as being surprisingly effective at reducing ADHD behaviours such as hyperactivity and motor impulsivity.

[0056] The present inventors have also identified, using the zebrafish model of ADHD, felodipine, a calcium antagonist accompanied with L-type calcium channel blocking activity typically used to treat hypertension stable angina pectoris, as being surprisingly effective at reducing ADHD behaviours such as hyperactivity and motor impulsivity.

[0057] The present inventors have also identified, using the zebrafish model of ADHD, verapamil, a calcium antagonist accompanied with L-type calcium channel blocking activity typically used to treat hypertension, stable angina, vasospastic angina and unstable angina, and paroxysmal supraventricular tachycardia, as being surprisingly effective at reducing ADHD behaviours such as hyperactivity and motor impulsivity.

[0058] The present inventors have also identified, using the zebrafish model of ADHD, nimodipine, a calcium antagonist accompanied with L-type calcium channel blocking activity typically used for the prevention of ischaemic neurological deficits following aneurysmal subarachnoid haemorrhage, as being surprisingly effective at reducing ADHD behaviours such as hyperactivity and motor impulsivity.

[0059] The present inventors have also identified, using the zebrafish model of ADHD, nifedipine, a calcium antagonist accompanied with L-type calcium channel blocking activity typically used to treat hypertension and for the prophylaxis of chronic stable angina pectoris, as being surprisingly effective at reducing ADHD behaviours such as hyperactivity and motor impulsivity. Thus, the present invention provides the compound of formula (I), (II), (III), (IV), (V), (VI) or (VII) (i.e. cilnidipine, nilvadipine, isradipine, felodipine, verapamil, nimodipine or nifedipine, respectively), or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment or prophylaxis of ADHD.

[0060] For the avoidance of doubt, in this document, it is intended that the compound of formula (I), (II), (III), (IV), (V), (VI) or (VII) includes all salts and solvates thereof, unless stated otherwise.

[0061] The compound of formula (I), (II), (III), (IV), (V), (VI) or (VII) may be prepared using methods known to those skilled in the art of organic chemistry. Pharmaceutical preparations of the compound of formula (I), (II), (III), (IV), (V), (VI) or (VII) suitable for use in the present invention are available from commercial sources. For example, pharmaceutical preparations of the compound of formula (I) are marketed under the name CINOD®, pharmaceutical preparations of the compound of formula (II) are marketed under the name NIVADIL®, pharmaceutical preparations of the compound of formula (III) are marketed under the name DYNACIRC®, pharmaceutical preparations of the compound of formula (IV) are marketed under the name PLENDIL®, pharmaceutical preparations of the compound of formula (V) are marketed under the name CALAN®, pharmaceutical preparations of the compound of formula (VI) are marketed under the name NIMOTOP®, and pharmaceutical preparations of the compound of formula (VII) are marketed under the name ADALAT®.

[0062] Generic pharmaceutical preparations of the compound of formula (I), (II), (III), (IV), (V), (VI) or (VII) are also available.

[0063] For the avoidance of doubt, in this document, it is intended that the compounds of formula (I), (II), (III), (IV), (V), (VI) or (VII) include all enantiomers thereof, unless stated otherwise. Also for the avoidance of doubt, in this document, it is intended that the compounds of formula (I), (II), (III), (IV), (V), (VI) or (VII) include compounds that differ by immaterial structural variations, and which are, therefore, expected to display similar properties to cilnidipine, nilvadipine, isradipine, felodipine, verapamil, nimodipine and / or nifedipine respectively in the ADHD model described herein.

[0064] For the avoidance of doubt, in this document, it is intended that compounds of formula (I), (II), (III), (IV), (V), (VI) or (VII) include compounds of formula (I), (II), (Ill), (IV), (V), (VI) or (VII) wherein one or more of the hydrogen atoms has been replaced by deuterium. Incorporation of deuterium may improve the pharmacokinetic and / or toxicity profile of drugs, potentially translating into improvements in efficacy and safety compared with the non-deuterated counterparts.

[0065] The compound of formula (I), (II), (III), (IV), (V), (VI) or (VII) may form salts or solvates. Salts of the compound of formula (I), (II), (III), (IV), (V), (VI) or (VII) which are suitable for use in the present invention are those wherein a counterion is pharmaceutically acceptable. However, the use of salts having non-pharmaceutically acceptable counter-ions are within the scope of the present invention, for example, for use as intermediates in the preparation of the compound of formula (I), (II), (III), (IV), (V), (VI) or (VII) and their pharmaceutically acceptable salts, and physiologically functional derivatives. Suitable salts for use according to the invention include those formed with organic or inorganic acids. In particular, suitable salts formed with acids for use according to the invention include those formed with mineral acids, strong organic carboxylic acids, such as alkanecarboxylic acids of 1 to 4 carbon atoms which are unsubstituted or substituted, for example, by halogen, such as saturated or unsaturated dicarboxylic acids, such as hydroxycarboxylic acids, such as amino acids, or with organic sulfonic acids, such as (Cj-C4)-alkyl- or aryl-sulfonic acids which are unsubstituted or substituted, for example by halogen. Pharmaceutically acceptable acid addition salts include those formed from hydrochloric, hydrobromic, sulphuric, nitric, citric, tartaric, acetic, phosphoric, lactic, pyruvic, acetic, trifluoroacetic, succinic, perchloric, fumaric, maleic, glycolic, lactic, salicylic, oxalic, oxaloacetic, methanesulfonic, ethanesulfonic, p-toluenesulfonic, formic, benzoic, malonic, naphthalene-2-sulfonic, benzenesulfonic, isethionic, ascorbic, malic, phthalic, aspartic, and glutamic acids, lysine and arginine. Suitable cations which may be present in salts include alkali metal cations, especially sodium, potassium and calcium, and ammonium or amino cations.

[0066] Those skilled in the art of organic chemistry will appreciate that many organic compounds can form complexes with solvents in which they are reacted or from which they are precipitated or crystallized. These complexes are known as "solvates". For example, a complex with water is known as a "hydrate". The complex may incorporate a solvent in stoichiometric or non-stoichiometric amounts. Solvates are described in Water-Insoluble Drug Formulation, 2nded R. Lui CRC Press, page 553 and Byrn et al Pharm Res 12(7), 1995, 945-954. Before it is made up in solution, the compound of formula (I), (II), (III), (IV), (V), (VI) or (VII) may be in the form of a solvate. Solvates of the compound of formula (I), (II), (III), (IV), (V), (VI) or (VII) which are suitable for use as a medicament according to the invention are those wherein the associated solvent is pharmaceutically acceptable. For example, a hydrate is a pharmaceutically acceptable solvate.

[0067] A compound which, upon administration to the recipient, is capable of being converted into the compound of formula (I), (II), (III), (IV), (V), (VI) or (VII), or an active metabolite or residue thereof, is known as a “prodrug”. Thus, in certain embodiments, the compound of formula (I), (II), (III), (IV), (V), (VI) or (VII) may be provided in the form of a prodrug. A prodrug may, for example, be converted within the body, e.g. by hydrolysis in the blood, into its active form that has medical effects. Pharmaceutical acceptable prodrugs are described in T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, Vol. 14 of the A. C. S. Symposium Series (1976); “Design of Prodrugs” ed. H. Bundgaard, Elsevier, 1985; and in Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergam on Press, 1987, which are incorporated herein by reference.

[0068] Pharmaceutical compositions

[0069] While it is possible for the compound of formula (I), (II), (III), (IV), (V), (VI) or (VII) to be administered alone, it is preferable for it to be present in a composition and particularly in a pharmaceutical composition. Pharmaceutical compositions of the present invention comprise the compound of formula (I), (II), (III), (IV), (V), (VI) or (VII); and one or more pharmaceutically acceptable excipients.

[0070] Pharmaceutical compositions include those suitable for oral, parenteral (including subcutaneous, intradermal, intraosseous infusion, intramuscular, intravascular (bolus or infusion), and intramedullary), intraperitoneal, transmucosal, transdermal, rectal and topical (including dermal, buccal, sublingual and intraocular) administration, although the most suitable route may depend upon the characteristics of the subject under treatment, for example the species, age, weight, sex, medical conditions, the particular type of ADHD (for example, “impulsive type / hyperactive type”, “inattentive type” and “combined type” ADHD) and its severity, and other relevant medical and physical factors. Formulations for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilised) condition requiring only the addition of the sterile liquid carrier, for example saline or water-for-inj ection, 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 can contain, for example, suitable non-toxic, parenterally acceptable diluents or solvents, such as mannitol, 1,3 -butanediol, water, Ringer’s solution, an isotonic sodium chloride solution, or other suitable dispersing or wetting and suspending agents, including synthetic mono- or diglycerides, and fatty acids, including oleic acid, or Cremaphor®.

[0071] Compositions for nasal, aerosol or inhalation administration include solutions in saline, which can contain, for example, benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, and / or other solubilizing or dispersing agents such as those known in the art.

[0072] Formulations for rectal administration may be presented as a suppository with carriers such as cocoa butter, synthetic glyceride esters or polyethylene glycol. Such carriers are typically solid at ordinary temperatures but liquefy and / or dissolve in the rectal cavity to release the drug.

[0073] Formulations for topical administration in the mouth, for example buccally or sublingually, include lozenges comprising the active ingredient in a flavoured basis such as sucrose and acacia or tragacanth, and pastilles comprising the active ingredient in a basis such as gelatine and glycerine or sucrose and acacia. Exemplary compositions for topical administration include a topical carrier such as Plastibase® (mineral oil gelled with polyethylene).

[0074] Pharmaceutical compositions suitable for oral administration may be presented as discrete units such as capsules, sachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The compound of formula (I), (II), (III), (IV), (V), (VI) or (VII) may also be presented as a bolus, electuary or paste. The pharmaceutical compositions may optionally be present in a form that provides slow or controlled release of the compound of formula (I), (II), (III), (IV), (V), (VI) or (VII) once administered to a subject. Various pharmaceutically acceptable carriers and their formulation are described in standard formulation treatises, e.g., Remington's Pharmaceutical Sciences by E. W. Martin. See also Wang, Y. J. and Hanson, M. A., Journal of Parenteral Science and Technology, Technical Report No. 10, Supp. 42:2S, 1988.

[0075] Preferred unit dosage compositions are those containing an exploratory dose or therapeutic dose, or an appropriate fraction thereof, of the compound of formula (I), (II), (III), (IV), (V), (VI) or (VII).

[0076] In preferred embodiments, a composition for use according to the present invention consists essentially of the compound of formula (I), (II), (III), (IV), (V), (VI) or (VII); and at least one pharmaceutically acceptable excipient.

[0077] An exemplary composition comprising the compound of formula (I) for use according to the present invention comprises one or more of the following pharmaceutically acceptable carriers: lactose, microcrystalline cellulose, sodium croscarmellose and magnesium stearate. A further exemplary composition comprising the compound of formula (I) for use according to the present invention is a tablet comprising one or more of the following excipients: lactose, microcrystalline cellulose, polyvinyl pyrrolidone, magnesium stearate, talc and croscarmellose sodium.

[0078] An exemplary composition comprising the compound of formula (II) for use according to the present invention is a capsule comprising maize starch, microcrystalline cellulose, povidone and croscarmellose sodium and a capsule shell comprising iron oxides, titanium dioxide and gelatin.

[0079] An exemplary composition comprising the compound of formula (III) for use according to the present invention comprises one or more of the following pharmaceutically acceptable carriers: starch, silicon dioxide, gelatin, lactose monohydrate, microcrystalline cellulose, polyethylene glycol, sodium lauryl sulfate, titanium dioxide, ferrosoferric oxide, butyl alcohol and propylene glycol.

[0080] An exemplary composition comprising the compound of formula (IV) for use according to the present invention comprises one or more of the following pharmaceutically acceptable carriers: lactose monohydrate, cellulose microcrystalline, hypromellose, povidone, propyl gallate, silica colloidal anhydrous, magnesium stearate, talc, and propylene glycol. A further exemplary composition comprising the compound of formula (IV) for use according to the present invention is a tablet comprising: a tablet core comprising: cellulose microcrystalline, lactose monohydrate, sodium lauryl sulfate, hypromellose and magnesium stearate, with a tablet coating comprising lactose monohydrate; hypromellose and polyethylene glycol.

[0081] An exemplary composition comprising the compound of formula (V) for use according to the present invention comprises one or more of the following pharmaceutically acceptable carriers: microcrystalline cellulose, sodium alginate, povidone k30, magnesium stearate, purified water, hypromellose 2910, polyethylene 400, polyethylene glycol 6000, talc and montan glycol wax. A further exemplary composition comprising the compound of formula (V) for use according to the present invention is an intravenous solution comprising water, sodium chloride and 10% hydrochloric acid as a pH adjuster. A further exemplary composition comprising the compound of formula (V) for use according to the present invention is a tablet with a tablet core comprising sodium alginate, microcrystalline cellulose, povidone, hypromellose 2208, colloidal anhydrous silica, magnesium stearate and a table coat comprising: hypromellose 2910, polyethylene glycol 400, and carnauba wax.

[0082] An exemplary composition comprising the compound of formula (VI) for use according to the present invention comprises one or more of the following pharmaceutically acceptable carriers: microcrystalline cellulose, maize starch, povidone, crospovidone, magnesium stearate, hypromellose and polyethylene glycol 4000. A further exemplary composition comprising the compound of formula (VI) for use according to the present invention is an intravenous formulation comprising ethanol 96%, polyethylene glycol 400, sodium citrate and citric acid.

[0083] An exemplary composition comprising the compound of formula (VII) for use according to the present invention comprises one or more of the following pharmaceutically acceptable carriers: colloidal anhydrous silica, lactose monohydrate, microcrystalline cellulose, polysorbate 80, starch pregelatinized, magnesium stearate, hypromellose, polyethylene glycol 6000, purified talc, purified water and carnauba wax. a further exemplary composition comprising the compound of formula (VII) for use according to the present invention is a tablet with a tablet core comprising povidone k30, talc, hypromellose, carboxypolymethylene, anhydrous colloidal silica, magnesium stearate and lactose monohydrate and a tablet coating comprising polyethylene glycol 4000, methyl methacrylate / dimethylaminoethyl methacrylate / butyl methacrylate copolymer, hypromellose, magnesium stearate and talc.

[0084] It should be understood that in addition to the ingredients particularly mentioned above, the compositions for use in this invention may include other agents conventional in the art having regard to the type of composition in question.

[0085] The compositions for use according to the invention may comprise one or more further therapeutic agents. Examples of further therapeutic agents that may be present in a composition for use according to the present invention include, but are not limited to, methylphenidate, amphetamine (for example dexamphetamine), lisdexamfetamine, serdexmethylphenidate, atomoxetine, viloxazine, clonidine, and guanfacine. Typically, one or more further therapeutic agents is a stimulant, such as amphetamine, methylphenidate and lisdexamfetamine.

[0086] Attention Deficit / Hyperactivity Disorder (ADHD)

[0087] The present inventors have found that the compounds of formula (I), (II), (III), (IV), (V), (VI) or (VII), and pharmaceutical compositions thereof, are particularly effective at reducing the symptoms of ADHD in a subject known or suspected of having ADHD, or delaying the onset of, or preventing ADHD in a subject known or suspected of being at risk of developing ADHD.

[0088] Thus, the compound of formula (I), (II), (III), (IV), (V), (VI) or (VII), or a pharmaceutical composition thereof, for use according to the present invention, may be administered to a subject known or suspected of having ADHD, or known or suspected of being at risk of developing ADHD. The subject may be a human subject, for example a human patient. The human subject may be a child (e.g. under the age of about 10 years old), an adolescent (e.g. between the ages of about 10 to 19 years old) or may be an adult (e.g. over the age of about 18 to 21 years old).

[0089] The subject known or suspected of having ADHD may have ADHD that is characterised by impulsive and hyperactive behaviours without impaired levels of attention (i.e. “impulsive type / hyperactive type” ADHD). Or, the subject known or suspected of having ADHD may have ADHD that is characterised by impaired levels of attention without hyperactivity or impulsivity (i.e. “inattentive type” ADHD). Or, the subject known or suspected of having ADHD may have ADHD that is characterised by a combination of reduced levels of attention with hyperactivity and impulsivity behaviours (i.e. “combined type” ADHD).

[0090] A subject known or suspected of being at risk of developing ADHD may be one who has a known or suspected genetic predisposition for developing ADHD, for example, the subject may have a mutation in the Latrophilin 3 (LPHN3) gene. Examples of further genetic mutations implicated in ADHD have been reported (see, for example, Faraone and Larsson, Molecular Psychiatry, 2019, 24, 562-575, which is incorporated herein by reference), and include, for example, mutations in one or more of the following genes: the serotonin transporter (5HTT) gene, the dopamine transporter (I)A Tl) gene, the 1)4 dopamine receptor (DRD4) gene, the D5 dopamine receptor (DRD5) gene, the serotonin IB receptor gene (HT1UB) and the Synaptosomal-Associated Protein (SNAP25) gene. Additionally, or alternatively, a subject known or suspected of being at risk of developing ADHD may be one who has been exposed to one or more potential environmental risk factors associated with ADHD, such as maternal pre-pregnancy obesity, pre-eclamp si a, hypertension, acetaminophen exposure, and smoking during pregnancy; and childhood atopic diseases.

[0091] Additionally, the subject known or suspected of having ADHD, or known or suspected of being at risk of developing ADHD, may also have signs or symptoms of other conditions such as depression, anxiety disorder, oppositional defiant disorder (ODD), conduct disorder, sleeps problems (for example, sleep-onset insomnia), autism spectrum disorder (ASD), bipolar disorder, epilepsy, Tourette’s syndrome and / or learning difficulties such as dyslexia. Typically, the subject is one who meets the diagnostic criteria for ADHD set out in the Diagnostic and Statistical Manual of Mental Disorders (DSM) or International Classification of Diseases (ICD).

[0092] Additionally, the subject known or suspected of having ADHD, or known or suspected of being at risk of developing ADHD, may also suffer from a substance abuse disorder, for example addiction and / or abuse of stimulants such as amphetamine.

[0093] For example, the compound of formula (I), (II), (III), (IV), (V), (VI) or (VII), or compositions thereof, for use according to the invention, may be administered to a subject for whom one or more established stimulant-based ADHD treatments (for example, methylphenidate, dexamphetamine, and lisdexamfetamine) are deemed to be unsuitable due to the subject being at risk, having a history of, or currently suffering from, a substance abuse disorder.

[0094] The present inventors have shown using a zebrafish model of ADHD that the compound of formula (I), (II), (III), (IV), (V), (VI) or (VII) is surprisingly effective at reducing hyperactivity and motor impulsivity. The efficacy of the compound of formula (I), (II), (III), (IV), (V), (VI) or (VII) at reducing hyperactivity and motor impulsivity in the zebrafish model of ADHD makes the compound of formula (I), (II), (III), (IV), (V), (VI) or (VII) an especially attractive treatment for ADHD that is characterised by hyperactivity and / or impulsivity behaviours (i.e. “impulsive type / hyperactive type” ADHD or “combined type” ADHD). Thus, in certain embodiments, the compound of formula (I), (II), (III), (IV), (V), (VI) or (VII) or a pharmaceutical composition thereof, for use according to the present invention, may be administered to a subject known or suspected of having ADHD that is characterised by impulsive and hyperactive behaviours without impaired levels of attention (i.e. “impulsive type / hyperactive type” ADHD), or ADHD that is characterised by a combination of reduced levels of attention with hyperactivity and impulsivity behaviours (i.e. “combined type” ADHD).

[0095] The compound of formula (I), (II), (III), (IV), (V), (VI) or (VII), or compositions thereof, for use according to the invention, may be administered to a subject for whom one or more established ADHD treatments (for example, methylphenidate, dexamphetamine, lisdexamfetamine, atomoxetine, viloxazine, guanfacine and clonidine) have been ineffective at reducing one or more of the symptoms of ADHD and / or induced intolerable adverse effects. Examples of adverse effects known or suspected of being caused by established ADHD treatments include impaired sleep, lack of appetite, increased blood pressure, stunted growth, disruption of circadian rhythm and neurotoxicity.

[0096] The compound of formula (I), (II), (III), (IV), (V), (VI) or (VII), and compositions thereof, as described herein finds utility in a method of treating or preventing ADHD, wherein said method comprises a step of administering the compound of formula (I), (II), (III), (IV), (V), (VI) or (VII), or a composition thereof, to a patient known or suspected of having ADHD, or known or suspected of being at risk of developing ADHD. The compound of formula (I), (II), (III), (IV), (V), (VI) or (VII) also finds use in the manufacture of a medicament for the treatment or prophylaxis of ADHD. Dosage regimens

[0097] The amount of the compound of formula (I), (II), (III), (IV), (V), (VI) or (VII) which is required to achieve a therapeutic effect will vary with the particular route of administration and the characteristics of the subject under treatment, for example the species, age, weight, sex, medical conditions, the particular type of ADHD (for example “impulsive type / hyperactive type”, “inattentive type” and “combined type” ADHD) and its severity, and other relevant medical and physical factors. An ordinarily skilled physician can readily determine and administer an effective amount of the compound of formula (I), (II), (III), (IV), (V), (VI) or (VII) required for treatment or prophylaxis of ADHD.

[0098] The compound of formula (I), (II), (III), (IV), (V), (VI) or (VII) may be administered daily (including several times daily), every second or third day, weekly, every second, third or fourth week or even as a single dose depending on the subject and the characteristics of the ADHD to be treated.

[0099] The compound of formula (I) (excluding the mass of any counterion or solvent) may be administered in an amount of about 0.1 mg to about 50 mg per administration, for example, a daily dose between about 5mg and about 20mg. For example, at least 0.1 mg, at least about 0.5 mg, at least about 1 mg, at least about 2 mg, at least about 4 mg, at least about 5 mg, at least about 8 mg, at least about 10 mg, at least about 12 mg, at least about 15mg, at least about 16 mg, at least about 20 mg, at least about 25mg, at least about 30mg, or at least about 40mg may be administered to a subject, for example, once daily. For example, about 0. Img to about lOmg, about 0.5mg to about 25mg, about Img to about 20mg dose is administered in the morning and the second dose is administered in the evening (for example, after 6 p.m.). The first dose may be the same or different to the second dose.

[0100] Typically, the compound of formula (I) is administered as a single daily dose. Alternatively, the compound of formula (I) is administered as a dose two, three or four times a day. For example, a dose is administered in two doses, wherein the first dose is administered in the morning and the second dose is administered in the evening (for example, after 6 p.m.). The first dose may be the same as doses two, three or four or the same. Preferably, the doses are the same.

[0101] 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 about 50 mg per administration, for example, a daily dose between about 4mg and about 16mg. For example, at least 0.1 mg, at least about 0.5 mg, at least about 1 mg, at least about 2 mg, at least about 4 mg, at least about 5 mg, at least about 8 mg, at least about 10 mg, at least about 12 mg, at least about 15mg, at least about 16 mg, at least about 20 mg, at least about 25 mg, at least about 30mg, or at least about 40mg may be administered to a subject, for example, once daily. For example, about 0. Img to about lOmg, about 0.5mg to about 25mg, about Img to about 25mg, for example, about 4mg to about 16mg or about 5mg to about 25mg may be administered to a subject, for example, once daily.

[0102] Typically, the compound of formula (II) is administered as a single daily dose. Alternatively, the compound of formula (II) is administered as a dose two, three or four times a day. For example, a dose is administered in two doses, wherein the first dose is administered in the morning and the second dose is administered in the evening (for example, after 6 p.m.).

[0103] 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 about 50 mg per administration, for example, a daily dose between about 2.5mg and about 20mg. For example, at least 0.1 mg, at least about 0.5 mg, at least about 1 mg, at least about 2 mg, at least about 4 mg, at least about 5 mg, at least about 8 mg, at least about 10 mg, at least about 12 mg, at least about 15mg, at least about 16 mg, at least about 20 mg, at least about 25 mg, at least about 30mg, or at least about 40mg may be administered to a subject, for example, once daily. For example, about O.lmg to about lOmg, about 0.5mg to about 25mg, about Img to about 25mg, for example, about 2.5mg to about 20mg or about 5mg to about 25mg may be administered to a subject, for example, once daily.

[0104] Typically, the compound of formula (III) is administered as a single daily dose. Alternatively, the compound of formula (III) is administered as a dose two, three or four times a day. For example, a dose is administered in two doses, wherein the first dose is administered in the morning and the second dose is administered in the evening (for example, after 6 p.m.).

[0105] The compound of formula (IV) (excluding the mass of any counterion or solvent) may be administered in an amount of about 0.1 mg to about 50 mg per administration, for example, a daily dose between about 2.5mg and about 20mg. For example, at least 0.1 mg, at least about 0.5 mg, at least about 1 mg, at least about 2 mg, at least about 4 mg, at least about 5 mg, at least about 8 mg, at least about 10 mg, at least about 12 mg, at least about 15mg, at least about 16 mg, at least about 20 mg, at least about 25 mg, at least about 30mg, or at least about 40mg may be administered to a subject, for example, once daily. For example, about O.lmg to about lOmg, about 0.5 mg to about 25 mg, about Img to about 25 mg, for example, about 2.5 mg to about 20mg or about 5mg to about 25mg may be administered to a subject, for example, once daily.

[0106] Typically, the compound of formula (IV) is administered as a single daily dose. Alternatively, the compound of formula (IV) is administered as a dose two, three or four times a day. For example, a dose is administered in two doses, wherein the first dose is administered in the morning and the second dose is administered in the evening (for example, after 6 p.m.).

[0107] The compound of formula (V) (excluding the mass of any counterion or solvent) may be administered in an amount of about 1 mg to about 200 mg per administration, for example, a dose, 3 -times a day, between about 40mg and about 120mg. For example, at least 1 mg, at least about 5 mg, at least about 10 mg, at least about 20 mg, at least about 40 mg, at least about 50 mg, at least about 80 mg, at least about 100 mg, at least about 120 mg, at least about 150mg, or at least about 180 mg. For example, about Img to about lOmg, about Img to about 20mg, about 40mg to about 120mg, about lOmg to about 25mg, for example, about 20mg to about lOOmg or about 30mg to about 80mg may be administered to a subject, for example, 3-times daily.

[0108] Typically, the compound of formula (V) is administered as a single daily dose. Alternatively, the compound of formula (V) is administered as a dose two, three or four times a day. For example, a dose is administered in two doses, wherein the first dose is administered in the morning and the second dose is administered in the evening (for example, after 6 p.m.) or a dose is administered in three doses, wherein the first dose is administered in the morning, the second dose is administered in the middle of the day, for example, lunchtime, and the third dose is administered in the evening.

[0109] The compound of formula (VI) (excluding the mass of any counterion or solvent) may be administered in an amount of about 1 mg to about 500mg per administration, for example, a dose, up to about 360mg per day. For example, at least 10 mg, at least about 20 mg, at least about 30 mg, at least about 40 mg, at least about 50 mg, at least about 75 mg, at least about 100 mg, at least about 120 mg, at least about 150 mg, at least about 175mg, at least about 200mg, at least about 225g, at least about 250g, at least about 275g, at least about 300g or at least about 350mg. For example, a daily dose of about lOmg to about lOOmg, about 50mg to about 400mg, about lOOmg to about 360mg, about lOOmg to about 360mg, for example, about lOOmg to about 200mg or about 200mg to about 300mg may be administered to a subject..

[0110] Typically, the compound of formula (VI) is administered as a single daily dose. Alternatively, the compound of formula (VI) is administered as a dose two, three or four times a day. For example, a dose is administered in two doses, wherein the first dose is administered in the morning and the second dose is administered in the evening (for example, after 6 p.m.).

[0111] The compound of formula (VII) (excluding the mass of any counterion or solvent) may be administered in an amount of about 0.1 mg to about 50 mg per administration, for example, a dose, 3-times daily, between about 5mg and about 20mg. For example, at least 0.1 mg, at least about 0.5 mg, at least about 1 mg, at least about 2 mg, at least about 4 mg, at least about 5 mg, at least about 8 mg, at least about 10 mg, at least about 12 mg, at least about 15mg, at least about 16 mg, at least about 20 mg, at least about 25mg, at least about 30mg, or at least about 40mg may be administered to a subject, for example, once daily. For example, about 0. Img to about lOmg, about 0.5mg to about 25mg or about 5mg to about 20mg is administered in the morning and the second dose is administered in the middle of the day and the third dose is administered in the evening (for example, after 6 p.m.).

[0112] Typically, the compound of formula (VII) is administered as a single daily dose. Alternatively, the compound of formula (VII) is administered as a dose two, three or four times a day. For example, a dose is administered in two doses, wherein the first dose is administered in the morning and the second dose is administered in the evening (for example, after 6 p.m.) or a dose is administered in three doses, wherein the first dose is administered in the morning and the second dose is administered in the middle of the day, for example, lunchtime and the third dose is administered in the evening.

[0113] In certain embodiments, the compound of formula (I), (II), (III), (IV), (V), (VI) or (VII) is administered as a composition. Preferably, the composition is a pharmaceutical composition for use according to the present invention.

[0114] Whilst the compound of formula (I), (II), (III), (IV), (V), (VI) or (VII) may be used as the sole active ingredient in the present invention, it is also possible for it to be used in combination with one or more further therapeutic interventions, and the use of such combinations provides one embodiment of the present invention. Examples of further therapeutic interventions include pharmacological interventions, dietetic interventions and psychological intervention.

[0115] Further pharmacological interventions may be therapeutic agents useful in the treatment or prophylaxis of ADHD, or other pharmaceutically active materials. Such agents are known in the art. Examples of further therapeutic agents for use in the present invention include those described herein. Typically, the further therapeutic agent is a stimulant, such as amphetamine, methylphenidate and lisdexamfetamine. Examples of suitable dietetic interventions include, for example, supplementary fatty acids and the exclusion of artificial food colour from the diet. Examples of suitable psychological interventions include, for example, cognitive behavioural therapy (CBT).

[0116] In a further embodiment of the invention, the further therapeutic interventions comprise one or more of the other compounds of formula (I), (II), (III), (IV), (V), (VI) or (VII).

[0117] The one or more further therapeutic interventions may be used simultaneously, sequentially or separately with / from the administration of the compound of formula

[0118] (I), (II), (III), (IV), (V), (VI) or (VII). The individual components of such combinations can be administered separately at different times during the course of therapy or concurrently in divided or single combination forms. An ordinarily skilled physician can readily determine and administer the effective amount of one or more therapeutic interventions required to have the desired therapeutic effect.

[0119] Preferred unit dosage compositions for use according to the invention are those containing an effective dose, or an appropriate fraction thereof, of the compound of formula (I), (II), (III), (IV), (V), (VI) or (VII). The release of the compound of formula (I), (II), (III), (IV), (V), (VI) or (VII) from certain composition may also be sustained, for example, if the composition contains suitable controlled-release excipients.

[0120] Kits

[0121] The present invention provides a kit comprising the compound of formula (I),

[0122] (II), (III), (IV), (V), (VI) or (VII), one or more pharmaceutically acceptable excipients, and optionally one or more further therapeutic agents that are useful in the treatment or prophylaxis of ADHD. Examples of such further therapeutic agents include those described herein as being suitable for use in the present invention and being optionally present in a pharmaceutical composition of the invention as a further therapeutic agent.

[0123] Kits of the present inventions may also contain instructions for a dietetic intervention and / or instructions for a psychological intervention suitable for ADHD. For example, the kits may include instructions for a nutrition plan suitable for the subject receiving treatment and / or the kit may comprise instruct ons / guidance for cognitive behavioural therapy (CBT).

[0124] Kits of the present invention find use in the treatment and prophylaxis of ADHD.

[0125] For the avoidance of doubt, the compound of formula (I), (II), (III), (IV), (V),

[0126] (VI) or (VII) present in a kit according to the present invention is in a form and quantity suitable for use according to the present invention. Suitable pharmaceutical compositions and formulations are described herein. The skilled person can readily determine a quantity of the compound of formula (I), (II), (III), (IV), (V), (VI) or

[0127] (VII) suitable for including in a kit of the invention, and for use according to the invention.

[0128] Metabolites

[0129] Active metabolites of the compound of formula (I), (II), (III), (IV), (V), (VI) or (VII) may be used in the treatment or prophylaxis of Attention Deficit / Hyperactivity Disorder (ADHD). In embodiments wherein the compound is an active metabolite of a compound of formula (I), (II), (III), (IV), (V), (VI) or (VII), the compound may be isolated from cells treated with the compound of formula (I), (II), (III), (IV), (V), (VI) or (VII), or may be prepared using standard organic chemistry techniques. For the avoidance of doubt, when the compound for use according to the present invention is an active metabolite of a compound of formula (I), (II), (III), (IV), (V), (VI) or (VII) , the compound may be used in the form of a composition and / or as medicaments in the same manner as described herein for the compound of formula (I), (II), (III), (IV), (V), (VI) or (VII). Equivalents

[0130] The invention has been described broadly and generically herein. Those of ordinary skill in the art will readily appreciate that all parameters, dimensions, materials, and configurations described herein are meant to be exemplary and that the actual parameters, dimensions, materials, and / or configurations will depend upon the specific application or applications for which the teachings of the present invention is / are used. Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. It is, therefore, to be understood that the foregoing embodiments are presented by way of example only and that, within the scope of the appended claims and equivalents thereto, the invention may be practiced otherwise than as specifically described and claimed. The present invention is directed 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, if such features, systems, articles, materials, kits, and / or methods are not mutually inconsistent, is included within the scope of the present invention. Further, each of the narrower species and subgeneric groupings falling within the generic disclosure also form part of the invention. This includes the generic description of the invention with a proviso or negative limitation removing any subject matter from the genus, regardless of whether or not the excised material is specifically recited herein.

[0131] Incorporation by Reference

[0132] The contents of the articles, patents, and patent applications, and all other documents and electronically available information mentioned or cited herein, are hereby incorporated 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 physically to incorporate into this application any and all materials and information from any such articles, patents, patent applications, or other physical and electronic documents.

[0133] The following Examples illustrate the invention. Examples

[0134] Zebrafish (Danio rerio) is gaining popularity in biological psychiatry. Their rich behavioral repertoire, the availability of well-established behavioral and automated behavioral assays, make zebrafish a useful model of various human brain disorders. The neuronal pathways involved in brain physiology are highly conserved, including all major neurotransmitter systems and high genetic homology. Gene editing technology allows precise modelling of human disorders. The lphn3.1 knock-out model of ADHD described herein robustly exhibits the hallmarks of human ADHD, that is: hyperactivity, hypersensitivity to known dopamine agonists, and rescue of the phenotype following administration of known anti ADHD compounds.

[0135] Material and methods:

[0136] Zebrafish larvae carrying a knock-out of the Latrophilin3 (I.phn3.1) gene were generated by CRISPR-Cas9. Zebrafish were kept in a 14: 10 light: dark cycle in 3 or 10 L multi tank constant flow system (Aquatic Habitats, Apopka, FL, USA). For behavioral analysis a total number of 735, 6 days-post fertilization (dpf) embryos carrying a homozygous knock-out of the Lphn3.1 gene were used in the study. Adult zebrafish with a homozygous knock-out of the Lphn3.1 gene and adult zebrafish with a wild-type Lphn3.1 gene were fed three times a day on a variable diet of TetraMin flakes (Tetra Holding GmbH, Melle, Germany) and live Artemia. Water temperature was held at a constant 28.5 °C and replaced at a rate of 10% per day. Eggs were collected between 10:00-12:00 a.m. and contained in 2 L tanks. The following day, dead eggs were removed and tanks were cleaned. Eggs were incubated for 4 days at 28.5 °C in system water mixed with methylene blue. All procedures in the study were carried out in strict compliance with the regulations of, and approved by, the National Bioethics Committee of Iceland (regulation 460 / 2017).

[0137] Genotyping

[0138] Strains were verified for knock-down of the Lphn3.1 gene using Western blot.

[0139] Behavioral Recordings

[0140] At 5 dpf, larvae were placed in individual wells of 96-microwell plates (Nunc, Roskilde, Denmark) in system water. The microwell plates were relocated to a custom-built activity monitoring system fitted with 24 infrared cameras (Ikegami, ICD-49E; Ikegami Tsushinki Co, Japan) which was thermo-regulated at 28,5°C, blocked from daylight and illuminated from below with white (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 acclimatize in the activity monitoring system for 24 hours prior to recording. Exclusion criterion was based on the percentage of samples during a recording where a larva was not tracked. The threshold was set at 10%, thus a larva that was tracked <90% of the total recording time was excluded from the study.

[0141] Motor Assay

[0142] Following a 24 hour acclimation period, behavioral recordings were made. Locomotor activity was recorded between 1.00 pm and 6.00 pm at 6 dpf during alternating light and dark conditions, presented in 30-minute intervals. For this period, average distance moved (mm) by the larvae was calculated as the mean of the total distance swum during five separate 30-minute intervals immediately after transition of light conditions.

[0143] Example 1: Efficacy of cilnidipine, nilvadipine, isradipine, felodipine, verapamil, nimodipine or nifedipine compared to atomoxetine in the zebrafish model of ADHD

[0144] Zebrafish larvae with a homozygous knock-out of the Lphn3.1 gene (herein referred to as “Lphn3.1 HOM”) and zebrafish larvae with a wild-type Lphn3.1 gene (herein referred to as “Lphn3.1 WT”) were exposed to the on-the-market ADHD drug atomoxetine hydrochloride (tomoxetine hydrochloride), cilnidipine (Prestwick, 67400 Illkirch, France), nilvadipine (Prestwick, 67400 Illkirch, France), isradipine (Prestwick, 67400 Illkirch, France), felodipine (Prestwick, 67400 Illkirch, France), verapamil (Prestwick, 67400 Illkirch, France), nimodipine (Prestwick, 67400 Illkirch, France), nifedipine (Prestwick, 67400 Illkirch, France) or a vehicle control before behavioral recordings started.

[0145] Drug preparation was performed on the day of recording. Drugs were diluted from stock solution using distilled water (Invitrogen, Paisley, PA4 9RF, UK). Three different concentrations of each drug were used, 1 pM, 10 pM and 30 pM. Additionally, 0.03% DMSO (Sigma-Aldrich, St. Louis, USA) solution was prepared for the vehicle control group. Drugs and vehicle control were added into the microwells on the day of recording, between 11.00 a.m. and 12.00 p.m.

[0146] Data was obtained using Etho Vision XT (Version 11.5.2016, Noldus) and exported to Microsoft Excel for analysis. Statistical analysis was performed using GraphPad Prism Software (Version 10.0.2, GraphPad Software Inc.). Figures were produced using Microsoft Excel and GraphPad Prism Software. Data are presented as mean ± standard error of the mean (s.e.m). For analysis of Lphn 3.1 HOM DMSO (i.e. larvae receiving only the DMSO vehicle control) and Lphn 3.1 WT DMSO larvae statistical differences were evaluated using unpaired t-test. For analysis of Lphn 3.1 larvae treated with cilnidipine, nilvadipine, isradipine, felodipine, verapamil, nimodipine and nifedipine compared to vehicle control statistical differences were evaluated using one-way ANOVA with Dunnett two-sided post hoc analysis. P<0.05 was considered statistically significant.

[0147] Results:

[0148] Following 24 hours of recording it was evident that the Lphn3.1 HOM larvae display a notable hyperactive phenotype. Higher peak velocities following lights-off (which results in a stereotypical short, increase in activity for zebrafish), as well as higher overall average velocity during the lights-on periods, were observed for Lphn3.1 HOM larvae (Figure 1). In Figure 1, the activity of the Lphn3.1 HOM larvae is shown in the upper line and the activity of the 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.

[0149] Using the average distance moved during lights-on periods it was demonstrated that Lphn3.1 homozygous larvae were indeed statistically significantly hypermotile compared to Lphn3.1 wild-types (Figure 2).

[0150] Comparison with Lphn3.1 HOM larvae that were administered the vehicle control, revealed that cilnidipine, nilvadipine, isradipine, felodipine, verapamil, nimodipine and nifedipine differed significantly from vehicle control (mostly in a dose dependent manner) (see (a) part Figure 3, 4, 5, 6, 7, 8 and 9, respectively). The effects of cilnidipine, nilvadipine, isradipine, felodipine, verapamil, nimodipine and nifedipine were also compared to optimal dose of atomoxetine (see (b) part Figure 3, 4, 5, 6, 7, 8 and 9, respectively). These data show that cilnidipine, nilvadipine, isradipine, felodipine, verapamil, nimodipine and nifedipine are effective at reducing ADHD-like phenotypes in Lphn3.1 HOM larvae.

Claims

Claims1. A compound according to formula (I):or a pharmaceutically acceptable salt, pro-drug or solvate thereof; or a compound according to formula (II):or a pharmaceutically acceptable salt, pro-drug or solvate thereof; or a compound according to formula (III):or a pharmaceutically acceptable salt, pro-drug or solvate thereof; ora compound according to formula (IV):or a pharmaceutically acceptable salt, pro-drug or solvate thereof; or a compound according to formula (V):or a pharmaceutically acceptable salt, pro-drug or solvate thereof; or a compound according to formula (VI):or a pharmaceutically acceptable salt, pro-drug or solvate thereof; ora compound according to formula (VII):or a pharmaceutically acceptable salt, pro-drug or solvate thereof; for use in the treatment or prophylaxis of Attention Deficit / Hyperactivity Disorder (ADHD).

2. The compound for use, as claimed in claim 1 wherein the compound is a compound of formula (I), or a pharmaceutically acceptable salt, pro-drug or solvate thereof.

3. The compound for use according to claim 2, wherein the compound of Formula (I) is administered in a daily dose of about 0. Img to about 50 mg (excluding the mass of any counterion or solvent).

4. The compound for use according to claim 2, wherein the compound of Formula(I) is administered in a daily dose of about 5mg to about 20 mg (excluding the mass of any counterion or solvent).

5. The compound for use, as claimed in claim 1 wherein the compound is a compound according to formula (II), or a pharmaceutically acceptable salt, prodrug or solvate thereof.

6. The compound for use according to claim 5, wherein the compound of Formula(II) is administered in a daily dose of about O.lmg to about 50 mg (excluding the mass of any counterion or solvent).

7. The compound for use according to claim 5, wherein the compound of Formula(II) is administered in a daily dose of about 4mg to about 16mg (excluding the mass of any counterion or solvent).

8. The compound for use, as claimed in claim 1 wherein the compound is a compound according to formula (III), or a pharmaceutically acceptable salt, prodrug or solvate thereof.

9. The compound for use according to claim 8, wherein the compound of Formula(III) is administered in a daily dose of about O.lmg to about 50 mg (excluding the mass of any counterion or solvent).

10. The compound for use according to claim 8, wherein the compound of Formula (III) is administered in a daily dose of about 2.5mg to about 20mg (excluding the mass of any counterion or solvent).

11. The compound for use, as claimed in claim 1 wherein the compound is a compound according to formula (IV), or a pharmaceutically acceptable salt, prodrug or solvate thereof.

12. The compound for use according to claim 11, wherein the compound of Formula (IV) is administered in a daily dose of about 0. Img to about 50 mg (excluding the mass of any counterion or solvent).

13. The compound for use according to claim 11, wherein the compound of Formula (IV) is administered in a daily dose of about 2.5mg to about 20mg (excluding the mass of any counterion or solvent).

14. The compound for use, as claimed in claim 1 wherein the compound is a compound according to formula (V), or a pharmaceutically acceptable salt, prodrug or solvate thereof.

15. The compound for use according to claim 14, wherein the compound of Formula (V) is administered in a dose of about Img to about 200 mg (excludingthe mass of any counterion or solvent), for example, administered 3-times per day.

16. The compound for use according to claim 14, wherein the compound of Formula (V) is administered in a dose of about 40mg to about 120mg (excluding the mass of any counterion or solvent), for example, administered 3- times per day.

17. The compound for use, as claimed in claim 1 wherein the compound is a compound according to formula (VI), or a pharmaceutically acceptable salt, prodrug or solvate thereof.18 The compound for use according to claim 17, wherein the compound of Formula (VI) is administered in a daily dose of about Img to about 500 mg (excluding the mass of any counterion or solvent).

19. The compound for use according to claim 17, wherein the compound of Formula (VI) is administered in a daily dose of up to about 360mg (excluding the mass of any counterion or solvent).

20. The compound for use, as claimed in claim 1 wherein the compound is a compound according to formula (VII), or a pharmaceutically acceptable salt, pro-drug or solvate thereof.21 The compound for use according to claim 20, wherein the compound of Formula (VII) is administered in a daily dose of about 0. Img to about 50 mg (excluding the mass of any counterion or solvent), for example, administered 3- times per day.

22. The compound for use according to claim 20, wherein the compound of Formula (VII) is administered in a daily dose of about 5mg to about 20mg (excluding the mass of any counterion or solvent), for example, administered 3- times per day.

23. The compound for use according to any one of claims 1 to 22, wherein the compound of formula (I), (II), (III), (IV), (V), (VI) or (VII) is administered simultaneously, sequentially or separately with one or more further therapeutic interventions, for example a dietetic intervention, psychological intervention and / or pharmacological intervention.

24. The compound for use according to claim 23, wherein the compound of formula (I), (II), (III), (IV), (V), (VI) or (VII) is administered simultaneously, sequentially or separately with one or more further pharmacological interventions selected from methylphenidate, dexamphetamine, lisdexamfetamine, atomoxetine, guanfacine and clonidine, or a pharmaceutically acceptable salts, pro-drugs or solvates thereof.

25. The compound for use according to any one of claims 1 to 24 wherein the treatment or prophylaxis of ADHD, comprising the step of administering a dose a compound defined in claim 1 to a patient known to have, suspected of having or at risk of developing ADHD.

26. A kit comprising a compound defined in claim 1 and one or more further pharmacological intervention, instructions for a dietetic intervention and / or instructions for a psychological intervention, for example, wherein the further pharmacological intervention is a compound listed in Claim 24, for example, a kit for use in the treatment or prophylaxis of ADHD.

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