WO2023084054A1 - Treatment of adhd using selective binders of the 11-imidazoline receptor - Google Patents

Treatment of adhd using selective binders of the 11-imidazoline receptor Download PDF

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Publication number
WO2023084054A1
WO2023084054A1 PCT/EP2022/081675 EP2022081675W WO2023084054A1 WO 2023084054 A1 WO2023084054 A1 WO 2023084054A1 EP 2022081675 W EP2022081675 W EP 2022081675W WO 2023084054 A1 WO2023084054 A1 WO 2023084054A1
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compound
adhd
use according
formula
independently
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PCT/EP2022/081675
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French (fr)
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Karl Ægir KARLSSON
Haraldur PORSTEINSSON
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3Z Ehf
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Priority claimed from GBGB2116339.9A external-priority patent/GB202116339D0/en
Priority claimed from GBGB2205070.2A external-priority patent/GB202205070D0/en
Application filed by 3Z Ehf filed Critical 3Z Ehf
Publication of WO2023084054A1 publication Critical patent/WO2023084054A1/en

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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/4021-aryl substituted, e.g. piretanide
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/13Amines
    • A61K31/135Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/13Amines
    • A61K31/135Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/138Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/16Amides, e.g. hydroxamic acids
    • A61K31/165Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/41641,3-Diazoles
    • A61K31/41681,3-Diazoles having a nitrogen attached in position 2, e.g. clonidine
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445Non condensed piperidines, e.g. piperocaine
    • A61K31/4458Non condensed piperidines, e.g. piperocaine only substituted in position 2, e.g. methylphenidate
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/53751,4-Oxazines, e.g. morpholine
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system

Definitions

  • 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.
  • ADHD Attention Deficit/Hyperactivity Disorder
  • Established treatments for ADHD include pharmacological treatments such as stimulants (for example, methylphenidate, dexamphetamine and lisdexamfetamine), norepinephrine reuptake inhibitor (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.
  • CBT cognitive behavioural therapy
  • dietary treatments for example, supplementary fatty acids and the exclusion of artificial food colour
  • exercise programs for example, exercise programs.
  • the present invention provides a compound according to formula (I) wherein,
  • R 1 , R 2 , R 3 , R 4 and R 5 are each independently H, halogen or Ci-4alkyl; or R 1 and R 2 together form a 5 membered carbocycle, and R 3 , R 4 and R 5 are each independently H, halogen or Ci-4alkyl; wherein, in either case, said Ci-4alkyl or said carbocycle is optionally substituted with 1 or 2 halogens; and one of R 6 , R 7 and R 8 is Ci-4alkyl, and the others are each H; or a tautomer thereof, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutically acceptable salt or solvate of a tautomer thereof, for use in the treatment or prophylaxis of Attention Deficit/Hyperactivity Disorder (ADHD).
  • ADHD Attention Deficit/Hyperactivity Disorder
  • the present invention further provides a method for the treatment and/or prophylaxis of ADHD, comprising a step of administering a dose of a compound of formula (I) to a patient known to have, suspected of having, or at risk of developing ADHD.
  • zebrafish diphn3.1 knock-out zebrafish larvae
  • Lphn3.1 HOM zebrafish larvae Lphn3.1 HOM zebrafish larvae
  • the invention also provides the use of the compound according to formula (I) for the manufacture of a medicament for the treatment and/or prophylaxis of ADHD.
  • the present invention further provides a kit comprising the compound according to formula (I) 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.
  • 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 without a test compound).
  • 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).
  • 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.
  • DMSO i.e. DMSO
  • Figure 3 shows a comparison of the distance moved by Lphn3.1 HOM larvae that received Example compound 1, atomoxetine (referred to as tomoxetin hydrochloride in Figure 3) or a vehicle control (i.e. DMSO).
  • Figure 4 shows the proton NMR spectrum of the batch of Example compound 1 used in Example 1.
  • Figure 5 shows the effects of 0.1 pM, 1 pM, 10 pM, 30 pM and 100 pM of Example compound 1 on sleep fragmentation, sleep ratio, velocity during sleep, wake bout duration(s) and sleep bout duration(s) in Lphn3.1 HOM zebrafish larvae.
  • a particular 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. 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.
  • 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.
  • Example compound 1 i.e. a compound of formula (I)
  • Example compound 1 is surprisingly effective at reducing ADHD behaviours such as hyperactivity and motor impulsivity.
  • the present invention provides a compound according to formula (I) or a tautomer thereof, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutically acceptable salt or solvate of a tautomer thereof, for use in the treatment or prophylaxis of Attention Deficit/Hyperactivity Disorder (ADHD).
  • ADHD Attention Deficit/Hyperactivity Disorder
  • R 1 , R 2 , R 3 , R 4 and R 5 may each independently be H, halogen or Ci-4alkyl.
  • R 1 , R 2 , R 3 , R 4 and R 5 may each independently be selected from the group consisting of H, Cl, F, Br and Ci-4alkyl (for example, methyl, methyl, ethyl, propyl or isopropyl).
  • said Ci-4alkyl is substituted with 1 or 2 halogens.
  • said Ci-4alkyl may be substituted with 1 or 2 Cl, F or Br, preferably 1 or 2 Cl.
  • R 1 is halogen or Ci-4alkyl
  • R 2 and R 3 are each independently H or halogen
  • R 4 and R 5 are each H.
  • R 1 may be Cl, F, Br or Ci-4alkyl (for example, methyl, ethyl, propyl or isopropyl)
  • R 2 and R 3 are each independently H, Cl, F or Br
  • R 4 and R 5 are each H.
  • R 1 and R 2 may together form a 5 membered carbocycle. That is to say, that the compound of formula (I) may be a compound according to formula (la)
  • R 3 , R 4 and R 5 are each independently H, halogen or Ci-4alkyl.
  • R 3 , R 4 and R 5 may each be H, Cl, F, Br or Ci-4alkyl (preferably, methyl).
  • said Ci-4alkyl is substituted with 1 or 2 halogens.
  • said Ci-4alkyl may be substituted with 1 or 2 Cl, F or Br, preferably 1 or 2 Cl.
  • R 3 is H, halogen or Ci-4alkyl (preferably, methyl), and R 4 and R 5 are each H.
  • R 3 , R 4 and R 5 may each be H.
  • R 3 may be Cl or Ci-4alkyl (preferably, methyl), and R 4 and R 5 may each be H.
  • one of R 6 , R 7 and R 8 is Ci-4alkyl, and the others are each H.
  • one of R 6 , R 7 and R 8 may be methyl, ethyl, propyl or isopropyl.
  • one of R 6 , R 7 and R 8 is methyl, and the others are each H.
  • R 6 and R 7 may each be H and R 8 may be methyl, or R 6 and R 8 may each be H and R 7 may be methyl, or R 7 and R 8 may each be H and R 6 may be methyl.
  • R 6 and R 7 are each be H and R 8 is methyl, or R 6 and R 8 are each be H and R 7 is methyl.
  • the compound of formula (I) is the compound of formula (lb) (i.e. Example compound 1): or a tautomer thereof; or a pharmaceutically acceptable salt or solvate thereof; or a pharmaceutically acceptable salt or solvate of a tautomer thereof.
  • the present inventors have found that the compound of formula (lb) is particularly effective at reducing ADHD behaviours such as hyperactivity and motor impulsivity in a zebrafish model of ADHD.
  • compounds of formula (I) include all tautomeric forms, salts and solvates thereof, unless stated otherwise.
  • a particular example of a tautomeric form of a compound of formula (I) is a compound of formula (II) wherein R 1 to R 8 of formula (II) are according to R 1 to R 8 in formula (I).
  • a particular example of a tautomeric form of a compound of formula (la), is a compound of formula (Ila) wherein R 3 to R 8 of formula (Ila) are according R 1 to R 8 in formula (la).
  • a particular example of a tautomeric form of a compound of formula (lb), is a compound of formula (lib)
  • the compounds for use according to the present invention may be prepared using methods known to those skilled in the art of organic chemistry.
  • compounds for use according to the invention may be prepared by reacting a suitable aniline or indanamine (e.g. 4-indanamine) with a suitable lactam, for example, in the presence of a dehydrating agent such as phosphoryl chloride (POCh), as shown in the scheme below:
  • a dehydrating agent such as phosphoryl chloride (POCh)
  • Methods for the syntheses of various compounds for use according to the invention are described in detail in WO2012/14366, US2014/0045910, EP2699545 and Gasparik et al. (2015) J. Med. Chem. 58, 878-887, which are each incorporated herein by reference.
  • Aniline, indanamine (e.g. 4-indanamine), lactam, and derivatives thereof are readily obtainable using methods known in the art, and in many cases, can be obtained as starting materials from commercial sources.
  • the compound for use according to the invention is:
  • the compound of formula (I) and (II) includes all salts and solvates thereof, unless stated otherwise.
  • the term “formula (I)” includes formulas (I), (la) and (lb), all tautomeric forms (for example, compounds of formula (II), (Ila) and (lib)), salts and solvates thereof, unless stated otherwise.
  • formula (I) includes all enantiomers thereof, unless stated otherwise.
  • the compound of formula (I) may form salts or solvates.
  • Salts of the compound of formula (I), which are suitable for use in the present invention, are those wherein a counterion is pharmaceutically acceptable.
  • 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) 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.
  • 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 (C 1 -C 4 )-alkyl- or aryl-sulfonic acids which are unsubstituted or substituted, for example by halogen.
  • mineral 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 (C 1 -C 4 )-alkyl- or aryl-sulfonic
  • 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.
  • An exemplary salt form of the compound of formula (I) suitable for use according to the present invention is a hydrochloride salt.
  • solvates are described in Water-Insoluble Drug Formulation, 2 nd ed R. Lui CRC Press, page 553 and Bym et al., Pharm Res 12(7), 1995, 945-954. Before it is made up in solution, the compound of formula (I) may be in the form of a solvate. Solvates of the compound of formula (I) 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.
  • a compound which, upon administration to the recipient, is capable of being converted into the compound of formula (I), or an active metabolite or residue thereof, is known as a “prodrug”.
  • the compound of formula (I) 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.
  • Compounds of formula (I) may have an appropriate group converted to an ester, an amide or a carbamate.
  • typical ester and amide groups formed from an acid group in the compound of the formula (I) include -COOR G , -CONR G 2, -SO 2 OR G , or -SO 2 N(R G ) 2
  • typical ester and amide and carbamate groups formed from an -OH or -NHR G group in the compound of the formula (I) include -OC(O)R G , -NR G C(O)R G , -NR G CO 2 R G , -OSO 2 R G , and -NR G SO 2 R G , where R G is selected from the group consisting of Ci-salkyl, C 2 -8alkenyl, C 2 -salkynyl, C3- scycloalkyl and Cs-scycloalkylCi-salkyl, haloCi-salkyl, dihalo
  • compositions of the present invention comprise the compound of formula (I) and one or more pharmaceutically acceptable excipients.
  • a composition described herein comprises a racemic mixture of the compound of formula (I).
  • a composition that contains only one of the enantiomers of the compound of formula (I), or different ratios of each enantiomer is also encompassed by the present invention.
  • 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.
  • parenteral including subcutaneous, intradermal, intraosseous infusion, intramuscular, intravascular (bolus or infusion), and intramedullary
  • intraperitoneal including transmucosal
  • transdermal rectal
  • topical including dermal, buccal, sublingual and intraocular administration
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • Formulations for topical administration in the mouth 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 gelatin and glycerine or sucrose and acacia.
  • exemplary compositions for topical administration include a topical carrier such as Plastibase (mineral oil gelled with polyethylene).
  • compositions suitable for oral administration may be presented as discrete units such as capsules, cachets 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) 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) 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.
  • Preferred unit dosage compositions are those containing an exploratory dose or therapeutic dose, or an appropriate fraction thereof, of the compound of formula (I).
  • a composition for use according to the present invention consists essentially of the compound of formula (I) and at least one pharmaceutically acceptable excipient.
  • An exemplary composition for use according to the present invention comprises one or more of the following pharmaceutically acceptable carriers: lactose, magnesium stearate, polyvinylpyrrolidone (for example, povidone K29-32), sodium stearyl fumarate, microcrystalline cellulose, sodium lauryl sulphate, sodium starch glycolate, butylhydroxytoluene, tocopherol, anhydrous colloidal 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 for use according to the present invention is a tablet with a core and a coating, wherein the core comprises polyethylene oxide, microcrystalline cellulose, povidone, butylhydroxytoluene, a- tocopherol, colloidal anhydrous silica, and sodium stearyl fumarate, and the coating comprises methacrylic acid/ethyl acrylate copolymer, colloidal anhydrous silica, Macrogol, and titanium dioxide.
  • compositions for use in this invention may include other agents conventional in the art having regard to the type of composition in question.
  • the compositions for use according to the invention may comprise one or more further therapeutic agents.
  • 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, atomoxetine, viloxazine, clonidine, and guanfacine.
  • one or more further therapeutic agents is a stimulant, such as amphetamine, methylphenidate and lisdexamfetamine.
  • ADHD Attention Deficit/Hyperactivity Disorder
  • the present inventors have found that the compounds of formula (I), 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.
  • the compound of formula (I), 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).
  • 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 reduced levels of attention with hyperactivity and impulsivity behaviours (i.e. “combined type” ADHD).
  • 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.
  • LPHN3 Latrophilin 3
  • 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 (DA T1) gene, the 1)4 dopamine receptor (DRD4) gene, the D5 dopamine receptor (DRD5) gene, the serotonin IB receptor gene (HTR1B) and the Synaptosomal- Associated Protein (SNAP25) gene.
  • 5HTT serotonin transporter
  • DA T1 dopamine transporter
  • D5 D5 dopamine receptor
  • 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-eclampsia, hypertension, acetaminophen exposure, and smoking during pregnancy; and childhood atopic diseases.
  • 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 diseases.
  • 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).
  • DSM Diagnostic and Statistical Manual of Mental Disorders
  • ICD International Classification of Diseases
  • 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, sleep problems (for example insomnia, such as sleep-onset insomnia), autism spectrum disorder (ASD), bipolar disorder, epilepsy, Tourette’s syndrome and/or leaning difficulties such as dyslexia.
  • ODD oppositional defiant disorder
  • DDD may also have signs or symptoms of other conditions such as depression, anxiety disorder, oppositional defiant disorder (ODD), conduct disorder, sleep problems (for example insomnia, such as sleep-onset insomnia), autism spectrum disorder (ASD), bipolar disorder, epilepsy, Tourette’s syndrome and/or leaning difficulties such as dyslexia.
  • the subject known or suspected of having ADHD, or known or suspected of being at risk of developing ADHD may also suffer from type 2 diabetes mellitus, hypertension, obesity and/or metabolic syndrome.
  • 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.
  • the compound of formula (I), 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.
  • one or more established stimulant-based ADHD treatments for example, methylphenidate, dexamphetamine, and lisdexamfetamine
  • the efficacy of the compound of formula (la) at reducing hyperactivity and motor impulsivity in the zebrafish model of ADHD makes the compound of formula (I) 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).
  • the compound of formula (I), 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).
  • the compound of formula (I), 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.
  • established ADHD treatments for example, methylphenidate, dexamphetamine, lisdexamfetamine, atomoxetine, viloxazine, guanfacine and clonidine
  • 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.
  • Sleep problems such as insomnia, sleep-disordered breathing, excessive daytime sleepiness and variability in sleep schedule, are common in patients with ADHD, and many established treatments of ADHD have been reported to exacerbate pre-existing sleep problems or cause sleep problems in patients.
  • Sleep related adverse effects can be very difficult for a patient to manage, particularly in the long term, and may also have dramatic negative impacts on a patient’s quality of life. Accordingly, sleep related adverse effects may cause patients to stop taking a treatment that was otherwise beneficial for controlling ADHD symptoms such as reduced levels of attention, hyperactivity and impulsivity behaviours.
  • the present inventors have found in a zebrafish assay of ADHD that the compound of formula (I) is surprisingly effective at reducing ADHD symptoms and improving sleep during night time periods.
  • treatment of Lphn3.1 HOM zebrafish larvae with Example compound 1 decreased sleep fragmentation (i.e. decreased the number of transitions between sleep and wake bouts per hour), wake bout duration (i.e. decrease the average length of wake bouts), and velocity (i.e. decreased the average velocity throughout the night time), and increased sleep ratio (i.e. increased the percentage of total night time that the fish were considered asleep) and sleep bout durations (i.e. increased the average length of sleep bouts).
  • the compound of formula (I), or a pharmaceutical composition thereof finds use in the treatment of ADHD and sleep problems associated with the ADHD.
  • the compound of formula (I), or a pharmaceutical composition thereof finds use in the treatment of ADHD and insomnia associated with the ADHD (i.e. ADHD-related insomnia).
  • the compounds of formula (I) may also be administered as a treatment to patients with ADHD who have experienced sleep related adverse effects associated with other treatments for ADHD, such as methylphenidate, dexamphetamine, lisdexamfetamine, atomoxetine, guanfacine and clonidine. Accordingly, in certain embodiments, the compound of formula (I), or a pharmaceutical composition thereof, for use according to the present invention, may be administered to a subject with ADHD who has previously received another medication for the treatment or prevention of ADHD, wherein said medication was ceased or reduced due to sleep related adverse events.
  • the compound of formula (I), or a pharmaceutical composition thereof, for use according to the present invention may be administered to a subject with ADHD who has previously received another medication for the treatment or prevention of ADHD, for example, wherein said medication was ceased or reduced due to sleep related adverse events.
  • the compound of formula (I), or a pharmaceutical composition thereof, for use according to the present invention may be administered to a subject with ADHD as second line therapy.
  • the compound of formula (I), and compositions thereof, as described herein find utility in a method of treating or preventing ADHD, wherein said method comprises a step of administering the compound of formula (I), 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) also find use in the manufacture of a medicament for the treatment or prophylaxis of ADHD.
  • the amount of the compound of formula (I) 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) required for treatment or prophylaxis of ADHD.
  • the compound of formula (I) may be administered daily (including several times daily), every second or third day, weekly, every second, third or fourth week or even as single dose depending on the subject and the characteristics of the ADHD to be treated.
  • 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 16 mg per administration. For example, 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 may be administered to a subject.
  • the compound of formula (I) may be administered as a single daily dose of 1 mg, 2 mg, 4 mg, 8 mg or 16 mg (excluding the mass of any counterion or solvent).
  • the compound of formula (I) may be administered as a dose of 1 mg, 2 mg, 4 mg, 8 mg or 16 mg (excluding the mass of any counterion or solvent), two, three or four times a day.
  • the compound of formula (I) is administered as a composition.
  • the composition is a pharmaceutical composition for use according to the present invention.
  • the compound of formula (I) 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.
  • further therapeutic interventions include pharmacological interventions, dietetic interventions and psychological intervention.
  • 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).
  • CBT cognitive behavioural therapy
  • the one or more further therapeutic interventions may be used simultaneously, sequentially or separately with/from the administration of the compound of formula (I).
  • 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.
  • 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).
  • the release of the compound of formula (I) from certain composition may also be sustained, for example, if the composition contains suitable controlled- release excipients.
  • the present invention provides a kit comprising the compound of formula (I), one or more pharmaceutically acceptable excipients, and optionally one or more further therapeutic agents that are useful in the treatment or prophylaxis of ADHD.
  • 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.
  • Kits of the present inventions may also contain instructions for a dietetic intervention and/or instructions for a psychological intervention suitable for ADHD.
  • the kits may include instructions for a nutrition plan suitable for the subject receiving treatment and/or the kit may comprise instructions/guidance for cognitive behavioural therapy (CBT).
  • CBT cognitive behavioural therapy
  • Kits of the present invention find use in the treatment and prophylaxis of ADHD.
  • the compound of formula (I) 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) suitable for including in a kit of the invention, and for use according to the invention.
  • Carboycle refers to rings comprising carbon atom.
  • Carbocycles include unsaturated, partially saturated and unsaturated carbon rings. Examples of ‘carbocycles’ include: cyclopentyl, cyclopentanyl and cylop entadiene,
  • the present invention is directed to each individual feature, system, article, material, kit, and/or method described herein.
  • 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.
  • 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.
  • Danio rerio (zebrafish) 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.
  • Zebrafish larvae carrying a knock-out of the Latrophilin3 (I.phnS. l) 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 881, 6 days-post fertilization (dpf) embryos carrying a homozygous knock-out of the Lphn3.1 gene were used in the study.
  • dpf days-post fertilization
  • 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.
  • Example compound 1 N-(3-Chloro-2-methylphenyl)-4-methylpyrrolidin-2-imine hydrochloride:
  • Example compound 1 used in the following examples had a purity of >95% by (NMR 1 H).
  • the proton NMR of the batch of Example compound 1 is in line with the NMR data provided for N-(3-Chloro-2-methylphenyl)-4-methylpyrrolidin-2- amine hydrochloride in US2014/0045910.
  • the proton NMR spectrum of the batch of Example compound 1 is shown in Figure 4.
  • Example 1 Efficacy of Example compound 1 compared to atomoxetine in the zebrafish model of ADHD
  • Lphn3.1 HOM zebrafish larvae with a homozygous knock-out of the Lphn3.1 gene
  • Lphn3.1 WT zebrafish larvae with a wild-type Lphn3.1 gene
  • Drug preparation was performed on the day of recording. Drugs were diluted from stock solution using distilled water (Invitrogen, Paisley, PA4 9RF, UK). Three to five different concentration of each drug were used, 0,1 pM, 1 pM, 10 pM, 30 pM and 100 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 11.30 a.m. and 12.30 p.m.
  • Example compound 1 was compared to optimal dose of atomoxetine (see Figure 3). Comparison with Lphn3.1 HOM larvae that were administered the vehicle control, revealed that all doses of Example compound 1 differed significantly from vehicle control and untreated larvae (in a dose dependent manner). These data show that Example compound 1 is effective at reducing ADHD-like phenotypes in Lphn3.1 HOM larvae.
  • Example 2 The effect of Example compound 1 on sleep behavior
  • Sleep fragmentation was defined as the number of transitions between sleep and wake bouts per hour. Sleep ratio was calculated as the percentage of total night time that the fish was considered asleep. Velocity during sleep (mm/s) was defined as the average velocity throughout the night time. Wake bout duration(s) was defined as the average length of wake bouts. Sleep bout duration(s) was defined as the average length of sleep bouts. Results:
  • sleep fragmentation decreased at 30 pM; sleep ratio increased at 10 pM, 30 pM and 100 pM; velocity decreased at 10 pM, 30 pM and 100 pM; wake bout durations decreased at 10 pM, 30 pM and 100 pM, and sleep bout durations increased at 30 pM and 100 pM of Example Compound 1.

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Abstract

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. Specifically, the invention provides a compound according to formula (I) wherein, R1, R2, R3, R4 and R5 are each independently H, halogen or C1-4alkyl; or R1 and R2 together form a 5 membered carbocycle, and R3, R4 and R5 are each independently H, halogen or C1-4alkyl; wherein, in either case, said C1-4alkyl or said carbocycle is optionally substituted with 1 or 2 halogens; and one of R6, R7 and R8 is C1-4alkyl, and the others are each H; or a tautomer thereof, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutically acceptable salt or solvate of a tautomer thereof, for use in the treatment or prophylaxis of Attention Deficit/Hyperactivity Disorder (ADHD).

Description

TREATMENT OF ADHD USING SELECTIVE BINDERS OF THE 11 -IMIDAZOLINE RECEPTOR
Field of the Invention
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.
Background of the Invention
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).
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.
Established treatments for ADHD include pharmacological treatments such as stimulants (for example, methylphenidate, dexamphetamine and lisdexamfetamine), norepinephrine reuptake inhibitor (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).
Thus, there remains a need for further treatments for ADHD that provide clinical benefits whilst also displaying good clinical tolerability.
Summary of the Invention
The present invention provides a compound according to formula (I)
Figure imgf000003_0001
wherein,
R1, R2, R3, R4 and R5 are each independently H, halogen or Ci-4alkyl; or R1 and R2 together form a 5 membered carbocycle, and R3, R4 and R5 are each independently H, halogen or Ci-4alkyl; wherein, in either case, said Ci-4alkyl or said carbocycle is optionally substituted with 1 or 2 halogens; and one of R6, R7 and R8 is Ci-4alkyl, and the others are each H; or a tautomer thereof, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutically acceptable salt or solvate of a tautomer thereof, for use in the treatment or prophylaxis of Attention Deficit/Hyperactivity Disorder (ADHD).
The present invention further provides a method for the treatment and/or prophylaxis of ADHD, comprising a step of administering a dose of a compound of formula (I) to a patient known to have, suspected of having, or at risk of developing ADHD.
The present inventors have found that in a zebrafish (Danio rerio) model of ADHD, a compound of formula (I) was surprisingly effective at reducing ADHD symptoms such as hyperactivity and motor impulsivity in Lphn3.1 knock-out zebrafish larvae (herein referred to as “Lphn3.1 HOM zebrafish larvae”).
The invention also provides the use of the compound according to formula (I) for the manufacture of a medicament for the treatment and/or prophylaxis of ADHD.
The present invention further provides a kit comprising the compound according to formula (I) 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.
Description of the Drawings
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 without a test compound). 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).
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. Non-significant interaction was observed between the genotype and vehicle (i.e. DMSO) (f=l,003, df=l, p= 0.317). A significant effect of genotype on distance moved, between Lphn3.1 HOM and Lphn3.1 WT larvae, was observed (f=l 17,67, df=l, p<.001). A non-significant effect of the vehicle was demonstrated between naive (i.e. larvae that received neither Example compound 1 or a vehicle control) and DMSO treated larvae (f=0,222 df=l, p=0.638).
Figure 3 shows a comparison of the distance moved by Lphn3.1 HOM larvae that received Example compound 1, atomoxetine (referred to as tomoxetin hydrochloride in Figure 3) 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=96). 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 Example compound 1 at a dosage of 0,1 pM 1 pM, 10 pM, 30 pM or 100 pM on the average distance moved by Lphn3.1 HOM larvae over the five lights-on phases (first round: n=24, second round: n=72) (all data presented with +/- SEM).
Statistically significant differences were found between larvae treated with Example compound 1 and larvae that received the vehicle control (first round: F(5, 132) = 21.33, df=5, p< 001, second round: F(3, 276) = 44.40, df=3, p< 001).
Figure 4 shows the proton NMR spectrum of the batch of Example compound 1 used in Example 1.
Figure 5 shows the effects of 0.1 pM, 1 pM, 10 pM, 30 pM and 100 pM of Example compound 1 on sleep fragmentation, sleep ratio, velocity during sleep, wake bout duration(s) and sleep bout duration(s) in Lphn3.1 HOM zebrafish larvae.
Detailed Description
As discussed in more detail below, the present inventors have found that compounds according to formula (I) are surprisingly effective at reducing ADHD-like behavioural phenotypes, such as hyperactivity and motor impulsivity, in an in vivo ADHD disease model.
A particular 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. 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.
The compounds of formula (I), which are known to be selective binders of the II- imidazoline receptor, have previously been disclosed as potential treatments of metabolic syndrome and/or hypertension (see for example, WO2012/143660, US2014/0045910, EP2699545 and Gasparik et al., J. Med. Chem. 2015, 58, 878-887). Using the zebrafish model of ADHD, the present inventors have shown that Example compound 1 (i.e. a compound of formula (I)) is surprisingly effective at reducing ADHD behaviours such as hyperactivity and motor impulsivity. Thus, the present invention provides a compound according to formula (I)
Figure imgf000006_0001
or a tautomer thereof, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutically acceptable salt or solvate of a tautomer thereof, for use in the treatment or prophylaxis of Attention Deficit/Hyperactivity Disorder (ADHD).
In the compound of formula (I), R1, R2, R3, R4 and R5 may each independently be H, halogen or Ci-4alkyl. For example, R1, R2, R3, R4 and R5 may each independently be selected from the group consisting of H, Cl, F, Br and Ci-4alkyl (for example, methyl, methyl, ethyl, propyl or isopropyl). Optionally, said Ci-4alkyl is substituted with 1 or 2 halogens. For example, said Ci-4alkyl may be substituted with 1 or 2 Cl, F or Br, preferably 1 or 2 Cl.
In certain embodiments, R1 is halogen or Ci-4alkyl, R2 and R3 are each independently H or halogen, and R4 and R5 are each H. For example, R1 may be Cl, F, Br or Ci-4alkyl (for example, methyl, ethyl, propyl or isopropyl), R2 and R3 are each independently H, Cl, F or Br, and R4 and R5 are each H.
Alternatively, in the compound of formula (I), R1 and R2 may together form a 5 membered carbocycle. That is to say, that the compound of formula (I) may be a compound according to formula (la)
Figure imgf000006_0002
In embodiments wherein R1 and R2 together form a 5 membered carbocycle, R3, R4 and R5 are each independently H, halogen or Ci-4alkyl. For example, when R1 and R2 together form a 5 membered carbocycle, R3, R4 and R5 may each be H, Cl, F, Br or Ci-4alkyl (preferably, methyl). Optionally, said Ci-4alkyl is substituted with 1 or 2 halogens. For example, said Ci-4alkyl may be substituted with 1 or 2 Cl, F or Br, preferably 1 or 2 Cl.
In certain preferred embodiments wherein R1 and R2 together form a 5 membered carbocycle, R3 is H, halogen or Ci-4alkyl (preferably, methyl), and R4 and R5 are each H. For example, when R1 and R2 together form a 5 membered carbocycle, R3, R4 and R5 may each be H. Or, for example, when R1 and R2 together form a 5 membered carbocycle, R3 may be Cl or Ci-4alkyl (preferably, methyl), and R4 and R5 may each be H.
In the compound of formula (I), one of R6, R7 and R8 is Ci-4alkyl, and the others are each H. For example, one of R6, R7 and R8 may be methyl, ethyl, propyl or isopropyl. In certain preferred embodiments, one of R6, R7 and R8 is methyl, and the others are each H. For example, R6 and R7 may each be H and R8 may be methyl, or R6 and R8 may each be H and R7 may be methyl, or R7 and R8 may each be H and R6 may be methyl. Preferably, R6 and R7 are each be H and R8 is methyl, or R6 and R8 are each be H and R7 is methyl.
In certain preferred embodiments, the compound of formula (I) is the compound of formula (lb) (i.e. Example compound 1):
Figure imgf000007_0001
or a tautomer thereof; or a pharmaceutically acceptable salt or solvate thereof; or a pharmaceutically acceptable salt or solvate of a tautomer thereof. The present inventors have found that the compound of formula (lb) is particularly effective at reducing ADHD behaviours such as hyperactivity and motor impulsivity in a zebrafish model of ADHD.
For the avoidance of doubt, in this document, it is intended that compounds of formula (I) (i.e. compounds of formula (I), (la) and (lb)) include all tautomeric forms, salts and solvates thereof, unless stated otherwise. A particular example of a tautomeric form of a compound of formula (I), is a compound of formula (II)
Figure imgf000008_0001
wherein R1 to R8 of formula (II) are according to R1 to R8 in formula (I). A particular example of a tautomeric form of a compound of formula (la), is a compound of formula (Ila)
Figure imgf000008_0002
wherein R3 to R8 of formula (Ila) are according R1 to R8 in formula (la). A particular example of a tautomeric form of a compound of formula (lb), is a compound of formula (lib)
Figure imgf000008_0003
The compounds for use according to the present invention may be prepared using methods known to those skilled in the art of organic chemistry. For example, compounds for use according to the invention may be prepared by reacting a suitable aniline or indanamine (e.g. 4-indanamine) with a suitable lactam, for example, in the presence of a dehydrating agent such as phosphoryl chloride (POCh), as shown in the scheme below:
Figure imgf000008_0004
Methods for the syntheses of various compounds for use according to the invention are described in detail in WO2012/14366, US2014/0045910, EP2699545 and Gasparik et al. (2015) J. Med. Chem. 58, 878-887, which are each incorporated herein by reference. Aniline, indanamine (e.g. 4-indanamine), lactam, and derivatives thereof, are readily obtainable using methods known in the art, and in many cases, can be obtained as starting materials from commercial sources.
In certain preferred embodiments, the compound for use according to the invention is:
(3-Chloro-2-methyl-phenyl)-(4-methyl-4,5-dihydro-3H-pyrrol-2-yl)-amine (i.e. Example compound 1);
Indan-4-yl-(5-methyl-4,5-dihydro-3H-pyrrol-2-yl)-amine;
(7-Chloro-indan-4-yl)-(4-methyl-4,5-dihydro-3H-pyrrol-2-yl)-amine; (7-Methyl-indan-4-yl)-(4-methyl-4,5-dihydro-3H-pyrrol-2-yl)-amine;
(2-Chlorophenyl)-(5-methyl-4,5-dihydro-3H-pyrrol-2-yl)-amine; or (7-Chloro-indan-4-yl)-(5-methyl-4,5-dihydro-3H-pyrrol-2-yl)-amine.
The synthesis of these compounds is described in WO2012/143660, US2014/0045910 and EP2699545, and each are shown therein to display high selectivity for the II- imidazoline receptor.
For the avoidance of doubt, in this document, it is intended that the compound of formula (I) and (II) includes all salts and solvates thereof, unless stated otherwise. Also for the avoidance of doubt, in this document, it is to be understood that the term “formula (I)” includes formulas (I), (la) and (lb), all tautomeric forms (for example, compounds of formula (II), (Ila) and (lib)), salts and solvates thereof, unless stated otherwise. In addition, in this document, it is intended that formula (I) includes all enantiomers thereof, unless stated otherwise.
The compound of formula (I) may form salts or solvates. Salts of the compound of formula (I), 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) 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 (C1-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. An exemplary salt form of the compound of formula (I) suitable for use according to the present invention is a hydrochloride salt.
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, 2nd ed R. Lui CRC Press, page 553 and Bym et al., Pharm Res 12(7), 1995, 945-954. Before it is made up in solution, the compound of formula (I) may be in the form of a solvate. Solvates of the compound of formula (I) 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.
A compound which, upon administration to the recipient, is capable of being converted into the compound of formula (I), or an active metabolite or residue thereof, is known as a “prodrug”. Thus, in certain embodiments, the compound of formula (I) 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.
Compounds of formula (I) may have an appropriate group converted to an ester, an amide or a carbamate. Thus typical ester and amide groups formed from an acid group in the compound of the formula (I) include -COORG, -CONRG2, -SO2ORG, or -SO2N(RG)2, while typical ester and amide and carbamate groups formed from an -OH or -NHRG group in the compound of the formula (I) include -OC(O)RG, -NRGC(O)RG, -NRGCO2RG, -OSO2RG, and -NRGSO2RG, where RG is selected from the group consisting of Ci-salkyl, C2-8alkenyl, C2-salkynyl, C3- scycloalkyl and Cs-scycloalkylCi-salkyl, haloCi-salkyl, dihaloCi-salkyl, trihaloCi-salkyl, phenyl and phenylCi-4alkyl; preferably RG is selected from the group consisting of Ci-ealkyl, C2-6alkenyl, C2-6alkynyl, Cs-scycloalkyl and Cs-scycloalkylCi- ealkyl; more preferably RG is selected from the group consisting of Ci-4alkyl, C2-4alkenyl, C2-4alkynyl, Cs-scycloalkyl and C3-8cycloalkylCi-4alkyl.
Pharmaceutical compositions
While it is possible for the compound of formula (I) 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) and one or more pharmaceutically acceptable excipients.
Typically, a composition described herein comprises a racemic mixture of the compound of formula (I). However, the use of a composition that contains only one of the enantiomers of the compound of formula (I), or different ratios of each enantiomer, is also encompassed by the present invention.
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.
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.
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.
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 gelatin and glycerine or sucrose and acacia. Exemplary compositions for topical administration include a topical carrier such as Plastibase (mineral oil gelled with polyethylene). Pharmaceutical compositions suitable for oral administration may be presented as discrete units such as capsules, cachets 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) 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) 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.
Preferred unit dosage compositions are those containing an exploratory dose or therapeutic dose, or an appropriate fraction thereof, of the compound of formula (I).
In preferred embodiments, a composition for use according to the present invention consists essentially of the compound of formula (I) and at least one pharmaceutically acceptable excipient. An exemplary composition for use according to the present invention comprises one or more of the following pharmaceutically acceptable carriers: lactose, magnesium stearate, polyvinylpyrrolidone (for example, povidone K29-32), sodium stearyl fumarate, microcrystalline cellulose, sodium lauryl sulphate, sodium starch glycolate, butylhydroxytoluene, tocopherol, anhydrous colloidal 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 for use according to the present invention is a tablet with a core and a coating, wherein the core comprises polyethylene oxide, microcrystalline cellulose, povidone, butylhydroxytoluene, a- tocopherol, colloidal anhydrous silica, and sodium stearyl fumarate, and the coating comprises methacrylic acid/ethyl acrylate copolymer, colloidal anhydrous silica, Macrogol, and titanium dioxide.
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. 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, atomoxetine, viloxazine, clonidine, and guanfacine. Typically, one or more further therapeutic agents is a stimulant, such as amphetamine, methylphenidate and lisdexamfetamine.
Attention Deficit/Hyperactivity Disorder (ADHD)
The present inventors have found that the compounds of formula (I), 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.
Thus, the compound of formula (I), 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).
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 reduced levels of attention with hyperactivity and impulsivity behaviours (i.e. “combined type” ADHD).
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 (DA T1) gene, the 1)4 dopamine receptor (DRD4) gene, the D5 dopamine receptor (DRD5) gene, the serotonin IB receptor gene (HTR1B) 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-eclampsia, hypertension, acetaminophen exposure, and smoking during pregnancy; and childhood atopic diseases.
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).
In certain embodiments, 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, sleep problems (for example insomnia, such as sleep-onset insomnia), autism spectrum disorder (ASD), bipolar disorder, epilepsy, Tourette’s syndrome and/or leaning difficulties such as dyslexia.
In certain embodiments, the subject known or suspected of having ADHD, or known or suspected of being at risk of developing ADHD, may also suffer from type 2 diabetes mellitus, hypertension, obesity and/or metabolic syndrome. In certain embodiments, 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. For example, the compound of formula (I), 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. The efficacy of the compound of formula (la) at reducing hyperactivity and motor impulsivity in the zebrafish model of ADHD makes the compound of formula (I) 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), 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).
In certain embodiments, the compound of formula (I), 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.
Sleep problems such as insomnia, sleep-disordered breathing, excessive daytime sleepiness and variability in sleep schedule, are common in patients with ADHD, and many established treatments of ADHD have been reported to exacerbate pre-existing sleep problems or cause sleep problems in patients.
Sleep related adverse effects can be very difficult for a patient to manage, particularly in the long term, and may also have dramatic negative impacts on a patient’s quality of life. Accordingly, sleep related adverse effects may cause patients to stop taking a treatment that was otherwise beneficial for controlling ADHD symptoms such as reduced levels of attention, hyperactivity and impulsivity behaviours.
The present inventors have found in a zebrafish assay of ADHD that the compound of formula (I) is surprisingly effective at reducing ADHD symptoms and improving sleep during night time periods. In particular, as described in Example 2, treatment of Lphn3.1 HOM zebrafish larvae with Example compound 1 decreased sleep fragmentation (i.e. decreased the number of transitions between sleep and wake bouts per hour), wake bout duration (i.e. decrease the average length of wake bouts), and velocity (i.e. decreased the average velocity throughout the night time), and increased sleep ratio (i.e. increased the percentage of total night time that the fish were considered asleep) and sleep bout durations (i.e. increased the average length of sleep bouts). Accordingly, in certain embodiments, the compound of formula (I), or a pharmaceutical composition thereof, finds use in the treatment of ADHD and sleep problems associated with the ADHD. In certain exemplary embodiments, the compound of formula (I), or a pharmaceutical composition thereof, finds use in the treatment of ADHD and insomnia associated with the ADHD (i.e. ADHD-related insomnia).
The compounds of formula (I) may also be administered as a treatment to patients with ADHD who have experienced sleep related adverse effects associated with other treatments for ADHD, such as methylphenidate, dexamphetamine, lisdexamfetamine, atomoxetine, guanfacine and clonidine. Accordingly, in certain embodiments, the compound of formula (I), or a pharmaceutical composition thereof, for use according to the present invention, may be administered to a subject with ADHD who has previously received another medication for the treatment or prevention of ADHD, wherein said medication was ceased or reduced due to sleep related adverse events.
In a further embodiment, the compound of formula (I), or a pharmaceutical composition thereof, for use according to the present invention, may be administered to a subject with ADHD who has previously received another medication for the treatment or prevention of ADHD, for example, wherein said medication was ceased or reduced due to sleep related adverse events.
In a further embodiment, the compound of formula (I), or a pharmaceutical composition thereof, for use according to the present invention, may be administered to a subject with ADHD as second line therapy.
The compound of formula (I), and compositions thereof, as described herein find utility in a method of treating or preventing ADHD, wherein said method comprises a step of administering the compound of formula (I), 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) also find use in the manufacture of a medicament for the treatment or prophylaxis of ADHD.
Dosage regimens
The amount of the compound of formula (I) 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) required for treatment or prophylaxis of ADHD.
The compound of formula (I) may be administered daily (including several times daily), every second or third day, weekly, every second, third or fourth week or even as single dose depending on the subject and the characteristics of the ADHD to be treated.
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 16 mg per administration. For example, 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 may be administered to a subject. The compound of formula (I) may be administered as a single daily dose of 1 mg, 2 mg, 4 mg, 8 mg or 16 mg (excluding the mass of any counterion or solvent). Alternatively, the compound of formula (I) may be administered as a dose of 1 mg, 2 mg, 4 mg, 8 mg or 16 mg (excluding the mass of any counterion or solvent), two, three or four times a day.
In certain embodiments, the compound of formula (I) is administered as a composition. Preferably, the composition is a pharmaceutical composition for use according to the present invention.
Whilst the compound of formula (I) 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.
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).
The one or more further therapeutic interventions may be used simultaneously, sequentially or separately with/from the administration of the compound of formula (I). 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.
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). The release of the compound of formula (I) from certain composition may also be sustained, for example, if the composition contains suitable controlled- release excipients.
Kits
The present invention provides a kit comprising the compound of formula (I), 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.
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 instructions/guidance for cognitive behavioural therapy (CBT).
Kits of the present invention find use in the treatment and prophylaxis of ADHD.
For the avoidance of doubt, the compound of formula (I) 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) suitable for including in a kit of the invention, and for use according to the invention.
The term ‘carboycle’ refers to rings comprising carbon atom. ‘Carbocycles’ include unsaturated, partially saturated and unsaturated carbon rings. Examples of ‘carbocycles’ include: cyclopentyl, cyclopentanyl and cylop entadiene,
Equivalents
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.
Incorporation by Reference
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.
The following Examples illustrate the invention.
Examples
Danio rerio (zebrafish) 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.
Material and methods:
Zebrafish larvae carrying a knock-out of the Latrophilin3 (I.phnS. l) 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 881, 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).
Genotyping
Strains were verified for knock-down of the Lphn3.1 gene using Western blot.
Behavioral Recordings
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.
Motor Assay
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.
Example compound 1 (N-(3-Chloro-2-methylphenyl)-4-methylpyrrolidin-2-imine hydrochloride):
Figure imgf000022_0001
The batch of Example compound 1 used in the following examples had a purity of >95% by (NMR 1H). The proton NMR of the batch of Example compound 1 is in line with the NMR data provided for N-(3-Chloro-2-methylphenyl)-4-methylpyrrolidin-2- amine hydrochloride in US2014/0045910. The proton NMR spectrum of the batch of Example compound 1 is shown in Figure 4.
Example 1: Efficacy of Example compound 1 compared to atomoxetine in the zebrafish model of ADHD
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), Example compound 1, or a vehicle control before behavioral recordings started.
Drug preparation was performed on the day of recording. Drugs were diluted from stock solution using distilled water (Invitrogen, Paisley, PA4 9RF, UK). Three to five different concentration of each drug were used, 0,1 pM, 1 pM, 10 pM, 30 pM and 100 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 11.30 a.m. and 12.30 p.m.
Data was obtained using Etho Vision 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, N. Y., 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 (s.e.m). For analysis of Lphn 3.1 naive (i.e. untreated larvae that do not receive a test compound or a vehicle control) and DMSO larvae (i.e. larvae receiving only the DMSO vehicle control), statistical differences were evaluated using two-way ANOVA. For analysis of Lphn 3.1 larvae treated with Example compound 1 statistical differences were evaluated using one-way ANOVA with Dunnett two-sided post hoc analysis. P<0.05 was considered statistically significant.
Results:
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.
Using the average distance moved during lights-on periods it was demonstrated, first, that homozygous larvae were indeed statistically significantly hypermotile compared to wild-types and, second, the vehicle (DMSO) had no effects on behavior (Figure 2).
The effects of Example compound 1 were compared to optimal dose of atomoxetine (see Figure 3). Comparison with Lphn3.1 HOM larvae that were administered the vehicle control, revealed that all doses of Example compound 1 differed significantly from vehicle control and untreated larvae (in a dose dependent manner). These data show that Example compound 1 is effective at reducing ADHD-like phenotypes in Lphn3.1 HOM larvae.
Example 2: The effect of Example compound 1 on sleep behavior
Sleep behavior in Lphn3.1 HOM zebrafish larvae treated with Example compound 1 or vehicle control (i.er. DMSO only) was recorded in a 96-well plate and analysed during the lights-off period (22:00 - 08:00). First, all behavior was dichotomized into 1-s bins of movement or non- movement. Prior, in-depth frame-by-frame video analysis by three independent evaluators resulted in the adoption of the speed of 1.0 mm/s as the threshold for movement for larval zebrafish. All activity that was slower than that threshold was computed as non-movement. Thus, rendering a dichotomized record of the behavior in either movement or non-movement. Next, the dichotomized record was transformed into bins of sleep and wake. Following previously established sleep criteria in adults, and adapted to larval fish (Yokogawa et al., PLoS Biol. 2007;5(10):2379-97, Sorribes et al., Front Neural Circuits. 2013;7: 178, and Sigurgeirsson et al., Behav Brain Res. 2013;256:377-90), six or more consecutive 1-s bins of non-movement were counted as sleep and all else was counted as wake. That is, the seventh second and above were classified as sleep; all other bouts were classified as wake. Once the number of sleep and wake bouts was calculated, five different sleep parameters were assessed (i.e. sleep fragmentation, sleep ratio, velocity during sleep, wake bout duration(s), and sleep bout duration(s)). Sleep fragmentation was defined as the number of transitions between sleep and wake bouts per hour. Sleep ratio was calculated as the percentage of total night time that the fish was considered asleep. Velocity during sleep (mm/s) was defined as the average velocity throughout the night time. Wake bout duration(s) was defined as the average length of wake bouts. Sleep bout duration(s) was defined as the average length of sleep bouts. Results:
Sleep fragmentation (F(5,408)=5.825, p<0.001), sleep ratio (F(5,408)=27.464, p<0.001), velocity (F(5,408)=32.004, p<0.001), wake bout durations (F(5,408)=7.781, p<0.001) and sleep bout durations (F(5,408)=21.474, p<0.001) were significantly affected following treatment with Example Compound 1. Specifically, sleep fragmentation decreased at 30 pM; sleep ratio increased at 10 pM, 30 pM and 100 pM; velocity decreased at 10 pM, 30 pM and 100 pM; wake bout durations decreased at 10 pM, 30 pM and 100 pM, and sleep bout durations increased at 30 pM and 100 pM of Example Compound 1.

Claims

Claims
1. A compound according to formula (I)
Figure imgf000026_0001
wherein,
R1, R2, R3, R4 and R5 are each independently H, halogen or Ci-4alkyl; or R1 and R2 together form a 5 membered carbocycle, and R3, R4 and R5 are each independently H, halogen or Ci-4alkyl; wherein, in either case, said Ci-4alkyl or said carbocycle is optionally substituted with 1 or 2 halogens; and one of R6, R7 and R8 is Ci-4alkyl, and the others are each independently H; or a tautomer thereof, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutically acceptable salt or solvate of a tautomer thereof, for use in the treatment or prophylaxis of Attention Deficit/Hyperactivity Disorder (ADHD).
2. The compound for use according to claim 1, wherein R1 is halogen or Ci-4alkyl, R2 and R3 are each independently H or halogen, and R4 and R5 are each independently H.
3. The compound for use according to claim 2, wherein R1 is Cl or methyl, R2 and R3 are each independently H or Cl, and R4 and R5 are each independently H.
4. The compound for use according to claim 1, wherein R1 and R2 together form a 5 membered carbocycle, R3 is H, halogen or Ci-4alkyl, and R4 and R5 are each independently H.
5. The compound for use according to claim 4, wherein R1 and R2 together form a 5 membered carbocycle, R3 is H, Cl or methyl, and R4 and R5 are each independently H.
6. The compound for use according to any one of claims 1 to 5, wherein one of R6, R7 and R8 is methyl, and the others are each independently H, for example, R6 and R7 may each independently be H and R8 may be methyl, or R6 and R8 may each independently be H and R7 may be methyl.
7. The compound for use according to claim 1, wherein the compound of formula (I) is the compound of formula (la):
Figure imgf000027_0001
or a tautomer thereof; or a pharmaceutically acceptable salt or solvate thereof; or a pharmaceutically acceptable salt or solvate of a tautomer thereof.
8. The compound for use according to any one of claims 1 to 7, wherein the compound is administered in a dose of about 0.1 mg to 16 mg (excluding the mass of any counterion or solvent).
9. The compound for use according to any one of claims 1 to 8, wherein the compound is administered simultaneously, sequentially or separately with one or more further therapeutic interventions, for example a dietetic intervention, psychological intervention and/or pharmacological intervention.
10. The compound for use according to any one of claims 1 to 9, wherein the compound is administered simultaneously, sequentially or separately with one or more further pharmacological interventions selected from methylphenidate, dexamphetamine, lisdexamfetamine, atomoxetine, viloxazine, clonidine and guanfacine.
11. The compound for use according to any one of claims 1 to 10, wherein the compound is 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 known or suspected of having ADHD that is characterised by reduced levels of attention with hyperactivity and impulsivity behaviours (i.e. “combined type” ADHD).
12. The compound for use according to any one of claims 1 to 10 wherein the compound of formula (I) is administered to a subject with ADHD who has previously received another medication for the treatment or prevention of ADHD.
13. The compound for use according to claim 12 wherein said medication was ceased or reduced due to sleep related adverse events.
14. The compound for use according to claim 12 or claim 13 wherein the medication is selected from: methylphenidate, dexamphetamine, lisdexamfetamine, atomoxetine, viloxazine, guanfacine and clonidine.
15. A method for the treatment or prophylaxis of ADHD, comprising the step of administering a dose of a compound defined in any one of claims 1 to 7 to a patient known to have, suspected of having or at risk of developing ADHD.
16. The method of claim 15, wherein the patient is 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 known or suspected of having ADHD that is characterised by a combination of reduced levels of attention with hyperactivity and impulsivity behaviours (i.e. “combined type” ADHD).
17. A compound defined in any one of claims 1 to 7, for use in the manufacture of a medicament for the treatment or prophylaxis of ADHD.
18. A kit comprising a compound defined in any one of claims 1 to 7 and one or more further pharmacological intervention, instructions for a dietetic intervention and/or instructions for a psychological intervention.
19. The kit of claim 18 for use in the treatment or prophylaxis of ADHD.
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