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WO2024013523A1 - Ergoline and tryptamine-based compounds, and uses of the same - Google Patents

Ergoline and tryptamine-based compounds, and uses of the same Download PDF

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Publication number
WO2024013523A1
WO2024013523A1 PCT/GB2023/051872 GB2023051872W WO2024013523A1 WO 2024013523 A1 WO2024013523 A1 WO 2024013523A1 GB 2023051872 W GB2023051872 W GB 2023051872W WO 2024013523 A1 WO2024013523 A1 WO 2024013523A1
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WIPO (PCT)
Prior art keywords
compound
alkyl
composition
compounds
membered heterocyclic
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/GB2023/051872
Other languages
French (fr)
Inventor
Massimo MURATORE
Amir Lotfi MOGHADDAM
Christopher Wong
Vinod VISHWAPATHI
Oliver MCGAW
Robert Downham
David Christopher GIBSON
Timothy Nash
Sophie Caroline Williams
Philip Fallon
Bernard Thomas Golding
Carl Young
Philip Alan BUTLER
Alistair Paul HENDERSON
Christopher John MATHESON
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Beckley Psytech Ltd
Original Assignee
Beckley Psytech Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from GBGB2210427.7A external-priority patent/GB202210427D0/en
Priority claimed from GBGB2210431.9A external-priority patent/GB202210431D0/en
Priority claimed from GBGB2210436.8A external-priority patent/GB202210436D0/en
Priority claimed from GBGB2216306.7A external-priority patent/GB202216306D0/en
Priority claimed from GBGB2218027.7A external-priority patent/GB202218027D0/en
Application filed by Beckley Psytech Ltd filed Critical Beckley Psytech Ltd
Publication of WO2024013523A1 publication Critical patent/WO2024013523A1/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic 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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/48—Ergoline derivatives, e.g. lysergic acid, ergotamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic 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
    • A61K31/403—Heterocyclic 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 condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system

Definitions

  • This invention relates to pharmaceutically acceptable ergoline and tryptamine-based compounds (e.g. analogues, prodrugs and salts thereof).
  • the invention relates to formulations and uses of the same as a medicament, alone or in combination with additional pharmaceutically acceptable compounds.
  • BACKGROUND TO THE INVENTION Neuropsychiatric diseases, including mood and anxiety disorders, are some of the leading causes of disability worldwide and place an enormous economic burden on society. Approximately one third of patients will not respond to current antidepressant drugs, and those who do will usually require at least 2 to 4 weeks of treatment before they experience any beneficial effects.
  • a method of increasing neural plasticity includes contacting a neuronal cell with an ergoline analogue, in an amount sufficient to increase neural plasticity of the neuronal cell.
  • a method of treating a brain disorder includes contacting a neuronal cell with an ergoline analogue, in an amount sufficient to increase neural plasticity of the neuronal cell.
  • the method includes administering to a subject in need thereof a therapeutically effective amount of an ergoline analogue, thereby treating the brain disorder, wherein the ergoline analogue increases neural plasticity of the neuronal cell.
  • the neuronal cells can be any type of neuron cells.
  • the neuron cell is a cortical neuron cell.
  • the neuron cell is a cortical pyramidal neuron cell.
  • a compound for use in treating a condition benefiting from an increase in neural plasticity wherein the compound is of Formula (I)A wherein: X is selected from methyl or isopropyl; and Y is selected from a bond, O, CONH, NH, N(C 1-6 alkyl), A-(CH 2 )n-B, wherein A is O, NH or N(C 1-6 alkyl), wherein B is a bond, O, or NH, wherein n is 1 to 4; and Z is selected from H, OH, NH 2 , NHC 1-6 alkyl, N(C 1-6 alkyl) 2 , C 1-6 alkyl, C 6-10 aryl, SO 2 -C 1-6 alkyl, SO 2 -C 6-10 aryl, C 3 -C 10 heteroaromatic or heterocyclic group comprising one, two or three heteroatoms independently selected from O and N; and wherein X and Z are different; or a pharmaceutically acceptable salt
  • Formula (I)A may simply be referred to as Formula (I).
  • X is methyl.
  • X is isopropyl.
  • Y is selected from a bond, O, CONH, NH or NCH 3 .
  • Y is A-(CH 2 ) n -B, wherein A is O or NH, wherein B is a bond, O or NH, wherein n is 1 to 4. In an embodiment, n is 2 or 3.
  • Z is selected from pyridine, morpholine, SO 2 -CH 3 , SO 2 -phenyl, 8-oxa-3-azabicyclo[3.2.1]octane and 2-oxa-5-azabicyclo[2.2.1]heptane.
  • Y-Z together are H or C 1-6 alkyl. In an embodiment, Y-Z together are H or C 5 alkyl.
  • Y-Z together form the group: O-(CH 2 ) 3 -N(CH 3 ) 2 , NH-(CH 2 ) 2 -OH, NH-(CH 2 ) 3 -OH, NH-(CH 2 ) 3 -OCH 3 , NH-(CH 2 ) 3 -SO 2 CH 3 , NH- (CH 2 ) 2 -NH-SO 2 CH 3 , or O-(CH 2 ) 2 -NH-SO 2 CH 3 .
  • Y-Z together form the group: NH-phenyl, pyridine, O-morpholine, NH-morpholine, NH-SO 2 -Phenyl, NCH 3 -SO 2 -Phenyl, CONH-Phenyl, 8-oxa-3-azabicyclo[3.2.1]octane or 2-oxa-5- azabicyclo[2.2.1]heptane.
  • the compound is selected from: or .
  • the compound is .
  • the compound is .
  • a compound for use in treating a condition benefiting from neurogenesis, neurite outgrowth or an increase in neuronal branching points wherein the compound is and wherein the compound increase or promotes neurogenesis, neurite outgrowth or neuronal branching points in a subject treated with the compound.
  • a compound for use in treating a condition benefiting from neurite outgrowth or an increase in neuronal branching points wherein the compound is and wherein the compound increase or promotes neurite outgrowth or neuronal branching points in a subject treated with the compound.
  • the condition is a brain disorder or neuropsychiatric disease.
  • the brain disorder is a psychiatric disorder including depression, anxiety, and/or post-traumatic stress disorder.
  • the brain disorder is depression.
  • the brain disorder is anxiety.
  • the brain disorder is post-traumatic stress disorder.
  • the psychiatric disorder is a behavioral or mental pattern that may cause suffering or a poor ability to function in life. Such features may be persistent, relapsing and remitting, or occur as a single episode. Depression is related to a mood disorder involving unusually intense and sustained sadness, melancholia, or despair. Anxiety or fear that interferes with normal functioning may be classified as an anxiety disorder.
  • the brain disorder is a substance use disorder. Addiction and dependence are components of a substance use disorder and addiction represents the most severe form of the disorder.
  • the brain disorder is a neurodegenerative disorder including Alzhemier's and/or Parkinson's diseases. In some embodiments, the brain disorder is Alzhemier's disease. In other embodiments, the brain disorder is Parkinson's diseases. Neurodegeneration is the progressive loss of structure or function of neurons, including death of neurons.
  • a pharmaceutical composition comprising a pharmaceutically effective amount of a compound as subsequently or previously described.
  • the composition comprises a dosage amount in the range of 0.05mg to 100mg.
  • the composition comprises a dosage amount in the range of 0.1mg to 50mg.
  • the composition comprises a dosage amount in the range of 0.5mg to 25mg.
  • the composition is formulated in a dosage form selected from: oral, transdermal, inhalable, intravenous, or rectal dosage form.
  • the composition is formulated in a dosage form selected from: tablet, capsule, granules, powder, free-flowing powder, inhalable powder, aerosol, nebulised, vaping, buccal, sublingual, sublabial, injectable, or suppository dosage form.
  • the composition is administered one or more times a month.
  • the composition is administered one or more times a week.
  • wherein the composition is administered one or more times a day.
  • X is selected from H or C 1-6 alkyl (optionally, X is methyl or isopropyl); and Y is selected from a bond, O, CONH, NH, N(C 1-6 alkyl), A-(CH 2 ) n -B, wherein A is O, NH or N(C 1-6 alkyl), wherein B is a bond, O, or NH, wherein n is 1 to 4; and Z is selected from H, OH, NH 2 , NHC 1-6 alkyl, N(C 1-6 alkyl) 2 , C 1-6 alkyl, C 6-10 aryl, SO 2 -C 1-6 alkyl, SO 2 -C 6-10 aryl, C 3 -C 10 heteroaromatic or heterocyclic group comprising one, two or three heteroatoms independently selected from O and N; and wherein X and Z are different; or is a pharmaceutically acceptable salt thereof.
  • X is selected from methyl or isopropyl; and Y is selected from a bond, O, CONH, NH, N(C 1-6 alkyl), A-(CH 2 )n-B, wherein A is O, NH or N(C 1-6 alkyl), wherein B is a bond, O, or NH, wherein n is 1 to 4; and Z is selected from H, OH, NH 2 , NHC 1-6 alkyl, N(C 1-6 alkyl) 2 , C 1-6 alkyl, C 6-10 aryl, SO 2 -C 1-6 alkyl, SO 2 -C 6-10 aryl, C 3 -C 10 heteroaromatic or heterocyclic group comprising one, two or three heteroatoms independently selected from O and N; and wherein X and Z are different; or a pharmaceutically acceptable salt thereof.
  • the alkyl group is straight, branched or a cyclic alkyl group. In an embodiment the alkyl group is a straight chain alkyl group. In an embodiment the alkyl group contains 1, 2 or 3 halogens.
  • X is methyl. In an embodiment X is isopropyl.
  • Y is selected from a bond, O, CONH, NH or NCH 3 . In an embodiment Y is A-(CH 2 ) n -B, wherein A is O or NH, wherein B is a bond, O or NH, wherein n is 1 to 4. In an embodiment n is 2 or 3.
  • Z is selected from pyridine, morpholine, SO 2 -CH 3 , SO 2 -phenyl, 8-oxa-3-azabicyclo[3.2.1]octane and 2-oxa-5-azabicyclo[2.2.1]heptane.
  • Y-Z together form the group: O-(CH 2 ) 3 -N(CH 3 ) 2 NH-(CH 2 ) 2 -OH NH-(CH 2 ) 3 -OH NH-(CH 2 )3-OCH 3 NH-(CH 2 ) 3 -SO 2 CH 3 NH-(CH 2 ) 2 -NH-SO 2 CH 3 , or O-(CH 2 ) 2 -NH-SO 2 CH 3 .
  • Y-Z together form the group: NH-phenyl, pyridine, O-morpholine, NH-morpholine, NH-SO 2 -Phenyl, NCH 3 -SO 2 -Phenyl, CONH-Phenyl, 8-oxa-3-azabicyclo[3.2.1]octane or 2-oxa-5-azabicyclo[2.2.1]heptane.
  • one or more compounds selected from: In an embodiment there is provided one or more compounds selected from:
  • the molecules depicted in this application in the protonated form also include within their scope/meaning the corresponding molecules in the free base form, and vice versa.
  • the protonated form of these molecules being readily accessible by the addition of an acid to the free base form of these molecules.
  • the protonated form of Compound 5 can be made from the (free base form of) Compound 5 by the addition of an acid, e.g. addition of acid 'H-A' gives the protonated form of compound 5 and where the corresponding counter ion is A-.
  • H-A is H-CI
  • H-A is H-benzoate
  • the counter ion will be a benzoate anion.
  • compounds 1 to 025 have not been drawn in all possible salt forms e.g. with anions selected from benzoate, fumarate, citrate, acetate, succinate, halide, fluoride, chloride, bromide, iodide, oxalate, or triflate salt.
  • the composition comprises a dosage amount in the range of 0.05mg to 100mg. In an embodiment the composition comprises a dosage amount in the range of 0.1mg to 50mg. In an embodiment the composition comprises a dosage amount in the range of 0.5mg to 25mg. In an embodiment the composition comprises a dosage amount in the range of 0.5mg to 10mg. In an embodiment the composition comprises a dosage amount in the range of 1mg to 10mg. In an embodiment the composition comprises a dosage amount in the range of lmg to 8mg. In an embodiment the composition comprises a dosage amount in the range of 3mg to 15mg. In an embodiment the composition comprises a dosage amount in the range of 0.005mg to 100mg.
  • the composition comprises a dosage amount in the range of 0.001mg to 100mg. In an embodiment the composition comprises a dosage amount in the range of 0.0005mg to 100mg.
  • the level of the active agent can be adjusted as required by need for example to suit a certain patient group (e.g. the elderly) or the conditions being treated.
  • the composition is formulated in a dosage form selected from: oral, transdermal, inhalable, intravenous, rectal dosage, intranasal, intramuscular, or any other parenteral form.
  • the composition is formulated in a dosage form selected from: oral, transdermal, inhalable, intravenous or rectal dosage. It is advantageous to be able to deliver the active agent in different forms, for example to suit a certain patient group (e.g. the elderly) or the conditions being treated.
  • the composition is formulated in a dosage form selected from: tablet, capsule, granules, powder, free-flowing powder, inhalable powder, aerosol, nebulised, vaping, buccal, sublingual, sublabial, injectable, or suppository dosage form.
  • the powder is suitable for administration by inhalation via a medicament dispenser selected from a reservoir dry powder inhaler, a unit-dose dry powder inhaler, a pre-metered multi-dose dry powder inhaler, a nasal inhaler or a pressurized metered dose inhaler.
  • the compound is in the form of a salt which is amorphous or crystalline.
  • the salt is in a polymorphic crystalline form.
  • the salt is a benzoate, fumarate, citrate, acetate, succinate, halide, fluoride, chloride, bromide, iodide, oxalate, or triflate salt, optionally the salt is the chloride, benzoate or fumarate salt.
  • the salt is formulated into a composition for mucosal delivery.
  • the salt is a benzoate salt.
  • the dosage amount is the equivalent amount of the free base delivered when the salt is taken.
  • 100 mg dosage amount may for example correspond to 117mg of a hydrochloride salt (i.e. both providing the same molar amount of the active substance).
  • the greater mass of the salt needed is due to the larger formula weight of the hydrogen chloride salt.
  • a slight increase in mass can be expected due to the increased formula weight of these isotopic compounds.
  • Amorphous and crystalline substances often show different chemical/physical properties, e.g. improved rate of dissolution in a solvent, or improved thermal stability. Similarly, different polymorphs may also show different and useful chemical/physical properties.
  • the composition comprises one or more pharmaceutically acceptable carriers or excipients.
  • the composition comprises one or more of: mucoadhesive enhancer, penetrating enhancer, cationic polymers, cyclodextrins, Tight Junction Modulators, enzyme inhibitors, surfactants, chelators, and polysaccharides.
  • the composition comprises one or more of: chitosan, chitosan derivatives (such as N,N,N- trimethyl chitosan (TMC), n-propyl-(QuatPropyl), n-butyl-(QuatButyl) and n-hexyl (QuatHexyl)-N,N-dimethyl chitosan, chitosan chloride), ⁇ -cyclodextrin, Clostridium perfringens enterotoxin, zonula occludens toxin (ZOT), human neutrophil elastase inhibitor (ER143), sodium taurocholate, sodium deoxycholate sodium, sodium lauryl sulphate, glycodeoxycholat, palmitic acid, palmitoleic acid, stearic acid, oleyl acid, oleyl alchohol, capric acid sodium salt, DHA, EPA, dipalmitoyl phophatidyl choline
  • the compound or composition defined herein above for use in a method of treatment of a human or animal subject by therapy.
  • the method of treatment is a method of treatment of: conditions caused by dysfunctions of the central nervous system, conditions caused by dysfunctions of the peripheral nervous system, conditions benefiting from sleep regulation (such as insomnia), conditions benefiting from analgesics (such as chronic pain), migraines, trigeminal autonomic cephalgias (such as shortlasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT), and short-lasting neuralgiform headaches with cranial autonomic symptoms (SUNA)), conditions benefiting from neurogenesis (such as stroke, traumatic brain injury, Parkinson's dementia), conditions benefiting from anti-inflammatory treatment, depression, anxiety, substance use disorder, addictive disorder, gambling disorder, eating disorders, obsessive-compulsive disorders, or body dysmorphic disorders, optionally the condition is SUNCT and/or SUNA.
  • sleep regulation such as insomnia
  • analgesics such as chronic pain
  • migraines migraines
  • trigeminal autonomic cephalgias such as shortlasting unilateral neuralgiform
  • the method of treatment is a method of treatment of more than one of the above conditions, for example, the method of treatment may be a method of treatment of depression and anxiety.
  • the composition is administered one or more times a year. In an embodiment the composition is administered one or more times a month. In an embodiment the composition is administered one or more times a week. In an embodiment the composition is administered one or more times a day. In an embodiment the composition is administered at such a frequency as to avoid tachyphylaxis.
  • the composition is administered together with a complementary treatment and/or with a further active agent. In an embodiment the further active agent is a psychedelic compound, optionally a further tryptamine.
  • the further active agent is a psychedelic compound, optionally a tryptamine.
  • the further active agent is psilocybin, psilocin or a prodrug thereof.
  • the complementary treatment is psychotherapy.
  • a composition comprising a pharmaceutically effective amount of a compound as described herein for use in a method of treatment of treatment resistant depression.
  • a nasal inhalation composition comprising a pharmaceutically effective amount of a compound as described herein for use in a method of treatment of treatment resistant depression.
  • DiPT, 5-MeO-DMT, psilocin or psilocybin or a pharmaceutical composition comprising DiPT, 5-MeO- DMT, psilocin or psilocybin, for use in a method of increasing neural plasticity.
  • DiPT, 5-MeO-DMT, psilocin or psilocybin or a pharmaceutical composition comprising DiPT, 5-MeO-DMT, psilocin or psilocybin, for use in a method of neurogenesis.
  • DiPT, 5-MeO-DMT, psilocin or psilocybin or a pharmaceutical composition comprising DiPT, 5-MeO- DMT, psilocin or psilocybin, for use in a method of promoting neurite outgrowth.
  • DiPT, 5-MeO-DMT, psilocin or psilocybin or a pharmaceutical composition comprising DiPT, 5-MeO-DMT, psilocin or psilocybin, for use in a method of increasing the number of neuronal branching points.
  • DiPT, 5-MeO-DMT, psilocin or psilocybin or a pharmaceutical composition comprising DiPT, 5-MeO- DMT, psilocin or psilocybin, for use in a method of treating a condition wherein said condition would benefit from increasing the number of neuronal branching points.
  • 5-MeO-DALT or norpsilocin or a pharmaceutical composition comprising 5-MeO-DALT or norpsilocin, for use in a method of increasing neural plasticity.
  • 5-MeO-DALT or norpsilocin or a pharmaceutical composition comprising 5-MeO-DALT or norpsilocin, for use in a method of treating a condition wherein said condition would benefit from increasing neural plasticity.
  • 5- MeO-DALT or norpsilocin or a pharmaceutical composition comprising 5-MeO-DALT or norpsilocin, for use in a method of treating a condition wherein said condition would benefit from promotion of neurite outgrowth.
  • 5-MeO-DALT or norpsilocin or a pharmaceutical composition comprising 5-MeO-DALT or norpsilocin, for use in a method of increasing the number of neuronal branching points.
  • 5-MeO-DALT or norpsilocin or a pharmaceutical composition comprising 5-MeO-DALT or norpsilocin, for use in a method of treating a condition wherein said condition would benefit from increasing the number of neuronal branching points.
  • compound 018, or a pharmaceutical composition comprising compound 018, for use in a method of neurogenesis for use in a method of neurogenesis.
  • compound 018, or a pharmaceutical composition comprising compound 018, for use in a method of promoting neurite outgrowth for use in a method of promoting neurite outgrowth.
  • compound 019, or a pharmaceutical composition comprising compound 019 for use in a method of promoting neurite outgrowth.
  • compound 019, or a pharmaceutical composition comprising compound 019, for use in a method of treating a condition wherein said condition would benefit from promotion of neurite outgrowth there is provided a method of increasing neuronal plasticity, said method comprising administering one or more of the compounds disclosed herein to a patient in a pharmaceutically acceptable amount.
  • a method of neurogenesis said method comprising administering one or more of the compounds disclosed herein to a patient in a pharmaceutically acceptable amount.
  • a method of increasing neurite outgrowth comprising administering one or more of the compounds disclosed herein to a patient in a pharmaceutically acceptable amount.
  • a method of the number of neuronal branching points comprising administering one or more of the compounds disclosed herein to a patient in a pharmaceutically acceptable amount.
  • tryptamine is a shared feature of certain aminergic neuromodulators including melatonin, serotonin, bufotenin as well as psychedelic derivatives such as dimethyltryptamine (DMT), psilocybin, psilocin. Tryptamine There remains a need in the art for improved psychedelic compounds and compositions and uses thereof.
  • a compound for use in treating a condition benefiting from an increase in neural plasticity wherein the compound is of Formula (I)B wherein: R 1 is selected from H or C 1-6 alkyl; and R 2 is CH 2 -CHR 4 -NR 5 R 6 , wherein R 4 is selected from H or C 1-6 alkyl, wherein R 5 is selected from H or C 1-6 alkyl, wherein R 6 is: wherein X is a bond, Y is N, Z is O and R 7 and R 8 together from a bringing group CH 2 CH 2 ; or wherein X is NH or O, Y is CH, Z is O and R 7 and R 8 are H; or NH(CH 2 ) 3 N(CH 3 ) 2 , O(CH 2 )OH or O(CH 2 ) 2 N(CH 3 ) 2 .
  • Formula (I)B may simply be referred to as Formula (I).
  • K is CH.
  • R 1 is H
  • R 2 is CH 2 -CHR 4 -NR 5 R 6
  • R 3 is H or L-R 9
  • K is CH.
  • R 4 is H or methyl.
  • R 5 is ethyl or isopropyl.
  • R 4 is H and R 5 is ethyl.
  • R 3 is L-R 9 and wherein L is O, O-O-CH 2 CH 2 , OCO or OCONH.
  • R 3 is L-R 9 and wherein R 9 is OH, COCH 3 , imidazole, pyrrolidine, piperidine, analine, pyrideine, morpholine or 6- oxa-3-azabicyclo[3.1.1]heptane. In an embodiment, R 3 is OCOCH 3 .
  • the compound is: In an embodiment, the compound is: In an embodiment, the compound is: or In an embodiment, the compound is: In an embodiment, the compound is: In an embodiment, the compound is: In an embodiment, the compound is: In an embodiment, the compound is: or In an embodiment, the compound is: , or In an embodiment, the compound is: In an embodiment, the compound is: In an embodiment, there is provided a pharmaceutical composition comprising a compound or salt as defined subsequently or previously. In an embodiment, the composition comprises a dosage amount in the range of 0.05mg to 100mg. In an embodiment, the composition comprises a dosage amount in the range of 0.1mg to 50mg.
  • the composition comprises a dosage amount in the range of 0.5mg to 25mg.
  • the composition is formulated in a dosage form selected from: oral, transdermal, inhalable, intravenous, or rectal dosage form.
  • the composition is formulated in a dosage form selected from: tablet, capsule, granules, powder, free-flowing powder, inhalable powder, aerosol, nebulised, vaping, buccal, sublingual, sublabial, injectable, or suppository dosage form.
  • the composition is administered one or more times a month.
  • the composition is administered one or more times a week.
  • wherein the composition is administered one or more times a day.
  • a pharmaceutical composition comprising a pharmaceutically effective amount of a compound of formula: for use in treating a condition benefiting from an increase in neural plasticity, wherein the compound increases neural plasticity in a patient in need thereof.
  • a pharmaceutical composition comprising a pharmaceutically effective amount of a compound of formula for use in treating a condition benefiting from an increase in neural plasticity, wherein the compound increases neural plasticity in a patient in need thereof.
  • the patient has depression, anxiety, post-traumatic stress disorder or a neurodegenerative condition, or a combination thereof.
  • the condition is a brain disorder or neuropsychiatric disease.
  • the brain disorder is a psychiatric disorder including depression, anxiety, and/or post- traumatic stress disorder.
  • the brain disorder is depression.
  • the brain disorder is anxiety.
  • the brain disorder is post-traumatic stress disorder.
  • the psychiatric disorder is a behavioral or mental pattern that may cause suffering or a poor ability to function in life. Such features may be persistent, relapsing and remitting, or occur as a single episode. Depression is related to a mood disorder involving unusually intense and sustained sadness, melancholia, or despair. Anxiety or fear that interferes with normal functioning may be classified as an anxiety disorder.
  • the brain disorder is a substance use disorder. Addiction and dependence are components of a substance use disorder and addiction represents the most severe form of the disorder.
  • the brain disorder is a neurodegenerative disorder including Alzhemier's and/or Parkinson's diseases. In some embodiments, the brain disorder is Alzhemier's disease. In other embodiments, the brain disorder is Parkinson's diseases. Neurodegeneration is the progressive loss of structure or function of neurons, including death of neurons.
  • R 1 is selected from H or C 1-6 alkyl
  • R 2 is selected from H, NH 2 -cyclopropyl or CH 2 -CHR 4 -NR 5 R 6
  • R 4 is selected from H or C 1-6 alkyl
  • R 5 is selected from H or C 1-6 alkyl
  • R 6 is selected from C 1-6 alkyl, A-(CH 2 )n-B or , wherein A is NH or O
  • B is NH 2 , NH(C 1-6 alkyl), N(C 1-6 alkyl) 2 or OH, wherein n is 0 to 4, wherein X is a bond, NH or O, wherein Y is selected from CH, N, wherein Z is selected from CH 2 , O, NH or N(
  • R 5 and R 6 are C 1-6 alkyl groups.
  • R 6 is methyl.
  • R 6 is and wherein X is a bond, Y is N, Z is O and R7 and R8 together from a bridging group CH 2 CH 2 .
  • R6 is wherein X is NH or O, Y is CH, Z is O and R 7 and R 8 are H.
  • R 6 is NH(CH 2 ) 3 N(CH 3 ) 2 , O(CH 2 )OH or O(CH 2 ) 2 N(CH 3 ) 2 .
  • R 1 is selected from H or C 1-6 alkyl; and R 2 is CH 2 -CHR 4 -NR 5 R 6 , wherein R 4 is selected from H or C 1-6 alkyl, wherein R 5 is selected from H or C 1-6 alkyl, wherein R6 is: wherein X is a bond, Y is N, Z is O and R 7 and R 8 together from a bringing group CH 2 CH 2 ; or wherein X is NH or O, Y is CH, Z is O and R 7 and R 8 are H; or NH(CH 2 ) 3 N(CH 3 ) 2 , O(CH 2 )OH or O(CH 2 ) 2 N(CH 3 ) 2 .
  • the alkyl group is straight, branched or a cyclic alkyl group.
  • the alkyl group is a straight chain alkyl group. In an embodiment the alkyl group contains 1, 2 or 3 halogens.
  • R 1 is H
  • R 2 is CH 2 -CHR 4 -NR 5 R 6
  • R 3 is H or L-R 9
  • K is CH.
  • R 4 is H or methyl.
  • R 5 is ethyl or isopropyl.
  • R 4 is H and R 5 is ethyl.
  • R 3 is L-R 9 and wherein L is O, O-O-CH 2 CH 2 , OCO or OCONH.
  • R 3 is L-R 9 and wherein R 9 is OH, COCH 3 , imidazole, pyrrolidine, piperidine, analine, pyrideine, morpholine or 6-oxa-3-azabicyclo[3.1.1]heptane.
  • R 3 is OCOCH 3 .
  • the molecules depicted in this application in the protonated form also include within their scope/meaning the corresponding molecules in the free base form, and vice versa.
  • the protonated form of these molecules being readily accessible by the addition of an acid to the free base form of these molecules.
  • the protonated form of Compound 5 can be made from the (free base form of) Compound 5 by the addition of an acid, e.g. addition of acid 'H-A' gives the protonated form of compound 5 and where the corresponding counter ion is A-.
  • H-A is H-CI
  • H-A is H-benzoate
  • the counter ion will be a benzoate anion.
  • compounds 1 to 020 have not been drawn in all possible salt forms e.g. with anions selected from benzoate, fumarate, citrate, acetate, succinate, halide, fluoride, chloride, bromide, iodide, oxalate, or triflate salt.
  • composition comprising a pharmaceutically effective amount of a compound as described previously.
  • the composition comprises a dosage amount in the range of 0.05mg to 100mg. In an embodiment the composition comprises a dosage amount in the range of 0.1mg to 50mg. In an embodiment the composition comprises a dosage amount in the range of 0.5mg to 25mg. In an embodiment the composition comprises a dosage amount in the range of 0.5mg to 10mg. In an embodiment the composition comprises a dosage amount in the range of lmg to 10mg. In an embodiment the composition comprises a dosage amount in the range of lmg to 8mg. In an embodiment the composition comprises a dosage amount in the range of 3mg to 15mg. In an embodiment the composition comprises a dosage amount in the range of 0.005mg to 100mg. In an embodiment the composition comprises a dosage amount in the range of 0.001mg to 100mg. In an embodiment the composition comprises a dosage amount in the range of 0.0005mg to 100mg.
  • the level of the active agent can be adjusted as required by need for example to suit a certain patient group (e.g. the elderly) or the conditions being treated.
  • the composition is formulated in a dosage form selected from: oral, transdermal, inhalable, intravenous, rectal dosage, intranasal, intramuscular, or any other parenteral form.
  • the composition is formulated in a dosage form selected from: oral, transdermal, inhalable, intravenous, or rectal dosage form. It is advantageous to be able to deliver the active agent in different forms, for example to suit a certain patient group (e.g. the elderly) or the conditions being treated.
  • composition is formulated in a dosage form selected from: tablet, capsule, granules, powder, free-flowing powder, inhalable powder, aerosol, nebulised, vaping, buccal, sublingual, sublabial, injectable, or suppository dosage form.
  • the powder is suitable for administration by inhalation via a medicament dispenser selected from a reservoir dry powder inhaler, a unit-dose dry powder inhaler, a pre-metered multi-dose dry powder inhaler, a nasal inhaler or a pressurized metered dose inhaler.
  • a medicament dispenser selected from a reservoir dry powder inhaler, a unit-dose dry powder inhaler, a pre-metered multi-dose dry powder inhaler, a nasal inhaler or a pressurized metered dose inhaler.
  • the powder comprises particles, the particles having a median diameter of less than 2000 ⁇ m, 1000 ⁇ m, 500 ⁇ m, 250 ⁇ m, 100 ⁇ m, 50 ⁇ m, or 1pm.
  • the powder comprises particles, the particles having a median diameter of greater than 500 ⁇ m, 250 ⁇ m, 100 ⁇ m, 50 ⁇ m, 1pm or 0.5pm.
  • the nature of the powder can be adjusted to suit need. For example, if being made for nasal inhalation, then the particles may be adjusted to be much finer than if the powder is going to be formulated into a gelatine capsule, or differently again if it is going to be compacted into a tablet.
  • the compound is in the form of a salt which is amorphous or crystalline.
  • the salt is in a polymorphic crystalline form.
  • the salt is a benzoate, fumarate, citrate, acetate, succinate, halide, fluoride, chloride, bromide, iodide, oxalate, or triflate salt, optionally the salt is the chloride, benzoate or fumarate salt.
  • the salt is formulated into a composition for mucosal delivery.
  • the salt is a benzoate salt.
  • the dosage amount is the equivalent amount of the free base (e.g. of 5-MeO-DMT) delivered when the salt is taken. So 100 mg dosage amount may for example correspond to 117mg of a hydrochloride salt (i.e. both providing the same molar amount of the active substance).
  • the greater mass of the salt needed is due to the larger formula weight of the hydrogen chloride salt.
  • a slight increase in mass can be expected due to the increased formula weight of these isotopic compounds.
  • compositions comprise one or more pharmaceutically acceptable carriers or excipients.
  • the composition comprises one or more of: mucoadhesive enhancer, penetrating enhancer, cationic polymers, cyclodextrins, Tight Junction Modulators, enzyme inhibitors, surfactants, chelators, and polysaccharides.
  • the composition comprises one or more of: chitosan, chitosan derivatives (such as N,N,N-trimethyl chitosan (TMC), n-propyl-(QuatPropyl), n-butyl-(QuatButyl) and n-hexyl (QuatHexyl)-N,N-dimethyl chitosan, chitosan chloride), ⁇ -cyclodextrin, Clostridium perfringens enterotoxin, zonula occludens toxin (ZOT), human neutrophil elastase inhibitor (ER143), sodium taurocholate, sodium deoxycholate sodium, sodium lauryl sulphate, glycodeoxycholat, palmitic acid, palmitoleic acid, stearic acid, oleyl acid, oleyl alchohol, capric acid sodium salt, DHA, EPA, dipalmitoyl phophatidyl choline
  • the compound or composition defined herein above for use i n a method of treatment of a human or animal subject by therapy.
  • the method of treatment is a method of treatment of: conditions caused by dysfunctions of the central nervous system, conditions caused by dysfunctions of the peripheral nervous system, conditions benefiting from sleep regulation (such as insomnia), conditions benefiting from analgesics (such as chronic pain), migraines, trigeminal autonomic cephalgias (such as short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT), and short-lasting neuralgiform headaches with cranial autonomic symptoms (SUNA)), conditions benefiting from neurogenesis (such as stroke, traumatic brain injury, Parkinson's dementia), conditions benefiting from anti-inflammatory treatment, depression, anxiety, substance use disorder, addictive disorder, gambling disorder, eating disorders, obsessive-compulsive disorders, or body dysmorphic disorders, optionally the condition is SUNCT and/or SUNA.
  • sleep regulation such as insomnia
  • analgesics such as chronic pain
  • migraines migraines
  • trigeminal autonomic cephalgias such as short-lasting unilateral neuralg
  • Treatment of the above conditions may be beneficially improved by taking the invention.
  • the method of treatment is a method of treatment of more than one of the above conditions, for example, the method of treatment may be a method of treatment of depression and anxiety.
  • the composition is administered one or more times a year. In an embodiment the composition is administered one or more times a month. In an embodiment the composition is administered one or more times a week. In an embodiment the composition is administered one or more times a day. In an embodiment the composition is administered at such a frequency as to avoid tachyphylaxis.
  • composition is administered together with a complementary treatment and/or with a further active agent.
  • the further active agent is a psychedelic compound, optionally a further tryptamine.
  • the further active agent is a psychedelic compound, optionally an ergoline.
  • the further active agent is lysergic acid diethylamide (LSD), psilocybin, psilocin or a prodrug thereof.
  • the complementary treatment is psychotherapy.
  • a composition comprising a pharmaceutically effective amount of a compound as described herein for use in a method of treatment of treatment resistant depression.
  • a nasal inhalation composition comprising a pharmaceutically effective amount of a compound as described herein for use in a method of treatment of treatment resistant depression.
  • DiPT, 5-MeO-DMT, psilocin or psilocybin or a pharmaceutical composition comprising DiPT, 5-MeO-DMT, psilocin or psilocybin, for use in a method of increasing neural plasticity.
  • DiPT, 5-MeO-DMT, psilocin or psilocybin or a pharmaceutical composition comprising DiPT, 5-MeO-DMT, psilocin or psilocybin, for use in a method of neurogenesis.
  • DiPT, 5-MeO-DMT, psilocin or psilocybin or a pharmaceutical composition comprising DiPT, 5-MeO-DMT, psilocin or psilocybin, for use in a method of promoting neurite outgrowth.
  • DiPT, 5-MeO-DMT, psilocin or psilocybin or a pharmaceutical composition comprising DiPT, 5-MeO- DMT, psilocin or psilocybin, for use in a method of increasing the number of neuronal branching points.
  • 5-MeO-DALT or norpsilocin or a pharmaceutical composition comprising 5-MeO-DALT or norpsilocin, for use in a method of increasing neural plasticity.
  • 5-MeO- DALT or norpsilocin or a pharmaceutical composition comprising 5-MeO-DALT or norpsilocin, for use in a method of treating a condition wherein said condition would benefit from increasing neural plasticity.
  • 5-MeO-DALT or norpsilocin or a pharmaceutical composition comprising 5-MeO-DALT or norpsilocin, for use in a method of treating a condition wherein said condition would benefit from promotion of neurite outgrowth.
  • 5-MeO-DALT or norpsilocin or a pharmaceutical composition comprising 5-MeO-DALT or norpsilocin, for use in a method of increasing the number of neuronal branching points.
  • 5-MeO-DALT or norpsilocin or a pharmaceutical composition comprising 5-MeO-DALT or norpsilocin, for use in a method of treating a condition wherein said condition would benefit from increasing the number of neuronal branching points.
  • compound 005, or a pharmaceutical composition comprising compound 005, for use in a method of neurogenesis for use in a method of neurogenesis.
  • compound 005, or a pharmaceutical composition comprising compound 005, for use in a method of treating a condition wherein said condition would benefit from promotion of neurite outgrowth there is provided compound 005, or a pharmaceutical composition comprising compound 005, for use in a method of increasing the number of neuronal branching points.
  • a method of increasing neuronal plasticity comprising administering one or more of the compounds disclosed herein to a patient in a pharmaceutically acceptable amount.
  • a method of neurogenesis comprising administering one or more of the compounds disclosed herein to a patient in a pharmaceutically acceptable amount.
  • a method of increasing neurite outgrowth comprising administering one or more of the compounds disclosed herein to a patient in a pharmaceutically acceptable amount.
  • a method of the number of neuronal branching points said method comprising administering one or more of the compounds disclosed herein to a patient in a pharmaceutically acceptable amount.
  • Psilocin is a psychoactive compound which is sensitive to oxidation. Psilocin is typically formed in the human body when a substance containing the naturally occurring compound psilocybin is ingested e.g. when ingesting 'magic mushrooms'.
  • R 1 is (CH 2 ) m NR 4 (R 5 ) wherein: m is selected from 1, 2, 3, 4, 5, 6, 7, or 8;
  • R 4 is C 1-6 alkyl
  • R 5 is C 1-6 alkyl
  • R 2 is H or C(O)C 1-6 ;
  • R 3 is O-X-Y wherein:
  • X is -CO-; -C(O)O-; -C(O)O(CH 2 ) n -; -CH 2 (CO)-; -CH 2 -O-; -CHR 6 -O-; -CH 2 -NH-; -CH 2 -NR 7 -; -CHR 8 -NH-; - CHR 9 -NR 10 -; -P(O)(OH)-; -P(O)OR 11 -; -CH 2 O-P(O)OH-; -CH 2 O-P(O)OR 12 -; or -CO(CH 2 ) n -C(O)OCH 2 -;
  • Y is -(CH 2 ) n -NH 2 ; -(CH 2 ) n -NHR 13 ; -(CH 2 ) n -NR 14 R 15 ; -C(O)CHR 1S R 17 ;
  • R 6 to R 21 are independently H or C 1-4 alkyl groups, and R 22 is a C 1-8 alkyl group and wherein n is independently 1 to 4.
  • Formula (l)C may simply be referred to as Formula (I).
  • R 3 may also be selected from: -O-C(O)-CH(CH 3 ) 2 , -O-CH 2 -O-P(O)(OH)-CH 2 CH 2 CH 2 CH 3 -O- CH 2 -O-P(O)(OH)-OCH 2 CH 2 CH 2 CH 3 , O-P(O)(OH)-CH 2 CH 2 CH 2 CH 3 , O-P(O)(OH)-OCH 2 CH 2 CH 2 CH 3 , -O-CH 2 -O- P(O)(OH) 2 , -O-CH 2 -O-P(O)(O-CH-(CH 3 ) 2 ) 2 , -O-CH 2 -O-P(O)(O-CH 2 CH 2 CH 2 CH 3 ) 2 , -O-CH 2 -O-P(O)(O-C(CH 3 ) 3 ) 2 and - O-CH 2 -O-P(O)OH(O-C(CH 3 )
  • alkyl groups may be independently optionally substituted.
  • R 2 is C(O)C 1-6 and is optionally substituted.
  • R 2 is C(O)C 1-6 and is substituted.
  • m is 2 or 3. In an embodiment m is 2. In an embodiment, R 4 and R 5 are both CH 3 .
  • R 2 is H. In an embodiment, R 2 is C(O)C 1-6 alkyl. In an embodiment, R 2 is C(O)CH 3 .
  • R 6 to R 21 are independently H or CH 3 groups. In an embodiment, R 6 to R 21 are H groups. In an embodiment, R 6 to R 21 are CH 3 groups.
  • R 22 is a C 1-8 alkyl group, optionally a t-butyl group.
  • Y is
  • X is CH(CH 3 )O
  • Y is C(O)CH(CH 3 ) 2 or C(O)N(CH 3 ) 2 .
  • X is C(O)O or C(O)O(CH 2 ) and Y is CH 2 N(CH 3 ) 2 .
  • X is -P(O)(OH)-; -P(O)(O-n-butyl)-; -CH 2 O-P(O)OH- ; -CH 2 O-P(O)(n-butyl)- and Y is or n-butyl, isopropyl, t-butyl or n-heptyl.
  • X is -CH 2 O-P(O)OH- and Y is t-butyl or n-heptyl.
  • X is CH 2 N(CH 3 ) and Y is C(O)OCH 3 , C(O)CH(CH 3 ) 2 or C(O)N(CH 3 ) 2 .
  • X is C(O) or-CH 2 (CO)-, and Yis
  • X is -CO(CH 2 )-C(O)OCH 2 - or CO(CH 2 ) 2 -C(O)OCH 2 - and Yis
  • X is CH(CH 3 )NH or CH 2 NH and Y is C(O)CH(CH 3 ) 2 .
  • n is 2, R 4 and R 5 are both CH 3 and R 2 is H.
  • n is 2, R 4 and R 5 are both CH 3 and R 2 is C(O)CH 3 .
  • the compound is selected from:
  • the compound is selected from: In an embodiment, the compound is: In an embodiment, the compound is:
  • the compound is selected from:
  • composition comprising a pharmaceutically effective amount of a compound as described hereinabove or herein below.
  • the composition comprises a dosage amount in the range of 0.05mg to 100mg. In an embodiment the composition comprises a dosage amount in the range of 0.1mg to 50mg. In an embodiment the composition comprises a dosage amount in the range of 0.5mg to 25mg. In an embodiment the composition comprises a dosage amount in the range of 0.5mg to 10mg. In an embodiment the composition comprises a dosage amount in the range of lmg to 10mg. In an embodiment the composition comprises a dosage amount in the range of lmg to 8mg. In an embodiment the composition comprises a dosage amount in the range of 3mg to 15mg. In an embodiment the composition comprises a dosage amount in the range of 0.005mg to 100mg. In an embodiment the composition comprises a dosage amount in the range of 0.0010mg to 100mg. In an embodiment the composition comprises a dosage amount in the range of 0.0005mg to 100mg.
  • the level of the active agent can be adjusted as required by need, for example to suit a certain patient group (e.g. the elderly) or the conditions being treated.
  • the composition is formulated in a dosage form selected from: oral, transdermal, inhalable, intravenous, rectal dosage, intranasal, intramuscular, or any other parenteral form.
  • the composition is formulated in a dosage form selected from: oral, transdermal, inhalable, intravenous, or rectal dosage form. It is advantageous to be able to deliver the active agent in different forms, for example to suit a certain patient group (e.g. the elderly) or the conditions being treated.
  • composition is formulated in a dosage form selected from: tablet, capsule, granules, powder, free-flowing powder, inhalable powder, aerosol, nebulised, vaping, buccal, sublingual, sublabial, injectable, microneedle array, or suppository dosage form.
  • the powder is suitable for administration by inhalation via a medicament dispenser selected from a reservoir dry powder inhaler, a unit-dose dry powder inhaler, a pre-metered multi-dose dry powder inhaler, a nasal inhaler or a pressurized metered dose inhaler.
  • a medicament dispenser selected from a reservoir dry powder inhaler, a unit-dose dry powder inhaler, a pre-metered multi-dose dry powder inhaler, a nasal inhaler or a pressurized metered dose inhaler.
  • the compound is in the form of a salt which is amorphous or crystalline.
  • the salt is in a polymorphic crystalline form.
  • the salt is a benzoate, fumarate, citrate, acetate, succinate, halide, fluoride, chloride, bromide, iodide, oxalate, or triflate salt, optionally the salt is the chloride, benzoate or fumarate salt.
  • the salt is formulated into a composition for mucosal delivery.
  • the salt is a benzoate salt.
  • the dosage amount is the equivalent amount of the free base delivered when the salt is taken. So 100 mg dosage amount may for example correspond to an increased amount of a hydrochloride salt (i.e. both providing the same molar amount of the active substance. The greater mass of the salt needed is due to the larger formula weight of the hydrogen chloride salt. Similarly, for the deuterated or triturated version of the compounds of the invention (also considered within the scope of the invention), a slight increase in mass can be expected due to the increased formula weight of these isotopic compounds.
  • compositions comprise one or more pharmaceutically acceptable carriers or excipients.
  • composition comprises one or more of: mucoadhesive enhancer, penetrating enhancer, cationic polymers, cyclodextrins, Tight Junction Modulators, enzyme inhibitors, surfactants, chelators, and polysaccharides.
  • the composition comprises one or more of: chitosan, chitosan derivatives (such as N,N,N-trimethyl chitosan (TMC), n-propyl-(QuatPropyl), n-butyl- (QuatButyl) and n-hexyl (QuatHexyl)-N,N-dimethyl chitosan, chitosan chloride), ⁇ -cyclodextrin, Clostridium perfringens enterotoxin, zonula occludens toxin (ZOT), human neutrophil elastase inhibitor (ER143), sodium taurocholate, sodium deoxycholate sodium, sodium lauryl sulphate, glycodeoxycholat, palmitic acid, palmitoleic acid, stearic acid, oleyl acid, oleyl alchohol, capric acid sodium salt, DHA, EPA, dipalmitoyl phophatidyl choline
  • the compounds or compositions defined herein are for use in a method of treatment of a human or animal subject by therapy. In an embodiment, the compounds or compositions defined herein, are used in a method of treatment of a human or animal subject by therapy.
  • the method of treatment is a method of treatment of: conditions caused by dysfunctions of the central nervous system, conditions caused by dysfunctions of the peripheral nervous system, conditions benefiting from sleep regulation (such as insomnia), conditions benefiting from analgesics (such as chronic pain), migraines, trigeminal autonomic cephalgias (such as short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT), and short-lasting neuralgiform headaches with cranial autonomic symptoms (SUNA)), conditions benefiting from neurogenesis (such as stroke, traumatic brain injury, Parkinson's dementia), conditions benefiting from anti-inflammatory treatment, depression, anxiety, substance use disorder, addictive disorder, gambling disorder, eating disorders, obsessive-compulsive disorders, or body dysmorphic disorders, optionally the condition is SUNCT and/or SUNA.
  • sleep regulation such as insomnia
  • analgesics such as chronic pain
  • migraines migraines
  • trigeminal autonomic cephalgias such as short-lasting unilateral neuralg
  • Treatment of the above conditions may be beneficially improved by taking the invention.
  • the method of treatment is a method of treatment of more than one of the above conditions, for example, the method of treatment may be a method of treatment of depression and anxiety.
  • the composition is administered one or more times a year. In an embodiment the composition is administered one or more times a month. In an embodiment the composition is administered one or more times a week. In an embodiment the composition is administered one or more times a day.
  • the composition is administered at such a frequency as to avoid tachyphylaxis.
  • the composition is administered together with a complementary treatment and/or with a further active agent.
  • the further active agent is a psychedelic compound, optionally a further tryptamine.
  • the further active agent is a psychedelic compound, optionally an ergoline.
  • the further active agent does not induce a psychedelic response in the subject, for example because it has been chemically modified, or it is administered in a sufficiently low dosage amount.
  • the further active agent is lysergic acid diethylamide (LSD), psilocybin, psilocin ora prodrug thereof.
  • the complementary treatment is psychotherapy.
  • the complementary treatment is a prescription digital therapeutic (PDT).
  • PDT prescription digital therapeutic
  • a composition comprising a pharmaceutically effective amount of the invention, as described herein for use in a method of treatment of treatment resistant depression.
  • a nasal inhalation composition comprising a pharmaceutically effective amount of the invention, as described herein for use in a method of treatment of treatment resistant depression.
  • X is selected from H or C 1-6 alkyl, and optionally wherein X is methyl or isopropyl;
  • Y is selected from a bond, O, CONH, NH, N(C 1-6 alkyl), A-(CH 2 ) n -B, wherein
  • A is O, NH or N(C 1-6 alkyl), wherein
  • B is a bond, O, or NH, wherein n is 1 to 4;
  • Z is selected from H, OH, NH 2 , NHC 1-6 alkyl, N(C 1-6 alkyl) 2 , C 1-6 alkyl, C 6-10 aryl, SO 2 -C 1-6 alkyl, SO 2 -C 6-10 aryl, C 3 -C 10 heteroaromatic or heterocyclic group comprising one, two or three heteroatoms independently selected from O and N; wherein X and Z are different; or a pharmaceutically acceptable salt thereof; and
  • the compound of formula (I) is selected from:
  • the compound of formula (I) is: In an embodiment, the compound of formula (I) is:
  • the compound of formula (I) is:
  • the serotonin receptor antagonist, or inverse agonist, of the combination pharmaceutical is an antagonist, or inverse agonist against one or more of the serotonin receptor subtypes 2a, 2b and 2c.
  • the serotonin receptor antagonist, or inverse agonist is selected from: lisuride, methysergide, clomipramine, doxepin, amoxapine, cariprazine, cyproheptadine, aripiprazole, mianserin, minaprine, asenapine, cyclobenzaprine, volinanserin or sarpogrelate.
  • the serotonin receptor antagonist, or inverse agonist is or a pharmaceutically acceptable salt thereof.
  • the serotonin receptor antagonist, or inverse agonist is or a pharmaceutically acceptable salt thereof.
  • the compound of formula (I) and the serotonin receptor antagonist, or inverse agonist are present in the same single dosage form.
  • the combination pharmaceutical is formulated in a dosage form selected from oral, transdermal, inhalable, intravenous, injectable or rectal dosage forms.
  • the compound of formula (I) and the serotonin receptor antagonist, or inverse agonist are present in different dosage forms.
  • the dosage forms are selected from oral, transdermal, inhalable, intravenous, injectable or rectal dosage forms.
  • a combination pharmaceutical according to any previous or subsequent embodiment in treating a condition benefiting from an increase in neural plasticity, wherein the combination pharmaceutical increases neural plasticity in a subject treated with the combination pharmaceutical.
  • the compound of formula (I) of the combination pharmaceutical and the serotonin receptor antagonist, or inverse agonist are administered on the same day.
  • the compound of formula (I) of the combination pharmaceutical and the serotonin receptor antagonist, or inverse agonist are administered at the same time on the same day.
  • the compound of formula (I) of the combination pharmaceutical and the serotonin receptor antagonist, or inverse agonist are administered at the same time on the same day. In an embodiment, the compound of formula (I) of the combination pharmaceutical and the serotonin receptor antagonist, or inverse agonist, are administered 1 minute, 2 minutes, 3 minutes, 4 minutes, 5 minutes, 10 minutes, 15 minutes, 20 minutes, 25 minutes, 30 minutes, 35 minutes, 40 minutes, 45 minutes, 50 minutes, 55 minutes or 60 minutes apart.
  • the compound of formula (I) of the combination pharmaceutical and the serotonin receptor antagonist, or inverse agonist are administered 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours,
  • the compound of formula (I) of the combination pharmaceutical and the serotonin receptor antagonist, or inverse agonist are administered 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days,
  • the compound of formula (I) of the combination pharmaceutical is administered multiple times whilst the serotonin antagonist is administered only once in any given treatment round.
  • a combination pharmaceutical comprising or a pharmaceutically acceptable salt, and a serotonin receptor antagonist, or inverse agonist, or a pharmaceutically acceptable salt thereof, in treating a condition benefiting from an increase in neural plasticity, wherein the combination pharmaceutical increases neural plasticity in a subject treated with the combination pharmaceutical.
  • the serotonin receptor antagonist, or inverse agonist is or a pharmaceutically acceptable salt thereof.
  • the serotonin receptor antagonist, or inverse agonist is or a pharmaceutically acceptable salt thereof.
  • the combination pharmaceutical increases neural plasticity in a subject treated with the combination pharmaceutical to a greater extent than administration of either active compounds of the combination pharmaceutical alone.
  • X is selected from H or C 1-10 branched or straight chain alkyl and optionally methyl, isopropyl;
  • Y is selected from a bond, O, CONH, NH, N(C 1-6 alkyl), A-(CH 2 ) n -B, C 1-6 alkyl, wherein
  • A is O, NH or N(C 1-6 alkyl), wherein B is a bond, O, or NH, wherein n is 1 to 4;
  • Z is selected from H, OH, NH 2 , NHC 1-6 alkyl, N(C 1-6 alkyl) 2 , C 1-6 alkyl, C 6-10 aryl, SO 2 -C 1-6 alkyl, SO 2 - C 6-10 aryl, C 3 -C 10 heteroaromatic or heterocyclic group comprising one, two or three heteroatoms independently selected from O and N; and wherein X and Z are the same or different; or a pharmaceutically acceptable salt thereof; and optionally additionally comprising
  • Formula (l)E may simply be referred to as Formula (I).
  • the alkyl group is straight, branched or a cyclic alkyl group.
  • the alkyl group is a straight chain alkyl group. In an embodiment the alkyl group contains 1, 2 or 3 halogens.
  • X is methyl. In an embodiment X is isopropyl.
  • Y is selected from a bond, O, CONH, NH or NCH 3 .
  • Y is A-(CH 2 ) n -B, wherein
  • A is O or NH, wherein
  • B is a bond, O or NH, wherein n is 1 to 4.
  • n 2 or 3.
  • Z is selected from pyridine, morpholine, SO 2 -CH 3 , SO 2 -phenyl, 8-oxa-3-azabicyclo[3.2.1]octane and 2-oxa-5-azabicyclo[2.2.1]heptane.
  • a compound of Formula (I) wherein X is absent, Y is a bond and Z is SO(C 1-6 alkyl) or SOR 1 R 2 ; wherein R 1 and R 2 are taken together with the S in between to form a heterocyclic ring, wherein said heterocyclic ring is selected from: a three membered heterocyclic ring, a four membered heterocyclic ring, a five membered heterocyclic ring, a six membered heterocyclic ring, a six membered bicyclic heterocyclic ring, a seven membered bicyclic heterocyclic ring, an eight membered bicyclic heterocyclic ring or a nine membered bicyclic heterocyclic ring.
  • the heterocyclic ring is optionally substituted at one or more positions with one or more of: a halogen, CH 2 -(C 3 -C 6 cycloalkyl).
  • a compound which is: In an embodiment there is provided one or more compounds selected from:
  • R is selected from a 5 membered heterocyclic ring with at least one N atom, a 5 membered heterocyclic ring with at least one O atom, a 5 membered heterocyclic ring with at least two N atoms, a 5 membered heterocyclic ring with at least one O and one N atom, a 5 membered heterocyclic ring with at least three N atoms, a 5 membered heterocyclic ring with at least four N atoms, and a 5 membered heterocyclic ring wherein all atoms of the ring are N;
  • R' is absent or is selected from:
  • H methyl, ethyl, isopropyl, propyl, butyl, pentyl, hexyl, heptyl, octyl;
  • R is tetrazole moiety. In an embodiment, R is a triazole moiety. In an embodiment, R is 1,2,4-triazole moiety. In an embodiment, R is imidazole moiety. In an embodiment, R is oxazole moiety. In an embodiment, R is dihydrooxazole moiety. In an embodiment, R is a 5-yl- tetrazole moiety. In an embodiment, R is a 5-yl- triazole moiety. In an embodiment, R is a 5-yl-1,2,4-triazole moiety. In an embodiment, R is a 2-yl- imidazole moiety. In an embodiment, R is a 2-yl-oxazole moiety.
  • R is a 2-yl-dihydrooxazole moiety.
  • R is a tetrazole and R' is absent; optionally it is a 5-yl- tetrazole (that is, the tetrazole connects to the main structure via the 5-position (i.e. -5-yl- position) of the tetrazole).
  • R is a triazole and R' is absent; optionally it is a 5-yl- triazole.
  • R is a 1,2,4- triazole and R' is absent ; optionally it is a 5-yl- 1,2,4-triazole.
  • R is an imidazole and R' is absent; optionally it is a 2-yl- imidazole. In an embodiment, R is an imidazole and R' is CH 3 , optionally it is a 2-yl- imidazole. In an embodiment, R is an oxazole and R' is absent, optionally it is a 2-yl- oxazole. In an embodiment, R is a triazole and R' is a C 3 alkyl; optionally it is a 5-yl- triazole. In an embodiment, R is a triazole and R' is is isopropyl; optionally it is a 5-yl- triazole.
  • R is a 1, 2, 4-triazole and R' is isopropyl; optionally it is a 5-yl- triazole.
  • R is an imidazole and R' is isopropyl; optionally it is a 2-yl- imidazole.
  • R is a dihydrooxazole and R' is CH 2 OH; optionally it is a 2-yl- dihydrooxazole.
  • R is an oxazole and R' is CH 2 OH; optionally it is a 2-yl- oxazole.
  • R is an imidazoline and R' is CH 2 OH; optionally it is a 2-yl- imidazole.
  • R is a tetrazole and R' is isopropyl; optionally it is a 5-yl- tetrazole.
  • R is a dihydrooxazole is CH 2 CH 2 SCH 3 ; optionally it is a 2-yl-dihydrooxazole.
  • R is a dihydrooxazole and R' is isopropyl; optionally it is a 2-yl-dihydrooxazole.
  • R is an oxazole and R' is CH 3 ; optionally it is a 2-yl-oxazole.
  • R is an oxazole and R' is is isopropyl; optionally it is a 2-yl-oxazole.
  • Rx and Ry are taken together with the N atom between them to form a heterocyclic ring, wherein said ring is selected from: a three membered heterocyclic ring, a four membered heterocyclic ring, a five membered heterocyclic ring, a six membered heterocyclic ring, a six membered heterocyclic bicyclic ring, a seven membered heterocyclic bicyclic ring, an eight membered heterocyclic bicyclic ring and a nine membered heterocyclic bicyclic ring; wherein one or more atoms of said heterocyclic ring are optionally replaced with one or more heteroatoms such as N, O or S; wherein said ring is optionally substituted at one or more positions with one or more of Rz, where Rz is independently selected from: a halogen,C 1-6 alkyl, C(O)CH 3 , C(O)C 1-6 alkyl, NH 2 , NHC 1-6 alkyl, N(C
  • Rx and Ry are taken together with the N atom between them to form a 5 membered heterocyclic ring comprising an O atom.
  • Rx and Ry are taken together with the N atom between them to form:
  • the N atom missing a valance/bond is the N atom between the Rx and Ry groups.
  • Rx and Ry are taken together with the N atom between them to form a 5 membered heterocyclic ring comprising an additional N atom, wherein said N atom is substituted with CH 3 .
  • Rx and Ry are taken together with the N atom between them to form a 6 membered bicyclic heterocyclic ring.
  • Figure 1 shows serotonin (la, lb, 2a, 2c and 7 receptors) cAMP assay results for compounds 018 and 019.
  • Figure 2 shows serotonin (2a, 2b and 2c receptors) inositol phosphate 1 (I Pi) assay results for compounds 018 and 019.
  • Figure 3 shows serotonin (2a, 2b and 2c receptors) calcium (Ca 2+ ) assay results for compounds 018 and 019.
  • Figure 4 shows serotonin (la, lb, 2a and 2c receptors) B-arrestin assay results for compounds 018 and 019.
  • FIG. 5 shows serotonin 2b receptor B-arrestin assay results for compounds 018 and 019.
  • Figure 10 shows serotonin (1a, 1b, 2a, 2c and 7 receptors) cAMP assay results for compounds T005, T008 and T018.
  • FIG 11 shows serotonin (2a, 2b and 2c receptors) inositol phosphate 1 (IP1) assay results for compounds T005, T008 and T018.
  • Figure 12 shows serotonin (2a, 2b and 2c receptors) calcium (Ca2+) assay results for compounds T005, T008 and T018.
  • Figure 13 shows serotonin (1a, 1b, 2a and 2c receptors) B-arrestin assay results for compounds T005, T008 and T018.
  • Figure 14 shows serotonin 2b receptor B-arrestin assay results for compounds T005, T008 and T018.
  • Figure 16 shows the effect of tested compounds on the number of neurons (A), the total neurite network (B) and the total number of branching points (C) in a primary culture of cortical neurons.
  • Figure 17 shows the effect of tested compounds on the number of neurons (A), the total neurite network (B) and the total number of branching points (C) in a primary culture of cortical neurons.
  • the above represents a generic synthesis route for compounds 044-051 starting from (6aR,9R)-Lysergic Acid.
  • the above represents a generic synthesis route for compounds 052-055, 073-082, 086-090 starting from (6aR,9R)-Lysergic Acid.
  • Salt formation is undertaken thereafter in the above routes as necessary, e.g. to give the benzoate, fumarate, citrate, acetate, succinate, halide, fluoride, chloride, bromide, iodide, oxalate, or triflate salt.
  • the addition of hydrogen chloride would provide the chloride salt and benzoic acid would give the benzoate salt.
  • a method of synthesis of any of the herein described compounds there is provided a method of synthesis of compound 001, 002, 003, 004, 005, 006, 007, 008, 009, 010, 011, 012, 013, 014, 015, 016, 017, 018 or 019 as herein disclosed.
  • HTR1A PathHunter® express HTR1A CHO-K1 P-Arrestin GPCR Assay 93-0696E2CP0M 200 dp (2 x 96-well)
  • MULTISCREENTM HEK293T Cell Line Stably Expressing Human 5-HT1A Receptor, Catalog DC1319a MULTISCREENTM HEK293T Cell Line Stably Expressing Human 5-HT1B Receptor, Catalog DC1320a MULTISCREENTM HEK293T Cell Line Stably Expressing Human 5HT1B Receptor, Catalog DC1320a MULTISCREENTM CHO-K1 Cell Line Stably Expressing Human 5-HT2A Receptor, Catalog DC1324-1 MULTISCREENTM CHO-K1 Cell Line Stably Expressing Human 5-HT2B Receptor, Catalog DC1325-1 MULTISCREENTM CHO-K1 Cell Line Stably Expressing Human 5-HT2C Receptor, Catalog DC1326-1 MULTISCREENTM HEK293T Cell Line Stably Expressing Human 5-HT7 Receptor, Catalog DC1334 For the B-arrestin assays the cells came with the kits apart from the 2b receptor assay (Valiscreen
  • Example 3 Effects of compounds 018 and 019 (several concentrations) on the neurite network (neurogenesis) in a primary culture of cortical neurons
  • Neuronal plasticity corresponds to the ability of the nervous system to reorganized itself by making new connections through neurogenesis, neuritogenesis and synaptogenesis. Lack of neuronal plasticity is found in neurodegenerative diseases, neurological disorders and during biological aging, or senescence. Low neuronal plasticity is associated with cognitive decline, depression and psychiatric diseases.
  • the aim of this study was to assess the effect of several test compounds (3-5 concentrations) on the number of neurons, the outgrowth of neurite network of cortical neurons, and the number of branching points, after 3 days of treatment. The treatment was applied on day 1 of culture.
  • Rat cortical neurons were cultured as described by Callizot et al., 2013 with modifications. Briefly pregnant female rat (Wistar) of 15 days of gestation was killed using a deep anesthesia with CO2 chamber and a cervical dislocation. Fetuses were collected and immediately placed in ice-cold L15 Leibovitz medium with a 2 % penicillin (10,000 U/mL) and streptomycin (10 mg/mL) solution (PS) and 1 % bovine serum albumin (BSA). Cortex were specifically dissected and then were treated for 20 min at 37 °C with a trypsin-EDTA solution at a final concentration of 0.05 % trypsin and 0.02 % EDTA.
  • PS penicillin
  • BSA bovine serum albumin
  • DMEM Dulbecco's modified Eagle's medium
  • FCS 10 % fetal calf serum
  • BDNF brain-derived neurotrophic factor
  • Viable cells were counted in a Neubauer cytometer, using the trypan blue exclusion test. The cells were seeded at a density of 25,000 per well in 96- well plate precoated with poly-L-lysine and were cultured at 37 °C in an air (95 %) - CO2 (5 %) incubator. For 96 well-plates, only 60 wells were used. The wells of first and last lines and columns were not used (to avoid any edge effect) and were filled with sterile water. Test compounds
  • Vehicle culture medium, 0.1% DMSO, or 0.1% acetonitrile, or 0.1% water.
  • the anti-MAP-2 antibody was revealed with a secondary Alexa Fluor 488 coupled goat anti-chicken antibody diluted at 1/400 in PBS containing 1 % FCS, 0.1 % saponin, for 1 hour at room temperature.
  • Test compounds were applied the day of the seeding, for 3 days.
  • BDNF 50 ng/ml
  • the positive control significantly increased the number of neurons, on the length of the neurite network and on the number of branching points.
  • DiPT applied from 0.1 ⁇ M to 10 ⁇ M
  • Psilocin increased the number of neurons (0.3 ⁇ M and 10 ⁇ M), promoted neurite outgrowth (0.3), and increased the number of branching points (10 ⁇ M). Maximal effect ranged between 0.3 and 10 ⁇ M, depending on the readouts. Psilocin was equivalent to BDNF in terms of efficacy.
  • Norpsilocin did not show any significant effect on the number of neurons and on neurite outgrowth. At 1 ⁇ M, this compound significantly increased the number of branching points.
  • Ergoline 18 from 0.1 ⁇ M to 10 ⁇ M
  • ergoline 19 from 0.1 ⁇ M to 10 ⁇ M
  • BDNF 50 ng/ml
  • the positive control significantly increased the number of neurons, on the length of the neurite network and on the number of branching points.
  • Ergoline 18 increased the number of neurons (0.3 ⁇ M and 1 ⁇ M), promoted neurite outgrowth (0.3 ⁇ M and 1 ⁇ M), and increased the number of branching points (from 0.1 to 10 ⁇ M). Maximal effect was observed between 0.3 and 10 ⁇ M, depending on the readouts
  • Ergoline 19 did not show any significant effect on the number of neurons but supported the neurite outgrowth (0.1 ⁇ M) and increased the number of branching points (from 0.1 to 1 ⁇ M, maximal effect at 0.3 ⁇ M).
  • ergoline 18 showed a stronger effect on branching points at 0.1 and 0.3 ⁇ M when compared to BDNF.
  • Psilocybin (from 0.1 ⁇ M to 10 ⁇ M) were applied the day of the seeding and let for 3 days.
  • BDNF 50 ng/ml
  • the positive control significantly increased the number of neurons, on the length of the neurite network and on the number of branching points.
  • Psilocybin increased the number of neurons (0.3 ⁇ M to 10 ⁇ M), promoted the neurite outgrowth (0.3 ⁇ M and 1 ⁇ M), and increased the number of branching points (from 0.3 ⁇ M).
  • Ergoline 018 showed strong beneficial effects on all investigated parameters.
  • Ergoline 019 displayed beneficial effects on neurite outgrowth and branching points.
  • Salt formation is undertaken thereafter in the above routes as necessary, e.g. to give the benzoate, fumarate, citrate, acetate, succinate, halide, fluoride, chloride, bromide, iodide, oxalate, or triflate salt.
  • the addition of hydrogen chloride would provide the chloride salt and benzoic acid would give the benzoate salt.
  • the reaction mixture was diluted with hexane (23mL) and cooled to -20°C for 18h.
  • the yellow precipitate was collected by suction filtration, washed with hexane (3 x 5mL) and dried to afford 1 as a yellow powder (2.73g, 90%) that was used directly.
  • T005, T008 and T018 were assayed using a serotonin (1a, 1b, 2a, 2c and 7 receptors) cAMP assay, provided by Multispan.
  • the reference used was 10 ⁇ M forskolin (a cAMP activator) to calculate the percentage relative response, serotonin was used as the control.
  • the results can be seen in Figure 10.
  • the results indicate T005 may have some activation of the cAMP pathway and subsequent cascade.
  • HTR1A PathHunter® express HTR1A CHO-K1 P-Arrestin GPCR Assay 93-0696E2CP0M 200 dp (2 x 96-well)
  • MULTISCREENTM HEK293T Cell Line Stably Expressing Human 5-HT1A Receptor, Catalog DC1319a MULTISCREENTM HEK293T Cell Line Stably Expressing Human 5-HT1B Receptor, Catalog DC1320a MULTISCREENTM HEK293T Cell Line Stably Expressing Human 5HT1B Receptor, Catalog DC1320a MULTISCREENTM CHO-K1 Cell Line Stably Expressing Human 5-HT2A Receptor, Catalog DC1324-1 MULTISCREENTM CHO-K1 Cell Line Stably Expressing Human 5-HT2B Receptor, Catalog DC1325-1 MULTISCREENTM CHO-K1 Cell Line Stably Expressing Human 5-HT2C Receptor, Catalog DC1326-1 MULTISCREENTM HEK293T Cell Line Stably Expressing Human 5-HT7 Receptor, Catalog DC1334 For the B-arrestin assays the cells came with the kits apart from the 2b receptor assay (Valiscreen
  • Example 7 Effects of compounds T005, T008 and T017 (several concentrations) on the neurite network (neurogenesis) in a primary culture of cortical neurons
  • Neuronal plasticity corresponds to the ability of the nervous system to reorganised itself by making new connections through neurogenesis, neuritogenesis and synaptogenesis. Lack of neuronal plasticity is found in neurodegenerative diseases, neurological disorders and during biological aging, or senescence. Low neuronal plasticity is associated with cognitive decline, depression and psychiatric diseases.
  • the aim of this study was to assess the effect of several test compounds (3-5 concentrations) on the number of neurons, the outgrowth of neurite network of cortical neurons, and the number of branching points, after 3 days of treatment. The treatment was applied on day 1 of culture.
  • Rat cortical neurons were cultured as described by Callizot et al., 2013 with modifications. Briefly pregnant female rat (Wistar) of 15 days of gestation was killed using a deep anesthesia with CO2 chamber and a cervical dislocation. Fetuses were collected and immediately placed in ice-cold L15 Leibovitz medium with a 2 % penicillin (10,000 U/mL) and streptomycin (10 mg/mL) solution (PS) and 1 % bovine serum albumin (BSA). Cortex were specifically dissected and then were treated for 20 min at 37 °C with a trypsin-EDTA solution at a final concentration of 0.05 % trypsin and 0.02 % EDTA.
  • PS penicillin
  • BSA bovine serum albumin
  • DMEM Dulbecco's modified Eagle's medium
  • FCS 10 % fetal calf serum
  • BDNF brain-derived neurotrophic factor
  • Viable cells were counted in a Neubauer cytometer, using the trypan blue exclusion test. The cells were seeded at a density of 25,000 per well in 96-well plate precoated with poly-L-lysine and were cultured at 37 °C in an air (95 %) - CO2 (5%) incubator. For 96 well-plates, only 60 wells were used. The wells of first and last lines and columns were not used (to avoid any edge effect) and were filled with sterile water.
  • BDNF brain-derived neurotrophic factor
  • Vehicle culture medium, 0.1% DMSO, or 0.1% acetonitrile, or 0.1% water.
  • the anti-MAP-2 antibody was revealed with a secondary Alexa Fluor 488 coupled goat anti-chicken antibody diluted at 1/400 in PBS containing 1 % FCS, 0.1 % saponin, for 1 hour at room temperature.
  • Test compounds were applied the day of the seeding, for 3 days.
  • BDNF 50 ng/ml
  • the positive control significantly increased the number of neurons, on the length of the neurite network and on the number of branching points.
  • DiPT applied from 0.1 ⁇ M to 10 ⁇ M
  • 5-MeO-DMT, psilocin and norpsilocin were applied the day of the seeding and let for 3 days.
  • BDNF 50 ng/ml
  • the positive control significantly increased the number of neurons, on the length of the neurite network and on the number of branching points.
  • 5-MeO-DMT increased the number of neurons (0.3 ⁇ M and 1 ⁇ M), promoted neurite outgrowth (0.3 ⁇ M to 10 ⁇ M), and increased the number of branching points (0.3 ⁇ M). Maximal effect was observed at 0.3 ⁇ M.
  • Psilocin increased the number of neurons (0.3 ⁇ M and 10 ⁇ M), promoted neurite outgrowth (0.3), and increased the number of branching points (10 ⁇ M). Maximal effect ranged between 0.3 and 10 ⁇ M, depending on the readouts. Psilocin was equivalent to BDNF in terms of efficacy.
  • Norpsilocin did not show any significant effect on the number of neurons and on neurite outgrowth. At 1 ⁇ M, this compound significantly increased the number of branching points.
  • Tryptamine 5, tryptamine 8 and tryptamine 18 were applied the day of the seeding and let for 3 days.
  • BDNF 50 ng/ml
  • the positive control significantly increased the number of neurons, on the length of the neurite network and on the number of branching points.
  • Tryptamine 8 increased the number of neurons (1 ⁇ M only), promoted neurite outgrowth (0.1 ⁇ M only), and increased the number of branching points (from 0.1 ⁇ M to 1 ⁇ M, with a maximal effect at 0.1 ⁇ M).
  • Psilocybin (from 0.1 ⁇ M to 10 ⁇ M) were applied the day of the seeding and let for 3 days.
  • BDNF 50 ng/ml
  • the positive control significantly increased the number of neurons, on the length of the neurite network and on the number of branching points.
  • Psilocybin increased the number of neurons (0.3 ⁇ M to 10 ⁇ M), promoted the neurite outgrowth (0.3 ⁇ M and 1 ⁇ M), and increased the number of branching points (from 0.3 ⁇ M).
  • DiPT, 5-MeO-DMT, psilocin and psilocybin displayed a strong beneficial effect on all investigated parameters indicating that these compounds have a positive effect on neuronal plasticity.
  • 5-MeO-DALT and norpsilocin displayed beneficial effect restricted to neurite outgrowth and/or branching points. Indeed, these two compounds did not support any increase in the number of neurons.
  • Tryptamine 005 and 008 showed strong beneficial effects on all investigated parameters.
  • Salt formation is undertaken thereafter in the above routes as necessary, e.g. to give the benzoate, fumarate, citrate, acetate, succinate, halide, fluoride, chloride, bromide, iodide, oxalate, or triflate salt.
  • the addition of hydrogen chloride to a freebase form would provide the chloride salt form and benzoic acid would give the benzoate salt form.
  • Example 9 Further investigations into the neurogenesis effect of select compounds in a primary cuIture of cortical neurons
  • the aim of this study was to assess the effect of several test compounds, co-applied with antagonists of 5-HT receptors, on the neurite network of cortical neurons, after 3 days of treatment starting on day 1 of culture.
  • the primary culture of cortical neurons was prepared as set out in Example 3.
  • Step 1 Dose selection of antagonist of 5-HT receptors
  • Step 2 Co-application of test compounds and antagonist of 5-HT receptors
  • Example 3 apart from the use of a secondary antibody goat anti-mouse IgG coupled with an Alexa Fluor 488 for revealing the anti-MAP-2 antibody.
  • a compound for use in treating a condition benefiting from an increase in neural plasticity wherein the compound is of Formula (l)A wherein:
  • X is selected from methyl or isopropyl
  • Y is selected from a bond, O, CONH, NH, N(C 1-6 alkyl), A-(CH 2 ) n -B, wherein
  • A is O, NH or N(C 1-6 alkyl), wherein
  • B is a bond, O, or NH, wherein n is 1 to 4.
  • Z is selected from H, OH, NH 2 , NHC 1-6 alkyl, N(C 1-6 alkyl)2, C 1-6 alkyl, C 6 - 10 aryl, SO 2 -C 1-6 alkyl, SO 2 -C 6-10 aryl, C 3 -C 10 heteroaromatic or heterocyclic group comprising one, two or three heteroatoms independently selected from O and N; and wherein X and Z are different; or a pharmaceutically acceptable salt thereof, and wherein the compound increases neural plasticity in a subject treated with the compound.
  • A is O or NH, wherein
  • B is a bond, O or NH, wherein n is 1 to 4.
  • a compound for use in treating a condition benefiting from neurogenesis, neurite outgrowth or an increase in neuronal branching points wherein the compound is and wherein the compound increase or promotes neurogenesis, neurite outgrowth or neuronal branching points in a subject treated with the compound.
  • a compound for use in treating a condition benefiting from neurite outgrowth or an increase in neuronal branching points wherein the compound is and wherein the compound increase or promotes neurite outgrowth or neuronal branching points in a subject treated with the compound.
  • a pharmaceutical composition comprising a pharmaceutically effective amount of a compound as defined in any one of clauses 1 to 16. 18. The pharmaceutical composition of clause 17, wherein the composition comprises a dosage amount in the range of 0.05mg to 100mg.
  • composition comprises a dosage amount in the range of 0.1mg to 50mg.
  • composition comprises a dosage amount in the range of 0.5mg to 25mg.
  • composition for use of any one of clauses 17 to 22, wherein the composition is administered one or more times a month.
  • the pharmaceutical composition for use of any one of clauses 17 to 22, wherein the composition is administered one or more times a week.
  • composition is administered one or more times a day.
  • a compound for use in treating a condition benefiting from an increase in neural plasticity, wherein the compound is of Formula (l)B wherein:
  • R 1 is selected from H or C 1-6 alkyl
  • R 2 is CH 2 -CHR 4 -NR 5 R 6 , wherein
  • R 4 is selected from H or C 1-6 alkyl, wherein
  • R 5 is selected from H or C 1-6 alkyl, wherein
  • R 6 is: a) wherein X is a bond, Y is N, Z is O and R 7 and R 8 together from a bringing group CH 2 CH 2 ; or b) wherein X is NH or O, Y is CH, Z is O and R 7 and R 8 are H; or c) NH(CH 2 ) 3 N(CH 3 ) 2 , O(CH 2 )OH or O(CH 2 ) 2 N(CH 3 ) 2 .
  • R 3 is selected from H or L-R 9 , wherein
  • L is selected from O, N, NH, O-O, CH 2 , CH 2 CH 2 , O-O-CH 2 CH 2 , CO, OCO, COO or OCONH, wherein
  • R 9 is selected from H, Ci-s alkyl, COOH, OH, COO-, O-, C 6 -C 10 aromatic, C 3 -C 10 heteroaromatic or heterocyclic group comprising one, two or three heteroatoms independently selected from O and N; and
  • a pharmaceutical composition comprising a compound or salt as defined in any one of clauses 26 to 46.
  • a pharmaceutical composition comprising a pharmaceutically effective amount of a compound of formula: for use in treating a condition benefiting from an increase in neural plasticity, wherein the compound increases neural plasticity in a patient in need thereof.
  • a pharmaceutical composition comprising a pharmaceutically effective amount of a compound of formula: for use in treating a condition benefiting from an increase in neural plasticity, wherein the compound increases neural plasticity in a patient in need thereof.
  • R 1 is (CH 2 ) m NR 4 (R 5 ) wherein: m is selected from 1, 2, 3, 4, 5, 6, 7, or 8;
  • R 4 is C 1-6 alkyl
  • R 5 is C 1-6 alkyl
  • R 2 is H or C(O)C 1-6 alkyl
  • R 3 is O-X-Y wherein:
  • Y is -(CH 2 ) n -NH 2 ; -(CH 2 ) n -NHR 13 ; -(CH 2 ) n -NR 14 R 15 ; -C(O)CHR 1S R 17 ;
  • R 6 to R 21 are independently H or C 1-4 alkyl groups and R 22 is a C 1-8 alkyl group n is independently 1 to 4
  • a pharmaceutical composition comprising a pharmaceutically effective amount of a compound as in any one of clauses 70 to 74.
  • a combination pharmaceutical comprising: (a) compound of Formula (l)D wherein:
  • X is selected from H or CMO branched or straight chain alkyl, and optionally wherein X is methyl or isopropyl;
  • Y is selected from a bond, O, CONK, NH, N(C 1-6 alkyl), A-(CH 2 ) n -B, wherein
  • A is O, NH or N(C 1-6 alkyl), wherein B is a bond, O, or NH, wherein n is 1 to 4;
  • Z is selected from H, OH, NH 2 , NHC 1-6 alkyl, N(C 1-6 alkyl) 2 , C 1-6 alkyl, C 6-10 aryl, SO 2 -C 1-6 alkyl, SO 2 -C 6-10 aryl, C 3 -C 10 heteroaromatic or heterocyclic group comprising one, two or three heteroatoms independently selected from O and N; wherein X and Z are different; or a pharmaceutically acceptable salt thereof; and

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Abstract

This invention relates to pharmaceutically acceptable ergoline and tryptamine-based compounds (e.g. analogues, prodrugs and salts thereof). In particular, though not exclusively, the invention relates to formulations and uses of the same as a medicament, alone or in combination with additional pharmaceutically acceptable compounds.

Description

ERGOLINE AND TRYPTAMINE-BASED COMPOUNDS, AND USES OF THE SAME FIELD OF THE INVENTION This invention relates to pharmaceutically acceptable ergoline and tryptamine-based compounds (e.g. analogues, prodrugs and salts thereof). In particular, though not exclusively, the invention relates to formulations and uses of the same as a medicament, alone or in combination with additional pharmaceutically acceptable compounds. BACKGROUND TO THE INVENTION Neuropsychiatric diseases, including mood and anxiety disorders, are some of the leading causes of disability worldwide and place an enormous economic burden on society. Approximately one third of patients will not respond to current antidepressant drugs, and those who do will usually require at least 2 to 4 weeks of treatment before they experience any beneficial effects. Evidence from a combination of human imaging, post-mortem studies, and animal models suggest that atrophy of neurons in the prefrontal cortex plays a key role in the pathophysiology of depression and related disorders. These structural changes, such as the retraction of neurites and loss of dendritic spines, can potentially be counteracted by compounds capable of promoting structural and functional neural plasticity. The non-classical psychedelic ketamine has shown clinical potential as a fast-acting antidepressant and anxiolytic, exhibiting efficacy in treatment-resistant populations. Animal models suggest that its therapeutic effects stem from its ability to promote the growth of dendritic spines, increase the synthesis of synaptic proteins, and strengthen synaptic responses. Clinical studies have demonstrated the potential for using psychedelic compounds to treat a variety of neuropsychiatric disorders including depression, anxiety, addiction, and posttraumatic disorders. However, their therapeutic mechanism of action is poorly understood, and concerns about safety have limited their use. Various synthetic modifications to the structure of various psychedelic compounds, such as to the ergoline LSD, have been made in the prior art. However, such modifications often result in a decrease in activity. Ineffective docking/binding of these compounds to the appropriate receptors may result from such structural modifications. The ergoline structure is the basis for a class of alkaloids including the well-known lysergic acid diethylamide (LSD).
Figure imgf000003_0001
LSD There remains a need in the art for improved psychedelic compounds and compositions and uses thereof. SUMMARY OF THE INVENTION First Aspect Definitions of chemical groups/names under the first aspect e.g. substituents X, Y and Z, relate to the chemical structures falling under the first aspect and any embodiments thereof. Similarly, numbering of chemical structures under this aspect relate to this aspect. Herein disclosed is there is provided a method of increasing neural plasticity. The method includes contacting a neuronal cell with an ergoline analogue, in an amount sufficient to increase neural plasticity of the neuronal cell. Herein disclosed is there is provided a method of treating a brain disorder. The method includes administering to a subject in need thereof a therapeutically effective amount of an ergoline analogue, thereby treating the brain disorder, wherein the ergoline analogue increases neural plasticity of the neuronal cell. The neuronal cells can be any type of neuron cells. In some embodiments, the neuron cell is a cortical neuron cell. In some embodiments, the neuron cell is a cortical pyramidal neuron cell. In a first aspect there is provided a compound for use in treating a condition benefiting from an increase in neural plasticity, wherein the compound is of Formula (I)A wherein:
Figure imgf000004_0001
X is selected from methyl or isopropyl; and Y is selected from a bond, O, CONH, NH, N(C1-6 alkyl), A-(CH2)n-B, wherein A is O, NH or N(C1-6 alkyl), wherein B is a bond, O, or NH, wherein n is 1 to 4; and Z is selected from H, OH, NH2, NHC1-6 alkyl, N(C1-6 alkyl)2, C1-6 alkyl, C6-10 aryl, SO2-C1-6 alkyl, SO2-C6-10 aryl, C3-C10 heteroaromatic or heterocyclic group comprising one, two or three heteroatoms independently selected from O and N; and wherein X and Z are different; or a pharmaceutically acceptable salt thereof, and wherein the compound increases neural plasticity in a subject treated with the compound. Hereafter, under this aspect, Formula (I)A may simply be referred to as Formula (I). In an embodiment, X is methyl. In an embodiment, X is isopropyl. In an embodiment, Y is selected from a bond, O, CONH, NH or NCH3. In an embodiment, Y is A-(CH2)n-B, wherein A is O or NH, wherein B is a bond, O or NH, wherein n is 1 to 4. In an embodiment, n is 2 or 3. In an embodiment, Z is selected from pyridine, morpholine, SO2-CH3, SO2-phenyl, 8-oxa-3-azabicyclo[3.2.1]octane and 2-oxa-5-azabicyclo[2.2.1]heptane. In an embodiment, Y-Z together are H or C1-6 alkyl. In an embodiment, Y-Z together are H or C5 alkyl. In an embodiment, Y-Z together form the group: O-(CH2)3-N(CH3)2, NH-(CH2)2-OH, NH-(CH2)3-OH, NH-(CH2)3-OCH3, NH-(CH2)3-SO2CH3, NH- (CH2)2-NH-SO2CH3, or O-(CH2)2-NH-SO2CH3. In an embodiment, Y-Z together form the group: NH-phenyl, pyridine, O-morpholine, NH-morpholine, NH-SO2-Phenyl, NCH3-SO2-Phenyl, CONH-Phenyl, 8-oxa-3-azabicyclo[3.2.1]octane or 2-oxa-5- azabicyclo[2.2.1]heptane. In an embodiment, the compound is selected from:
Figure imgf000005_0001
Figure imgf000006_0001
Figure imgf000007_0001
or
Figure imgf000007_0002
. In an embodiment, the compound is .
Figure imgf000007_0003
In an embodiment, the compound is
Figure imgf000007_0004
. In an embodiment, there is provided a compound for use in treating a condition benefiting from neurogenesis, neurite outgrowth or an increase in neuronal branching points, wherein the compound is
Figure imgf000007_0005
and wherein the compound increase or promotes neurogenesis, neurite outgrowth or neuronal branching points in a subject treated with the compound. In an embodiment, there is provided a compound for use in treating a condition benefiting from neurite outgrowth or an increase in neuronal branching points, wherein the compound is
Figure imgf000008_0001
and wherein the compound increase or promotes neurite outgrowth or neuronal branching points in a subject treated with the compound. In an embodiment, the condition is a brain disorder or neuropsychiatric disease. In an embodiment, the brain disorder is a psychiatric disorder including depression, anxiety, and/or post-traumatic stress disorder. In some embodiments, the brain disorder is depression. In some embodiments, the brain disorder is anxiety. In other embodiments, the brain disorder is post-traumatic stress disorder. The psychiatric disorder is a behavioral or mental pattern that may cause suffering or a poor ability to function in life. Such features may be persistent, relapsing and remitting, or occur as a single episode. Depression is related to a mood disorder involving unusually intense and sustained sadness, melancholia, or despair. Anxiety or fear that interferes with normal functioning may be classified as an anxiety disorder. Commonly recognized categories include specific phobias, generalized anxiety disorder, social anxiety disorder, panic disorder, agoraphobia, obsessive- compulsive disorder and post-traumatic stress disorder. In an embodiment, the brain disorder is a substance use disorder. Addiction and dependence are components of a substance use disorder and addiction represents the most severe form of the disorder. In an embodiment, the brain disorder is a neurodegenerative disorder including Alzhemier's and/or Parkinson's diseases. In some embodiments, the brain disorder is Alzhemier's disease. In other embodiments, the brain disorder is Parkinson's diseases. Neurodegeneration is the progressive loss of structure or function of neurons, including death of neurons. Many neurodegenerative diseases including amyotrophic lateral sclerosis, Parkinson's, Alzheimer's, and Huntington's occur as a result of neurodegenerative processes. In an embodiment, there is provided a pharmaceutical composition comprising a pharmaceutically effective amount of a compound as subsequently or previously described. In an embodiment, the composition comprises a dosage amount in the range of 0.05mg to 100mg. In an embodiment, the composition comprises a dosage amount in the range of 0.1mg to 50mg. In an embodiment, the composition comprises a dosage amount in the range of 0.5mg to 25mg. In an embodiment, the composition is formulated in a dosage form selected from: oral, transdermal, inhalable, intravenous, or rectal dosage form. In an embodiment, the composition is formulated in a dosage form selected from: tablet, capsule, granules, powder, free-flowing powder, inhalable powder, aerosol, nebulised, vaping, buccal, sublingual, sublabial, injectable, or suppository dosage form. In an embodiment, the composition is administered one or more times a month. In an embodiment, the composition is administered one or more times a week. In an embodiment, wherein the composition is administered one or more times a day. Herein disclosed is a compound of Formula (I) wherein:
Figure imgf000009_0002
X is selected from H or C1-6 alkyl (optionally, X is methyl or isopropyl); and Y is selected from a bond, O, CONH, NH, N(C1-6 alkyl), A-(CH2)n-B, wherein A is O, NH or N(C1-6 alkyl), wherein B is a bond, O, or NH, wherein n is 1 to 4; and Z is selected from H, OH, NH2, NHC1-6 alkyl, N(C1-6 alkyl)2, C1-6 alkyl, C6-10 aryl, SO2-C1-6 alkyl, SO2-C6-10 aryl, C3-C10 heteroaromatic or heterocyclic group comprising one, two or three heteroatoms independently selected from O and N; and wherein X and Z are different; or is a pharmaceutically acceptable salt thereof. Herein disclosed, there is provided compound of Formula (I) wherein:
Figure imgf000009_0001
X is selected from methyl or isopropyl; and Y is selected from a bond, O, CONH, NH, N(C1-6 alkyl), A-(CH2)n-B, wherein A is O, NH or N(C1-6 alkyl), wherein B is a bond, O, or NH, wherein n is 1 to 4; and Z is selected from H, OH, NH2, NHC1-6 alkyl, N(C1-6 alkyl)2, C1-6 alkyl, C6-10 aryl, SO2-C1-6 alkyl, SO2-C6-10 aryl, C3-C10 heteroaromatic or heterocyclic group comprising one, two or three heteroatoms independently selected from O and N; and wherein X and Z are different; or a pharmaceutically acceptable salt thereof. In an embodiment the alkyl group is straight, branched or a cyclic alkyl group. In an embodiment the alkyl group is a straight chain alkyl group. In an embodiment the alkyl group contains 1, 2 or 3 halogens. In an embodiment X is methyl. In an embodiment X is isopropyl. In an embodiment Y is selected from a bond, O, CONH, NH or NCH3. In an embodiment Y is A-(CH2)n-B, wherein A is O or NH, wherein B is a bond, O or NH, wherein n is 1 to 4. In an embodiment n is 2 or 3. In an embodiment Z is selected from pyridine, morpholine, SO2-CH3, SO2-phenyl, 8-oxa-3-azabicyclo[3.2.1]octane and 2-oxa-5-azabicyclo[2.2.1]heptane. In an embodiment Y-Z together form the group: O-(CH2)3-N(CH3)2 NH-(CH2)2-OH NH-(CH2)3-OH NH-(CH2)3-OCH3 NH-(CH2)3-SO2CH3 NH-(CH2)2-NH-SO2CH3, or O-(CH2)2-NH-SO2CH3. In an embodiment Y-Z together form the group: NH-phenyl, pyridine, O-morpholine, NH-morpholine, NH-SO2-Phenyl, NCH3-SO2-Phenyl, CONH-Phenyl, 8-oxa-3-azabicyclo[3.2.1]octane or 2-oxa-5-azabicyclo[2.2.1]heptane. In an embodiment there is provided one or more compounds selected from:
Figure imgf000010_0001
Figure imgf000011_0001
Figure imgf000012_0001
Figure imgf000013_0001
Figure imgf000014_0002
In an embodiment there is provided one or more compounds selected from:
Figure imgf000014_0001
Figure imgf000015_0002
It should be understood that the molecules depicted in this application in the protonated form (e.g. with protonated amine groups) also include within their scope/meaning the corresponding molecules in the free base form, and vice versa. The protonated form of these molecules being readily accessible by the addition of an acid to the free base form of these molecules. For example, the protonated form of Compound 5 can be made from the (free base form of) Compound 5 by the addition of an acid, e.g. addition of acid 'H-A' gives the protonated form of compound 5 and where the corresponding counter ion is A-. As such if H-A is H-CI the corresponding anion is CI-, whereas if H-A is H-benzoate the counter ion will be a benzoate anion. While within the scope of an embodiment of the invention, for the purposes of simplicity only, compounds 1 to 025 (and elsewhere in this specification) have not been drawn in all possible salt forms e.g. with anions selected from benzoate, fumarate, citrate, acetate, succinate, halide, fluoride, chloride, bromide, iodide, oxalate, or triflate salt.
In an embodiment, there is provided one or more compounds selected from:
Figure imgf000015_0001
Figure imgf000016_0001
In an embodiment there is provided a composition comprising a pharmaceutically effective amount of a compound as described previously. In an embodiment, the nitrogen atom on the core six-membered ring is not methylated (e.g. Compound 025 is not methylated). In an embodiment, the nitrogen atom on the core six-membered ring is methylated (e.g. Compound 025 is methylated).
In an embodiment the composition comprises a dosage amount in the range of 0.05mg to 100mg. In an embodiment the composition comprises a dosage amount in the range of 0.1mg to 50mg. In an embodiment the composition comprises a dosage amount in the range of 0.5mg to 25mg. In an embodiment the composition comprises a dosage amount in the range of 0.5mg to 10mg. In an embodiment the composition comprises a dosage amount in the range of 1mg to 10mg. In an embodiment the composition comprises a dosage amount in the range of lmg to 8mg. In an embodiment the composition comprises a dosage amount in the range of 3mg to 15mg. In an embodiment the composition comprises a dosage amount in the range of 0.005mg to 100mg. In an embodiment the composition comprises a dosage amount in the range of 0.001mg to 100mg. In an embodiment the composition comprises a dosage amount in the range of 0.0005mg to 100mg. The level of the active agent can be adjusted as required by need for example to suit a certain patient group (e.g. the elderly) or the conditions being treated.
In an embodiment the composition is formulated in a dosage form selected from: oral, transdermal, inhalable, intravenous, rectal dosage, intranasal, intramuscular, or any other parenteral form. In an embodiment the composition is formulated in a dosage form selected from: oral, transdermal, inhalable, intravenous or rectal dosage. It is advantageous to be able to deliver the active agent in different forms, for example to suit a certain patient group (e.g. the elderly) or the conditions being treated.
In an embodiment the composition is formulated in a dosage form selected from: tablet, capsule, granules, powder, free-flowing powder, inhalable powder, aerosol, nebulised, vaping, buccal, sublingual, sublabial, injectable, or suppository dosage form. In an embodiment the powder is suitable for administration by inhalation via a medicament dispenser selected from a reservoir dry powder inhaler, a unit-dose dry powder inhaler, a pre-metered multi-dose dry powder inhaler, a nasal inhaler or a pressurized metered dose inhaler.
In an embodiment the powder comprises particles, the particles having a median diameter of less than 2000μm, 1000μm, 500μm, 250μm, 100μm, 50μm, or 1μm. In an embodiment the powder comprises particles, the particles having a median diameter of greater than 500μm, 250μm, 100μm, 50μm, 1μm or 0.5μm. In an embodiment the powder comprises particles, and wherein the powder has a particle size distribution of d10=20-60μm, and/or d50=80-120μm, and/or d90=130-300μm. The nature of the powder can be adjusted to suit need. For example, if being made for nasal inhalation, then the particles may be adjusted to be much finer than if the powder is going to be formulated into a gelatine capsule, or differently again if it is going to be compacted into a tablet.
In an embodiment the compound is in the form of a salt which is amorphous or crystalline. In an embodiment the salt is in a polymorphic crystalline form. In an embodiment the salt is a benzoate, fumarate, citrate, acetate, succinate, halide, fluoride, chloride, bromide, iodide, oxalate, or triflate salt, optionally the salt is the chloride, benzoate or fumarate salt. In an embodiment the salt is formulated into a composition for mucosal delivery. In an embodiment, the salt is a benzoate salt. For the salt, the dosage amount is the equivalent amount of the free base delivered when the salt is taken. So 100 mg dosage amount may for example correspond to 117mg of a hydrochloride salt (i.e. both providing the same molar amount of the active substance). The greater mass of the salt needed is due to the larger formula weight of the hydrogen chloride salt. Similarly, for the deuterated or triturated version of the compounds of the invention (also considered within the scope of the invention), a slight increase in mass can be expected due to the increased formula weight of these isotopic compounds. Amorphous and crystalline substances often show different chemical/physical properties, e.g. improved rate of dissolution in a solvent, or improved thermal stability. Similarly, different polymorphs may also show different and useful chemical/physical properties. In an embodiment the composition comprises one or more pharmaceutically acceptable carriers or excipients.
In an embodiment the composition comprises one or more of: mucoadhesive enhancer, penetrating enhancer, cationic polymers, cyclodextrins, Tight Junction Modulators, enzyme inhibitors, surfactants, chelators, and polysaccharides.
In an embodiment the composition comprises one or more of: chitosan, chitosan derivatives (such as N,N,N- trimethyl chitosan (TMC), n-propyl-(QuatPropyl), n-butyl-(QuatButyl) and n-hexyl (QuatHexyl)-N,N-dimethyl chitosan, chitosan chloride), β-cyclodextrin, Clostridium perfringens enterotoxin, zonula occludens toxin (ZOT), human neutrophil elastase inhibitor (ER143), sodium taurocholate, sodium deoxycholate sodium, sodium lauryl sulphate, glycodeoxycholat, palmitic acid, palmitoleic acid, stearic acid, oleyl acid, oleyl alchohol, capric acid sodium salt, DHA, EPA, dipalmitoyl phophatidyl choline, soybean lecithin, lysophosphatidylcholine, dodecyl maltoside, tetradecyl maltoside, EDTA, lactose, cellulose, and citric acid.
In an embodiment the compound or composition defined herein above for use in a method of treatment of a human or animal subject by therapy.
In an embodiment the method of treatment is a method of treatment of: conditions caused by dysfunctions of the central nervous system, conditions caused by dysfunctions of the peripheral nervous system, conditions benefiting from sleep regulation (such as insomnia), conditions benefiting from analgesics (such as chronic pain), migraines, trigeminal autonomic cephalgias (such as shortlasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT), and short-lasting neuralgiform headaches with cranial autonomic symptoms (SUNA)), conditions benefiting from neurogenesis (such as stroke, traumatic brain injury, Parkinson's dementia), conditions benefiting from anti-inflammatory treatment, depression, anxiety, substance use disorder, addictive disorder, gambling disorder, eating disorders, obsessive-compulsive disorders, or body dysmorphic disorders, optionally the condition is SUNCT and/or SUNA.
Treatment of the above conditions may be beneficially improved by taking the invention. In an embodiment the method of treatment is a method of treatment of more than one of the above conditions, for example, the method of treatment may be a method of treatment of depression and anxiety. In an embodiment the composition is administered one or more times a year. In an embodiment the composition is administered one or more times a month. In an embodiment the composition is administered one or more times a week. In an embodiment the composition is administered one or more times a day. In an embodiment the composition is administered at such a frequency as to avoid tachyphylaxis. In an embodiment the composition is administered together with a complementary treatment and/or with a further active agent. In an embodiment the further active agent is a psychedelic compound, optionally a further tryptamine. In an embodiment the further active agent is a psychedelic compound, optionally a tryptamine. In an embodiment the further active agent is psilocybin, psilocin or a prodrug thereof. In an embodiment the complementary treatment is psychotherapy.
In an embodiment, there is provided a composition comprising a pharmaceutically effective amount of a compound as described herein for use in a method of treatment of treatment resistant depression. In an embodiment, there is provided a nasal inhalation composition comprising a pharmaceutically effective amount of a compound as described herein for use in a method of treatment of treatment resistant depression. Treatment of the above conditions may be beneficially improved by taking the invention together with some complementary treatments; also these treatments may occur much less regularly than some other treatments that require daily treatments or even multiple treatments a day. In an embodiment, there is provided DiPT, 5-MeO-DMT, psilocin or psilocybin, or a pharmaceutical composition comprising DiPT, 5-MeO- DMT, psilocin or psilocybin, for use in a method of increasing neural plasticity. In an embodiment, there is provided DiPT, 5-MeO-DMT, psilocin or psilocybin, or a pharmaceutical composition comprising DiPT, 5-MeO- DMT, psilocin or psilocybin, for use in a method of treating a condition wherein said condition would benefit from increasing neural plasticity. In an embodiment, there is provided DiPT, 5-MeO-DMT, psilocin or psilocybin, or a pharmaceutical composition comprising DiPT, 5-MeO-DMT, psilocin or psilocybin, for use in a method of neurogenesis. In an embodiment, there is provided DiPT, 5-MeO-DMT, psilocin or psilocybin, or a pharmaceutical composition comprising DiPT, 5-MeO-DMT, psilocin or psilocybin, for use in a method of treating a condition wherein said condition would benefit from neurogenesis. In an embodiment, there is provided DiPT, 5-MeO-DMT, psilocin or psilocybin, or a pharmaceutical composition comprising DiPT, 5-MeO- DMT, psilocin or psilocybin, for use in a method of promoting neurite outgrowth. In an embodiment, there is provided DiPT, 5-MeO-DMT, psilocin or psilocybin, or a pharmaceutical composition comprising DiPT, 5- MeO-DMT, psilocin or psilocybin, for use in a method of treating a condition wherein said condition would benefit from promotion of neurite outgrowth. In an embodiment, there is provided DiPT, 5-MeO-DMT, psilocin or psilocybin, or a pharmaceutical composition comprising DiPT, 5-MeO-DMT, psilocin or psilocybin, for use in a method of increasing the number of neuronal branching points. In an embodiment, there is provided DiPT, 5-MeO-DMT, psilocin or psilocybin, or a pharmaceutical composition comprising DiPT, 5-MeO- DMT, psilocin or psilocybin, for use in a method of treating a condition wherein said condition would benefit from increasing the number of neuronal branching points. In an embodiment, there is provided 5-MeO-DALT or norpsilocin, or a pharmaceutical composition comprising 5-MeO-DALT or norpsilocin, for use in a method of increasing neural plasticity. In an embodiment, there is provided 5-MeO-DALT or norpsilocin, or a pharmaceutical composition comprising 5-MeO-DALT or norpsilocin, for use in a method of treating a condition wherein said condition would benefit from increasing neural plasticity. In an embodiment, there is provided 5-MeO-DALT or norpsilocin, or a pharmaceutical composition comprising 5-MeO-DALT or norpsilocin, for use in a method of promoting neurite outgrowth. In an embodiment, there is provided 5- MeO-DALT or norpsilocin, or a pharmaceutical composition comprising 5-MeO-DALT or norpsilocin, for use in a method of treating a condition wherein said condition would benefit from promotion of neurite outgrowth. In an embodiment, there is provided 5-MeO-DALT or norpsilocin, or a pharmaceutical composition comprising 5-MeO-DALT or norpsilocin, for use in a method of increasing the number of neuronal branching points. In an embodiment, there is provided 5-MeO-DALT or norpsilocin, or a pharmaceutical composition comprising 5-MeO-DALT or norpsilocin, for use in a method of treating a condition wherein said condition would benefit from increasing the number of neuronal branching points. In an embodiment, there is provided any one of compounds 002-025, or a pharmaceutical composition comprising any one of compounds 002-025, for use in a method of increasing neural plasticity. In an embodiment, there is provided any one of compounds 002-025, or a pharmaceutical composition comprising any one of compounds 002-025, for use in a method of treating a condition wherein said condition would benefit from increasing neural plasticity. In an embodiment, there is provided any one of compounds 002- 025, or a pharmaceutical composition comprising any one of compounds 002-025, for use in a method of neurogenesis. In an embodiment, there is provided any one of compounds 002-025, or a pharmaceutical composition comprising any one of compounds 002-025, for use in a method of treating a condition wherein said condition would benefit from neurogenesis. In an embodiment, there is provided any one of compounds 002-025, or a pharmaceutical composition comprising any one of compounds 002-025, for use in a method of promoting neurite outgrowth. In an embodiment, there is provided any one of compounds 002-025, or a pharmaceutical composition comprising any one of compounds 002-025, for use in a method of treating a condition wherein said condition would benefit from promotion of neurite outgrowth. In an embodiment, there is provided any one of compounds 002-025, or a pharmaceutical composition comprising any one of compounds 002-025, for use in a method of increasing neural plasticity. In an embodiment, there is provided compound 018, or a pharmaceutical composition comprising compound 018, for use in a method of treating a condition wherein said condition would benefit from increasing neural plasticity. In an embodiment, there is provided compound 018, or a pharmaceutical composition comprising compound 018, for use in a method of neurogenesis. In an embodiment, there is provided compound 018, or a pharmaceutical composition comprising compound 018, for use in a method of treating a condition wherein said condition would benefit from neurogenesis. In an embodiment, there is provided compound 018, or a pharmaceutical composition comprising compound 018, for use in a method of promoting neurite outgrowth. In an embodiment, there is provided compound 018, or a pharmaceutical composition comprising compound 018, for use in a method of treating a condition wherein said condition would benefit from promotion of neurite outgrowth. In an embodiment, there is provided compound 019, or a pharmaceutical composition comprising compound 019, for use in a method of treating a condition wherein said condition would benefit from increasing neural plasticity. In an embodiment, there is provided compound 019, or a pharmaceutical composition comprising compound 019, for use in a method of promoting neurite outgrowth. In an embodiment, there is provided compound 019, or a pharmaceutical composition comprising compound 019, for use in a method of treating a condition wherein said condition would benefit from promotion of neurite outgrowth. In an embodiment, there is provided a method of increasing neuronal plasticity, said method comprising administering one or more of the compounds disclosed herein to a patient in a pharmaceutically acceptable amount. In an embodiment, there is provided a method of neurogenesis, said method comprising administering one or more of the compounds disclosed herein to a patient in a pharmaceutically acceptable amount. In an embodiment, there is provided a method of increasing neurite outgrowth, said method comprising administering one or more of the compounds disclosed herein to a patient in a pharmaceutically acceptable amount. In an embodiment, there is provided a method of the number of neuronal branching points, said method comprising administering one or more of the compounds disclosed herein to a patient in a pharmaceutically acceptable amount. Second Aspect Definitions of chemical groups/names under the second aspect e.g. substituents R1, R2 and R3 relate to the chemical structures falling under the second aspect and any embodiments thereof. Similarly, numbering of chemical structures under this aspect relate to this aspect. Various synthetic modifications to the structure of various psychedelic compounds, such as tryptamine have been made, e.g. structural changes at the 1, 4, 5, 6 and 7 positions. However, such modifications often result in a decrease in activity. Ineffective docking/binding of these compounds to the appropriate receptors may result from such structural modifications. The structure of tryptamine is a shared feature of certain aminergic neuromodulators including melatonin, serotonin, bufotenin as well as psychedelic derivatives such as dimethyltryptamine (DMT), psilocybin, psilocin.
Figure imgf000021_0001
Tryptamine There remains a need in the art for improved psychedelic compounds and compositions and uses thereof. In second aspect there is provided a compound for use in treating a condition benefiting from an increase in neural plasticity, wherein the compound is of Formula (I)B wherein:
Figure imgf000021_0002
R1 is selected from H or C1-6 alkyl; and R2 is CH2-CHR4-NR5R6, wherein R4 is selected from H or C1-6 alkyl, wherein R5 is selected from H or C1-6 alkyl, wherein R6 is:
Figure imgf000021_0003
wherein X is a bond, Y is N, Z is O and R7 and R8 together from a bringing group CH2CH2; or
Figure imgf000021_0004
wherein X is NH or O, Y is CH, Z is O and R7 and R8 are H; or NH(CH2)3N(CH3)2, O(CH2)OH or O(CH2)2N(CH3)2. R3 is selected from H or L-R9, wherein L is selected from O, N, NH, O-O, CH2, CH2CH2, O-O-CH2CH2, CO, OCO, COO or OCONH, wherein R9 is selected from H, C1-6 alkyl, COOH, OH, COO-, O-, C6-C10 aromatic, C3-C10 heteroaromatic or heterocyclic group comprising one, two or three heteroatoms independently selected from O and N; and K is CH, CH-CH=CR3 or NH-CH=CH-C(O); or is a pharmaceutically acceptable salt thereof, and wherein the compound increases neural plasticity in a subject treated with the compound. Hereafter, under this aspect, Formula (I)B may simply be referred to as Formula (I). In an embodiment, K is CH. In an embodiment, R1 is H, R2 is CH2-CHR4-NR5R6, R3 is H or L-R9, and K is CH. In an embodiment, R4 is H or methyl. In an embodiment, R5 is ethyl or isopropyl. In an embodiment, R4 is H and R5 is ethyl. In an embodiment, R3 is L-R9 and wherein L is O, O-O-CH2CH2, OCO or OCONH. In an embodiment, R3 is L-R9 and wherein R9 is OH, COCH3, imidazole, pyrrolidine, piperidine, analine, pyrideine, morpholine or 6- oxa-3-azabicyclo[3.1.1]heptane. In an embodiment, R3 is OCOCH3. In an embodiment, the compound is:
Figure imgf000022_0001
In an embodiment, the compound is:
Figure imgf000022_0002
In an embodiment, the compound is:
Figure imgf000022_0003
or
Figure imgf000022_0004
In an embodiment, the compound is:
Figure imgf000023_0001
In an embodiment, the compound is:
Figure imgf000023_0002
In an embodiment, the compound is:
Figure imgf000023_0003
In an embodiment, the compound is:
Figure imgf000023_0004
In an embodiment, the compound is:
Figure imgf000024_0001
In an embodiment, the compound is:
Figure imgf000024_0002
or
Figure imgf000024_0003
In an embodiment, the compound is:
Figure imgf000024_0004
, or
Figure imgf000024_0006
Figure imgf000024_0005
In an embodiment, the compound is:
Figure imgf000025_0001
In an embodiment, the compound is:
Figure imgf000025_0002
In an embodiment, there is provided a pharmaceutical composition comprising a compound or salt as defined subsequently or previously. In an embodiment, the composition comprises a dosage amount in the range of 0.05mg to 100mg. In an embodiment, the composition comprises a dosage amount in the range of 0.1mg to 50mg. In an embodiment, the composition comprises a dosage amount in the range of 0.5mg to 25mg. In an embodiment, the composition is formulated in a dosage form selected from: oral, transdermal, inhalable, intravenous, or rectal dosage form. In an embodiment, the composition is formulated in a dosage form selected from: tablet, capsule, granules, powder, free-flowing powder, inhalable powder, aerosol, nebulised, vaping, buccal, sublingual, sublabial, injectable, or suppository dosage form. In an embodiment, the composition is administered one or more times a month. In an embodiment, the composition is administered one or more times a week. In an embodiment, wherein the composition is administered one or more times a day. In an embodiment, there is provided a pharmaceutical composition comprising a pharmaceutically effective amount of a compound of formula:
Figure imgf000026_0001
for use in treating a condition benefiting from an increase in neural plasticity, wherein the compound increases neural plasticity in a patient in need thereof. In an embodiment, there is provided a pharmaceutical composition comprising a pharmaceutically effective amount of a compound of formula
Figure imgf000026_0002
for use in treating a condition benefiting from an increase in neural plasticity, wherein the compound increases neural plasticity in a patient in need thereof. In an embodiment, the patient has depression, anxiety, post-traumatic stress disorder or a neurodegenerative condition, or a combination thereof. In an embodiment, the condition is a brain disorder or neuropsychiatric disease. In an embodiment, the brain disorder is a psychiatric disorder including depression, anxiety, and/or post- traumatic stress disorder. In some embodiments, the brain disorder is depression. In some embodiments, the brain disorder is anxiety. In other embodiments, the brain disorder is post-traumatic stress disorder. The psychiatric disorder is a behavioral or mental pattern that may cause suffering or a poor ability to function in life. Such features may be persistent, relapsing and remitting, or occur as a single episode. Depression is related to a mood disorder involving unusually intense and sustained sadness, melancholia, or despair. Anxiety or fear that interferes with normal functioning may be classified as an anxiety disorder. Commonly recognized categories include specific phobias, generalized anxiety disorder, social anxiety disorder, panic disorder, agoraphobia, obsessive- compulsive disorder and post-traumatic stress disorder. In an embodiment, the brain disorder is a substance use disorder. Addiction and dependence are components of a substance use disorder and addiction represents the most severe form of the disorder. In an embodiment, the brain disorder is a neurodegenerative disorder including Alzhemier's and/or Parkinson's diseases. In some embodiments, the brain disorder is Alzhemier's disease. In other embodiments, the brain disorder is Parkinson's diseases. Neurodegeneration is the progressive loss of structure or function of neurons, including death of neurons. Many neurodegenerative diseases including amyotrophic lateral sclerosis, Parkinson's, Alzheimer's, and Huntington's occur as a result of neurodegenerative processes. Herein disclosed a compound of Formula (I)
Figure imgf000027_0001
wherein: R1 is selected from H or C1-6 alkyl; and R2 is selected from H, NH2-cyclopropyl or CH2-CHR4-NR5R6, wherein R4 is selected from H or C1-6 alkyl, wherein R5 is selected from H or C1-6 alkyl, wherein R6 is selected from C1-6 alkyl, A-(CH2)n-B or
Figure imgf000027_0002
, wherein A is NH or O, wherein B is NH2, NH(C1-6 alkyl), N(C1-6 alkyl)2 or OH, wherein n is 0 to 4, wherein X is a bond, NH or O, wherein Y is selected from CH, N, wherein Z is selected from CH2, O, NH or N(C1-6 alkyl), wherein R7 and R8 are H, or R7 and R8 together from a bridging group CH2CH2, CH2O or CH2NH, wherein R5 and R6 are different; and R3 is selected from H or L-R9, wherein L is selected from O, N, NH, O-O, CH2, CH2CH2, O-O-CH2CH2, CO, OCO, COO or OCONH, wherein R9 is selected from H, C1-6 alkyl, COOH, OH, COO-, O-, C6-C10 aromatic, C3-C10 hetroaromatic or heterocyclic group comprising one, two or three heteroatoms independently selected from O and N; and K is CH, or the group defined by K=CH-CH=CR3 is NH-CH=CH-C(O); or is a pharmaceutically acceptable salt thereof. Herein disclosed R5 and R6 are C1-6 alkyl groups. Herein disclosed R6 is methyl. Herein disclosed R6 is
Figure imgf000028_0001
and wherein X is a bond, Y is N, Z is O and R7 and R8 together from a bridging group CH2CH2. Herein disclosed R6 is
Figure imgf000028_0002
wherein X is NH or O, Y is CH, Z is O and R7 and R8 are H. Herein disclosed R6 is NH(CH2)3N(CH3)2, O(CH2)OH or O(CH2)2N(CH3)2. Herein disclosed, there is provided a compound of Formula (I) wherein:
Figure imgf000028_0003
R1 is selected from H or C1-6 alkyl; and R2 is CH2-CHR4-NR5R6, wherein R4 is selected from H or C1-6 alkyl, wherein R5 is selected from H or C1-6 alkyl, wherein R6 is:
Figure imgf000028_0004
wherein X is a bond, Y is N, Z is O and R7 and R8 together from a bringing group CH2CH2; or
Figure imgf000029_0001
wherein X is NH or O, Y is CH, Z is O and R7 and R8 are H; or NH(CH2)3N(CH3)2, O(CH2)OH or O(CH2)2N(CH3)2. R3 is selected from H or L-R9, wherein L is selected from O, N, NH, O-O, CH2, CH2CH2, O-O-CH2CH2, CO, OCO, COO or OCONH, wherein R9 is selected from H, C1-6 alkyl, COOH, OH, COO-, O-, C6-C10 aromatic, C3-C10 heteroaromatic or heterocyclic group comprising one, two or three heteroatoms independently selected from O and N; and K is CH, CH-CH=CR3 or NH-CH=CH-C(O); or is a pharmaceutically acceptable salt thereof. In an embodiment the alkyl group is straight, branched or a cyclic alkyl group. In an embodiment the alkyl group is a straight chain alkyl group. In an embodiment the alkyl group contains 1, 2 or 3 halogens. In an embodiment R1 is H, R2 is CH2-CHR4-NR5R6, R3 is H or L-R9, and K is CH. In an embodiment R4 is H or methyl. In an embodiment R5 is ethyl or isopropyl. In an embodiment R4 is H and R5 is ethyl. In an embodiment R3 is L-R9 and wherein L is O, O-O-CH2CH2, OCO or OCONH. In an embodiment R3 is L-R9 and wherein R9 is OH, COCH3, imidazole, pyrrolidine, piperidine, analine, pyrideine, morpholine or 6-oxa-3-azabicyclo[3.1.1]heptane. In an embodiment R3 is OCOCH3. In an embodiment there is provided one or more compounds selected from the tables below:
Figure imgf000029_0002
Figure imgf000030_0001
Figure imgf000031_0001
Figure imgf000032_0001
Figure imgf000033_0001
It should be understood that the molecules depicted in this application in the protonated form (e.g. with protonated amine groups) also include within their scope/meaning the corresponding molecules in the free base form, and vice versa. The protonated form of these molecules being readily accessible by the addition of an acid to the free base form of these molecules. For example, the protonated form of Compound 5 can be made from the (free base form of) Compound 5 by the addition of an acid, e.g. addition of acid 'H-A' gives the protonated form of compound 5 and where the corresponding counter ion is A-. As such if H-A is H-CI the corresponding anion is CI-, whereas if H-A is H-benzoate the counter ion will be a benzoate anion. While within the scope of an embodiment of the invention, for the purposes of simplicity only, compounds 1 to 020 have not been drawn in all possible salt forms e.g. with anions selected from benzoate, fumarate, citrate, acetate, succinate, halide, fluoride, chloride, bromide, iodide, oxalate, or triflate salt.
In an embodiment, there is provided a compound selected from:
Figure imgf000034_0001
Figure imgf000035_0001
Figure imgf000036_0001
In an embodiment there is provided a composition comprising a pharmaceutically effective amount of a compound as described previously.
In an embodiment the composition comprises a dosage amount in the range of 0.05mg to 100mg. In an embodiment the composition comprises a dosage amount in the range of 0.1mg to 50mg. In an embodiment the composition comprises a dosage amount in the range of 0.5mg to 25mg. In an embodiment the composition comprises a dosage amount in the range of 0.5mg to 10mg. In an embodiment the composition comprises a dosage amount in the range of lmg to 10mg. In an embodiment the composition comprises a dosage amount in the range of lmg to 8mg. In an embodiment the composition comprises a dosage amount in the range of 3mg to 15mg. In an embodiment the composition comprises a dosage amount in the range of 0.005mg to 100mg. In an embodiment the composition comprises a dosage amount in the range of 0.001mg to 100mg. In an embodiment the composition comprises a dosage amount in the range of 0.0005mg to 100mg.
The level of the active agent can be adjusted as required by need for example to suit a certain patient group (e.g. the elderly) or the conditions being treated.
In an embodiment the composition is formulated in a dosage form selected from: oral, transdermal, inhalable, intravenous, rectal dosage, intranasal, intramuscular, or any other parenteral form. In an embodiment the composition is formulated in a dosage form selected from: oral, transdermal, inhalable, intravenous, or rectal dosage form. It is advantageous to be able to deliver the active agent in different forms, for example to suit a certain patient group (e.g. the elderly) or the conditions being treated. In an embodiment the composition is formulated in a dosage form selected from: tablet, capsule, granules, powder, free-flowing powder, inhalable powder, aerosol, nebulised, vaping, buccal, sublingual, sublabial, injectable, or suppository dosage form.
In an embodiment the powder is suitable for administration by inhalation via a medicament dispenser selected from a reservoir dry powder inhaler, a unit-dose dry powder inhaler, a pre-metered multi-dose dry powder inhaler, a nasal inhaler or a pressurized metered dose inhaler.ln an embodiment the powder comprises particles, the particles having a median diameter of less than 2000μm, 1000μm, 500μm, 250μm, 100μm, 50μm, or 1pm. In an embodiment the powder comprises particles, the particles having a median diameter of greater than 500μm, 250μm, 100μm, 50μm, 1pm or 0.5pm. In an embodiment the powder comprises particles, and wherein the powder has a particle size distribution of dl0=20-60μm, and/or d50=80- 120μm, and/or d90=130-300μm. The nature of the powder can be adjusted to suit need. For example, if being made for nasal inhalation, then the particles may be adjusted to be much finer than if the powder is going to be formulated into a gelatine capsule, or differently again if it is going to be compacted into a tablet.
In an embodiment the compound is in the form of a salt which is amorphous or crystalline. In an embodiment the salt is in a polymorphic crystalline form. In an embodiment the salt is a benzoate, fumarate, citrate, acetate, succinate, halide, fluoride, chloride, bromide, iodide, oxalate, or triflate salt, optionally the salt is the chloride, benzoate or fumarate salt. In an embodiment the salt is formulated into a composition for mucosal delivery. In an embodiment, the salt is a benzoate salt.
For the salt, the dosage amount is the equivalent amount of the free base (e.g. of 5-MeO-DMT) delivered when the salt is taken. So 100 mg dosage amount may for example correspond to 117mg of a hydrochloride salt (i.e. both providing the same molar amount of the active substance). The greater mass of the salt needed is due to the larger formula weight of the hydrogen chloride salt. Similarly, for the deuterated or triturated version of the compounds of the invention (also considered within the scope of the invention), a slight increase in mass can be expected due to the increased formula weight of these isotopic compounds.
Amorphous and crystalline substances often show different chemical/physical properties, e.g. improved rate of dissolution in a solvent, or improved thermal stability. Similarly, different polymorphs may also show different and useful chemical/physical properties. In an embodiment the composition comprises one or more pharmaceutically acceptable carriers or excipients.
In an embodiment the composition comprises one or more of: mucoadhesive enhancer, penetrating enhancer, cationic polymers, cyclodextrins, Tight Junction Modulators, enzyme inhibitors, surfactants, chelators, and polysaccharides. In an embodiment the composition comprises one or more of: chitosan, chitosan derivatives (such as N,N,N-trimethyl chitosan (TMC), n-propyl-(QuatPropyl), n-butyl-(QuatButyl) and n-hexyl (QuatHexyl)-N,N-dimethyl chitosan, chitosan chloride), β-cyclodextrin, Clostridium perfringens enterotoxin, zonula occludens toxin (ZOT), human neutrophil elastase inhibitor (ER143), sodium taurocholate, sodium deoxycholate sodium, sodium lauryl sulphate, glycodeoxycholat, palmitic acid, palmitoleic acid, stearic acid, oleyl acid, oleyl alchohol, capric acid sodium salt, DHA, EPA, dipalmitoyl phophatidyl choline, soybean lecithin, lysophosphatidylcholine, dodecyl maltoside, tetradecyl maltoside, EDTA, lactose, cellulose, and citric acid.
In an embodiment the compound or composition defined herein above for use i n a method of treatment of a human or animal subject by therapy.
In an embodiment the method of treatment is a method of treatment of: conditions caused by dysfunctions of the central nervous system, conditions caused by dysfunctions of the peripheral nervous system, conditions benefiting from sleep regulation (such as insomnia), conditions benefiting from analgesics (such as chronic pain), migraines, trigeminal autonomic cephalgias (such as short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT), and short-lasting neuralgiform headaches with cranial autonomic symptoms (SUNA)), conditions benefiting from neurogenesis (such as stroke, traumatic brain injury, Parkinson's dementia), conditions benefiting from anti-inflammatory treatment, depression, anxiety, substance use disorder, addictive disorder, gambling disorder, eating disorders, obsessive-compulsive disorders, or body dysmorphic disorders, optionally the condition is SUNCT and/or SUNA.
Treatment of the above conditions may be beneficially improved by taking the invention.
In an embodiment the method of treatment is a method of treatment of more than one of the above conditions, for example, the method of treatment may be a method of treatment of depression and anxiety.
In an embodiment the composition is administered one or more times a year. In an embodiment the composition is administered one or more times a month. In an embodiment the composition is administered one or more times a week. In an embodiment the composition is administered one or more times a day. In an embodiment the composition is administered at such a frequency as to avoid tachyphylaxis.
In an embodiment the composition is administered together with a complementary treatment and/or with a further active agent. In an embodiment the further active agent is a psychedelic compound, optionally a further tryptamine. In an embodiment the further active agent is a psychedelic compound, optionally an ergoline. In an embodiment the further active agent is lysergic acid diethylamide (LSD), psilocybin, psilocin or a prodrug thereof.
In an embodiment the complementary treatment is psychotherapy. In an embodiment, there is provided a composition comprising a pharmaceutically effective amount of a compound as described herein for use in a method of treatment of treatment resistant depression. In an embodiment, there is provided a nasal inhalation composition comprising a pharmaceutically effective amount of a compound as described herein for use in a method of treatment of treatment resistant depression. Treatment of the above conditions may be beneficially improved by taking the invention together with some complementary treatments; also these treatments may occur much less regularly than some other treatments that require daily treatments or even multiple treatments a day. In an embodiment, there is provided DiPT, 5-MeO-DMT, psilocin or psilocybin, or a pharmaceutical composition comprising DiPT, 5-MeO-DMT, psilocin or psilocybin, for use in a method of increasing neural plasticity. In an embodiment, there is provided DiPT, 5-MeO-DMT, psilocin or psilocybin, or a pharmaceutical composition comprising DiPT, 5-MeO-DMT, psilocin or psilocybin, for use in a method of treating a condition wherein said condition would benefit from increasing neural plasticity. In an embodiment, there is provided DiPT, 5-MeO-DMT, psilocin or psilocybin, or a pharmaceutical composition comprising DiPT, 5-MeO-DMT, psilocin or psilocybin, for use in a method of neurogenesis. In an embodiment, there is provided DiPT, 5-MeO-DMT, psilocin or psilocybin, or a pharmaceutical composition comprising DiPT, 5-MeO-DMT, psilocin or psilocybin, for use in a method of treating a condition wherein said condition would benefit from neurogenesis. In an embodiment, there is provided DiPT, 5-MeO-DMT, psilocin or psilocybin, or a pharmaceutical composition comprising DiPT, 5-MeO-DMT, psilocin or psilocybin, for use in a method of promoting neurite outgrowth. In an embodiment, there is provided DiPT, 5-MeO-DMT, psilocin or psilocybin, or a pharmaceutical composition comprising DiPT, 5-MeO-DMT, psilocin or psilocybin, for use in a method of treating a condition wherein said condition would benefit from promotion of neurite outgrowth. In an embodiment, there is provided DiPT, 5-MeO-DMT, psilocin or psilocybin, or a pharmaceutical composition comprising DiPT, 5-MeO- DMT, psilocin or psilocybin, for use in a method of increasing the number of neuronal branching points. In an embodiment, there is provided DiPT, 5-MeO-DMT, psilocin or psilocybin, or a pharmaceutical composition comprising DiPT, 5-MeO-DMT, psilocin or psilocybin, for use in a method of treating a condition wherein said condition would benefit from increasing the number of neuronal branching points. In an embodiment, there is provided 5-MeO-DALT or norpsilocin, or a pharmaceutical composition comprising 5-MeO-DALT or norpsilocin, for use in a method of increasing neural plasticity. In an embodiment, there is provided 5-MeO- DALT or norpsilocin, or a pharmaceutical composition comprising 5-MeO-DALT or norpsilocin, for use in a method of treating a condition wherein said condition would benefit from increasing neural plasticity. In an embodiment, there is provided 5-MeO-DALT or norpsilocin, or a pharmaceutical composition comprising 5- MeO-DALT or norpsilocin, for use in a method of promoting neurite outgrowth. In an embodiment, there is provided 5-MeO-DALT or norpsilocin, or a pharmaceutical composition comprising 5-MeO-DALT or norpsilocin, for use in a method of treating a condition wherein said condition would benefit from promotion of neurite outgrowth. In an embodiment, there is provided 5-MeO-DALT or norpsilocin, or a pharmaceutical composition comprising 5-MeO-DALT or norpsilocin, for use in a method of increasing the number of neuronal branching points. In an embodiment, there is provided 5-MeO-DALT or norpsilocin, or a pharmaceutical composition comprising 5-MeO-DALT or norpsilocin, for use in a method of treating a condition wherein said condition would benefit from increasing the number of neuronal branching points. In an embodiment, there is provided any one of compounds 001-020, or a pharmaceutical composition comprising any one of compounds 001-020, for use in a method of increasing neural plasticity. In an embodiment, there is provided any one of compounds 001-020, or a pharmaceutical composition comprising any one of compounds 001-020, for use in a method of treating a condition wherein said condition would benefit from increasing neural plasticity. In an embodiment, there is provided any one of compounds 001- 020, or a pharmaceutical composition comprising any one of compounds 001-020, for use in a method of neurogenesis. In an embodiment, there is provided any one of compounds 001-020, or a pharmaceutical composition comprising any one of compounds 001-020, for use in a method of treating a condition wherein said condition would benefit from neurogenesis. In an embodiment, there is provided any one of compounds 001-020, or a pharmaceutical composition comprising any one of compounds 001-020, for use in a method of promoting neurite outgrowth. In an embodiment, there is provided any one of compounds 001-020, or a pharmaceutical composition comprising any one of compounds 001-020, for use in a method of treating a condition wherein said condition would benefit from promotion of neurite outgrowth. In an embodiment, there is provided any one of compounds 001-020, or a pharmaceutical composition comprising any one of compounds 001-020, for use in a method of increasing neural plasticity. In an embodiment, there is provided compound 005, or a pharmaceutical composition comprising compound 005, for use in a method of treating a condition wherein said condition would benefit from increasing neural plasticity. In an embodiment, there is provided compound 005, or a pharmaceutical composition comprising compound 005, for use in a method of neurogenesis. In an embodiment, there is provided compound 005, or a pharmaceutical composition comprising compound 005, for use in a method of treating a condition wherein said condition would benefit from neurogenesis. In an embodiment, there is provided compound 005, or a pharmaceutical composition comprising compound 005, for use in a method of promoting neurite outgrowth. In an embodiment, there is provided compound 005, or a pharmaceutical composition comprising compound 005, for use in a method of treating a condition wherein said condition would benefit from promotion of neurite outgrowth. In an embodiment, there is provided compound 005, or a pharmaceutical composition comprising compound 005, for use in a method of increasing the number of neuronal branching points. In an embodiment, there is provided compound 005, or a pharmaceutical composition comprising compound 005, for use in a method of treating a condition wherein said condition would benefit from increasing the number of neuronal branching points. In an embodiment, there is provided compound 008, or a pharmaceutical composition comprising compound 008, for use in a method of treating a condition wherein said condition would benefit from increasing neural plasticity. In an embodiment, there is provided compound 008, or a pharmaceutical composition comprising compound 008, for use in a method of neurogenesis. In an embodiment, there is provided compound 008, or a pharmaceutical composition comprising compound 008, for use in a method of treating a condition wherein said condition would benefit from neurogenesis. In an embodiment, there is provided compound 008, or a pharmaceutical composition comprising compound 008, for use in a method of promoting neurite outgrowth. In an embodiment, there is provided compound 008, or a pharmaceutical composition comprising compound 008, for use in a method of treating a condition wherein said condition would benefit from promotion of neurite outgrowth. In an embodiment, there is provided compound 008, or a pharmaceutical composition comprising compound 008, for use in a method of increasing the number of neuronal branching points. In an embodiment, there is provided compound 008, or a pharmaceutical composition comprising compound 008, for use in a method of treating a condition wherein said condition would benefit from increasing the number of neuronal branching points. In an embodiment, there is provided a method of increasing neuronal plasticity, said method comprising administering one or more of the compounds disclosed herein to a patient in a pharmaceutically acceptable amount. In an embodiment, there is provided a method of neurogenesis, said method comprising administering one or more of the compounds disclosed herein to a patient in a pharmaceutically acceptable amount. In an embodiment, there is provided a method of increasing neurite outgrowth, said method comprising administering one or more of the compounds disclosed herein to a patient in a pharmaceutically acceptable amount. In an embodiment, there is provided a method of the number of neuronal branching points, said method comprising administering one or more of the compounds disclosed herein to a patient in a pharmaceutically acceptable amount.
Third Aspect
Definitions of chemical groups/names under the third aspect e.g. substituents R1, R2 and R3 relate to the chemical structures falling under the third aspect and any embodiments thereof. Similarly, numbering of chemical structures under this aspect relate to this aspect.
Psilocin is a psychoactive compound which is sensitive to oxidation. Psilocin is typically formed in the human body when a substance containing the naturally occurring compound psilocybin is ingested e.g. when ingesting 'magic mushrooms'.
Figure imgf000040_0001
Psilocybin Psilocin To date, medical and clinical studies administer psilocybin as a means to form psilocin in the human body. The industrial synthesis of psilocybin is a complicated and costly process often incorporating the use of carcinogenic catalysts, the use of which has important GMP implications. There is a need in the art for pharmaceutically acceptable prodrugs of psilocin.
In third aspect of the invention, there is provided a compound of Formula (l)C wherein:
Figure imgf000041_0001
R1 is (CH2)mNR4(R5) wherein: m is selected from 1, 2, 3, 4, 5, 6, 7, or 8;
R4 is C1-6 alkyl;
R5 is C1-6 alkyl;
R2 is H or C(O)C1-6;
R3 is O-X-Y wherein:
X is -CO-; -C(O)O-; -C(O)O(CH2)n-; -CH2(CO)-; -CH2-O-; -CHR6-O-; -CH2-NH-; -CH2-NR7-; -CHR8-NH-; - CHR9-NR10-; -P(O)(OH)-; -P(O)OR11-; -CH2O-P(O)OH-; -CH2O-P(O)OR12-; or -CO(CH2)n-C(O)OCH2 -;
Y is -(CH2)n-NH2; -(CH2)n-NHR13; -(CH2)n-NR14R15; -C(O)CHR1SR17;
C(O)OR18; -C(O)NHR19; -C(O)NR20R21; -OR22 or a C5-6hetrocycle
R6 to R21 are independently H or C1-4 alkyl groups, and R22 is a C1-8 alkyl group and wherein n is independently 1 to 4.
Hereafter, under this aspect, Formula (l)C may simply be referred to as Formula (I).
In an embodiment, R3 may also be selected from: -O-C(O)-CH(CH3)2, -O-CH2-O-P(O)(OH)-CH2CH2CH2CH3 -O- CH2-O-P(O)(OH)-OCH2CH2CH2CH3, O-P(O)(OH)-CH2CH2CH2CH3, O-P(O)(OH)-OCH2CH2CH2CH3, -O-CH2-O- P(O)(OH)2, -O-CH2-O-P(O)(O-CH-(CH3)2)2, -O-CH2-O-P(O)(O-CH2CH2CH2CH3)2, -O-CH2-O-P(O)(O-C(CH3)3)2 and - O-CH2-O-P(O)OH(O-C(CH3)3).
In an embodiment the alkyl groups may be independently optionally substituted. In an embodiment R2 is C(O)C1-6 and is optionally substituted. In an embodiment R2 is C(O)C1-6 and is substituted.
In an embodiment, m is 2 or 3. In an embodiment m is 2. In an embodiment, R4 and R5 are both CH3. In an embodiment, R2 is H. In an embodiment, R2 is C(O)C1-6 alkyl. In an embodiment, R2 is C(O)CH3. In an embodiment, R6 to R21 are independently H or CH3 groups. In an embodiment, R6 to R21 are H groups. In an embodiment, R6 to R21 are CH3 groups. In an embodiment, R22 is a C1-8 alkyl group, optionally a t-butyl group. In an embodiment, Y is
Figure imgf000042_0001
In an embodiment, X is CH(CH3)O, and Y is C(O)CH(CH3)2 or C(O)N(CH3)2. In an embodiment, X is C(O)O or C(O)O(CH2) and Y is CH2N(CH3)2. In an embodiment, X is -P(O)(OH)-; -P(O)(O-n-butyl)-; -CH2O-P(O)OH- ; -CH2O-P(O)(n-butyl)- and Y is or n-butyl, isopropyl, t-butyl or n-heptyl. In an embodiment, X is -CH2O-P(O)OH- and Y is t-butyl or n-heptyl. In an embodiment, X is CH2N(CH3) and Y is C(O)OCH3, C(O)CH(CH3)2 or C(O)N(CH3)2. In an embodiment, X is C(O) or-CH2(CO)-, and Yis
Figure imgf000042_0002
In an embodiment, X is -CO(CH2)-C(O)OCH2 - or CO(CH2)2-C(O)OCH2 - and Yis
Figure imgf000042_0003
In an embodiment, X is CH(CH3)NH or CH2NH and Y is C(O)CH(CH3)2. In an embodiment, n is 2, R4 and R5 are both CH3 and R2 is H. In an embodiment, n is 2, R4 and R5 are both CH3 and R2 is C(O)CH3. In an embodiment, the compound is selected from:
Figure imgf000042_0004
Figure imgf000043_0001
In an embodiment, the compound is selected from:
Figure imgf000043_0002
In an embodiment, the compound is:
Figure imgf000043_0003
In an embodiment, the compound is:
Figure imgf000044_0001
In an embodiment, the compound is selected from:
Figure imgf000044_0002
In an embodiment there is provided a pharmaceutical composition comprising a pharmaceutically effective amount of a compound as described hereinabove or herein below.
In an embodiment the composition comprises a dosage amount in the range of 0.05mg to 100mg. In an embodiment the composition comprises a dosage amount in the range of 0.1mg to 50mg. In an embodiment the composition comprises a dosage amount in the range of 0.5mg to 25mg. In an embodiment the composition comprises a dosage amount in the range of 0.5mg to 10mg. In an embodiment the composition comprises a dosage amount in the range of lmg to 10mg. In an embodiment the composition comprises a dosage amount in the range of lmg to 8mg. In an embodiment the composition comprises a dosage amount in the range of 3mg to 15mg. In an embodiment the composition comprises a dosage amount in the range of 0.005mg to 100mg. In an embodiment the composition comprises a dosage amount in the range of 0.0010mg to 100mg. In an embodiment the composition comprises a dosage amount in the range of 0.0005mg to 100mg.
The level of the active agent can be adjusted as required by need, for example to suit a certain patient group (e.g. the elderly) or the conditions being treated.
In an embodiment the composition is formulated in a dosage form selected from: oral, transdermal, inhalable, intravenous, rectal dosage, intranasal, intramuscular, or any other parenteral form. In an embodiment the composition is formulated in a dosage form selected from: oral, transdermal, inhalable, intravenous, or rectal dosage form. It is advantageous to be able to deliver the active agent in different forms, for example to suit a certain patient group (e.g. the elderly) or the conditions being treated. In an embodiment the composition is formulated in a dosage form selected from: tablet, capsule, granules, powder, free-flowing powder, inhalable powder, aerosol, nebulised, vaping, buccal, sublingual, sublabial, injectable, microneedle array, or suppository dosage form.
In an embodiment the powder is suitable for administration by inhalation via a medicament dispenser selected from a reservoir dry powder inhaler, a unit-dose dry powder inhaler, a pre-metered multi-dose dry powder inhaler, a nasal inhaler or a pressurized metered dose inhaler.
In an embodiment the powder comprises particles, the particles having a median diameter of less than 2000μm, 1000μm, 500μm, 250μm, 100μm, 50μm, or 1μm. In an embodiment the powder comprises particles, the particles having a median diameter of greater than 500μm, 250μm, 100μm, 50μm, 1pm or 0.5μm. In an embodiment the powder comprises particles, and wherein the powder has a particle size distribution of d10=20-60μm, and/or d50=80-120μm, and/or d90=130-300μm. The nature of the powder can be adjusted to suit need. For example, if being made for nasal inhalation, then the particles may be adjusted to be much finer than if the powder is going to be formulated into a gelatine capsule, or differently again if it is going to be compacted into a tablet.
In an embodiment the compound is in the form of a salt which is amorphous or crystalline. In an embodiment the salt is in a polymorphic crystalline form. In an embodiment the salt is a benzoate, fumarate, citrate, acetate, succinate, halide, fluoride, chloride, bromide, iodide, oxalate, or triflate salt, optionally the salt is the chloride, benzoate or fumarate salt. In an embodiment the salt is formulated into a composition for mucosal delivery. In an embodiment, the salt is a benzoate salt.
For the salt, the dosage amount is the equivalent amount of the free base delivered when the salt is taken. So 100 mg dosage amount may for example correspond to an increased amount of a hydrochloride salt (i.e. both providing the same molar amount of the active substance. The greater mass of the salt needed is due to the larger formula weight of the hydrogen chloride salt. Similarly, for the deuterated or triturated version of the compounds of the invention (also considered within the scope of the invention), a slight increase in mass can be expected due to the increased formula weight of these isotopic compounds.
Amorphous and crystalline substances often show different chemical/physical properties, e.g. improved rate of dissolution in a solvent, or improved thermal stability. Similarly, different polymorphs may also show different and useful chemical/physical properties. In an embodiment the composition comprises one or more pharmaceutically acceptable carriers or excipients. In an embodiment the composition comprises one or more of: mucoadhesive enhancer, penetrating enhancer, cationic polymers, cyclodextrins, Tight Junction Modulators, enzyme inhibitors, surfactants, chelators, and polysaccharides. In an embodiment the composition comprises one or more of: chitosan, chitosan derivatives (such as N,N,N-trimethyl chitosan (TMC), n-propyl-(QuatPropyl), n-butyl- (QuatButyl) and n-hexyl (QuatHexyl)-N,N-dimethyl chitosan, chitosan chloride), β-cyclodextrin, Clostridium perfringens enterotoxin, zonula occludens toxin (ZOT), human neutrophil elastase inhibitor (ER143), sodium taurocholate, sodium deoxycholate sodium, sodium lauryl sulphate, glycodeoxycholat, palmitic acid, palmitoleic acid, stearic acid, oleyl acid, oleyl alchohol, capric acid sodium salt, DHA, EPA, dipalmitoyl phophatidyl choline, soybean lecithin, lysophosphatidylcholine, dodecyl maltoside, tetradecyl maltoside, EDTA, lactose, cellulose, and citric acid.
In an embodiment, the compounds or compositions defined herein, are for use in a method of treatment of a human or animal subject by therapy. In an embodiment, the compounds or compositions defined herein, are used in a method of treatment of a human or animal subject by therapy.
In an embodiment the method of treatment is a method of treatment of: conditions caused by dysfunctions of the central nervous system, conditions caused by dysfunctions of the peripheral nervous system, conditions benefiting from sleep regulation (such as insomnia), conditions benefiting from analgesics (such as chronic pain), migraines, trigeminal autonomic cephalgias (such as short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT), and short-lasting neuralgiform headaches with cranial autonomic symptoms (SUNA)), conditions benefiting from neurogenesis (such as stroke, traumatic brain injury, Parkinson's dementia), conditions benefiting from anti-inflammatory treatment, depression, anxiety, substance use disorder, addictive disorder, gambling disorder, eating disorders, obsessive-compulsive disorders, or body dysmorphic disorders, optionally the condition is SUNCT and/or SUNA.
Treatment of the above conditions may be beneficially improved by taking the invention.
In an embodiment the method of treatment is a method of treatment of more than one of the above conditions, for example, the method of treatment may be a method of treatment of depression and anxiety. In an embodiment the composition is administered one or more times a year. In an embodiment the composition is administered one or more times a month. In an embodiment the composition is administered one or more times a week. In an embodiment the composition is administered one or more times a day.
In an embodiment the composition is administered at such a frequency as to avoid tachyphylaxis. In an embodiment the composition is administered together with a complementary treatment and/or with a further active agent. In an embodiment the further active agent is a psychedelic compound, optionally a further tryptamine. In an embodiment the further active agent is a psychedelic compound, optionally an ergoline. In an embodiment the further active agent does not induce a psychedelic response in the subject, for example because it has been chemically modified, or it is administered in a sufficiently low dosage amount. In an embodiment the further active agent is lysergic acid diethylamide (LSD), psilocybin, psilocin ora prodrug thereof. In an embodiment the complementary treatment is psychotherapy. In an embodiment, the complementary treatment is a prescription digital therapeutic (PDT). In an embodiment, there is provided a composition comprising a pharmaceutically effective amount of the invention, as described herein for use in a method of treatment of treatment resistant depression. In an embodiment, there is provided a nasal inhalation composition comprising a pharmaceutically effective amount of the invention, as described herein for use in a method of treatment of treatment resistant depression. Treatment of the above conditions may be beneficially improved by taking the invention together with some complementary treatments; beneficially, these treatments may occur much less regularly than some other treatments that require daily treatments or even multiple treatments a day.
In an embodiment, there is provided a compound selected from the table below:
Figure imgf000047_0001
Figure imgf000048_0001
Figure imgf000049_0001
Figure imgf000050_0001
Figure imgf000051_0001
Figure imgf000052_0002
Fourth Aspect
Definitions of chemical groups/names under the fourth aspect e.g. substituents X, Y and Z relate to the chemical structures falling under the fourth aspect and any embodiments thereof. Similarly, numbering of chemical structures under this aspect relate to this aspect.
In fourth aspect, there is provided a combination pharmaceutical comprising
(a) compound of Formula (l)D
Figure imgf000052_0001
wherein:
X is selected from H or C1-6 alkyl, and optionally wherein X is methyl or isopropyl;
Y is selected from a bond, O, CONH, NH, N(C1-6 alkyl), A-(CH2)n-B, wherein
A is O, NH or N(C1-6 alkyl), wherein
B is a bond, O, or NH, wherein n is 1 to 4;
Z is selected from H, OH, NH2, NHC1-6 alkyl, N(C1-6 alkyl)2, C1-6 alkyl, C6-10 aryl, SO2-C1-6 alkyl, SO2-C6-10 aryl, C3-C10 heteroaromatic or heterocyclic group comprising one, two or three heteroatoms independently selected from O and N; wherein X and Z are different; or a pharmaceutically acceptable salt thereof; and
(b) serotonin receptor antagonist or inverse agonist inverse agonist, or a pharmaceutically acceptable salt thereof. Hereafter, under this aspect, Formula (l)D may simply be referred to as Formula (I).
In an embodiment, the compound of formula (I) is selected from:
Figure imgf000053_0001
In an embodiment, the compound of formula (I) is:
Figure imgf000053_0002
In an embodiment, the compound of formula (I) is:
Figure imgf000054_0001
In an embodiment, the compound of formula (I) is:
Figure imgf000054_0002
In an embodiment, the serotonin receptor antagonist, or inverse agonist, of the combination pharmaceutical is an antagonist, or inverse agonist against one or more of the serotonin receptor subtypes 2a, 2b and 2c.
In an embodiment, the serotonin receptor antagonist, or inverse agonist is selected from: lisuride, methysergide, clomipramine, doxepin, amoxapine, cariprazine, cyproheptadine, aripiprazole, mianserin, minaprine, asenapine, cyclobenzaprine, volinanserin or sarpogrelate. In an embodiment, the serotonin receptor antagonist, or inverse agonist, is
Figure imgf000054_0003
or a pharmaceutically acceptable salt thereof.
In an embodiment, the serotonin receptor antagonist, or inverse agonist, is
Figure imgf000054_0004
or a pharmaceutically acceptable salt thereof.
In an embodiment, the compound of formula (I) and the serotonin receptor antagonist, or inverse agonist, are present in the same single dosage form. In an embodiment, the combination pharmaceutical is formulated in a dosage form selected from oral, transdermal, inhalable, intravenous, injectable or rectal dosage forms. In an embodiment, the compound of formula (I) and the serotonin receptor antagonist, or inverse agonist, are present in different dosage forms. In an embodiment, the dosage forms are selected from oral, transdermal, inhalable, intravenous, injectable or rectal dosage forms.
In an embodiment, there is provided the use of a combination pharmaceutical according to any previous or subsequent embodiment in treating a condition benefiting from an increase in neural plasticity, wherein the combination pharmaceutical increases neural plasticity in a subject treated with the combination pharmaceutical. In an embodiment, the compound of formula (I) of the combination pharmaceutical and the serotonin receptor antagonist, or inverse agonist, are administered on the same day. In an embodiment, wherein the compound of formula (I) of the combination pharmaceutical and the serotonin receptor antagonist, or inverse agonist, are administered at the same time on the same day.
In an embodiment, the compound of formula (I) of the combination pharmaceutical and the serotonin receptor antagonist, or inverse agonist, are administered at the same time on the same day. In an embodiment, the compound of formula (I) of the combination pharmaceutical and the serotonin receptor antagonist, or inverse agonist, are administered 1 minute, 2 minutes, 3 minutes, 4 minutes, 5 minutes, 10 minutes, 15 minutes, 20 minutes, 25 minutes, 30 minutes, 35 minutes, 40 minutes, 45 minutes, 50 minutes, 55 minutes or 60 minutes apart.
In an embodiment, the compound of formula (I) of the combination pharmaceutical and the serotonin receptor antagonist, or inverse agonist, are administered 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours,
7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours or 24 hours apart.
In an embodiment, the compound of formula (I) of the combination pharmaceutical and the serotonin receptor antagonist, or inverse agonist, are administered 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days,
8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days or 30 days apart.
In an embodiment, the compound of formula (I) of the combination pharmaceutical is administered multiple times whilst the serotonin antagonist is administered only once in any given treatment round.
In an embodiment, there is provided the use of a combination pharmaceutical comprising
Figure imgf000055_0001
or a pharmaceutically acceptable salt, and a serotonin receptor antagonist, or inverse agonist, or a pharmaceutically acceptable salt thereof, in treating a condition benefiting from an increase in neural plasticity, wherein the combination pharmaceutical increases neural plasticity in a subject treated with the combination pharmaceutical. In an embodiment, the serotonin receptor antagonist, or inverse agonist, is
Figure imgf000056_0001
or a pharmaceutically acceptable salt thereof.
In an embodiment, the serotonin receptor antagonist, or inverse agonist, is
Figure imgf000056_0002
or a pharmaceutically acceptable salt thereof.
In an embodiment, the combination pharmaceutical increases neural plasticity in a subject treated with the combination pharmaceutical to a greater extent than administration of either active compounds of the combination pharmaceutical alone.
Fifth Aspect
Definitions of chemical groups/names under the fifth aspect e.g. substituents X, Y and Z relate to the chemical structures falling under the fifth aspect and any embodiments thereof. Similarly, numbering of chemical structures under this aspect relate to this aspect.
In aspect fifth aspect of the invention, there is provided compound of Formula (l)E wherein:
Figure imgf000056_0003
X is selected from H or C1-10 branched or straight chain alkyl and optionally methyl, isopropyl; and
Y is selected from a bond, O, CONH, NH, N(C1-6 alkyl), A-(CH2)n-B, C1-6 alkyl, wherein
A is O, NH or N(C1-6 alkyl), wherein B is a bond, O, or NH, wherein n is 1 to 4;
Z is selected from H, OH, NH2, NHC1-6 alkyl, N(C1-6 alkyl)2, C1-6 alkyl, C6-10aryl, SO2-C1-6 alkyl, SO2- C6-10 aryl, C3-C10 heteroaromatic or heterocyclic group comprising one, two or three heteroatoms independently selected from O and N; and wherein X and Z are the same or different; or a pharmaceutically acceptable salt thereof; and optionally additionally comprising
(b) serotonin receptor antagonist or inverse agonist inverse agonist, or a pharmaceutically acceptable salt thereof.
Hereafter, under this aspect, Formula (l)E may simply be referred to as Formula (I).
In an embodiment the alkyl group is straight, branched or a cyclic alkyl group.
In an embodiment the alkyl group is a straight chain alkyl group. In an embodiment the alkyl group contains 1, 2 or 3 halogens.
In an embodiment X is methyl. In an embodiment X is isopropyl.
In an embodiment Y is selected from a bond, O, CONH, NH or NCH3.
In an embodiment Y is A-(CH2)n-B, wherein
A is O or NH, wherein
B is a bond, O or NH, wherein n is 1 to 4.
In an embodiment n is 2 or 3.
In an embodiment Z is selected from pyridine, morpholine, SO2-CH3, SO2-phenyl, 8-oxa-3-azabicyclo[3.2.1]octane and 2-oxa-5-azabicyclo[2.2.1]heptane.
In an embodiment Y-Z together form the group:
O-(CH2)3-N(CH3)2
NH-(CH2)2-OH
NH-(CH2)3-OH
NH-(CH2)3-OCH3
NH-(CH2)3-SO2CH3
NH-(CH2)2-NH-SO2CH3, or
O-(CH2)2-NH-SO2CH3.
In an embodiment Y-Z together form the group:
NH-phenyl, pyridine, O-morpholine, NH-morpholine, NH- SO2-Phenyl, NCH3- SO2-Phenyl, CONH-Phenyl, 8-oxa-3-azabicyclo[3.2.1]octane or 2-oxa-5-azabicyclo[2.2.1]heptane. In an embodiment, there is provided a compound of Formula (I) wherein X is absent, Y is a bond and Z is SO(C1-6alkyl) or SOR1R2; wherein R1 and R2 are taken together with the S in between to form a heterocyclic ring, wherein said heterocyclic ring is selected from: a three membered heterocyclic ring, a four membered heterocyclic ring, a five membered heterocyclic ring, a six membered heterocyclic ring, a six membered bicyclic heterocyclic ring, a seven membered bicyclic heterocyclic ring, an eight membered bicyclic heterocyclic ring or a nine membered bicyclic heterocyclic ring.
In an embodiment, there is provided a compound which is:
Figure imgf000058_0001
In an embodiment, there is provided a compound of Formula (I) wherein X is H or methyl, Y is a bond and Z is a heterocyclic ring, wherein said heterocyclic ring is selected from: a three membered heterocyclic ring, a four membered heterocyclic ring, a five membered heterocyclic ring, a six membered heterocyclic ring, a six membered heterocyclic bicyclic ring, a seven membered heterocyclic bicyclic ring, an eight membered heterocyclic bicyclic ring or a nine membered heterocyclic bicyclic ring. In an embodiment, the heterocyclic ring is optionally substituted at one or more positions with one or more of: a halogen, CH2-(C3-C6 cycloalkyl).
In an embodiment, there is provided a compound which is:
Figure imgf000058_0002
In an embodiment there is provided one or more compounds selected from:
Figure imgf000059_0001
Figure imgf000060_0001
Figure imgf000061_0001
Figure imgf000062_0001
Figure imgf000063_0001
Figure imgf000064_0001
Figure imgf000065_0001
Figure imgf000066_0001
Figure imgf000067_0001
Sixth Aspect
Definitions of chemical groups/names under the sixth aspect e.g. substituents R and R' relate to the chemical structures falling under the sixth aspect and any embodiments thereof. Similarly, numbering of chemical structures under this aspect relate to this aspect. In aspect sixth aspect , there is provided a compound of Formula (II):
Figure imgf000068_0001
wherein
R is selected from a 5 membered heterocyclic ring with at least one N atom, a 5 membered heterocyclic ring with at least one O atom, a 5 membered heterocyclic ring with at least two N atoms, a 5 membered heterocyclic ring with at least one O and one N atom, a 5 membered heterocyclic ring with at least three N atoms, a 5 membered heterocyclic ring with at least four N atoms, and a 5 membered heterocyclic ring wherein all atoms of the ring are N;
R' is absent or is selected from:
H, methyl, ethyl, isopropyl, propyl, butyl, pentyl, hexyl, heptyl, octyl;
CH2OH, CH2CH2OH, CH2CH(OH)CH3, CH2CH2CH(OH)CH3, CH2CH2CH2OH, CH(OH)CH2CH2CH3; or
SCH3, SCH2CH3, CH2SCH3, CH2CH2SCH3,
In an embodiment, R is tetrazole moiety. In an embodiment, R is a triazole moiety. In an embodiment, R is 1,2,4-triazole moiety. In an embodiment, R is imidazole moiety. In an embodiment, R is oxazole moiety. In an embodiment, R is dihydrooxazole moiety. In an embodiment, R is a 5-yl- tetrazole moiety. In an embodiment, R is a 5-yl- triazole moiety. In an embodiment, R is a 5-yl-1,2,4-triazole moiety. In an embodiment, R is a 2-yl- imidazole moiety. In an embodiment, R is a 2-yl-oxazole moiety. In an embodiment, R is a 2-yl-dihydrooxazole moiety. In an embodiment, R is a tetrazole and R' is absent; optionally it is a 5-yl- tetrazole (that is, the tetrazole connects to the main structure via the 5-position (i.e. -5-yl- position) of the tetrazole). In an embodiment, R is a triazole and R' is absent; optionally it is a 5-yl- triazole. In an embodiment, R is a 1,2,4- triazole and R' is absent ; optionally it is a 5-yl- 1,2,4-triazole. In an embodiment, R is an imidazole and R' is absent; optionally it is a 2-yl- imidazole. In an embodiment, R is an imidazole and R' is CH3, optionally it is a 2-yl- imidazole. In an embodiment, R is an oxazole and R' is absent, optionally it is a 2-yl- oxazole. In an embodiment, R is a triazole and R' is a C3 alkyl; optionally it is a 5-yl- triazole. In an embodiment, R is a triazole and R' is isopropyl; optionally it is a 5-yl- triazole. In an embodiment, R is a 1, 2, 4-triazole and R' is isopropyl; optionally it is a 5-yl- triazole. In an embodiment, R is an imidazole and R' is isopropyl; optionally it is a 2-yl- imidazole. In an embodiment, R is a dihydrooxazole and R' is CH2OH; optionally it is a 2-yl- dihydrooxazole. In an embodiment, R is an oxazole and R' is CH2OH; optionally it is a 2-yl- oxazole. In an embodiment, R is an imidazoline and R' is CH2OH; optionally it is a 2-yl- imidazole.
In an embodiment, R is a tetrazole and R' is isopropyl; optionally it is a 5-yl- tetrazole. In an embodiment, R is a dihydrooxazole is CH2CH2SCH3; optionally it is a 2-yl-dihydrooxazole. In an embodiment, R is a dihydrooxazole and R' is isopropyl; optionally it is a 2-yl-dihydrooxazole. In an embodiment, R is an oxazole and R' is CH3; optionally it is a 2-yl-oxazole. In an embodiment, R is an oxazole and R' is isopropyl; optionally it is a 2-yl-oxazole. Seventh Aspect
Definitions of chemical groups/names under the seventh aspect e.g. substituents Rx and Ry relate to the chemical structures falling under the sixth aspect and any embodiments thereof. Similarly, numbering of chemical structures under this aspect relate to this aspect.
In aspect seventh aspect, there is provided a compound of Formula (III):
Figure imgf000069_0001
wherein
Rx and Ry are taken together with the N atom between them to form a heterocyclic ring, wherein said ring is selected from: a three membered heterocyclic ring, a four membered heterocyclic ring, a five membered heterocyclic ring, a six membered heterocyclic ring, a six membered heterocyclic bicyclic ring, a seven membered heterocyclic bicyclic ring, an eight membered heterocyclic bicyclic ring and a nine membered heterocyclic bicyclic ring; wherein one or more atoms of said heterocyclic ring are optionally replaced with one or more heteroatoms such as N, O or S; wherein said ring is optionally substituted at one or more positions with one or more of Rz, where Rz is independently selected from: a halogen,C1-6alkyl, C(O)CH3, C(O)C1-6alkyl, NH2, NHC1-6alkyl, N(C1-6alkyl)2, OH, OC1-6alkyl,C1-6alkyl-O-C1-6alkyl, C(O)NH2, C(O)NHCi-6alkyl, or C(O)(NC1-6alkyl)2.
In an embodiment, Rx and Ry are taken together with the N atom between them to form a 5 membered heterocyclic ring comprising an O atom.
In an embodiment, Rx and Ry are taken together with the N atom between them to form:
Figure imgf000069_0002
The N atom missing a valance/bond is the N atom between the Rx and Ry groups. In an embodiment, Rx and Ry are taken together with the N atom between them to form a 5 membered heterocyclic ring comprising an additional N atom, wherein said N atom is substituted with CH3.
In an embodiment, Rx and Ry are taken together with the N atom between them to form a 6 membered bicyclic heterocyclic ring.
The person skilled in the art will appreciate that the compounds, embodiments and/or combinations of any aspect may be formulated as one or more pharmaceutical compositions as described in any other aspect.
BRIEF DESCRIPTION OF THE FIGURES
Figure 1 shows serotonin (la, lb, 2a, 2c and 7 receptors) cAMP assay results for compounds 018 and 019.
Figure 2 shows serotonin (2a, 2b and 2c receptors) inositol phosphate 1 (I Pi) assay results for compounds 018 and 019.
Figure 3 shows serotonin (2a, 2b and 2c receptors) calcium (Ca2+) assay results for compounds 018 and 019.
Figure 4 shows serotonin (la, lb, 2a and 2c receptors) B-arrestin assay results for compounds 018 and 019.
Figure 5 shows serotonin 2b receptor B-arrestin assay results for compounds 018 and 019.
Figure 6 shows the effect of 5-MeO-DALT, 5-MeO-MiPT and DiPT on the number of neurons (A, D), the total neurite network (B, E) and the total number of branching points (C, F) in a primary culture of cortical neurons. Results are expressed as a percentage of control condition as mean +/- SEM (n = 4-6). One-way ANOVA followed by Fisher's LSD test (*, p<0.05 was considered significant).
Figure 7 shows the effect of 5-MeO-DMT, psilocin and norpsilocin on the number of neurons (A, D), the total neurite network (B, E) and the total number of branching points (C, F) in a primary culture of cortical neurons. Results are expressed as a percentage of control condition as mean +/- SEM (n = 4-6). One-way ANOVA followed by Fisher's LSD test (*, p<0.05 was considered significant).
Figure 8 shows the effect of compounds 018 and 019 on the number of neurons (A), the total neurite network (B) and the total number of branching points (C) in a primary culture of cortical neurons. Results are expressed as a percentage of control condition as mean +/- SEM (n = 4-6). One-way ANOVA followed by Fisher's LSD test (*, p<0.05 was considered significant).
Figure 9 shows the effect of psilocybin on the number of neurons (A), the total neurite network (B) and the total number of branching points (C) in a primary culture of cortical neurons. Results are expressed as a percentage of control condition as mean +/- SEM (n = 4-6). One-way ANOVA followed by Fisher's LSD test (*, p<0.05 was considered significant).
Figure 10 shows serotonin (1a, 1b, 2a, 2c and 7 receptors) cAMP assay results for compounds T005, T008 and T018.
Figure 11 shows serotonin (2a, 2b and 2c receptors) inositol phosphate 1 (IP1) assay results for compounds T005, T008 and T018. Figure 12 shows serotonin (2a, 2b and 2c receptors) calcium (Ca2+) assay results for compounds T005, T008 and T018.
Figure 13 shows serotonin (1a, 1b, 2a and 2c receptors) B-arrestin assay results for compounds T005, T008 and T018. Figure 14 shows serotonin 2b receptor B-arrestin assay results for compounds T005, T008 and T018.
Figure 15 shows the effect of tryptamine 5, tryptamine 8 and tryptamine 17 on the number of neurons (A, D), the total neurite network (B, E) and the total number of branching points (C, F) in a primary culture of cortical neurons. Results are expressed as a percentage of control condition as mean +/- SEM (n = 4-6). Oneway ANOVA followed by Fisher's LSD test (*, p<0.05 was considered significant). Figure 16 shows the effect of tested compounds on the number of neurons (A), the total neurite network (B) and the total number of branching points (C) in a primary culture of cortical neurons.
Figure 17 shows the effect of tested compounds on the number of neurons (A), the total neurite network (B) and the total number of branching points (C) in a primary culture of cortical neurons.
DESCRIPTION Example 1: Synthetic routes
Figure imgf000071_0001
Figure imgf000072_0001
Figure imgf000073_0001
Figure imgf000074_0001
Figure imgf000075_0001
Figure imgf000076_0001
The above represents a generic synthesis route for compounds 039-042 starting from (6aR,9R)-Lysergic Acid.
Figure imgf000076_0002
The above represents a generic synthesis route for compounds 044-051 starting from (6aR,9R)-Lysergic Acid.
Figure imgf000076_0003
The above represents a generic synthesis route for compounds 052-055, 073-082, 086-090 starting from (6aR,9R)-Lysergic Acid.
Figure imgf000077_0002
The above represents a generic synthesis route for compounds 057-072 starting from (6aR,9R)-Lysergic Acid.
Figure imgf000077_0003
The above represents a generic synthesis route for compounds 056, 083-085 starting from (6aR,9R)-Lysergic Acid.
Salt formation is undertaken thereafter in the above routes as necessary, e.g. to give the benzoate, fumarate, citrate, acetate, succinate, halide, fluoride, chloride, bromide, iodide, oxalate, or triflate salt. For example, the addition of hydrogen chloride would provide the chloride salt and benzoic acid would give the benzoate salt.
In an embodiment, there is provided a method of synthesis of any of the herein described compounds. In an embodiment, there is provided a method of synthesis of compound 001, 002, 003, 004, 005, 006, 007, 008, 009, 010, 011, 012, 013, 014, 015, 016, 017, 018 or 019 as herein disclosed.
Example 2: Further characterisation of compounds 018 and 019
Figure imgf000077_0001
cAMP
Compounds 018 (above, right) and 019 (above, left) were assayed using a serotonin (la, lb, 2a, 2c and 7 receptors) cAMP assay, provided by Multispan. The reference used was lOμM forskolin (a cAMP activator) to calculate the percentage relative response, serotonin was used as the control. The results can be seen in Figure 1. Compound 019 was active against in all other receptor assays. The results indicate that compound 019 stimulates the 5HT2aR leading to downstream activation of cAMP, although the curve response seems atypical compared to the serotonin control.
IP1
Compounds 018 and 019 were assayed using a serotonin (2a, 2b and 2c receptors) inositol phosphate 1 (IP1) assay, provided by Multispan. The reference used was 1μM serotonin to calculate the percentage relative response. The results can be seen in Figure 2. Both compounds appear to some activity against all three target receptors in this assay. This may imply that the compounds do not activate any Gαq/11 pathway.
Ca2+
Compounds 018 and 019 were assayed using a serotonin (2a, 2b and 2c receptors) calcium (Ca2+) assay, provided by Multispan. The reference used was 10μM serotonin to calculate the percentage relative response in relative light units (RLU). The results can be seen in Figure 3. Both compounds have some activity against the 2a and 2c receptors.
B-arrestin
Compounds 018 and 019 were assayed using a serotonin (la, lb, 2a and 2c receptors) B-arrestin assay, provided by DiscoverX. The reference used was 10μM serotonin to calculate the percentage relative response. The results can be seen in Figure 4. In general, both compounds exhibited some activity in comparison to serotonin.
The compounds were also assayed in a serotonin 2b receptor B-arrestin assay, the results of which can be seen in Figure 5.
Reagent information
B-arrestin:
HTR1A PathHunter® express HTR1A CHO-K1 P-Arrestin GPCR Assay 93-0696E2CP0M 200 dp (2 x 96-well)
HTR1B PathHunter® eXpress HTR1B U2OS P-Arrestin GPCR Assay 93-0697E3CP6M 200 dp (2 x 96-well)
HTR2A PathHunter® eXpress HTR2A U2OS P-Arrestin GPCR Assay 93-0401E3CP19M 200 dp (2 x 96-well)
HTR2C PathHunter® eXpress HTR2C U2OS P-Arrestin GPCR Assay 93-0289E3CP3M 200 dp (2 x 96-well)
Multispan p-arrestin assay with CHO-Kl-5HT2bR cells - Catalog C1350-la
Homogeneous Time Resolved Fluorescence (HTRF) and Calcium:
IP-One Gq kit - cisbio - cat. No. 62IPAPEB cAMP Gs dynamic kit - cisbio - cat. No. 62AM4PEC
FLIPR calcium 6 assay explorer kit - VWR - cat. No. MLDVR8190 Cells used in HTRF and calcium assays:
MULTISCREEN™ HEK293T Cell Line Stably Expressing Human 5-HT1A Receptor, Catalog DC1319a MULTISCREEN™ HEK293T Cell Line Stably Expressing Human 5-HT1B Receptor, Catalog DC1320a MULTISCREEN™ HEK293T Cell Line Stably Expressing Human 5HT1B Receptor, Catalog DC1320a MULTISCREEN™ CHO-K1 Cell Line Stably Expressing Human 5-HT2A Receptor, Catalog DC1324-1 MULTISCREEN™ CHO-K1 Cell Line Stably Expressing Human 5-HT2B Receptor, Catalog DC1325-1 MULTISCREEN™ CHO-K1 Cell Line Stably Expressing Human 5-HT2C Receptor, Catalog DC1326-1 MULTISCREEN™ HEK293T Cell Line Stably Expressing Human 5-HT7 Receptor, Catalog DC1334 For the B-arrestin assays the cells came with the kits apart from the 2b receptor assay (Valiscreen serotonin 5HT-2B (human) cell line - ES-314-C, Perkin Elmer).
Example 3: Effects of compounds 018 and 019 (several concentrations) on the neurite network (neurogenesis) in a primary culture of cortical neurons
Rationale
Neuronal plasticity corresponds to the ability of the nervous system to reorganized itself by making new connections through neurogenesis, neuritogenesis and synaptogenesis. Lack of neuronal plasticity is found in neurodegenerative diseases, neurological disorders and during biological aging, or senescence. Low neuronal plasticity is associated with cognitive decline, depression and psychiatric diseases.
The aim of this study was to assess the effect of several test compounds (3-5 concentrations) on the number of neurons, the outgrowth of neurite network of cortical neurons, and the number of branching points, after 3 days of treatment. The treatment was applied on day 1 of culture.
Primary culture of cortical neurons
All experiments were carried out in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals and followed current European Union regulations (Directive 2010 / 63 / EU). Agreement number: B1301310.
Rat cortical neurons were cultured as described by Callizot et al., 2013 with modifications. Briefly pregnant female rat (Wistar) of 15 days of gestation was killed using a deep anesthesia with CO2 chamber and a cervical dislocation. Fetuses were collected and immediately placed in ice-cold L15 Leibovitz medium with a 2 % penicillin (10,000 U/mL) and streptomycin (10 mg/mL) solution (PS) and 1 % bovine serum albumin (BSA). Cortex were specifically dissected and then were treated for 20 min at 37 °C with a trypsin-EDTA solution at a final concentration of 0.05 % trypsin and 0.02 % EDTA. The dissociation was stopped by addition of Dulbecco's modified Eagle's medium (DMEM) with 4.5 g/L of glucose, containing DNAse I grade II (final concentration 0.5 mg/mL) and 10 % fetal calf serum (FCS). Cells were mechanically dissociated by three forced passages through the tip of a 10-mL pipette. Cells were then centrifuged at 515 x g for 10 min at 4 °C. The supernatant was discarded, and the pellet was resuspended in a defined culture medium consisting of Neurobasal medium with a 2 % solution of B27 supplement, 2 mmol/liter of L-glutamine, 2 % of PS solution, and 10 ng/mL of brain-derived neurotrophic factor (BDNF). Viable cells were counted in a Neubauer cytometer, using the trypan blue exclusion test. The cells were seeded at a density of 25,000 per well in 96- well plate precoated with poly-L-lysine and were cultured at 37 °C in an air (95 %) - CO2 (5 %) incubator. For 96 well-plates, only 60 wells were used. The wells of first and last lines and columns were not used (to avoid any edge effect) and were filled with sterile water. Test compounds
Vehicle: culture medium, 0.1% DMSO, or 0.1% acetonitrile, or 0.1% water.
Treatment: On day 1 (day of seeding), compounds were applied on the culture and let for 3 days.
Organisation of culture plates The compounds were tested on 96-well plate (n = 6 culture wells per condition). Compounds were applied as follow:
Figure imgf000080_0001
Figure imgf000080_0002
Figure imgf000080_0003
Immunostaining: MAP-2 positive neurons
3 days after the treatment (and after seeding), the supernatant was removed, and kept frozen. Cells were then fixed by a cold solution of ethanol (95 %) and acetic acid (5 %) for 5 min at -20 °C and washed twice in PBS. Cell membranes were permeabilized and non-specific sites were blocked with a solution of PBS containing 0.1 % of saponin and 1 % FCS for 15 min at room temperature. Cells were incubated for 2 hours at room temperature with a primary chicken polyclonal antibody anti-MAP-2 (microtubule-associated protein 2), at a dilution of 1/400 in PBS containing 1 % FCS and 0.1 % of saponin. This antibody binds specifically neurons and neurites, allowing study of neuronal cell survival and neurite network.
The anti-MAP-2 antibody was revealed with a secondary Alexa Fluor 488 coupled goat anti-chicken antibody diluted at 1/400 in PBS containing 1 % FCS, 0.1 % saponin, for 1 hour at room temperature.
Cell nuclei were counterstained with the fluorescent dye Hoechst.
Automatic computer-assisted analysis
For each condition, 30 pictures (representative of the whole well area) per well were automatically taken using ImageXpress® (Molecular Devices) at 20x magnification. All images were generated using the same acquisition parameters. From images, analyses were automatically performed by MetaXpress® software (Molecular Devices).
The following read-outs were automatically assessed:
Total neuron survival (number of MAP-2 positive neuron);
Total neurite network (length of MAP-2 positive neurite in pm);
Number of total branching points (branching point of MAP-2 positive neuron)
Statistics
All values are expressed as mean +/- SEM (standard error of the mean). Normality was verified and outliers were identified with Grubb's test. Statistical analysis was performed by one-way ANOVA followed by Fisher's LSD test. p< 0.05 will be considered significant.
Results
Test compounds were applied the day of the seeding, for 3 days. BDNF (50 ng/ml), the positive control, significantly increased the number of neurons, on the length of the neurite network and on the number of branching points.
• 5-MeO-DALT (applied from 0.1 μM to 10 μM) increased the number of MAP2(+) neurons in the culture at 0.1 μM, without significant effect on neurite outgrowth or branching points.
• 5-MeO-MiPT (applied from 0.1 μM to 10 μM) did not show any significant effect.
• DiPT (applied from 0.1 μM to 10 μM) increased the number of neurons and promoted the neurite outgrowth (0.3 and 1 μM) and increased the number of branching points (0.1 μM to 10 μM).
The above results can be seen in Figure 6. 5-MeO-DMT, psilocin and norpsilocin (all from 0.1 μM to 10 μM) were applied the day of the seeding and let for 3 days. BDNF (50 ng/ml), the positive control, significantly increased the number of neurons, on the length of the neurite network and on the number of branching points.
• 5-MeO-DMT increased the number of neurons (0.3 μM and 1 μM), promoted neurite outgrowth (0.3 μM to 10 μM), and increased the number of branching points (0.3 μM). Maximal effect was observed at 0.3 μM.
• Psilocin increased the number of neurons (0.3 μM and 10 μM), promoted neurite outgrowth (0.3), and increased the number of branching points (10 μM). Maximal effect ranged between 0.3 and 10 μM, depending on the readouts. Psilocin was equivalent to BDNF in terms of efficacy.
• Norpsilocin did not show any significant effect on the number of neurons and on neurite outgrowth. At 1 μM, this compound significantly increased the number of branching points.
The above results can be seen in Figure 7.
Ergoline 18 (from 0.1 μM to 10 μM) and ergoline 19 (from 0.1 μM to 10 μM) were applied the day of the seeding and let for 3 days. BDNF (50 ng/ml), the positive control, significantly increased the number of neurons, on the length of the neurite network and on the number of branching points.
• Ergoline 18 increased the number of neurons (0.3 μM and 1 μM), promoted neurite outgrowth (0.3 μM and 1 μM), and increased the number of branching points (from 0.1 to 10 μM). Maximal effect was observed between 0.3 and 10 μM, depending on the readouts
• Ergoline 19 did not show any significant effect on the number of neurons but supported the neurite outgrowth (0.1 μM) and increased the number of branching points (from 0.1 to 1 μM, maximal effect at 0.3 μM).
Interestingly, the effect of ergoline 18 on the neuron of neurons at 1 μM was more important than the one obtained with BDNF. Similarly, ergoline 19 showed a stronger effect on branching points at 0.1 and 0.3 μM when compared to BDNF.
The above results can be seen in Figure 8.
Psilocybin (from 0.1 μM to 10 μM) were applied the day of the seeding and let for 3 days. As expected, BDNF (50 ng/ml), the positive control, significantly increased the number of neurons, on the length of the neurite network and on the number of branching points.
• Psilocybin increased the number of neurons (0.3 μM to 10 μM), promoted the neurite outgrowth (0.3 μM and 1 μM), and increased the number of branching points (from 0.3 μM).
The above results can be seen in Figure 9.
Discussion
This study was designed to assess the effects of several test compounds on the neurogenesis and neuroplasticity. The tested compounds have a well-known affinity for serotonergic receptors (e.g. 5-HTla, 5- HT2b). Compounds were applied on primary cortical neurons, from seeding, and let for 3 days. Based on the results, the following conclusions could be made:
• DiPT, 5-MeO-DMT, psilocin and psilocybin displayed a strong beneficial effect on all investigated parameters indicating that these compounds have a positive effect on neuronal plasticity.
• 5-MeO-DALT and norpsilocin displayed beneficial effect restricted to neurite outgrowth and/or branching points. Indeed, these two compounds did not support any increase in the number of neurons.
• 5-MeO-MiPT was inactive in the assay.
Regarding the novel chemical entities, derivatives of ergoline, the following conclusions could be made:
• Ergoline 018 showed strong beneficial effects on all investigated parameters. • Ergoline 019 displayed beneficial effects on neurite outgrowth and branching points.
Example 4: Synthetic routes
Figure imgf000083_0001
Figure imgf000084_0001
Figure imgf000085_0001
Figure imgf000086_0001
Figure imgf000087_0001
Figure imgf000088_0001
Figure imgf000089_0001
Salt formation is undertaken thereafter in the above routes as necessary, e.g. to give the benzoate, fumarate, citrate, acetate, succinate, halide, fluoride, chloride, bromide, iodide, oxalate, or triflate salt. For example, the addition of hydrogen chloride would provide the chloride salt and benzoic acid would give the benzoate salt.
In an embodiment, there is provided a method of synthesis of any of the herein described compounds.
Example 5 - Detailed synthesis of Compound T005
Figure imgf000089_0002
3-(2-(N-Methyl-N-ethylamino)-2-oxoethanoyl1-1H-indol-4-yl ethanoate (2)
To a stirred suspension of 4-indolyl acetate (2.0g, 11.4mmol) in diethyl ether (11.4mL) at 0°C was added dropwise oxalyl chloride (2.2g, 1.5mL, 17.1mmol), maintaining a reaction temperature under 5°C, and stirring was continued at 0°C for 30min.
The reaction mixture was diluted with hexane (23mL) and cooled to -20°C for 18h. The yellow precipitate was collected by suction filtration, washed with hexane (3 x 5mL) and dried to afford 1 as a yellow powder (2.73g, 90%) that was used directly.
To a cooled suspension of 1 (2.73g, 10.3mmol) in THF (llmL) at 0°C was added dropwise N-ethylmethylamine (736 mg, 1.07mL, 12.4mmol) and pyridine (978 mg, 1.0m L, 12.4mmol) and the reaction mixture was allowed to warm to room temperature with stirring for 18h.
The reaction mixture was concentrated and partitioned between water (25mL) and ethyl acetate (25mL). Layers were separated and the aqueous phase was extracted with ethyl acetate (2 x 25mL). Combined organic layers were dried (Na2SO4) and concentrated to afford the title compound as a yellow powder (2.3g, 77%) that was used without purification. LC-MS (Method 2.5 basic): Rt 0.98mins; MS m/z 287.3 = [M-H]- (98% @ 254nm)
3-[2-(N-Methyl-N-ethylamino)-2-oxoethanoyl]-1H-indol-4-yl ethanoate (3)
To a stirred, cooled solution of 2 (2.3g, 8.0mmol) in 2-methyltetrahydrofuran (54mL) at 0°C was added dropwise lithium aluminium hydride solution (10.0mL, 23.9mmol, 2.4M in THF) over 10min and the reaction mixture was heated to reflux for 3h.
The mixture was cooled to 0°C and quenched by dropwise addition of THF/water (1:4, 2.8mL). Sodium sulfate (5.43g), silica (2.73g) and dichloromethane (24mL) were added. The product was filtered, eluted with 10% methanol in dichloromethane (3 x 70mL) and the filtrate was concentrated to afford a dark brown solid (1.4g).
Purification by reversed-phase chromatography (C18, 32g, 2 → 35 → 50% acetonitrile in aq. 0.1% ammonia solution) gave the title compound as a dark green/blue solid (802 mg, 46%).
LC-MS (Method 2.5 basic): Rt 1.01min; MS m/z 287.3 = [M+H]+ (100% @ 254nm)
1H NMR (500 MHz, DMSO-d6) δ 11.10 - 11.05 (m, 1H), 10.58 (s, 1H), 6.92 (d, J = 2.2 Hz, 2H), 6.80 (t, J = 7.8 Hz, 1H), 6.74 (d, J = 7.9 Hz, 1H), 6.26 (d, J = 7.3 Hz, 1H), 2.88 (t, J = 6.5 Hz, 2H), 2.61 (t, J = 6.5 Hz, 2H), 2.45 (q, J = 7.2 Hz, 2H), 2.24 (s, 3H), 0.98 (t, J = 7.1 Hz, 3H).
Phenylamino 3-[2-(N-methyl-N-ethylamino)ethyl]-1H-indole-4-carboxylate hydrochloride (T005).
To a stirred mixture of 3 (50 mg, 0.23mmol) in acetonitrile was added phenyl isocyanate (27 mg, 25 μL, 0.23mmol) and stirring was continued at room temperature for 10min. The material was purified by reversed- phase chromatography by direct injection (C18 20g, 15 → 45% acetonitrile in aq. 0.01% HCI) to afford the title compound as an off-white solid (42 mg, 54%).
LC-MS (Method 8min acid): Rt 2.64min; MS m/z 338.1 = [M+H]+ (100% @ 254nm)
1H NMR (500 MHz, DMSO-d6) δ 11.26 (br s, 1H), 10.43 (br s, 1H), 10.16 (br s, 1H), 7.59 (d, J = 8.0 Hz, 2H), 7.37
- 7.31 (m, 2H), 7.28 (d, J = 8.1 Hz, 2H), 7.13 - 7.03 (m, 2H), 6.84 (d, J = 7.6 Hz, 1H), 3.24 - 3.11 (m, 3H), 3.08
- 2.99 (m, 1H), 2.75 - 2.70 (m, 3H), 1.15 (t, J = 7.3 Hz, 3H).
In an embodiment there is provided a method of synthesis of compound T005. In an embodiment there is provided a method of synthesis of Compound T005 as described above.
Example 6 - Further characterisation of compounds T005, T008 and T018 cAMP
Compounds T005, T008 and T018 were assayed using a serotonin (1a, 1b, 2a, 2c and 7 receptors) cAMP assay, provided by Multispan. The reference used was 10μM forskolin (a cAMP activator) to calculate the percentage relative response, serotonin was used as the control. The results can be seen in Figure 10. The results indicate T005 may have some activation of the cAMP pathway and subsequent cascade.
IP1
Compounds T005, T008 and T018 were assayed using a serotonin (2a, 2b and 2c receptors) inositol phosphate 1 (IP1) assay, provided by Multispan. The reference used was 1μM serotonin to calculate the percentage relative response. The results can be seen in Figure 11. All compounds produced incomplete response curves in this assay, showing agonistic activity, implying that the compounds may not active any Gaq/n pathway.
Ca2+
Compounds T005, T008 and T018 were assayed using a serotonin (2a, 2b and 2c receptors) calcium (Ca2+) assay, provided by Multispan. The reference used was 10μM serotonin to calculate the percentage relative response in relative light units (RLU). The results can be seen in Figure 12. Some activity for compound 005 in the 2c receptor assay was detected.
B-arrestin
Compounds T005, T008 and T018 were assayed using a serotonin (1a, 1b, 2a and 2c receptors) B-arrestin assay, provided by DiscoverX. The reference used was 10μM serotonin to calculate the percentage relative response. The results can be seen in Figure 4. Some activity for all compounds in the 2a receptor activity was detected, whilst only compound T005 appeared to have activity in the 2c receptor assay.
The compounds were also assayed in a serotonin 2b receptor B-arrestin assay, the results of which can be seen in Figure 13.
Reagent information
B-arrestin:
HTR1A PathHunter® express HTR1A CHO-K1 P-Arrestin GPCR Assay 93-0696E2CP0M 200 dp (2 x 96-well)
HTR1B PathHunter® eXpress HTR1B U2OS P-Arrestin GPCR Assay 93-0697E3CP6M 200 dp (2 x 96-well)
HTR2A PathHunter® eXpress HTR2A U2OS P-Arrestin GPCR Assay 93-0401E3CP 19 M 200 dp (2 x 96-well)
HTR2C PathHunter® eXpress HTR2C U2OS P-Arrestin GPCR Assay 93-0289E3CP3M 200 dp (2 x 96-well)
Multispan p-arrestin assay with CHO-Kl-5HT2bR cells - Catalog C1350-la
Homogeneous Time Resolved Fluorescence (HTRF) and Calcium:
IP-One Gq kit - cisbio - cat. No. 62IPAPEB cAMP Gs dynamic kit - cisbio - cat. No. 62AM4PEC
FLIPR calcium 6 assay explorer kit - VWR - cat. No. MLDVR8190
Cells used in HTRF and calcium assays:
MULTISCREEN™ HEK293T Cell Line Stably Expressing Human 5-HT1A Receptor, Catalog DC1319a MULTISCREEN™ HEK293T Cell Line Stably Expressing Human 5-HT1B Receptor, Catalog DC1320a MULTISCREEN™ HEK293T Cell Line Stably Expressing Human 5HT1B Receptor, Catalog DC1320a MULTISCREEN™ CHO-K1 Cell Line Stably Expressing Human 5-HT2A Receptor, Catalog DC1324-1 MULTISCREEN™ CHO-K1 Cell Line Stably Expressing Human 5-HT2B Receptor, Catalog DC1325-1 MULTISCREEN™ CHO-K1 Cell Line Stably Expressing Human 5-HT2C Receptor, Catalog DC1326-1 MULTISCREEN™ HEK293T Cell Line Stably Expressing Human 5-HT7 Receptor, Catalog DC1334 For the B-arrestin assays the cells came with the kits apart from the 2b receptor assay (Valiscreen serotonin 5HT-2B (human) cell line - ES-314-C, Perkin Elmer)
Example 7 - Effects of compounds T005, T008 and T017 (several concentrations) on the neurite network (neurogenesis) in a primary culture of cortical neurons
Rationale
Neuronal plasticity corresponds to the ability of the nervous system to reorganised itself by making new connections through neurogenesis, neuritogenesis and synaptogenesis. Lack of neuronal plasticity is found in neurodegenerative diseases, neurological disorders and during biological aging, or senescence. Low neuronal plasticity is associated with cognitive decline, depression and psychiatric diseases.
The aim of this study was to assess the effect of several test compounds (3-5 concentrations) on the number of neurons, the outgrowth of neurite network of cortical neurons, and the number of branching points, after 3 days of treatment. The treatment was applied on day 1 of culture.
Primary culture of cortical neurons
All experiments were carried out in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals and followed current European Union regulations (Directive 2010 / 63 / EU). Agreement number: B1301310.
Rat cortical neurons were cultured as described by Callizot et al., 2013 with modifications. Briefly pregnant female rat (Wistar) of 15 days of gestation was killed using a deep anesthesia with CO2 chamber and a cervical dislocation. Fetuses were collected and immediately placed in ice-cold L15 Leibovitz medium with a 2 % penicillin (10,000 U/mL) and streptomycin (10 mg/mL) solution (PS) and 1 % bovine serum albumin (BSA). Cortex were specifically dissected and then were treated for 20 min at 37 °C with a trypsin-EDTA solution at a final concentration of 0.05 % trypsin and 0.02 % EDTA. The dissociation was stopped by addition of Dulbecco's modified Eagle's medium (DMEM) with 4.5 g/L of glucose, containing DNAse I grade II (final concentration 0.5 mg/mL) and 10 % fetal calf serum (FCS). Cells were mechanically dissociated by three forced passages through the tip of a 10-mL pipette. Cells were then centrifuged at 515 x g for 10 min at 4 °C. The supernatant was discarded, and the pellet was resuspended in a defined culture medium consisting of Neurobasal medium with a 2 % solution of B27 supplement, 2 mmol/liter of L- glutamine, 2 % of PS solution, and 10 ng/mL of brain-derived neurotrophic factor (BDNF). Viable cells were counted in a Neubauer cytometer, using the trypan blue exclusion test. The cells were seeded at a density of 25,000 per well in 96-well plate precoated with poly-L-lysine and were cultured at 37 °C in an air (95 %) - CO2 (5%) incubator. For 96 well-plates, only 60 wells were used. The wells of first and last lines and columns were not used (to avoid any edge effect) and were filled with sterile water.
Test compounds
Vehicle: culture medium, 0.1% DMSO, or 0.1% acetonitrile, or 0.1% water.
Treatment: On day 1 (day of seeding), compounds were applied on the culture and let for 3 days.
Organisation of culture plates
The compounds were tested on 96-well plate (n = 6 culture wells per condition). Compounds were applied as follow:
Figure imgf000093_0001
Figure imgf000093_0002
Figure imgf000093_0003
Figure imgf000093_0004
Immunostaining: MAP-2 positive neurons
3 days after the treatment (and after seeding), the supernatant was removed, and kept frozen. Cells were then fixed by a cold solution of ethanol (95 %) and acetic acid (5 %) for 5 min at -20 °C and washed twice in PBS. Cell membranes were permeabilized and non-specific sites were blocked with a solution of PBS containing 0.1 % of saponin and 1 % FCS for 15 min at room temperature. Cells were incubated for 2 hours at room temperature with a primary chicken polyclonal antibody anti-MAP-2 (microtubule-associated protein 2), at a dilution of 1/400 in PBS containing 1 % FCS and 0.1 % of saponin. This antibody binds specifically neurons and neurites, allowing study of neuronal cell survival and neurite network.
The anti-MAP-2 antibody was revealed with a secondary Alexa Fluor 488 coupled goat anti-chicken antibody diluted at 1/400 in PBS containing 1 % FCS, 0.1 % saponin, for 1 hour at room temperature.
Cell nuclei were counterstained with the fluorescent dye Hoechst.
Automatic computer-assisted analysis
For each condition, 30 pictures (representative of the whole well area) per well were automatically taken using ImageXpress® (Molecular Devices) at 20x magnification. All images were generated using the same acquisition parameters. From images, analyses were automatically performed by MetaXpress® software (Molecular Devices).
The following read-outs were automatically assessed:
Total neuron survival (number of MAP-2 positive neuron);
Total neurite network (length of MAP-2 positive neurite in pm);
Number of total branching points (branching point of MAP-2 positive neuron)
Statistics
All values are expressed as mean +/- SEM (standard error of the mean). Normality was verified and outliers were identified with Grubb's test. Statistical analysis was performed by one-way ANOVA followed by Fisher's LSD test. p< 0.05 will be considered significant.
Results
Test compounds were applied the day of the seeding, for 3 days. BDNF (50 ng/ml), the positive control, significantly increased the number of neurons, on the length of the neurite network and on the number of branching points.
• 5-MeO-DALT (applied from 0.1 μM to 10 μM) increased the number of MAP2(+) neurons in the culture at 0.1 μM, without significant effect on neurite outgrowth or branching points.
• 5-MeO-MiPT (applied from 0.1 μM to 10 μM) did not show any significant effect.
• DiPT (applied from 0.1 μM to 10 μM) increased the number of neurons and promoted the neurite outgrowth (0.3 and 1 μM) and increased the number of branching points (0.1 μM to 10 μM).
The above results can be seen in Figure 6.
5-MeO-DMT, psilocin and norpsilocin (all from 0.1 μM to 10 μM) were applied the day of the seeding and let for 3 days. BDNF (50 ng/ml), the positive control, significantly increased the number of neurons, on the length of the neurite network and on the number of branching points. • 5-MeO-DMT increased the number of neurons (0.3 μM and 1 μM), promoted neurite outgrowth (0.3 μM to 10 μM), and increased the number of branching points (0.3 μM). Maximal effect was observed at 0.3 μM.
• Psilocin increased the number of neurons (0.3 μM and 10 μM), promoted neurite outgrowth (0.3), and increased the number of branching points (10 μM). Maximal effect ranged between 0.3 and 10 μM, depending on the readouts. Psilocin was equivalent to BDNF in terms of efficacy.
• Norpsilocin did not show any significant effect on the number of neurons and on neurite outgrowth. At 1 μM, this compound significantly increased the number of branching points.
The above results can be seen in Figure 7.
Tryptamine 5, tryptamine 8 and tryptamine 18 (all from 0.1 μM to 10 μM) were applied the day of the seeding and let for 3 days. BDNF (50 ng/ml), the positive control, significantly increased the number of neurons, on the length of the neurite network and on the number of branching points.
• Tryptamine 5 increased the number of neurons (all investigated concentrations), promoted the neurite outgrowth (all investigated concentrations), and increased the number of branching points (all investigated concentrations). Interestingly, the effect on the number of neurons was already plateaued at 0.1 μM. Effects on the neurite outgrowth and on the branching points were both dose dependent, with a maximal effect at 10 μM.
Tryptamine 8 increased the number of neurons (1 μM only), promoted neurite outgrowth (0.1 μM only), and increased the number of branching points (from 0.1 μM to 1 μM, with a maximal effect at 0.1 μM).
The above results can be seen in Figure 15.
Psilocybin (from 0.1 μM to 10 μM) were applied the day of the seeding and let for 3 days. As expected, BDNF (50 ng/ml), the positive control, significantly increased the number of neurons, on the length of the neurite network and on the number of branching points.
• Psilocybin increased the number of neurons (0.3 μM to 10 μM), promoted the neurite outgrowth (0.3 μM and 1 μM), and increased the number of branching points (from 0.3 μM).
The above results can be seen in Figure 9.
Discussion
This study was designed to assess the effects of several test compounds on the neurogenesis and neuroplasticity. The tested compounds have a well-known affinity for serotonergic receptors (e.g. 5-HTla, 5- HT2b). Compounds were applied on primary cortical neurons, from seeding, and left for 3 days.
Based on the results, the following conclusions could be made:
DiPT, 5-MeO-DMT, psilocin and psilocybin displayed a strong beneficial effect on all investigated parameters indicating that these compounds have a positive effect on neuronal plasticity. • 5-MeO-DALT and norpsilocin displayed beneficial effect restricted to neurite outgrowth and/or branching points. Indeed, these two compounds did not support any increase in the number of neurons.
• 5-MeO-MiPT was inactive in the assay. Regarding the novel chemical entities, derivatives of tryptamine, the following conclusion could be made:
Tryptamine 005 and 008 showed strong beneficial effects on all investigated parameters.
Example 8 - Synthetic Routes
Figure imgf000096_0001
Figure imgf000097_0001
Figure imgf000098_0001
Figure imgf000099_0001
Figure imgf000100_0001
Figure imgf000101_0001
Figure imgf000102_0001
Figure imgf000103_0001
Additional routes to N-acyl compounds
Salt formation is undertaken thereafter in the above routes as necessary, e.g. to give the benzoate, fumarate, citrate, acetate, succinate, halide, fluoride, chloride, bromide, iodide, oxalate, or triflate salt. For example, the addition of hydrogen chloride to a freebase form would provide the chloride salt form and benzoic acid would give the benzoate salt form. In an embodiment, there is provided a method of synthesis of any of the herein described compounds.
Example 9: Further investigations into the neurogenesis effect of select compounds in a primary cuIture of cortical neurons
The aim of this study was to assess the effect of several test compounds, co-applied with antagonists of 5-HT receptors, on the neurite network of cortical neurons, after 3 days of treatment starting on day 1 of culture.
4 antagonists were tested (M 100907, WAY-635, Ritanserin and Sarpogrelate (selective 2A antagonist).
Primary culture of cortical neurons
All experiments were carried out in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals and followed current European Union regulations (Directive 2010 / 63 / EU). Agreement number: B1301310.
The primary culture of cortical neurons was prepared as set out in Example 3.
Test compounds
Vehicle: culture medium, 0.1% DMSO
Treatment: On day 1 (day of seeding), the antagonists, alone or combined with the compounds were co- applied on the culture and left for 3 days (72h).
Organisation of culture plates
The compounds were tested on 96-well plate (n = 6 culture wells per condition). Compounds were applied as follows:
Step 1: Dose selection of antagonist of 5-HT receptors
Figure imgf000103_0002
Figure imgf000104_0001
Step 2: Co-application of test compounds and antagonist of 5-HT receptors
Figure imgf000104_0003
The results can be seen in the Table below and in Figure 16.
Figure imgf000104_0002
Figure imgf000104_0004
The results can be seen in the Table below and in Figure 17.
Figure imgf000105_0001
Immunostaining: MAP-2 positive neurons
As per Example 3, apart from the use of a secondary antibody goat anti-mouse IgG coupled with an Alexa Fluor 488 for revealing the anti-MAP-2 antibody.
Automatic computer-assisted analysis
As per Example 3.
Statistics
As per Example 3. Results
Regarding the number of neurons in a primary culture of cortical neurons, the results show:
Ergoline 019 alone is no better than control.
Clauses:
1. A compound for use in treating a condition benefiting from an increase in neural plasticity, wherein the compound is of Formula (l)A wherein:
Figure imgf000106_0001
X is selected from methyl or isopropyl; and
Y is selected from a bond, O, CONH, NH, N(C1-6 alkyl), A-(CH2)n-B, wherein
A is O, NH or N(C1-6 alkyl), wherein
B is a bond, O, or NH, wherein n is 1 to 4; and
Z is selected from H, OH, NH2, NHC1-6 alkyl, N(C1-6 alkyl)2, C1-6 alkyl, C6-10 aryl, SO2-C1-6 alkyl, SO2-C6-10 aryl, C3-C10 heteroaromatic or heterocyclic group comprising one, two or three heteroatoms independently selected from O and N; and wherein X and Z are different; or a pharmaceutically acceptable salt thereof, and wherein the compound increases neural plasticity in a subject treated with the compound.
2. A compound of clause 1, wherein X is methyl.
3. A compound of clause 1, wherein X is isopropyl.
4. A compound of any one of the preceding clauses, wherein Y is selected from a bond, O, CONH, NH or NCH3.
5. A compound of any one of clauses 1 to 3 wherein, Y is A-(CH2)n-B, wherein
A is O or NH, wherein
B is a bond, O or NH, wherein n is 1 to 4.
6. A compound of clause 5, wherein n is 2 or 3.
7. A compound any one of the preceding clauses, wherein Z is selected from pyridine, morpholine, SO2-CH3, SO2-phenyl, 8-oxa-3-azabicyclo[3.2.1]octane and 2-oxa-5-azabicyclo[2.2.1]heptane. 8. A compound of any one of clauses 1 to 3, wherein Y-Z together are H or C1-6 alkyl.
9. A compound of any one of clauses 1 to 3, wherein Y-Z together are H or C5 alkyl.
10. A compound of any one of clauses 1 to 3, wherein Y-Z together form the group:
O-(CH2)3-N(CH3)2 NH-(CH2)2-OH
NH-(CH2)3-OH
NH-(CH2)3-OCH3
NH-(CH2)3-SO2CH3
NH-(CH2)2-NH-SO2CH3, or R6 is 11. A compound of any one of clauses 1 to 3, wherein Y-Z together form the group:
NH-phenyl, pyridine, O-morpholine, NH-morpholine, NH-SO2-Phenyl, NCH3-SO2-Phenyl, CONH-Phenyl, 8-oxa-3-azabicyclo[3.2.1]octane or 2-oxa-5-azabicyclo[2.2.1]heptane.
12. A compound of clause 1, wherein the compound is selected from:
Figure imgf000107_0001
Figure imgf000108_0001
Figure imgf000109_0001
13. A compound of clause 1, wherein the compound is
Figure imgf000109_0002
14. A compound of clause 1, wherein the compound is
Figure imgf000110_0001
15. A compound for use in treating a condition benefiting from neurogenesis, neurite outgrowth or an increase in neuronal branching points, wherein the compound is
Figure imgf000110_0002
and wherein the compound increase or promotes neurogenesis, neurite outgrowth or neuronal branching points in a subject treated with the compound.
16. A compound for use in treating a condition benefiting from neurite outgrowth or an increase in neuronal branching points, wherein the compound is
Figure imgf000110_0003
and wherein the compound increase or promotes neurite outgrowth or neuronal branching points in a subject treated with the compound.
17. A pharmaceutical composition comprising a pharmaceutically effective amount of a compound as defined in any one of clauses 1 to 16. 18. The pharmaceutical composition of clause 17, wherein the composition comprises a dosage amount in the range of 0.05mg to 100mg.
19. The pharmaceutical composition of clause 17, wherein the composition comprises a dosage amount in the range of 0.1mg to 50mg. The pharmaceutical composition of clause 17, wherein the composition comprises a dosage amount in the range of 0.5mg to 25mg. The pharmaceutical composition of any one of clauses 17 to 20, wherein the composition is formulated in a dosage form selected from: oral, transdermal, inhalable, intravenous, or rectal dosage form. The pharmaceutical composition for use of any one of clauses 17 to 21, wherein the composition is formulated in a dosage form selected from: tablet, capsule, granules, powder, free-flowing powder, inhalable powder, aerosol, nebulised, vaping, buccal, sublingual, sublabial, injectable, or suppository dosage form. The pharmaceutical composition for use of any one of clauses 17 to 22, wherein the composition is administered one or more times a month. The pharmaceutical composition for use of any one of clauses 17 to 22, wherein the composition is administered one or more times a week. The pharmaceutical composition for use of any one of clauses 17 to 22, wherein the composition is administered one or more times a day. A compound for use in treating a condition benefiting from an increase in neural plasticity, wherein the compound is of Formula (l)B wherein:
Figure imgf000111_0001
R1 is selected from H or C1-6 alkyl; and
R2 is CH2-CHR4-NR5R6, wherein
R4 is selected from H or C1-6 alkyl, wherein
R5 is selected from H or C1-6 alkyl, wherein
R6 is:
Figure imgf000111_0002
a) wherein X is a bond, Y is N, Z is O and R7 and R8 together from a bringing group CH2CH2; or
Figure imgf000112_0001
b) wherein X is NH or O, Y is CH, Z is O and R7 and R8 are H; or c) NH(CH2)3N(CH3)2, O(CH2)OH or O(CH2)2N(CH3)2.
R3 is selected from H or L-R9, wherein
L is selected from O, N, NH, O-O, CH2, CH2CH2, O-O-CH2CH2, CO, OCO, COO or OCONH, wherein
R9 is selected from H, Ci-s alkyl, COOH, OH, COO-, O-, C6-C10 aromatic, C3-C10 heteroaromatic or heterocyclic group comprising one, two or three heteroatoms independently selected from O and N; and
K is CH, CH-CH=CR3 or NH-CH=CH-C(O); or is a pharmaceutically acceptable salt thereof, and wherein the compound increases neural plasticity in a subject treated with the compound.
27. A compound of clause 26 wherein K is CH.
28. A compound of clause 26 or 27 wherein R1 is H, R2 is CH2-CHR4-NR5R6, R3 is H or L-R9, and K is CH.
29. A compound of any one of clauses 26 to 28 wherein R4 is H or methyl.
30. A compound of any one of clauses 26 to 29 wherein R5 is ethyl or isopropyl.
31. A compound of any one of clauses 26 to 30 wherein R4 is H and R5 is ethyl.
32. A compound of any one of clauses 26 to 31 wherein R3 is L-R9 and wherein L is O, O-O-CH2CH2, OCO or OCONH.
33. A compound of any one of clauses 26 to 32 wherein R3 is L-R9 and wherein R9 is OH, COCH3, imidazole, pyrrolidine, piperidine, analine, pyrideine, morpholine or 6-oxa-3-azabicyclo[3.1.1]heptane.
34. A compound of any one of clauses 26 to 33 wherein R3 is OCOCH3.
35. A compound of any one of clauses 26 to 34 wherein the compound is:
Figure imgf000112_0002
36. A compound of any one of clauses 26 to 34 wherein the compound is:
Figure imgf000113_0001
37. A compound of any one of clauses 26 to 34 wherein the compound is:
Figure imgf000113_0002
or 38. A compound of any one of clauses 26 to 34 wherein the compound is:
Figure imgf000113_0003
39. A compound of any one of clauses 26 to 34 wherein the compound is:
Figure imgf000113_0004
40. A compound of any one of clauses 26 to 34 wherein the compound is:
Figure imgf000114_0001
41. A compound of any one of clauses 26 to 34 wherein the compound is:
Figure imgf000114_0002
42. A compound of any one of clauses 26 to 34 wherein the compound is:
Figure imgf000114_0003
43. A compound of any one of clauses 26 to 34 wherein the compound is:
Figure imgf000114_0004
44. A compound of any one of clauses 26 to 34 wherein the compound is:
Figure imgf000115_0001
45. A compound of any one of clauses 26 to 34 wherein the compound is:
Figure imgf000115_0002
46. A compound of any one of clauses 26 to 34 wherein the compound is:
Figure imgf000115_0003
47. A pharmaceutical composition comprising a compound or salt as defined in any one of clauses 26 to 46. 48. A pharmaceutical composition comprising a pharmaceutically effective amount of a compound of formula:
Figure imgf000116_0001
for use in treating a condition benefiting from an increase in neural plasticity, wherein the compound increases neural plasticity in a patient in need thereof.
49. A pharmaceutical composition comprising a pharmaceutically effective amount of a compound of formula:
Figure imgf000116_0002
for use in treating a condition benefiting from an increase in neural plasticity, wherein the compound increases neural plasticity in a patient in need thereof.
50. A pharmaceutical composition defined in clause 48 or clause 49, wherein the patient has depression, anxiety, post-traumatic stress disorder or a neurodegenerative condition, or a combination thereof.
51. A compound of Formula (l)C wherein:
Figure imgf000116_0003
R1 is (CH2)mNR4(R5) wherein: m is selected from 1, 2, 3, 4, 5, 6, 7, or 8;
R4 is C1-6 alkyl;
R5 is C1-6 alkyl; R2 is H or C(O)C1-6 alkyl;
R3 is O-X-Y wherein:
X is -
CO-; -C(O)O-; -C(O)O(CH2)n-; -CH2(CO)-; -CH2-O-; -CHRS-O-; -CH2-NH-; -CH2-NR7-; -CHR8-NH-; - CHR9-NR10-; -P(O)(OH)-; -P(O)OR11-; -CH2O-P(O)OH-; -CH2O-P(O)OR12-; or -CO(CH2)n-C(O)OCH2 -;
Y is -(CH2)n-NH2; -(CH2)n-NHR13; -(CH2)n-NR14R15; -C(O)CHR1SR17;
C(O)OR18; -C(O)NHR19; -C(O)NR20R21; -OR22 or a C5-6hetrocycle
R6 to R21 are independently H or C1-4 alkyl groups and R22 is a C1-8 alkyl group n is independently 1 to 4
52. The compound of clause 51, wherein m is 2.
53. The compound of clause 51 or clause 52, wherein R4 and R5 are both CH3.
54. The compound of any one of clauses 51 to 53, wherein R2 is H.
55. The compound of any one of clauses 51 to 53, wherein R2 is C(O)C1-6 alkyl.
56. The compound of clause 55, wherein R2 is C(O)CH3.
57. The compound of any one of clauses 51 to 56, wherein R6 to R21 are independently H or CH3 groups
58. The compound of any one of clauses 51 to 57, wherein R22 is a C8 alkyl group or a t-butyl group.
59. The compound of any one of clauses 51 to 58, wherein Y is
Figure imgf000117_0001
60. The compound of clause 51, wherein X is CH(CH3)O, and Y is C(O)CH(CH3)2 or C(O)N(CH3)2.
61. The compound of clause 51, wherein X is C(O)O or C(O)O(CH2) and Y is CH2N(CH3)2.
62. The compound of clause 51, wherein X is -P(O)(OH)-; -P(O)(O-n-butyl)-; -CH2O-P(O)OH- ; -CH2O-P(O)(n-butyl)- and Y is or O-n-butyl, O-t-butyl, O-n-heptyl, n-butyl, t-butyl or n-heptyl.
63. The compound of clause 51, wherein X is -CH2O-P(O)OH- and Y is O-t-butyl or O-n-heptyl, t-butyl or n-heptyl.
64. The compound of clause 51, wherein X is CH2N(CH3) and Y is C(O)OCH3, C(O)CH(CH3)2 or C(O)N(CH3)2.
65. The compound of clause 51, wherein X is C(O) or -CH2(CO)-, and Yis
Figure imgf000118_0001
66. The compound of clause 51, wherein X is -CO(CH2)-C(O)OCH2 - or CO(CH2)2-C(O)OCH2 - and Y is
Figure imgf000118_0002
67. The compound of clause 51, wherein X is CH(CH3)NH or CH2NH and Yis C(O)CH(CH3)2- 68. The compound of any one of clauses 60 to 67, wherein n is 2, R4 and R5 are both CH3 and R2 is H.
69. The compound of any one of clauses 60 to 67, wherein n is 2, R4 and R5 are both CH3 and R2 is C(O)CH3.
70. The compound of clause 51, wherein the compound is selected from:
Figure imgf000118_0003
71. The compound of clause 51, wherein the compound is selected from:
Figure imgf000119_0001
72. The compound of clause 51, wherein the compound is:
Figure imgf000119_0002
73. The compound of clause 51, wherein the compound is:
Figure imgf000119_0003
74. The compound of clause 51, wherein the compound is selected from:
Figure imgf000120_0001
75. A pharmaceutical composition comprising a pharmaceutically effective amount of a compound as in any one of clauses 70 to 74.
76. A combination pharmaceutical comprising: (a) compound of Formula (l)D
Figure imgf000121_0001
wherein:
X is selected from H or CMO branched or straight chain alkyl, and optionally wherein X is methyl or isopropyl;
Y is selected from a bond, O, CONK, NH, N(C1-6 alkyl), A-(CH2)n-B, wherein
A is O, NH or N(C1-6 alkyl), wherein B is a bond, O, or NH, wherein n is 1 to 4;
Z is selected from H, OH, NH2, NHC1-6 alkyl, N(C1-6 alkyl)2, C1-6 alkyl, C6-10 aryl, SO2-C1-6 alkyl, SO2-C6-10 aryl, C3-C10 heteroaromatic or heterocyclic group comprising one, two or three heteroatoms independently selected from O and N; wherein X and Z are different; or a pharmaceutically acceptable salt thereof; and
(b) serotonin receptor antagonist or inverse agonist, or a pharmaceutically acceptable salt thereof.
77. The combination pharmaceutical of clause 76, wherein the compound of Formula (I) is selected from:
Figure imgf000121_0002
Figure imgf000122_0001
78. The combination pharmaceutical of clause 76, wherein the compound of Formula (I) is:
Figure imgf000122_0002
79. The combination pharmaceutical of clause 76, wherein the compound of Formula (I) is:
Figure imgf000122_0003
80. The combination pharmaceutical of clause 76, wherein the compound of Formula (I) is:
Figure imgf000122_0004
81. The combination pharmaceutical of any one of clauses 76 to 80, wherein the serotonin receptor antagonist, or inverse agonist, is an antagonist, or inverse agonist against one or more of the serotonin receptor subtypes 2a, 2b and 2c.
82. The combination pharmaceutical of any one of clauses 76 to 80, wherein the serotonin receptor antagonist, or inverse agonist is selected from: lisuride, methysergide, clomipramine, doxepin, amoxapine, cariprazine, cyproheptadine, aripiprazole, mianserin, minaprine, asenapine, cyclobenzaprine, volinanserin or sarpogrelate.
83. The combination pharmaceutical of any one of clauses 76 to 80, wherein the serotonin receptor antagonist, or inverse agonist, is
Figure imgf000123_0001
or a pharmaceutically acceptable salt thereof.
84. The combination pharmaceutical of any one of clauses 76 to 80, wherein the serotonin receptor antagonist, or inverse agonist, is
Figure imgf000123_0002
or a pharmaceutically acceptable salt thereof.
85. The combination pharmaceutical of any one of clauses 76 to 84, wherein the compound of Formula (I) and the serotonin receptor antagonist, or inverse agonist, are present in the same single dosage form.
86. The combination pharmaceutical of clause 85, wherein the combination pharmaceutical is formulated in a dosage form selected from oral, transdermal, inhalable, intravenous, injectable or rectal dosage forms.
87. The combination pharmaceutical of any one of clauses 76 to 84, wherein the compound of Formula (I) and the serotonin receptor antagonist, or inverse agonist, are present in different dosage forms.
88. The combination pharmaceutical of clause 87, wherein the dosage forms are selected from oral, transdermal, inhalable, intravenous, injectable or rectal dosage forms. 89. The use of a combination pharmaceutical according to any one of clauses 86 to 88 in treating a condition benefiting from an increase in neural plasticity, wherein the combination pharmaceutical increases neural plasticity in a subject treated with the combination pharmaceutical.
90. The use of a combination pharmaceutical according to clause 87 or clause 88 in treating a condition benefiting from an increase in neural plasticity, wherein the compound of Formula (I) of the combination pharmaceutical and the serotonin receptor antagonist, or inverse agonist, are administered on the same day.
91. The use of a combination pharmaceutical according to clause 90, wherein the compound of Formula (I) of the combination pharmaceutical and the serotonin receptor antagonist, or inverse agonist, are administered at the same time on the same day.
92. The use of a combination pharmaceutical according to clause 90, wherein the compound of Formula (I) of the combination pharmaceutical and the serotonin receptor antagonist, or inverse agonist, are administered at the same time on the same day.
93. The use of a combination pharmaceutical according to clause 90, wherein the compound of Formula (I) of the combination pharmaceutical and the serotonin receptor antagonist, or inverse agonist, are administered 1 minute, 2 minutes, 3 minutes, 4 minutes, 5 minutes, 10 m inutes, 15 minutes, 20 minutes, 25 minutes, 30 minutes, 35 minutes, 40 minutes, 45 minutes, 50 minutes, 55 minutes or 60 minutes apart.
94. The use of a combination pharmaceutical according to clause 87 or clause 88 in treating a condition benefiting from an increase in neural plasticity, wherein the compound of Formula (I) of the combination pharmaceutical and the serotonin receptor antagonist, or inverse agonist, are administered 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours or 24 hours apart.
95. The use of a combination pharmaceutical according to clause 87 or clause 88 in treating a conditi on benefiting from an increase in neural plasticity, wherein the compound of Formula (I) of the combination pharmaceutical and the serotonin receptor antagonist, or inverse agonist, are administered 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days or 30 days apart.
96. The use of a combination pharmaceutical according to clause 87 or clause 88 in treating a condition benefiting from an increase in neural plasticity, wherein the compound of Formula (I) of the combination pharmaceutical is administered multiple times whilst the serotonin antagonist is administered only once in any given treatment round. 97. The use of a combination pharmaceutical comprising
Figure imgf000125_0001
or a pharmaceutically acceptable salt, and a serotonin receptor antagonist, or inverse agonist, or a pharmaceutically acceptable salt thereof, in treating a condition benefiting from an increase in neural plasticity, wherein the combination pharmaceutical increases neural plasticity in a subject treated with the combination pharmaceutical.
98. The use of clause 97, wherein the serotonin receptor antagonist, or inverse agonist, is
Figure imgf000125_0002
or a pharmaceutically acceptable salt thereof. 99. The use of clause 87, wherein the serotonin receptor antagonist, or inverse agonist, is
Figure imgf000125_0003
or a pharmaceutically acceptable salt thereof.
100. The use of clause 94 or clause 95 wherein the combination pharmaceutical increases neural plasticity in a subject treated with the combination pharmaceutical to a greater extent than administration of either active compounds of the combination pharmaceutical alone.

Claims

CLAIMS:
1. A compound for use in treating a condition benefiting from an increase in neural plasticity, wherein the compound is of Formula (l)A wherein:
Figure imgf000126_0001
X is selected from methyl or isopropyl; and
Y is selected from a bond, O, CONH, NH, N(C1-6 alkyl), A-(CH2)n-B, wherein
A is O, NH or N(C1-6 alkyl), wherein
B is a bond, O, or NH, wherein n is 1 to 4; and
Z is selected from H, OH, NH2, NHC1-6 alkyl, N(C1-6 alkyl)2, C1-6 alkyl, C6-10 aryl, SO2-C1-6 alkyl, SO2-C6-10 aryl, C3-C10 heteroaromatic or heterocyclic group comprising one, two or three heteroatoms independently selected from O and N; and wherein X and Z are different; or a pharmaceutically acceptable salt thereof, and wherein the compound increases neural plasticity in a subject treated with the compound.
2. A compound of claim 1, wherein X is methyl.
3. A compound of claim 1, wherein X is isopropyl.
4. A compound of any one of the preceding claims, wherein Y is selected from a bond, O, CONH, NH or
NCH3.
5. A compound of any one of claims 1 to 3 wherein, Y is A-(CH2)n-B, wherein
A is O or NH, wherein
B is a bond, O or NH, wherein n is 1 to 4.
6. A compound of claim 5, wherein n is 2 or 3.
7. A compound any one of the preceding claims, wherein Z is selected from pyridine, morpholine, SO2-CH3, SO2-phenyl, 8-oxa-3-azabicyclo[3.2.1]octane and 2-oxa-5-azabicyclo[2.2.1]heptane.
8. A compound of any one of claims 1 to 3, wherein Y-Z together are H or C1-6 alkyl. A compound of any one of claims 1 to 3, wherein Y-Z together are H or C5 alkyl. A compound of any one of claims 1 to 3, wherein Y-Z together form the group:
O-(CH2)3-N(CH3)2
NH-(CH2)2-OH
NH-(CH2)3-OH
NH-(CH2)3-OCH3
NH-(CH2)3-SO2CH3
NH-(CH2)2-NH-SO2CH3, or O-(CH2)2-NH-SO2CH3. A compound of any one of claims 1 to 3, wherein Y-Z together form the group:
NH-phenyl, pyridine, O-morpholine, NH-morpholine, NH-SO2-Phenyl, NCH3-SO2-Phenyl, CONH-Phenyl, 8-oxa-3-azabicyclo[3.2.1]octane or 2-oxa-5-azabicyclo[2.2.1]heptane. A compound of claim 1, wherein the compound is selected from:
Figure imgf000127_0001
Figure imgf000128_0001
Figure imgf000129_0001
13. A compound of claim 1, wherein the compound is
Figure imgf000129_0002
14. A compound of claim 1, wherein the compound is
Figure imgf000130_0001
15. A compound for use in treating a condition benefiting from neurogenesis, neurite outgrowth or an increase in neuronal branching points, wherein the compound is
Figure imgf000130_0002
and wherein the compound increase or promotes neurogenesis, neurite outgrowth or neuronal branching points in a subject treated with the compound.
16. A compound for use in treating a condition benefiting from neurite outgrowth or an increase in neuronal branching points, wherein the compound is
Figure imgf000130_0003
and wherein the compound increase or promotes neurite outgrowth or neuronal branching points in a subject treated with the compound.
17. A pharmaceutical composition comprising a pharmaceutically effective amount of a compound as defined in any one of claims 1 to 16.
18. The pharmaceutical composition of claim 17, wherein the composition comprises a dosage amount in the range of 0.05mg to 100mg.
19. The pharmaceutical composition of claim 17, wherein the composition comprises a dosage amount in the range of 0.1mg to 50mg.
20. The pharmaceutical composition of claim 17, wherein the composition comprises a dosage amount in the range of 0.5mg to 25mg.
21. The pharmaceutical composition of any one of claims 17 to 20, wherein the composition is formulated in a dosage form selected from: oral, transdermal, inhalable, intravenous, or rectal dosage form.
22. The pharmaceutical composition for use of any one of claims 17 to 21, wherein the composition is formulated in a dosage form selected from: tablet, capsule, granules, powder, free-flowing powder, inhalable powder, aerosol, nebulised, vaping, buccal, sublingual, sublabial, injectable, or suppository dosage form.
23. The pharmaceutical composition for use of any one of claims 17 to 22, wherein the composition is administered one or more times a month.
24. The pharmaceutical composition for use of any one of claims 17 to 22, wherein the composition is administered one or more times a week.
25. The pharmaceutical composition for use of any one of claims 17 to 22, wherein the composition is administered one or more times a day.
26. A compound for use in treating a condition benefiting from an increase in neural plasticity, wherein the compound is of Formula (l)B wherein:
Figure imgf000131_0001
R1 is selected from H or C1-6 alkyl; and
R2 is CH2-CHR4-NR5R6, wherein
R4 is selected from H or Ci-s alkyl, wherein
R5 is selected from H or Ci-s alkyl, wherein
Rs is:
Figure imgf000131_0002
a) wherein X is a bond, Y is N, Z is O and R7 and R8 together from a bringing group
CH2CH2; or
Figure imgf000131_0003
b) wherein X is NH or O, Y is CH, Z is O and R7 and R8 are H; or c) NH(CH2)3N(CH3)2, O(CH2)OH or O(CH2)2N(CH3)2.
R3 is selected from H or L-R9, wherein
L is selected from O, N, NH, O-O, CH2, CH2CH2, O-O-CH2CH2, CO, OCO, COO or OCONH, wherein
R9 is selected from H, Ci-s alkyl, COOK, OH, COO-, O-, C6-C10 aromatic, C3-C10 heteroaromatic or heterocyclic group comprising one, two or three heteroatoms independently selected from O and N; and
K is CH, CH-CH=CR3 or NH-CH=CH-C(O); or is a pharmaceutically acceptable salt thereof, and wherein the compound increases neural plasticity in a subject treated with the compound. 27. A compound of Formula (l)C wherein:
Figure imgf000132_0001
R1 is (CH2)mNR4(R5) wherein: m is selected from 1, 2, 3, 4, 5, 6, 7, or 8;
R4 is C1-6 alkyl;
R5 is C1-6 alkyl;
R2 is H or C(O)C1-6 alkyl;
R3 is O-X-Y wherein:
X is -
CO-; -C(O)O-; -C(O)O(CH2)n-; -CH2(CO)-; -CH2-O-; -CHRS-O-; -CH2-NH-; -CH2-NR7-; -CHR8-NH-; - CHR9-NR10-; -P(O)(OH)-; -P(O)ORn-; -CH2O-P(O)OH-; -CH2O-P(O)OR12-; or -CO(CH2)n-C(O)OCH2 -;
Y is -(CH2)n-NH2; -(CH2)n-NHR13; -(CH2)n-NR14R15; -C(O)CHR1SR17;
C(O)OR18; -C(O)NHR19; -C(O)NR20R21; -OR22 or a C5-6hetrocycle
R6 to R21 are independently H or C1-4 alkyl groups and R22 is a C1-8 alkyl group n is independently 1 to 4
28. The compound of claim 27, wherein the compound is selected from:
Figure imgf000133_0001
29. A combination pharmaceutical comprising:
(a) compound of Formula (l)E
Figure imgf000133_0002
wherein:
X is selected from H or C1-10 branched or straight chain alkyl, and optionally wherein X is methyl or isopropyl; Y is selected from a bond, O, CONH, NH, N(C1-6 alkyl), A-(CH2)n-B, wherein
A is O, NH or N(C1-6 alkyl), wherein B is a bond, O, or NH, wherein n is 1 to 4;
Z is selected from H, OH, NH2, NHC1-6 alkyl, N(C1-6 alkyl)2, C1-6 alkyl, C6-10 aryl, SO2-C1-6 alkyl, SO2-C6-10 aryl, C3-C10 heteroaromatic or heterocyclic group comprising one, two or three heteroatoms independently selected from O and N; wherein X and Z are different; or a pharmaceutically acceptable salt thereof; and
(b) serotonin receptor antagonist or inverse agonist, or a pharmaceutically acceptable salt thereof.
30. The combination pharmaceutical of claim 29, wherein the compound of Formula (I) is selected from:
Figure imgf000134_0001
31. A compound of Formula (II):
Figure imgf000135_0001
wherein
R is selected from a 5 membered heterocyclic ring with at least one N atom, a 5 membered heterocyclic ring with at least one O atom, a 5 membered heterocyclic ring with at least two N atoms, a 5 membered heterocyclic ring with at least one O and one N atom, a 5 membered heterocyclic ring with at least three N atoms, a 5 membered heterocyclic ring with at least four N atoms, and a 5 membered heterocyclic ring wherein all atoms of the ring are N;
R' is absent or is selected from:
H, methyl, ethyl, isopropyl, propyl, butyl, pentyl, hexyl, heptyl, octyl;
CH2OH, CH2CH2OH, CH2CH(OH)CH3, CH2CH2CH(OH)CH3, CH2CH2CH2OH, CH(OH)CH2CH2CH3; or
SCH3, SCH2CH3, CH2SCH3, CH2CH2SCH3.
32. A compound of Formula (III):
Figure imgf000135_0002
wherein
Rx and Ry are taken together with the N atom between them to form a heterocyclic ring, wherein said ring is selected from: a three membered heterocyclic ring, a four membered heterocyclic ring, a five membered heterocyclic ring, a six membered heterocyclic ring, a six membered heterocyclic bicyclic ring, a seven membered heterocyclic bicyclic ring, an eight membered heterocyclic bicyclic ring and a nine membered heterocyclic bicyclic ring; wherein one or more atoms of said heterocyclic ring are optionally replaced with one or more heteroatoms such as N, O or S; wherein said ring is optionally substituted at one or more positions with one or more of Rz, where Rz is independently selected from: a halogen, C1-6alkyl, C(O)CH3, C(O)C1-6alkyl, NH2, NHC1-6alkyl, N(C1- 6alkyl)2, OH, OC1-6alkyl, Ci-6alkyl-O-C1-6alkyl, C(O)NH2, C(O)NHC1-6alkyl, or C(O)(NC1-6alkyl)2.
PCT/GB2023/051872 2022-07-15 2023-07-17 Ergoline and tryptamine-based compounds, and uses of the same Ceased WO2024013523A1 (en)

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GB2210427.7 2022-07-15
GBGB2210431.9A GB202210431D0 (en) 2022-07-15 2022-07-15 Ergoline analogues
GBGB2210436.8A GB202210436D0 (en) 2022-07-15 2022-07-15 Tryptamine analogues
GBGB2216306.7A GB202216306D0 (en) 2022-11-02 2022-11-02 Combination pharmaceutical
GB2216306.7 2022-11-02
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WO2018064465A1 (en) * 2016-09-29 2018-04-05 The Regents Of The University Of California Compounds for increasing neural plasticity
WO2020176597A1 (en) * 2019-02-27 2020-09-03 The Regents Of The University Of California N-substituted indoles and other heterocycles for treating brain disorders
WO2020181194A1 (en) * 2019-03-07 2020-09-10 University Of Padova Compositions and methods of use comprising substances with neural plasticity actions administered at non-psychedelic/psychotomimetic dosages and formulations
WO2021019023A1 (en) * 2019-08-01 2021-02-04 The Beckley Foundation Compounds for use in a method of treating or preventing neurological and/or psychiatric disorders
WO2021076572A1 (en) * 2019-10-14 2021-04-22 The Regents Of The University Of California Ergoline-like compounds for promoting neural plasticity
WO2022153266A1 (en) * 2021-01-15 2022-07-21 Beckley Psytech Limited Ergoline analogues

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WO2018064465A1 (en) * 2016-09-29 2018-04-05 The Regents Of The University Of California Compounds for increasing neural plasticity
WO2020176597A1 (en) * 2019-02-27 2020-09-03 The Regents Of The University Of California N-substituted indoles and other heterocycles for treating brain disorders
WO2020181194A1 (en) * 2019-03-07 2020-09-10 University Of Padova Compositions and methods of use comprising substances with neural plasticity actions administered at non-psychedelic/psychotomimetic dosages and formulations
WO2021019023A1 (en) * 2019-08-01 2021-02-04 The Beckley Foundation Compounds for use in a method of treating or preventing neurological and/or psychiatric disorders
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