[go: up one dir, main page]

WO2019220138A1 - Dérivés de kétamine pour traiter des maladies neurologiques ou psychologiques - Google Patents

Dérivés de kétamine pour traiter des maladies neurologiques ou psychologiques Download PDF

Info

Publication number
WO2019220138A1
WO2019220138A1 PCT/GB2019/051372 GB2019051372W WO2019220138A1 WO 2019220138 A1 WO2019220138 A1 WO 2019220138A1 GB 2019051372 W GB2019051372 W GB 2019051372W WO 2019220138 A1 WO2019220138 A1 WO 2019220138A1
Authority
WO
WIPO (PCT)
Prior art keywords
disorder
compound
neurocognitive
disease
pharmaceutically acceptable
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/GB2019/051372
Other languages
English (en)
Inventor
Peter RANDS
Marie LAYZELL
Richard MYERSON
Trevor ROBBINS
Benjamin Phillips
Tiffanie BENWAY
Zelah JOEL
Ellen James
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.)
Small Pharma Ltd
Original Assignee
Small Pharma 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
Application filed by Small Pharma Ltd filed Critical Small Pharma Ltd
Publication of WO2019220138A1 publication Critical patent/WO2019220138A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/366—Lactones having six-membered rings, e.g. delta-lactones

Definitions

  • n 0, 1, 2, 3, 4 or 5
  • R 1 , R 2 , R 4 , R 5 , and R 6 are each independently selected from H and Ci-C 4 alkyl, each R 3 is independently selected from OH, 0-(Ci-C 4 alkyl), F, Cl, Br, I, and -CF 3.
  • Compounds of the present invention are neurologically active by virtue of modulation of the glutamatergic system, and find therapeutic applications in a range of diseases and conditions of the central nervous system.
  • compounds of Formula I are useful for treating disorders selected from neurocognitive, neurodevelopmental, and neuropsychiatric disorders.
  • ketamine metabolite 2R,6R-hydroxynorketamine has recently been implicated as a contributor to the antidepressant effects observed in depression patients treated with ketamine (Zanos et al , Nature, (2016), 533, 481-486), providing preclinical support for an
  • a first aspect of the present invention provides a lactone compound of Formula I, or a pharmaceutically acceptable salt thereof;
  • n 0, 1, 2, 3, 4 or 5
  • R 1 , R 2 , R 4 , R 5 , and R 6 are each independently selected from H and Ci-C 4 alkyl, each R 3 is independently selected from OH, 0-(Ci-C 4 alkyl), F, Cl, Br, I, and -CF 3.
  • a second aspect of the present invention provides a lactone compound of Formula I, or a pharmaceutically acceptable salt thereof, for use in increasing one or more of executive function, perceptual function, learning ability, memory, and attention in a human;
  • n 0, 1, 2, 3, 4 or 5
  • n 0, 1, 2, 3, 4 or 5
  • R 1 , R 2 , R 4 , R 5 , and R 6 are each independently selected from H and Ci-C 4 alkyl, each R 3 is independently selected from OH, 0-(Ci-C 4 alkyl), F, Cl, Br, I, and -CF 3 , and wherein
  • the neurocognitive disorder is selected from (i) delirium, (ii) pseudodementia, (iii) frontotemporal neurocognitive disorder, (iv) dementia with Lewy Bodies (v) vascular neurocognitive disorder, (vi) multi-infarct dementia, (vii) a tauopathy, (viii) Parkinson's disease, (ix) Huntingdon's disease, (x) transmissible spongiform encephalopathy, (xi) traumatic brain injury, (xii) post-concussion syndrome, (xiii) amnesia, (xiv) substance-induced
  • neurocognitive disorder (xv) alcohol-induced neurocognitive disorder, and (xvi) stroke disorder, (xvii) hypersomnia, and (xviii) clonic perseveration, (xvii) brain injury disorder, and (xviii) progressive supranuclear palsy, or b.
  • the neurodevelopmental disorder is selected from (i) intellectual disability, (ii) learning disability, (iii) dyslexia, (iv) dyscalculia, (v) dyspraxia, (vi) dysgraphia, (vii) autism-spectrum disorder, (viii) stereotypic movement disorder, (ix) tic disorder, (x) cerebral palsy (xi) fragile-X syndrome, (xii) Down Syndrome, (xiii) attention-deficit disorder, (xiv) hypogonadotropic hypogonadal syndrome (xv) neurotoxicant poisoning, (xvi) foetal alcohol spectrum disorder, (xvii) Minamata disease, and (xviii) Rett Syndrome.
  • the compound of Formula I is wherein n is 1 and R 3 is selected from F, Cl, and OMe.
  • the compound of Formula I is wherein R 1 is H and R 2 is selected from H, Me, or Et.
  • the compound of Formula I is wherein R 4 , R 5 , and R 6 are each H.
  • the compound of Formula I is wherein one or both of R 4 and R 6 are Me and R 5 is H, or R 4 and R 6 are H and R 5 is tBu.
  • a fourth aspect of the present invention provides a compound of the first or second aspect of the present invention, or a pharmaceutically acceptable salt thereof, for use in treating a patient suffering from one or more of a neurocognitive disorder, a neurodevelopmental disorder, and a psychocognitive disorder.
  • the neurocognitive disorder is selected from (i) delirium, (ii) Alzheimer’s disease, (iii) pseudodementia, (iv) frontotemporal neurocognitive disorder, (v) dementia with Lewy Bodies (vi) vascular neurocognitive disorder, (vii) multi-infarct dementia, (viii) a tauopathy, (ix) Parkinson's Disease, (x) Huntingdon's disease, (xi) transmissible spongiform encephalopathy, (xii) amyotrophic lateral sclerosis, (xiii) traumatic brain injury, (xiv) post-concussion syndrome, (xv) amnesia, (xvi) substance-induced neurocognitive disorder, (xvii) alcohol-induced neurocognitive disorder, and (xviii) stroke disorder, (xix) hypersomnia, and (xx) clonic perseveration.
  • neurodevelopmental disorder is selected from (i) intellectual disability, (ii) learning disability, (iii) dyslexia, (iv) dyscalculia, (v) dyspraxia, (vi) dysgraphia, (vii) autism-spectrum disorder, (viii) stereotypic movement disorder, (ix) tic disorder, (x) cerebral palsy (xi) fragile-X syndrome, (xii) Down Syndrome, (xiii) attention-deficit disorder, (xiv) hypogonadotropic hypogonadal syndrome (xv) neurotoxicant poisoning, (xvi) foetal alcohol spectrum disorder, (xvii) Minamata disease, and (xviii) Rett Syndrome.
  • the psychocognitive disorder is selected from (i) an obsessive compulsive disorder, (ii) a depressive disorder, (iii) a schizophrenia disorder, (iv) a schizotypal disorder, (v) an anxiety disorder, (vi) substance abuse, and (vii) an avolition disorder.
  • a fifth aspect of the present invention provides a compound according to the first, second, third or fourth aspect of the present invention for use in treating a disorder of diminished motivation in a patient.
  • the compound is for use in treating a disorder of diminished motivation in a patient suffering from a comorbid disorder selected from a neurocognitive disorder, a neurodevelopmental disorder, and a psychocognitive disorder.
  • the compound of Formula I is for use in treating a patient suffering delirium.
  • the compound of Formula I is for use in treating a patient suffering Alzheimer’s disease.
  • the compound of Formula I is for use in treating a patient suffering pseudodementia.
  • the compound of Formula I is for use in treating a patient suffering frontotemporal neurocognitive disorder.
  • the compound of Formula I is for use in treating a patient suffering dementia with Lewy Bodies.
  • the compound of Formula I is for use in treating a patient suffering multi-infarct dementia. In a preferred embodiment of the first or second aspect of the invention, the compound of Formula I is for use in treating a patient suffering a tauopathy.
  • the compound of Formula I is for use in treating a patient suffering Parkinson's Disease.
  • the compound of Formula I is for use in treating a patient suffering Huntingdon's disease.
  • the compound of Formula I is for use in treating a patient suffering amyotrophic lateral sclerosis.
  • the compound of Formula I is for use in treating a patient suffering traumatic brain injury.
  • the compound of Formula I is for use in treating a patient suffering post-concussion syndrome.
  • the compound of Formula I is for use in treating a patient suffering amnesia.
  • the compound of Formula I is for use in treating a patient suffering substance-induced neurocognitive disorder.
  • the compound of Formula I is for use in treating a patient suffering alcohol-induced neurocognitive disorder.
  • the compound of Formula I is for use in treating a patient suffering stroke disorder.
  • the compound of Formula I is for use in treating a patient suffering progressive clonic perseveration.
  • the compound of Formula I is for use in treating a patient suffering intellectual disability.
  • the compound of Formula I is for use in treating a patient suffering dyslexia.
  • the compound of Formula I is for use in treating a patient suffering dyscalculia.
  • the compound of Formula I is for use in treating a patient suffering dyspraxia. In a preferred embodiment of the first or second aspect of the invention, the compound of Formula I is for use in treating a patient suffering dysgraphia.
  • the compound of Formula I is for use in treating a patient suffering autism-spectrum disorder.
  • the compound of Formula I is for use in treating a patient suffering tic disorder.
  • the compound of Formula I is for use in treating a patient suffering fragile-X syndrome.
  • the compound of Formula I is for use in treating a patient suffering Down Syndrome.
  • the compound of Formula I is for use in treating a patient suffering hypogonadotropic hypogonadal syndrome.
  • the compound of Formula I is for use in treating a patient suffering neurotoxicant poisoning.
  • the compound of Formula I is for use in treating a patient suffering foetal alcohol spectrum disorder.
  • the compound of Formula I is for use in treating a patient suffering Minamata disease.
  • the compound of Formula I is for use in treating a patient suffering Rett Syndrome.
  • the compound of Formula I is for use in treating a patient suffering an obsessive compulsive disorder.
  • the compound of Formula I is for use in treating a patient suffering a schizotypal disorder.
  • the compound of Formula I is for use in treating a patient suffering an anxiety disorder. In a preferred embodiment of the first or second aspect of the invention, the compound of Formula I is for use in treating substance abuse.
  • the compound of Formula I is for use in treating a patient suffering an avolition disorder.
  • the compound of Formula I is for use in treating apathy.
  • the compound of Formula I is for use in treating aboulia.
  • the compound of Formula I is for use in treating akinetic mutism.
  • the composition is non-neurotoxic. In preferred embodiments of the first or second aspect of the present invention, the composition is non-sedating.
  • a sixth aspect of the present invention provides a solid oral dosage form comprising the compound of any aspect of the present invention.
  • the solid oral dosage form is selected from a tablet and a capsule.
  • a seventh aspect of the present invention provides compounds or solid oral dosage forms according to any other aspect of the invention for use as an adjunct to behavioural therapy.
  • An eighth aspect of the present invention provides a kit comprising a package and one or more unit dose(s) of the dosage form of any preceding aspect.
  • the kit comprises 28 unit doses.
  • the kit comprises unit doses packaged in individual blisters in one or more blister packs.
  • each blister pack comprises a number of unit doses selected from 7, 14, 21, 28 and 56. More preferably each blister pack comprises 14 unit doses.
  • a ninth aspect of the present invention provides a method of treating a patient suffering from a disorder selected from a neurocognitive disorder, a neurodevelopmental disorder, and a psychocognitive disorder, wherein said method comprises the steps of
  • identifying a deficit in a cognitive domain of said patient wherein the cognitive domain is selected from executive function, perceptual function, learning ability, memory, and attention, and b. administering to said patient a composition comprising a compound of
  • composition any composition or dosage form as defined herein.
  • the present invention relates to lactone analogues of ketamine which are resistant to hydroxylation at the 6-position, but nevertheless maintain electrostatic characteristics similar to 2R,6R-hydroxynorketamine.
  • Compounds of the present invention are believed to be neurologically active by virtue of modulation of the glutamatergic system, and find therapeutic applications in a range of diseases and conditions of the central nervous system.
  • an aspect of the present invention provides a lactone compound of Formula I, or a pharmaceutically acceptable salt thereof;
  • n 0, 1, 2, 3, 4 or 5
  • An aspect of the present invention provides a lactone compound of Formula I, or a pharmaceutically acceptable salt thereof, for use in increasing one or more of executive function, perceptual function, learning ability, memory, and attention in a human;
  • n 0, 1, 2, 3, 4 or 5
  • R 1 , R 2 , R 4 , R 5 , and R 6 are each independently selected from H and Ci-C 4 alkyl, each R 3 is independently selected from OH, 0-(Ci-C 4 alkyl), F, Cl, Br, I, -CF 3 ,
  • X is selected from CR 7 , CHR 7 , O, N, N(R 7 ) + , NR 7 , and S,
  • An aspect of the present invention provides a lactone compound of Formula I, or a pharmaceutically acceptable salt thereof, for use in treating a patient suffering from a disorder selected from a neurocognitive disorder and a neurodevelopmental disorder,
  • R 1 , R 2 , R 4 , R 5 , and R 6 are each independently selected from H and C1-C4 alkyl, each R 3 is independently selected from OH, 0-(Ci-C 4 alkyl), F, Cl, Br, I, and -CF 3 , and wherein
  • the neurocognitive disorder is selected from (i) delirium, (ii) pseudodementia, (iii) frontotemporal neurocognitive disorder, (iv) dementia with Lewy Bodies (v) vascular neurocognitive disorder, (vi) multi-infarct dementia, (vii) a tauopathy, (viii) Parkinson's disease, (ix) Huntingdon's disease, (x)
  • the neurodevelopmental disorder is selected from (i) intellectual disability, (ii) learning disability, (iii) dyslexia, (iv) dyscalculia, (v) dyspraxia, (vi) dysgraphia, (vii) autism-spectrum disorder, (viii) stereotypic movement disorder, (ix) tic disorder, (x) cerebral palsy (xi) fragile-X syndrome, (xii) Down Syndrome, (xiii) attention-deficit disorder, (xiv) hypogonadotropic hypogonadal syndrome (xv) neurotoxicant poisoning, (xvi) foetal alcohol spectrum disorder, (xvii) Minamata disease, and (xviii) Rett Syndrome.
  • the compound of Formula I is wherein n is 1 and R 3 is selected from F, Cl, and OMe.
  • the compound of Formula I is wherein R 3 is selected from ortho-Cl and meta-OMe.
  • the compound of Formula I is wherein R 1 is H and R 2 is selected from H, Me, or Et.
  • the compound of Formula I is wherein R 4 , R 5 , and R 6 are each H.
  • the compound of Formula I is wherein one or both of R 4 and R 6 are Me and R 5 is H, or R 4 and R 6 are H and R 5 is tBu.
  • the term ‘pharmaceutically acceptable salt’ is defined as the product of an acid addition reaction in which an amine group of a compound of the invention is protonated by an organic or inorganic acid to form a non-toxic salt, or as the product of a base addition reaction in which an acidic group in a compound of the invention is deprotonated by an organic or inorganic base to form a non-toxic salt.
  • pharmaceutically acceptable salt includes solvates thereof. Wherever a compound is referred to by its generic or systematic name, the term is taken to include all pharmaceutically acceptable salts.
  • ⁇ means a hydrogen atom. Also encompassed in the definition of hydrogen atom are isotopes of hydrogen, for example deuterium or tritium.
  • -SO 3 H can also mean -SO 3 and collectively with the oxygen atom to which it is attached represents a sulphate group.
  • the presence of a phosphate group or a sulphate group in compounds of the present invention facilitates formation of a zwitterion wherein the phosphate is deprotonated and thus negatively charged and the amino group is protonated and thus positively charged.
  • 2R,6R-hydroxynorketamine refers to 2R,6R-2-(2-Chlorophenyl)- 2-(amino)-6-hydroxycyclohexanone.
  • An aspect of the present invention provides a compound of Formula I, or a pharmaceutically acceptable salt thereof, for use in treating a patient suffering from one or more of a neurocognitive disorder, a neurodevelopmental disorder, and a psychocognitive disorder.
  • the neurocognitive disorder is selected from (i) delirium, (ii) Alzheimer’s disease, (iii) pseudodementia, (iv) frontotemporal neurocognitive disorder, (v) dementia with Lewy Bodies (vi) vascular neurocognitive disorder, (vii) multi-infarct dementia, (viii) a tauopathy, (ix) Parkinson's Disease, (x) Huntingdon's disease, (xi) transmissible spongiform encephalopathy, (xii) amyotrophic lateral sclerosis, (xiii) traumatic brain injury, (xiv) post-concussion syndrome, (xv) amnesia, (xvi) substance-induced neurocognitive disorder, (xvii) alcohol-induced neurocognitive disorder, and (xviii) stroke disorder, (xix) hypersomnia, and (xx) clonic perseveration.
  • the neurodevelopmental disorder is selected from (i) intellectual disability, (ii) learning disability, (iii) dyslexia, (iv) dyscalculia, (v) dyspraxia, (vi) dysgraphia, (vii) autism-spectrum disorder, (viii) stereotypic movement disorder, (ix) tic disorder, (x) cerebral palsy (xi) fragile-X syndrome, (xii) Down Syndrome, (xiii) attention-deficit disorder, (xiv) hypogonadotropic hypogonadal syndrome (xv) neurotoxicant poisoning, (xvi) foetal alcohol spectrum disorder, (xvii) Minamata disease, and (xviii) Rett Syndrome.
  • neurological disorder means any disorder of the nervous system, including diseases, conditions, or symptoms resulting from structural, biochemical or electrical abnormalities in the brain, spinal cord or other nerves.
  • psychiatric disorder is a clinically significant behavioural or psychological pattern that occurs in an individual and that is associated with present distress (eg. a painful symptom), disability (ie. impairment in one or more important areas of functioning) or state of being with significantly increased risk of suffering death, pain, disability, or an important loss of freedom.
  • present distress eg. a painful symptom
  • disability ie. impairment in one or more important areas of functioning
  • state of being with significantly increased risk of suffering death, pain, disability, or an important loss of freedom.
  • complex attention describes the behavioural and cognitive process of selectively concentrating on a discrete aspect of information, whether deemed subjective or objective, while ignoring other perceivable information.
  • Complex attention may be regarded as a set of processes of cognitive resource allocation, and include basic cognitive processes such as sustained attention, divided attention, selective attention and processing speed.
  • execution function refers to a set of cognitive processes that are necessary for the cognitive control of behaviour.
  • Executive functions include basic cognitive processes such as planning, decision making, response to feedback, cognitive inhibition, inhibitory control, working memory, and cognitive flexibility.
  • cognitive control means the ability of an individual to select and successfully monitor behaviours that facilitate the attainment of chosen goals. An individual’s elicited behaviour results from an interaction between cognitive control and stimulus control.
  • learning and memory is the process of acquiring and storing for future recall of new knowledge, behaviours, skills, values, or preferences, or the modification of those existing. Subdomains involved in learning and memory include free recall, cued recall, recognition memory, semantic and autobiographic long-term memory, and implicit learning.
  • language describes a system that consists of the development, acquisition, maintenance and use of complex systems of communication, including object naming, word finding, grammar and syntax, receptive language, and fluency.
  • perceptual-motor function is a mode of comprehension by organisation, identification, and interpretation of sensory information in order to represent and understand the presented information, or the environment which generated the information.
  • Perceptual-motor function involves subdomains including visual perception, visuocontructional reasoning and perceptual-motor coordination.
  • social cognition means a cognitive domain which focuses on how a cognitive subject processes, stores, and applies information about other subjects and social situations.
  • Social cognition includes subdomains including emotional recognition, insight and theory of mind.
  • compounds of the present invention have been found to be effective in increasing one or more cognitive domain selected from executive function, perceptual function, learning ability, memory, and attention in a human.
  • Specific subdomains of perceptual function which may be improved by compounds of the present invention include visuoconstructional reasoning and sensory memory.
  • Specific subdomains of learning and memory which may be improved by compounds of the present invention include cued recall, recognition memory, implicit learning, and associative learning.
  • Specific subdomains of attention which may be improved by compounds of the present invention include sustained attention, selective attention, and processing speed.
  • Specific subdomains of executive function which may be improved by compounds of the present invention include working memory, responding to feedback, and sensory memory.
  • the term‘patient’ refers to a mammal, preferably a human, in need of therapy.
  • the term does not encompass laboratory mammals.
  • the composition is non-sedating.
  • non-sedating describes a method or composition which does not assist the induction of sleep.
  • the composition is for increasing motivation in an individual to whom the method or composition is administered.
  • DSM-5 Diagnostic criteria for neurocognitive disorders, neurodevelopmental disorders, and psychocognitive disorders referred to herein are provided in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, (DSM-5), the contents of which are incorporated herein by reference.
  • the neurocognitive disorder is selected from (i) delirium, (ii) Alzheimer’s disease, (iii) pseudodementia, (iv) frontotemporal neurocognitive disorder, (v) dementia with Lewy Bodies (vi) vascular neurocognitive disorder, (vii) multi-infarct dementia, (viii) a tauopathy, (ix) Parkinson's Disease, (x) Huntingdon's disease, (xi) transmissible spongiform encephalopathy, (xii) amyotrophic lateral sclerosis, (xiii) traumatic brain injury, (xiv) post-concussion syndrome, (xv) amnesia, (xvi) substance-induced neurocognitive disorder, (xvii) alcohol-induced neurocognitive disorder, and (xviii) stroke disorder, (xix) hypersomnia, and (xx) clonic perseveration.
  • Alzheimer’s disease describes a neurodegenerative disease characterised by the build-up of proteins in the brain to form structures called plaques or tangles. Alzheimer’s disease is the most common cause of dementia. Symptoms can include memory loss and difficulties with thinking, problem-solving or language.
  • the term ‘pseudodementia’ refers to a disorder which results in a dementia like phenotype having predominantly cognitive symptoms such as loss of memory, and vagueness, as well as prominent slowing of movement and reduced or slowed speech.
  • frontotemporal neurocognitive disorder also referred to as frontotemporal dementia (FTD) refers to a neurocognitive disorder involving the frontal or temporal lobes.
  • FTD frontotemporal dementia
  • Types of frontotemporal neurocognitive disorder include behavioural variant of FTD, primary progressive aphasia (semantic variant or nonfluent agrammatic),
  • corticobasal syndrome progressive supranuclear palsy, and FTD associated with motor neuron disease.
  • dementia with Lewy Bodies refers to a type of dementia which involves widespread deposits of abnormal clumps of alpha-synuclein protein in neurons, known as Lewy bodies.
  • a feature of dementia with Lewy Bodies is REM sleep behaviour disorder (RBD), in which individuals lose normal muscle paralysis during REM sleep. Other frequent symptoms include visual hallucinations; marked fluctuations in attention or alertness; and slowness of movement, trouble walking, or rigidity.
  • vascular neurocognitive disorder refers to cognitive impairment caused by restriction of supply of blood to the brain.
  • Transmissible spongiform encephalopathy refers to a group of progressive, invariably fatal, conditions that affect the brain and nervous system caused by prions, a form of infectious protein.
  • Transmissible spongiform encephalopathies include kuru, Creutzfeldt-Jakob disease (CJD), variant Creutzfeldt-Jakob disease (vCJD or nvCJD), Gerstmann-Straussler-Scheinker syndrome (GSS), and fatal familial insomnia.
  • post-concussion syndrome is a set of symptoms that may continue for a period of time following a mild traumatic brain injury.
  • the syndrome is charactierised by physical symptoms, such as headache, cognitive symptoms, such as difficulty
  • amnesia refers to a deficit in memory caused by brain damage, disease, or psychological trauma.
  • neurocognitive disorder which is caused or exacerbated by substance abuse.
  • alcohol-induced neurocognitive disorder refers to a neurocognitive disorder which is caused or exacerbated by alcohol abuse.
  • hypoomnia refers to a disorder of excessive time spent sleeping or excessive sleepiness.
  • the neurodevelopmental disorder is selected from (i) intellectual disability, (ii) learning disability, (iii) dyslexia, (iv) dyscalculia, (v) dyspraxia, (vi) dysgraphia, (vii) autism-spectrum disorder, (viii) stereotypic movement disorder, (ix) tic disorder, (x) cerebral palsy (xi) fragile-X syndrome, (xii) Down Syndrome, (xiii) attention-deficit disorder, (xiv) hypogonadotropic hypogonadal syndrome (xv) neurotoxicant poisoning, (xvi) foetal alcohol spectrum disorder, (xvii) Minamata disease, and (xviii) Rett Syndrome.
  • Teaming disability refers to a significant general impairment in intellectual functioning acquired during childhood.
  • dislexia refers to difficulty in reading despite normal intelligence.
  • the term‘dyscalculia’ refers to difficulty in learning or comprehending arithmetic.
  • the term‘dyspraxia’ refers to is a chronic neurological disorder beginning in childhood, which affects the planning of movements and motor co-ordination. It may also affect speech. Dyspraxia is thought to occur as a result of brain messages not being accurately transmitted to the body.
  • disgraphia refers to a deficiency in the ability to write.
  • amperger syndrome describes a range of developmental conditions, including Asperger syndrome, that affect a person's social interaction
  • An individual with an autism spectrum disorder often presents with social problems that include difficulty communicating and interacting with others, repetitive behaviours, as well as limited interests or activities.
  • stereotypic movement disorder refers to a motor disorder with onset in childhood involving repetitive, nonfunctional motor behaviour that interferes with normal activities, or results in bodily injury.
  • tic disorder refers to a disorder characterised by sudden, rapid, nonrhythmic movements.
  • Tic disorders include Tourette’s syndrome, which is characterised by motor tics alongside at least one vocal tic.
  • Cerebral palsy refers to a group of permanent disorders of the development of movement and posture, causing activity limitation, that are attributed to non progressive disturbances that occurred in the developing foetal or infant brain.
  • fragment X syndrome describes a condition typically caused by an expansion of the CGG triplet repeat within the Fragile X mental retardation 1 gene on the X chromosome. This genetic mutation results in a range of developmental problems including learning disabilities and cognitive impairment. Typically males are more severely affected by this disorder than females.
  • Affected individuals usually have delayed development of speech and language, with mild to moderate intellectual disability observed with development.
  • the majority of males and about half of females with fragile X syndrome have characteristic physical features that become more apparent with age, including a long and narrow face, large ears, a prominent jaw and forehead, unusually flexible fingers, flat feet, and in males, enlarged testicles.
  • Down Syndrome also known as trisomy 21, is a genetic disorder caused by the presence of all or part of a third copy of chromosome 21.
  • hypogonadotropic hypogonada syndrome refers to a condition characterised by hypogonadism due to an impaired secretion of gonadotropins, including follicle-stimulating hormone (FSH) and luteinizing hormone (LH), by the pituitary gland in the brain, and in turn decreased gonadotropin levels and a resultant lack of sex steroid production.
  • FSH follicle-stimulating hormone
  • LH luteinizing hormone
  • neurotoxicant poisoning refers to an adverse effect on the structure or function of the central and/or peripheral nervous system caused by a biological or chemical agent.
  • foetal alcohol spectrum disorder refers to a group of conditions that can occur in a person whose mother drank alcohol during pregnancy. The most severe form of the condition is known as foetal alcohol syndrome (FAS). Other types include partial foetal alcohol syndrome (pFAS), alcohol-related neurodevelopmental disorder (ARND) and alcohol-related birth defects (ARBD).
  • FAS foetal alcohol syndrome
  • pFAS partial foetal alcohol syndrome
  • ARND alcohol-related neurodevelopmental disorder
  • ARBD alcohol-related birth defects
  • Minamata disease refers to a neurological syndrome caused by severe mercury poisoning.
  • the psychocognitive disorder is selected from an (i) obsessive compulsive disorder, (ii) a depressive disorder, (iii) a schizophrenia disorder, (iv) a schizotypal disorder, (v) an anxiety disorder, (vi) substance abuse, and (vii) an avolition disorder.
  • obsessions are defined by the presence of either obsessions or compulsions, but commonly both.
  • the symptoms can cause significant functional impairment and/or distress.
  • An obsession is defined as an unwanted intrusive thought, image or urge that repeatedly enters the person's mind.
  • Compulsions are repetitive behaviours or mental acts that the person feels driven to perform.
  • OCD obsessive-compulsive disorder
  • a compulsion can either be overt and observable by others, such as checking that a door is locked, or a covert mental act that cannot be observed, such as repeating a certain phrase in one's mind.
  • depression disorder includes major depressive disorder, persistent depressive disorder, bipolar disorder, and bipolar depression.
  • major depressive disorder (MDD, also referred to as major depression or clinical depression) is defined as the presence of five or more of the following symptoms over a period of two-weeks or more (also referred to herein as a‘major depressive episode’), most of the day, nearly every day.
  • At least one of the symptoms must be either a depressed mood or a loss of interest or pleasure.
  • Persistent depressive disorder also known as dysthymia
  • dysthymia is defined as a patient exhibiting the following two features:
  • A. has depressed mood for most the time almost every day for at least two years. Children and adolescents may have irritable mood, and the time frame is at least one year.
  • bipolar disorder also known as manic-depressive illness, is a disorder that causes unusual shifts in mood, energy, activity levels, and the ability to carry out day-to-day tasks.
  • bipolar disorder There are three defined sub-categories of bipolar disorder; all of them involve clear changes in mood, energy, and activity levels. These moods range from periods of extremely“up,” elated, and energised behaviour (known as manic episodes, and defined further below) to very sad,“down,” or hopeless periods (known as depressive episodes). Less severe manic periods are known as hypomanic episodes.
  • Bipolar I Disorder defined by manic episodes that last at least 7 days, or by manic symptoms that are so severe that the person needs immediate hospital care. Usually, depressive episodes occur as well, typically lasting at least 2 weeks. Episodes of depression with mixed features (having depression and manic symptoms at the same time) are also possible.
  • Bipolar II Disorder defined by a pattern of depressive episodes and hypomanic episodes, but not the full-blown manic episodes described above.
  • bipolar depression is defined as an individual who is experiencing depressive symptoms with a previous or coexisting episode of manic symptoms, but does not fit the clinical criteria for bipolar disorder.
  • schizophrenia disorder means is a mental disorder characterised by abnormal social behaviour and failure to understand what is real.
  • the patient to meet the criteria for diagnosis of schizophrenia, the patient must have experienced at least 2 of the following symptoms: delusions, hallucinations, disorganised speech, disorganised or catatonic behaviour, negative symptoms. At least one of the symptoms must be the presence of delusions, hallucinations, or disorganised speech.
  • a schizotypal disorder refers to a disorder characterised by severe social anxiety, thought disorder, paranoid ideation, derealisation, transient psychosis, and often unconventional beliefs.
  • anxiety disorder includes generalised anxiety disorder, phobia, panic disorder, social anxiety disorder, and post-traumatic stress disorder.
  • GAD Generalised anxiety disorder
  • GAD means a chronic disorder characterised by long-lasting anxiety that is not focused on any one object or situation. Those suffering from GAD experience non-specific persistent fear and worry, and become overly concerned with everyday matters. GAD is characterised by chronic excessive worry accompanied by three or more of the following symptoms: restlessness, fatigue, concentration problems, irritability, muscle tension, and sleep disturbance.
  • Phobia is defined as a persistent fear of an object or situation the affected person will go to great lengths to avoid, typically disproportional to the actual danger posed. If the feared object or situation cannot be avoided entirely, the affected person will endure it with marked distress and significant interference in social or occupational activities.
  • a patient suffering a from a‘panic disorder’ is defined as one who experiences one or more brief attack (also referred to as a panic attack) of intense terror and apprehension, often marked by trembling, shaking, confusion, dizziness, nausea, and/or difficulty breathing.
  • a panic attack is defined as a fear or discomfort that abruptly arises and peaks in less than ten minutes.
  • Social anxiety disorder is defined as an intense fear and avoidance of negative public scrutiny, public embarrassment, humiliation, or social interaction. Social anxiety often manifests specific physical symptoms, including blushing, sweating, and difficulty speaking.
  • Post-traumatic stress disorder is an anxiety disorder that results from a traumatic experience. Post-traumatic stress can result from an extreme situation, such as combat, natural disaster, rape, hostage situations, child abuse, bullying, or even a serious accident. Common symptoms include hypervigilance, flashbacks, avoidant behaviours, anxiety, anger and depression.
  • the term‘substance abuse’ means a patterned use of a drug in which the user consumes the substance in amounts or with methods which are harmful to themselves or others.
  • an avolition disorder refers to a disorder which includes as a symptom the decrease in motivation to initiate and perform self-directed purposeful activities.
  • the composition is for use in treating a disorder of diminished motivation.
  • a disorder of diminished motivation refers to a disorder which manifests in a deficit in a person’s ability to direct behaviour, or in a subject’s ability or desire to repeat a behaviour.
  • the disorder of diminished motivation is selected from (i) apathy, (ii) aboulia, and (iii) akinetic mutism.
  • akinetic mutism refers to a disorder in which a subject lacks most motor functions such as speech, facial expressions, and gestures, but demonstrate apparent alertness.
  • the disorder of diminished motivation is apathy and the neurocognitive disorder, neurodevelopmental disorder, or psychocognitive disorder is selected from (i) an obsessive-compulsive disorder, (ii) a depressive disorder, (iii) an anxiety disorder, (iv) a schizophrenia disorder, (v) substance abuse, (vi) attention-deficit hyperactivity disorder, (viii) Alzheimer's disease, (ix) Parkinson's disease, (x) Huntington's disease, (xi) amyotrophic lateral sclerosis, (xii) a stroke disorder, and (xiii) a brain injury disorder.
  • the neurocognitive disorder is selected from (i) an obsessive-compulsive disorder, (ii) a depressive disorder, (iii) an anxiety disorder, (iv) a schizophrenia disorder, (v) substance abuse, (vi) attention-deficit hyperactivity disorder, (viii) Alzheimer's disease, (ix) Parkinson's disease, (x) Huntington's
  • neurodevelopmental disorder or psychocognitive disorder is selected from (i) an obsessive- compulsive disorder, (ii) a depressive disorder, (iii) an anxiety disorder, and (iv) a
  • compositions of the present invention are particularly useful in enhancing a cognitive subdomain selected from (i) visuocontructional reasoning, (ii) cued recall, (iii) recognition memory, (iv) implicit learning, (v) associative learning, (vi) sustained attention, (vii) selective attention, (viii) processing speed, (ix) working memory, and (x) sensory memory.
  • the compound of the invention may be administered in any formulation suitable for pharmaceutical administration.
  • the composition of the present invention is in a dosage form selected from a tablet, a pill, a capsule, a caplet, a powder, granules,
  • the dosage form of the compound of the present invention is selected from orodispersible tablet, sublingual spray, sublingual patch, sublingual film, buccal patch, buccal spray, buccal film, intranasal sprayable solution, intranasal sprayable suspension, and intranasal powder, and is preferably a dosage form suitable for intranasal administration.
  • the compound of the present invention is preferably used an adjunct to behavioural therapy.
  • Behavioural therapy can be particularly effective in disorders described herein when performed in conjunction with pharmaceutical treatment with a compound, composition or dosage form of the present invention.
  • behavioural therapy means psychotherapy and/or behaviour analysis falling within a discipline selected from applied behaviour analysis (ABA), the teaching-family model (TFM), positive behaviour support (PBS) and cognitive behaviour therapy (CBT).
  • ABA applied behaviour analysis
  • TMM teaching-family model
  • PBS positive behaviour support
  • CBT cognitive behaviour therapy
  • the compound of the present invention is for use as a first-line therapy.
  • first-line therapy is defined as the first course of pharmaceutical treatment administered in response to an episode of a disorder, and preferably the first episode of said disorder experienced by the patient.
  • the term‘episode’ refers to a single noteworthy happening, often in the course of a longer series of events, such as one critical period of several during a prolonged disorder.
  • An aspect of the present invention is a solid oral dosage form comprising a compound of the present invention for use in treating a disorder as described hereinabove.
  • solid oral dosage form is defined as a solid pharmaceutical formulation which can be swallowed whole, chewed and swallowed, or dissolved, dispersed or absorbed via the oral cavity.
  • Solid oral dosage forms include tablets, pills, capsules, caplets, orodispersible tablets, powders, granules and gums. Solid oral dosage forms are not taken to include liquid or aerosol formulations, powders for inhalation, or powders for injection.
  • the solid oral dosage form of the present invention is for use in a patient who has not previously been treated. In a preferred embodiment of the invention, the solid oral dosage form is for use in a patient who has failed to achieve adequate control of disorder symptoms using psychotherapy alone.
  • Solid oral dosage forms according to the present invention may be prepared by mixing the principle active agent(s) with a pharmaceutical carrier, e.g. com starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, or dicalcium phosphate, and other pharmaceutical diluents, e.g. water, to form a solid preformulation composition containing a homogenous mixture of the active agent(s).
  • a pharmaceutical carrier e.g. com starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, or dicalcium phosphate
  • other pharmaceutical diluents e.g. water
  • Solid oral dosage forms according to the present invention are preferably formulated in unit doses for administration between once a day and once a week, or between once every two days and twice a week. In a preferred embodiment the unit dose is for administration once a day.
  • An aspect of the present invention provides a method of treating a patient suffering from a disorder selected from a neurocognitive disorder, a neurodevelopmental disorder, and a psychocognitive disorder, wherein said method comprises the steps of a. Identifying a deficit in a cognitive domain of said patient, wherein the
  • cognitive domain is selected from executive function, perceptual function, learning ability, memory, and attention, and b.
  • Administering to said patient a composition comprising a compound of
  • the compound for use according to the method of the present invention is preferably comprised in a pharmaceutical composition, in particular a solid dosage form, as described hereinabove.
  • the patient is preferably suffering from a disorder selected from a neurocognitive disorder selected from (i) delirium, (ii) Alzheimer’s disease, (iii) pseudodementia, (iv) frontotemporal neurocognitive disorder, (v) dementia with Lewy Bodies (vi) vascular neurocognitive disorder, (vii) multi-infarct dementia, (viii) a tauopathy, (ix) Parkinson's Disease, (x) Huntingdon's disease, (xi) transmissible spongiform
  • a neurocognitive disorder selected from (i) delirium, (ii) Alzheimer’s disease, (iii) pseudodementia, (iv) frontotemporal neurocognitive disorder, (v) dementia with Lewy Bodies (vi) vascular neurocognitive disorder, (vii) multi-infarct dementia, (viii) a tauopathy, (ix) Parkinson's Disease, (x) Huntingdon's disease, (xi) transmissible spong
  • encephalopathy (xii) amyotrophic lateral sclerosis, (xiii) traumatic brain injury, (xiv) post- concussion syndrome, (xv) amnesia, (xvi) substance-induced neurocognitive disorder, (xvii) alcohol-induced neurocognitive disorder, and (xviii) stroke disorder, (xix) hypersomnia, and (xx) clonic perseveration; a neurodevelopmental disorder selected from (i) intellectual disability, (ii) learning disability, (iii) dyslexia, (iv) dyscalculia, (v) dyspraxia, (vi) dysgraphia, (vii) autism-spectrum disorder, (viii) stereotypic movement disorder, (ix) tic disorder, (x) cerebral palsy (xi) fragile-X syndrome, (xii) Down Syndrome, (xiii) attention- deficit disorder, (xiv) hypogonadotropic hypogonadal syndrome (xv) neurotoxicant poisoning, (xvi) foetal
  • the deficit in said cognitive domain is identified using a computer-based cognitive assessment.
  • the method is effective in increasing motivation. In preferred embodiments of the invention, the method is effective in treating diminished motivation, in particular apathy.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

La présente invention concerne un composé de formule (I), ou son sel pharmaceutiquement acceptable ; n étant 0, 1, 2, 3, 4 ou 5, R1, R2, R4, R5 et R6 étant chacun indépendamment choisis parmi H et C1-C4alkyle, chaque R3 étant indépendamment choisi parmi OH, O-(C1-C4alkyle), F, Cl, Br, I et -CF3. Les composés selon la présente invention sont neurologiquement actifs grâce à la modulation du système glutamatergique, et trouvent des applications thérapeutiques dans une plage de maladies et d'affections du système nerveux central. En particulier, les composés de formule (I) sont utiles pour traiter des troubles choisis parmi des troubles neurocognitifs, neurodéveloppementaux et neuropsychiatriques.
PCT/GB2019/051372 2018-05-18 2019-05-17 Dérivés de kétamine pour traiter des maladies neurologiques ou psychologiques Ceased WO2019220138A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GBGB1808150.5A GB201808150D0 (en) 2018-05-18 2018-05-18 Therapeutic compounds
GB1808150.5 2018-05-18

Publications (1)

Publication Number Publication Date
WO2019220138A1 true WO2019220138A1 (fr) 2019-11-21

Family

ID=62812455

Family Applications (2)

Application Number Title Priority Date Filing Date
PCT/GB2019/051372 Ceased WO2019220138A1 (fr) 2018-05-18 2019-05-17 Dérivés de kétamine pour traiter des maladies neurologiques ou psychologiques
PCT/GB2019/051373 Ceased WO2019220139A1 (fr) 2018-05-18 2019-05-17 Dérivés de la kétamine pour traiter des troubles neurologiques ou psychologiques

Family Applications After (1)

Application Number Title Priority Date Filing Date
PCT/GB2019/051373 Ceased WO2019220139A1 (fr) 2018-05-18 2019-05-17 Dérivés de la kétamine pour traiter des troubles neurologiques ou psychologiques

Country Status (2)

Country Link
GB (1) GB201808150D0 (fr)
WO (2) WO2019220138A1 (fr)

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA3165903A1 (fr) 2019-12-26 2021-07-01 Gilgamesh Pharmaceuticals, Inc. Derives arylcyclohexylamine et leur utilisation dans le traitement de troubles psychiatriques
LT4084791T (lt) 2020-02-18 2025-02-25 Gilgamesh Pharmaceuticals, Inc. Specifiniai triptaminai, skirti nuotaikos sutrikimams gydyti
US12129234B1 (en) 2023-08-03 2024-10-29 Gilgamesh Pharmaceuticals, Inc. Crystalline salts of N-ethyl-(5-fluoro-1H-indol-3-yl)-N-methylethan-1-amine
US12157722B1 (en) 2023-08-03 2024-12-03 Gilgamesh Pharmaceuticals, Inc. Crystalline hydrochloride salts of N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethan-1-amine

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017087691A1 (fr) * 2015-11-17 2017-05-26 The Trustees Of Columbia University In The City Of New York Agents prophylactiques pharmacologiques contre des troubles affectifs induits par le stress et leurs symptômes associés
WO2017087388A1 (fr) * 2015-11-18 2017-05-26 Mitchell Woods Pharmaceuticals, Inc. Dérivés de phényl cyclohexanone et procédés de production et d'utilisation de ceux-ci
WO2019058145A1 (fr) 2017-09-25 2019-03-28 Small Pharma Ltd Formes galéniques solides orales de dérivés de kétamine

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP6296985B2 (ja) 2011-10-14 2018-03-20 ザ ユナイテッド ステイツ オブ アメリカ， アズ リプレゼンテッド バイ ザ セクレタリー， デパートメント オブ ヘルス アンド ヒューマン サービシーズ うつ病及び神経障害性疼痛の治療における（２ｒ，６ｒ）−ヒドロキシノルケタミン、（ｓ）−デヒドロノルケタミン及び他の（ｒ，ｓ）−ケタミンの立体異性デヒドロ及びヒドロキシル化代謝生成物の使用
WO2014117089A1 (fr) * 2013-01-25 2014-07-31 Case Western Reserve University Compositions et méthodes de traitement de troubles envahissants du développement
CN110035997A (zh) * 2016-09-16 2019-07-19 生物制药沃克斯有限公司 羟基去甲氯胺酮前药
IL315066A (en) * 2016-10-27 2024-10-01 Univ Chiba Nat Univ Corp Application of (s)-norketamine and salt therof as pharmaceutical
US20210113493A1 (en) * 2016-11-30 2021-04-22 Philip E. Wolfson Ketamine for the treatment of menstrually related symptoms

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017087691A1 (fr) * 2015-11-17 2017-05-26 The Trustees Of Columbia University In The City Of New York Agents prophylactiques pharmacologiques contre des troubles affectifs induits par le stress et leurs symptômes associés
WO2017087388A1 (fr) * 2015-11-18 2017-05-26 Mitchell Woods Pharmaceuticals, Inc. Dérivés de phényl cyclohexanone et procédés de production et d'utilisation de ceux-ci
WO2019058145A1 (fr) 2017-09-25 2019-03-28 Small Pharma Ltd Formes galéniques solides orales de dérivés de kétamine

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
NAGENDRA S. SINGH ET AL: "Ketamine Metabolites Enantioselectively Decrease Intracellular D-Serine Concentrations in PC-12 Cells", PLOS ONE, vol. 11, no. 4, 20 April 2016 (2016-04-20), pages e0149499, XP055376843, DOI: 10.1371/journal.pone.0149499 *
OBRECHT D ET AL: "Eine neue lactonsynthese via 2-oxazolin-5-one als zwischenprodukte", TETRAHEDRON LETTERS, ELSEVIER, AMSTERDAM, NL, vol. 25, no. 16, 1 January 1984 (1984-01-01), pages 1717 - 1720, XP026646002, ISSN: 0040-4039, [retrieved on 19840101], DOI: 10.1016/S0040-4039(01)81153-9 *
RS MARINRC BIEDRZYCKIS FIRINCIOGULLARI: "Reliability and Validity of the Apathy Evaluation Scale", PSYCHIATRY RESEARCH, vol. 38, 1991, pages 143 - 162
ZANOS ET AL., BR. J PHARMACOL, 2019
ZANOS ET AL., NATURE, vol. 533, 2016, pages 481 - 486

Also Published As

Publication number Publication date
WO2019220139A1 (fr) 2019-11-21
GB201808150D0 (en) 2018-07-11

Similar Documents

Publication Publication Date Title
WO2019220138A1 (fr) Dérivés de kétamine pour traiter des maladies neurologiques ou psychologiques
CN106068256B (zh) 用于治疗认知损害的苯并二氮杂*衍生物、组合物和方法
US20100152179A9 (en) Treatment of central nervous system disorders
JP2023103256A (ja) 非ラセミ混合物およびその使用
EP3310785B1 (fr) Dérivés de benzodiazépine, compositions et méthodes de traitement de la déficience cognitive
KR20180031721A (ko) 가복사돌로 발달장애들을 치료하는 방법들
JP2011521954A (ja) 神経及び精神障害の治療法
EP3687515B1 (fr) Formes galéniques solides orales de dérivés de kétamine
JP2013542266A (ja) 認知障害を処置するためのベンゾジアゼピン誘導体、組成物、および方法
JP2025511081A (ja) 睡眠障害の治療における使用のための５－ＭｅＯ－ＤＭＴ
US20180155318A1 (en) Methods of use of cyclic amide derivatives to treat schizophrenia
JPH0920666A (ja) 成熟遅延および類似疾患の治療用医薬組成物
CN110785171A (zh) H3r反向激动剂用于治疗换班工作障碍的用途
WO2025188976A1 (fr) Composés amino-pyrimidine fusionnés pour le traitement de troubles neurodégénératifs
AU2023246680A1 (en) Treatment of mental disorders
WO2024163890A1 (fr) Méthodes de traitement du syndrome de dravet
WO2014153180A1 (fr) Procédés et compositions pour améliorer la fonction cognitive
HK40035970B (en) Solid oral dosage forms of ketamine derivatives
HK40035970A (en) Solid oral dosage forms of ketamine derivatives
Lazowski An Investigation of Sleep Architecture and Consequent Cognitive Changes in Olanzapine Treated Patients with Depression
MX2007008642A (es) Composicion farmaceutica que comprende la combinacion de un agente derivado benzisoxazolico y un agente inhibidor reversible de la enzima colinesterasa, indicada para el control y tratamiento de trastornos psicoticos y demencias.
HK1158065A (en) Treatment for neurological and mental disorders
HK1254300B (en) Benzodiazepine derivatives, compositions, and methods for treating cognitive impairment
HK1254300A1 (en) Benzodiazepine derivatives, compositions, and methods for treating cognitive impairment

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 19730423

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 19730423

Country of ref document: EP

Kind code of ref document: A1