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WO1999064009A1 - Use of an nk-1 receptor antagonist for treating cognitive disorders - Google Patents

Use of an nk-1 receptor antagonist for treating cognitive disorders Download PDF

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Publication number
WO1999064009A1
WO1999064009A1 PCT/GB1999/001818 GB9901818W WO9964009A1 WO 1999064009 A1 WO1999064009 A1 WO 1999064009A1 GB 9901818 W GB9901818 W GB 9901818W WO 9964009 A1 WO9964009 A1 WO 9964009A1
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WO
WIPO (PCT)
Prior art keywords
treatment
disorders
cognitive disorders
triazol
bis
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Ceased
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PCT/GB1999/001818
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French (fr)
Inventor
Nadia Melanie Rupniak
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Organon Pharma UK Ltd
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Merck Sharp and Dohme Ltd
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Priority to AU42795/99A priority Critical patent/AU4279599A/en
Priority to EP99955426A priority patent/EP1119358A1/en
Priority to CA002334606A priority patent/CA2334606A1/en
Publication of WO1999064009A1 publication Critical patent/WO1999064009A1/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol

Definitions

  • This invention relates to the treatment or prevention of certain cognitive disorders by the administration of a NK-1 receptor antagonist, in particular, 2-(R)-(l-(S)-(3,5-bis(trifluoromethyl)phenyl)-2-hydroxyethoxy)- 3-(S)-(4-fluorophenyl)-4-(l,2,4-triazol-3-yl)methylmorpholine, or a pharmaceutically acceptable salt thereof.
  • a NK-1 receptor antagonist in particular, 2-(R)-(l-(S)-(3,5-bis(trifluoromethyl)phenyl)-2-hydroxyethoxy)- 3-(S)-(4-fluorophenyl)-4-(l,2,4-triazol-3-yl)methylmorpholine, or a pharmaceutically acceptable salt thereof.
  • Cognitive disorders include dementia, amnestic disorders and cognitive disorders not otherwise specified.
  • the prominent disturbance associated with these conditions is a clinically significant deficit in cognition or memory that represents a significant change from a previous level of functioning.
  • dementia is now defined as a syndrome consisting of progressive impairment in two or more areas of cognition (i.e. memory, language, visuospatial and perceptual ability, thinking and problem solving, and personality) sufficient to interfere with work, social function or relationships.
  • areas of cognition i.e. memory, language, visuospatial and perceptual ability, thinking and problem solving, and personality
  • An amnestic disorder is characterised by memory impairment in the absence of other significant cognitive impairments.
  • Neurokinin 1 (NK-1; substance P) receptor antagonists are being developed for the treatment of a number of physiological disorders associated with an excess or imbalance of tachykinins, and in particular substance P.
  • Examples of conditions in which substance P has been imphcated include disorders of the central nervous system such as anxiety, depression and psychosis (see, for instance, International (PCT) patent specification Nos. WO 95/16679, WO 95/18124 and WO 95/23798). More recently, International (PCT) patent specification No.
  • WO 96/24353 suggests that a more efficacious and safe treatment of psychiatric disorders would be achieved using a combination of a tachykinin antagonist and a serotonin agonist or selective serotonin reuptake inhibitor (SSRI).
  • SSRI serotonin agonist or selective serotonin reuptake inhibitor
  • the present invention provides the use of 2-(R)-(l-(S)-(3,5- bis(trifluoromethyl)phenyl)-2-hydroxyethoxy)-3-(S)-(4-fluorophenyl)-4- (l,2,4-triazol-3-yl)methylmorpholine, or a pharmaceutically acceptable salt thereof in an oral, once-a-day medicament for the treatment of cognitive disorders.
  • the compounds of this class advantageously exhibit a rapid onset of action and a reduced side-effect profile when compared against conventional antidepressant or antipsychotic agents.
  • the exceptional pharmacology of the NK- 1 receptor antagonist of use in the present invention enables the treatment of cognitive disorders, without the need for concomitant therapy using tricyclic antidepr ess ants or monoamine oxidase inhibitors, or antipsychotic agents, or in particular, without the need for concomitant use of a serotonin agonist or an SSRI. Furthermore, the exceptional pharmacology of the NK- 1 receptor antagonist of use in the present invention results in a rapid onset of action.
  • the present invention accordingly provides the use of 2-(R)-(l-(S)- (3,5-bis(trifluoromethyl)phenyl)-2-hydroxyethoxy)-3-(S)-(4-fluorophenyl)- 4-(l,2,4-triazol-3-yl)methylmorphohne, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament adapted for oral administration for the treatment or prevention of cognitive disorders.
  • the present invention also provides a method for the treatment or prevention of cognitive disorders, which method comprises the oral administration to a patient in need of such treatment of an effective amount of 2-(R)-(l-(S)-(3,5-bis(trifluoromethyl)phenyl)-2-hydroxyethoxy)- 3-(S)-(4-fluorophenyl)-4-(l,2,4-triazol-3-yl)methylmorphohne, or a pharmaceutically acceptable salt thereof.
  • an oral pharmaceutical composition for the treatment of cognitive disorders which comprises 2-(R)-(l-(S)-(3,5-bis(trifluoromethyl)phenyl)-2- hydroxyethoxy)-3-(S)-(4-fluorophenyl)-4-(l,2,4-triazol-3- yl)methylmorpholine, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier or excipient.
  • the present invention accordingly provides the use of 2-(R)-(l-(S)- (3 , 5 -bis(trifluoromethyl)phenyl) -2 -hy droxy ethoxy)- 3 - (S) - (4-fl.uorophenyl) - 4-(l,2,4-triazol-3-yl)methylmorpholine, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament adapted for oral administration for the treatment or prevention of cognitive disorders in a patient who is non-responsive to heterocycHc antidepressants (TCAs, tetracyclics, and the like), SSRIs, serotonin agonists or antagonists, mixed serotonin and norepinephrine selective reuptake inhibitors, dopamine reuptake inhibitors or MAOIs, or for whom heterocycHc antidepressants (TCAs, tetracycHcs, and the Hke), SSRIs, serot
  • the present invention also provides a method for the treatment or prevention of cognitive disorders in a patient who is non-responsive to heterocycHc antidepressants (TCAs, tetracycHcs, and the Hke), SSRIs, serotonin agonists or antagonists, mixed serotonin and norepinephrine selective reuptake inhibitors, dopamine reuptake inhibitors or MAOIs, or for whom heterocycHc antidepressants (TCAs, tetracycHcs, and the Hke), SSRIs, serotonin agonists or antagonists, mixed serotonin and norepinephrine selective reuptake inhibitors, dopamine reuptake inhibitors or MAOIs are contraindicated, which method comprises oral administration to the patient in need of such treatment of an effective amount of 2 - (R) - ( 1 - (S) - (3 , 5 -bis(trifluoromethyl)phenyl) - 2
  • the present invention also provides a method for the treatment or prevention of cognitive disorders in the patient who is non-responsive to antipsychotic agents, or for whom antipsychotic agents are contraindicated, which method comprises oral administration to the patient in need of such treatment of an effective amount of 2-(R)-(l-(S)- (3 , 5 -bis(trifluoromethyl)phenyl) -2 -hy droxyethoxy)- 3 - (S)- (4-fluorophenyl) - 4-(l,2,4-triazol-3-yl)methylmorphoHne, or a pharmaceuticaUy acceptable salt thereof.
  • the term "cognitive disorders” includes dementia, amnestic disorders and cognitive disorders not otherwise specified.
  • the term "cognitive disorders” includes dementia caused by degenerative disorders, lesions, trauma, infections, vascular disorders, toxins, anoxia, vitamin deficiency and endocrine disorders.
  • specific examples of these causes include degenerative disorders such as Alzheimer's disease, multiple sclerosis, Parkinson's disease, normal pressure hydrocephalus and Huntington's chorea; space occupying lesions including tumors and chronic subdural haematoma; trauma including severe head injury; infections including postencephaHtis and syphiHs; vascular disorders including multi-infarct dementia; toxins including alcohol; anoxia caused by cardiac arrest and carbon monoxide poisoning, vitamin deficiencies including lack of vitamin B12; and endocrine disorders including hypothyroidism.
  • cognitive disorders includes amnestic disorders caused by alcohol (Korsakoff psychosis) and other causes of thiamine deficiency; bilateral temporal lobe damage due to herpes simplex encephafitis and other Hmbic encephahtis, neuronal loss secondary to anoxia/hypoglycaemia/severe convulsions, and surgery; degenerative disorders including Alzheimer's and Pick's diseases; vascular disorders including bilateral infarction, hippocampal infarction and bilateral cingulate cortex infarction; and pathology around ventricle III including tumors, chronic meningitis and neurosarcoidosis.
  • cognitive disorders includes cognitive impairment resulting from other medical conditions, most especiaUy resulting from depression and/or anxiety.
  • treatment refers both to the treatment and to the prevention or prophylactic therapy of the aforementioned conditions.
  • Suitable pharmaceuticaUy acceptable salts of the NK-1 receptor antagonist of use in the present invention include acid addition salts which may, for example, be formed by mixing a solution of the compound with a solution of a pharmaceuticaUy acceptable non-toxic acid such as hydrochloric acid, fumaric acid, maleic acid, succinic acid, acetic acid, citric acid, tartaric acid, carbonic acid, phosphoric acid or sulphuric acid.
  • Salts of amine groups may also comprise the quaternary ammonium salts in which the amino nitrogen atom carries an alkyl, alkenyl, alkynyl or aralkyl group.
  • compositions containing the NK-1 receptor antagonist of use according to the present invention are in unit dosage forms such as tablets, piUs, capsules, wafers and the Hke.
  • the NK- 1 receptor antagonist of use according to the present invention may be presented as granules or powders for extemporaneous formulation as volume defined solutions or suspensions.
  • the NK-1 receptor antagonist of use according to the present invention may be presented in ready-prepared volume defined solutions or suspensions.
  • Preferred forms are tablets and capsules.
  • soHd compositions such as tablets
  • the principal active ingredient is mixed with a pharmaceutical carrier, e.g. conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical dUuents, e.g. water, to form a soHd preformulation composition containing a homogeneous mixture of a compound of the present invention, or a non-toxic pharmaceuticaUy acceptable salt thereof.
  • a pharmaceutical carrier e.g. conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical dUuents, e.g. water
  • preformulation compositions when referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be reacUly subdivided into equaUy effective unit dosage forms such as tablets, piUs and capsules.
  • This soHd preformulation composition is then subdivided into unit dosage forms of the type described above containing from 0.1 to about 500 mg of the active ingredient of the present invention.
  • the tablets or pills of the novel composition can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action.
  • the tablet or piU can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former.
  • the two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release.
  • enteric layers or coatings such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as sheUac, cetyl alcohol and ceUulose acetate.
  • compositions of the present invention may be incorporated for administration oraUy
  • aqueous solutions suitably flavoured syrups, aqueous or oU suspensions, and flavoured emulsions with edible oUs such as cottonseed oU, sesame oU, coconut oU, peanut oU or soybean oU, as weU as ehxirs and similar pharmaceutical vehicles.
  • Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylceUulose, methylceUulose, polyvinyl-pyrroHdone or gelatin.
  • Compositions of the present invention may also be administered via the buccal cavity using conventional technology, for example, absorption wafers.
  • compositions in the form of tablets, piUs, capsules or wafers for oral administration are particularly preferred.
  • a minimum dosage level for the NK- 1 receptor antagonist is about lmg per day, preferably about 5mg per day and especiaUy about lOmg per day.
  • a maximum dosage level for the NK-1 receptor antagonist is about 1500mg per day, preferably about lOOOmg per day and especiaUy about 500mg per day. The compounds are administered once a day.
  • the amount of the NK- 1 receptor antagonist required for use in the treatment or prevention of cognitive disorders wiU vary not only with the particular compounds or compositions selected but also with the route of administration, the nature of the condition being treated, and the age and condition of the patient, and wiU ultimately be at the discretion of the patient's physician or pharmacist.
  • the activity of the NK- 1 receptor antagonist of use in the present invention may be measured using the foUowing assays:
  • NK-1 Receptor binding NK-1 receptor binding assays are performed in intact Chinese hamster ovary (CHO) ceUs expressing the human NK- 1 receptor using a modification of the assay conditions described by Cascieri et al, J. Pharmacol. Exp. Ther.. 1992, 42, 458.
  • TypicaUy the receptor is expressed at a level of 3xl0 5 receptors per ceU.
  • CeUs are grown in monolayer culture, detached from the plate with enzyme-free dissociation solution (SpeciaHty Media Inc.), and washed prior to use in the assay.
  • I-Tyr 8 - substance P (O.lnM, 2000Ci/mmol; New England Nuclear) is incubated in the presence or absence of test compounds (dissolved in 5 ⁇ l dimethylsulphoxide, DMSO) with 5xl0 4 CHO ceUs. Ligand binding is performed in 0.25ml of 50mM Tris-HCl, pH7.5, containing 5mM MnCl 2>
  • GerbU Foot-Tapping CNS-penetrant NK-1 receptor antagonists for use in the present invention can be identified by their abiHty to inhibit foot tapping in gerbUs induced by anxiogenic agents (such as pentagastrin) or central infusion of NK-1 receptor agonists such as GR73632, or caused by aversive stimulation such as foot shock or single housing, based on the method of Rupniak & WiUiams, Eur. J. Pharmacol., 1994, 265, 179.
  • Male or female MongoHan gerbUs (35-70g) are anaesthetised by inhalation of an isoflurane/oxygen mixture to permit exposure of the jugular vein in order to permit administration of test compounds or vehicle in an injection volume of 5ml/kg i.v.
  • test compounds may be administered oraUy or by subcutaneous or intraperitoneal routes. A skin incision is then made in the midHne of the scalp to expose the skuU.
  • An anxiogenic agent e.g. pentagastrin
  • a selective NK-1 receptor agonist e.g.
  • GR73632 (d Ala[L-Pro 9 ,Me-Leu 10 ] -substance P-(7-l l)) is infused directly into the cerebral ventricles (e.g. 3pmol in 5 ⁇ l i.c.v., depending on test substance) by vertical insertion of a cuffed 27 gauge needle to a depth of 4.5mm below bregma. The scalp incision is closed and the animal aUowed to recover from anaesthesia in a clear perspex observation box (25cm x 20cm x 20cm). The duration and/or intensity of hind foot tapping is then recorded continuously for approximately 5 minutes. Alternatively, the ability of test compounds to inhibit foot tapping evoked by aversive stimulation, such as foot shock or single housing, may be studied using a similar method of quantification.
  • ASSAY 3 Ferret Emesis IndividuaUy housed male ferrets (1.0 -2.5 kg) are dosed oraUy by gavage with test compound. Ten minutes later they are fed with approximately lOOg of tinned cat food. At 60 minutes foUowing oral dosing, cisplatin (lOmg/kg) is given i.v. via a jugular vein catheter inserted under a brief period of halothane anaesthesia. The catheter is then removed, the jugular vein Hgated and the skin incision closed. The ferrets recover rapidly from the anaesthetic and are mobUe within 10-20 minutes.
  • the animals are observed continuously during recovery from the anaesthetic and for 4 hours foUowing the cisplatin injection, after which time the animals are kiUed humanely.
  • the numbers of retches and vomits occurring during the 4 hours after cisplatin administration are recorded by trained observers.
  • mice Male and female guinea-pigs pups are housed in family groups with their mothers and Httermates throughout the study. Experiments are commenced after weaning when the pups are 2 weeks old. Before entering an experiment, the pups are screened to ensure that a vigorous vocaHsation response is reproducibly eHcited foUowing maternal separation. The pups are placed individuaUy in an observation cage (55cm x 39cm x 19cm) in a room physically isolated from the home cage for 15 minutes and the duration of vocaHsation during this baseHne period is recorded.
  • CNS-penetrant refers to NK-1 receptor antagonists which are able to inhibit NK-1 receptor antagonist-induced foot-tapping in the gerbU as hereinafter defined.
  • the NK- 1 receptor antagonist is administered oraUy, 1 hour prior to GR73632 chaUenge, wherein the foot- tapping over a period of five minutes foUowing recovery from anaesthesia is inhibited with an IDso ⁇ 30mg/kg, and preferably with an IDso ⁇ lOmg/kg.
  • CNS-penetrant NK-1 receptor antagonists of use in the present invention are also effective in the attenuation of separation-induced vocaHsations by guinea-pig pups as hereinafter defined.
  • a vocaHsation response in guinea-pig pups is induced by isolation from their mothers and Httermates, which response is attenuated when a CNS-penetrant NK-1 receptor antagonist is administered subcutaneously 30 minutes prior to isolation, wherein vocaHsations during the first 15 minutes of isolation are attenuated with an ID5o ⁇ 20mg/kg, preferably with an ID ⁇ o ⁇ lOmg/kg, and especiaUy with an IDso ⁇ mg/kg.
  • the NK-1 receptor antagonist is administered oraUy, 4 hours prior to isolation, wherein vocaHsations during the first 15 minutes of isolation are attenuated with an IDso ⁇ 20mg/kg, preferably with an IDso ⁇ lOmg/kg, and especially with an IDso ⁇ mg/kg.
  • a suitable selection cascade for NKi antagonists of use according to the present invention is as foUows: (i) Determine affinity for human NKi receptor in radioHgand binding studies (Assay 1); select compounds with IC ⁇ o ⁇ lOnM, preferably IC50 ⁇ 2nM, especiaUy ICso ⁇ InM.
  • step (iv) Determine oral bioavaUabiHty of compounds by pharmacokinetic analysis, activity in gerbU foot tapping assay foUowing oral administration and/or by abiHty to inhibit cisplatin-induced emesis in ferrets (Assay 3); select compounds with ID90 ⁇ 3mg/kg p.o., and preferably Particularly preferred compounds of use in the present invention are identified using steps (i) to (iv) foUowed by step (v):
  • step (v) Determine activity of compounds in assays sensitive to conventional antidepressant/anxiolytic drugs (inhibition of pharmacologicaUy evoked foot tapping in gerbUs and/or inhibition of distress vocaHsations in guinea-pig pups (Assay 4)).
  • Yet further preferred compounds of use in the present invention may be selected from those compounds which satisfy the NK-1 receptor binding criteria of step (i) which, in addition, have ⁇ 5-fold shift in affinity when incubated in the presence of human serum albumin (HSA) to show non-specific protein binding.
  • HSA human serum albumin
  • the NK- 1 receptor antagonist of use in the present invention is the compound 2-(R)-(l-(S)-(3,5-bis(trifl.uoromethyl)phenyl)-2-hydroxyethoxy)- 3-(S)-(4-fluorophenyl)-4-(l,2,4-triazol-3-yl)methylmorphoHne, the preparation of which is described in International Patent Specification No. WO 95/18124 and US Patent No. 5,612,337. In the aforementioned assays, this compound has the foUowing activity:
  • the foUowing example illustrates pharmaceutical compositions according to the invention.

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Abstract

The present invention provides the use of an NK-1 receptor antagonist for the manufacture of a medicament adapted for oral administration for the treatment or prevention of cognitive disorders, methods of medical treatment using such an NK-1 receptor antagonist and pharmaceutical compositions comprising it.

Description

USE OF A NK-1 RECEPTOR ANTAGONIST FOR TREATING COGNITIVE DISORDERS
This invention relates to the treatment or prevention of certain cognitive disorders by the administration of a NK-1 receptor antagonist, in particular, 2-(R)-(l-(S)-(3,5-bis(trifluoromethyl)phenyl)-2-hydroxyethoxy)- 3-(S)-(4-fluorophenyl)-4-(l,2,4-triazol-3-yl)methylmorpholine, or a pharmaceutically acceptable salt thereof.
Cognitive disorders include dementia, amnestic disorders and cognitive disorders not otherwise specified. The prominent disturbance associated with these conditions is a clinically significant deficit in cognition or memory that represents a significant change from a previous level of functioning.
For instance, dementia is now defined as a syndrome consisting of progressive impairment in two or more areas of cognition (i.e. memory, language, visuospatial and perceptual ability, thinking and problem solving, and personality) sufficient to interfere with work, social function or relationships.
An amnestic disorder is characterised by memory impairment in the absence of other significant cognitive impairments.
Pharmacological treatment of such cognitive disorders is poorly developed. In some instances, antidepressants, hypnotics or antipsychotics may be used in order to manage specific behavioural disturbances associated with the cognitive disorder. Such treatments, however, may be compromised by the side effects associated with these classes of pharmacological agent and, as such, are far from ideal means for treating cognitive disorders.
Neurokinin 1 (NK-1; substance P) receptor antagonists are being developed for the treatment of a number of physiological disorders associated with an excess or imbalance of tachykinins, and in particular substance P. Examples of conditions in which substance P has been imphcated include disorders of the central nervous system such as anxiety, depression and psychosis (see, for instance, International (PCT) patent specification Nos. WO 95/16679, WO 95/18124 and WO 95/23798). More recently, International (PCT) patent specification No. WO 96/24353 (pubhshed 15th August 1996) suggests that a more efficacious and safe treatment of psychiatric disorders would be achieved using a combination of a tachykinin antagonist and a serotonin agonist or selective serotonin reuptake inhibitor (SSRI). However, such as regimen would not be free of side-effects due to the serotonin agonist or SSRI. In view of the short-comings of existing therapy, there is a need for new, safe and effective treatment for cognitive disorders.
The present invention provides the use of 2-(R)-(l-(S)-(3,5- bis(trifluoromethyl)phenyl)-2-hydroxyethoxy)-3-(S)-(4-fluorophenyl)-4- (l,2,4-triazol-3-yl)methylmorpholine, or a pharmaceutically acceptable salt thereof in an oral, once-a-day medicament for the treatment of cognitive disorders. The compounds of this class advantageously exhibit a rapid onset of action and a reduced side-effect profile when compared against conventional antidepressant or antipsychotic agents.
The exceptional pharmacology of the NK- 1 receptor antagonist of use in the present invention enables the treatment of cognitive disorders, without the need for concomitant therapy using tricyclic antidepr ess ants or monoamine oxidase inhibitors, or antipsychotic agents, or in particular, without the need for concomitant use of a serotonin agonist or an SSRI. Furthermore, the exceptional pharmacology of the NK- 1 receptor antagonist of use in the present invention results in a rapid onset of action.
The present invention accordingly provides the use of 2-(R)-(l-(S)- (3,5-bis(trifluoromethyl)phenyl)-2-hydroxyethoxy)-3-(S)-(4-fluorophenyl)- 4-(l,2,4-triazol-3-yl)methylmorphohne, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament adapted for oral administration for the treatment or prevention of cognitive disorders. The present invention also provides a method for the treatment or prevention of cognitive disorders, which method comprises the oral administration to a patient in need of such treatment of an effective amount of 2-(R)-(l-(S)-(3,5-bis(trifluoromethyl)phenyl)-2-hydroxyethoxy)- 3-(S)-(4-fluorophenyl)-4-(l,2,4-triazol-3-yl)methylmorphohne, or a pharmaceutically acceptable salt thereof.
In a further aspect of the present invention, there is provided an oral pharmaceutical composition for the treatment of cognitive disorders which comprises 2-(R)-(l-(S)-(3,5-bis(trifluoromethyl)phenyl)-2- hydroxyethoxy)-3-(S)-(4-fluorophenyl)-4-(l,2,4-triazol-3- yl)methylmorpholine, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier or excipient.
There exists a patient population in whom cognitive disorders are inadequately treated with existing antidepressant therapy. Furthermore, some patients may be adversely affected by the side-effects of existing antidepressant drugs.
The present invention accordingly provides the use of 2-(R)-(l-(S)- (3 , 5 -bis(trifluoromethyl)phenyl) -2 -hy droxy ethoxy)- 3 - (S) - (4-fl.uorophenyl) - 4-(l,2,4-triazol-3-yl)methylmorpholine, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament adapted for oral administration for the treatment or prevention of cognitive disorders in a patient who is non-responsive to heterocycHc antidepressants (TCAs, tetracyclics, and the like), SSRIs, serotonin agonists or antagonists, mixed serotonin and norepinephrine selective reuptake inhibitors, dopamine reuptake inhibitors or MAOIs, or for whom heterocycHc antidepressants (TCAs, tetracycHcs, and the Hke), SSRIs, serotonin agonists or antagonists, mixed serotonin and norepinephrine selective reuptake inhibitors, dopamine reuptake inhibitors or MAOIs are contraindicated. The present invention also provides a method for the treatment or prevention of cognitive disorders in a patient who is non-responsive to heterocycHc antidepressants (TCAs, tetracycHcs, and the Hke), SSRIs, serotonin agonists or antagonists, mixed serotonin and norepinephrine selective reuptake inhibitors, dopamine reuptake inhibitors or MAOIs, or for whom heterocycHc antidepressants (TCAs, tetracycHcs, and the Hke), SSRIs, serotonin agonists or antagonists, mixed serotonin and norepinephrine selective reuptake inhibitors, dopamine reuptake inhibitors or MAOIs are contraindicated, which method comprises oral administration to the patient in need of such treatment of an effective amount of 2 - (R) - ( 1 - (S) - (3 , 5 -bis(trifluoromethyl)phenyl) - 2 -hy droxy ethoxy ) - 3-(S)-(4-fluorophenyl)-4-(l,2,4-triazol-3-yl)methylmorphoHne, or a pharmaceuticaUy acceptable salt thereof.
Furthermore, there exists a patient population in whom cognitive disorders are inadequately treated with existing antipsychotic therapy. Furthermore, some patients may be adversely affected by the side-effects of antipsychotic drugs. The present invention accordingly provides the use of 2-(R)-(l-(S)-
(3,5-bis(trifluoromethyl)phenyl)-2-hydroxyethoxy)-3-(S)-(4-fluorophenyl)- 4-(l,2,4-triazol-3-yl)methylmorphoHne, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament adapted for oral administration for the treatment or prevention of cognitive disorders in a patient who is non-responsive to antipsychotic agents, or for whom antipsychotic agents are contraindicated.
The present invention also provides a method for the treatment or prevention of cognitive disorders in the patient who is non-responsive to antipsychotic agents, or for whom antipsychotic agents are contraindicated, which method comprises oral administration to the patient in need of such treatment of an effective amount of 2-(R)-(l-(S)- (3 , 5 -bis(trifluoromethyl)phenyl) -2 -hy droxyethoxy)- 3 - (S)- (4-fluorophenyl) - 4-(l,2,4-triazol-3-yl)methylmorphoHne, or a pharmaceuticaUy acceptable salt thereof. As used herein, the term "cognitive disorders" includes dementia, amnestic disorders and cognitive disorders not otherwise specified. In particular, the term "cognitive disorders" includes dementia caused by degenerative disorders, lesions, trauma, infections, vascular disorders, toxins, anoxia, vitamin deficiency and endocrine disorders. Specific examples of these causes include degenerative disorders such as Alzheimer's disease, multiple sclerosis, Parkinson's disease, normal pressure hydrocephalus and Huntington's chorea; space occupying lesions including tumors and chronic subdural haematoma; trauma including severe head injury; infections including postencephaHtis and syphiHs; vascular disorders including multi-infarct dementia; toxins including alcohol; anoxia caused by cardiac arrest and carbon monoxide poisoning, vitamin deficiencies including lack of vitamin B12; and endocrine disorders including hypothyroidism.
Furthermore, the term "cognitive disorders" includes amnestic disorders caused by alcohol (Korsakoff psychosis) and other causes of thiamine deficiency; bilateral temporal lobe damage due to herpes simplex encephafitis and other Hmbic encephahtis, neuronal loss secondary to anoxia/hypoglycaemia/severe convulsions, and surgery; degenerative disorders including Alzheimer's and Pick's diseases; vascular disorders including bilateral infarction, hippocampal infarction and bilateral cingulate cortex infarction; and pathology around ventricle III including tumors, chronic meningitis and neurosarcoidosis.
Also, as used herein, the term "cognitive disorders" includes cognitive impairment resulting from other medical conditions, most especiaUy resulting from depression and/or anxiety. As used herein, the term "treatment" refers both to the treatment and to the prevention or prophylactic therapy of the aforementioned conditions.
In particular, the NK-1 receptor antagonist of use in the present invention is the compound 2-(R)-(l-(S)-(3,5-bis(trifluoromethyl)phenyl)-2- hydxoxyethoxy)-3-(S)-(4-fluorophenyl)-4-(l,2,4-triazol-3- yl)methylmorphohne, or a pharmaceuticaUy acceptable salt thereof. FuU descriptions of the preparation of the NK-1 receptor antagonist which may be employed in the present invention may be found in International Patent Specification No. WO 95/18124 and US Patent No. 5,612,337. Suitable pharmaceuticaUy acceptable salts of the NK-1 receptor antagonist of use in the present invention include acid addition salts which may, for example, be formed by mixing a solution of the compound with a solution of a pharmaceuticaUy acceptable non-toxic acid such as hydrochloric acid, fumaric acid, maleic acid, succinic acid, acetic acid, citric acid, tartaric acid, carbonic acid, phosphoric acid or sulphuric acid. Salts of amine groups may also comprise the quaternary ammonium salts in which the amino nitrogen atom carries an alkyl, alkenyl, alkynyl or aralkyl group.
Preferably the compositions containing the NK-1 receptor antagonist of use according to the present invention are in unit dosage forms such as tablets, piUs, capsules, wafers and the Hke. AdditionaUy, the NK- 1 receptor antagonist of use according to the present invention may be presented as granules or powders for extemporaneous formulation as volume defined solutions or suspensions. Alternatively, the NK-1 receptor antagonist of use according to the present invention may be presented in ready-prepared volume defined solutions or suspensions. Preferred forms are tablets and capsules.
For preparing soHd compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical carrier, e.g. conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical dUuents, e.g. water, to form a soHd preformulation composition containing a homogeneous mixture of a compound of the present invention, or a non-toxic pharmaceuticaUy acceptable salt thereof. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be reacUly subdivided into equaUy effective unit dosage forms such as tablets, piUs and capsules. This soHd preformulation composition is then subdivided into unit dosage forms of the type described above containing from 0.1 to about 500 mg of the active ingredient of the present invention. The tablets or pills of the novel composition can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or piU can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as sheUac, cetyl alcohol and ceUulose acetate.
The Hquid forms in which the novel compositions of the present invention may be incorporated for administration oraUy include aqueous solutions, suitably flavoured syrups, aqueous or oU suspensions, and flavoured emulsions with edible oUs such as cottonseed oU, sesame oU, coconut oU, peanut oU or soybean oU, as weU as ehxirs and similar pharmaceutical vehicles. Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylceUulose, methylceUulose, polyvinyl-pyrroHdone or gelatin. Compositions of the present invention may also be administered via the buccal cavity using conventional technology, for example, absorption wafers.
Compositions in the form of tablets, piUs, capsules or wafers for oral administration are particularly preferred. A minimum dosage level for the NK- 1 receptor antagonist is about lmg per day, preferably about 5mg per day and especiaUy about lOmg per day. A maximum dosage level for the NK-1 receptor antagonist is about 1500mg per day, preferably about lOOOmg per day and especiaUy about 500mg per day. The compounds are administered once a day.
It will be appreciated that the amount of the NK- 1 receptor antagonist required for use in the treatment or prevention of cognitive disorders wiU vary not only with the particular compounds or compositions selected but also with the route of administration, the nature of the condition being treated, and the age and condition of the patient, and wiU ultimately be at the discretion of the patient's physician or pharmacist.
The activity of the NK- 1 receptor antagonist of use in the present invention may be measured using the foUowing assays:
ASSAY 1: NK-1 Receptor binding NK-1 receptor binding assays are performed in intact Chinese hamster ovary (CHO) ceUs expressing the human NK- 1 receptor using a modification of the assay conditions described by Cascieri et al, J. Pharmacol. Exp. Ther.. 1992, 42, 458. TypicaUy the receptor is expressed at a level of 3xl05 receptors per ceU. CeUs are grown in monolayer culture, detached from the plate with enzyme-free dissociation solution (SpeciaHty Media Inc.), and washed prior to use in the assay. i25I-Tyr8- substance P (O.lnM, 2000Ci/mmol; New England Nuclear) is incubated in the presence or absence of test compounds (dissolved in 5μl dimethylsulphoxide, DMSO) with 5xl04 CHO ceUs. Ligand binding is performed in 0.25ml of 50mM Tris-HCl, pH7.5, containing 5mM MnCl2>
150mM NaCl, 0.02% bovine serum albumin (Sigma), 50μg/ml chymostatin (Peninsula), O. lnM phenylmethylsulphonyl fluoride, 2μg/ml pepstatin, 2μg/ml leupeptin and 2.8μg/ml furoyl saccharine. The incubation proceeds at room temperature untU equihbrium is achieved (>40 minutes) and the receptor-Hgand complex is harvested by filtration over GF/C filters pre- soaked in 0.1% polyethylenimine using a Tomtek 96-weU harvester. Non- specific binding is determined using excess substance P (lμM) and represents <10% of total binding.
ASSAY 2: GerbU Foot-Tapping CNS-penetrant NK-1 receptor antagonists for use in the present invention can be identified by their abiHty to inhibit foot tapping in gerbUs induced by anxiogenic agents (such as pentagastrin) or central infusion of NK-1 receptor agonists such as GR73632, or caused by aversive stimulation such as foot shock or single housing, based on the method of Rupniak & WiUiams, Eur. J. Pharmacol., 1994, 265, 179.
Male or female MongoHan gerbUs (35-70g) are anaesthetised by inhalation of an isoflurane/oxygen mixture to permit exposure of the jugular vein in order to permit administration of test compounds or vehicle in an injection volume of 5ml/kg i.v. Alternatively, test compounds may be administered oraUy or by subcutaneous or intraperitoneal routes. A skin incision is then made in the midHne of the scalp to expose the skuU. An anxiogenic agent (e.g. pentagastrin) or a selective NK-1 receptor agonist (e.g. GR73632 (d Ala[L-Pro9,Me-Leu10] -substance P-(7-l l)) is infused directly into the cerebral ventricles (e.g. 3pmol in 5μl i.c.v., depending on test substance) by vertical insertion of a cuffed 27 gauge needle to a depth of 4.5mm below bregma. The scalp incision is closed and the animal aUowed to recover from anaesthesia in a clear perspex observation box (25cm x 20cm x 20cm). The duration and/or intensity of hind foot tapping is then recorded continuously for approximately 5 minutes. Alternatively, the ability of test compounds to inhibit foot tapping evoked by aversive stimulation, such as foot shock or single housing, may be studied using a similar method of quantification.
ASSAY 3: Ferret Emesis IndividuaUy housed male ferrets (1.0 -2.5 kg) are dosed oraUy by gavage with test compound. Ten minutes later they are fed with approximately lOOg of tinned cat food. At 60 minutes foUowing oral dosing, cisplatin (lOmg/kg) is given i.v. via a jugular vein catheter inserted under a brief period of halothane anaesthesia. The catheter is then removed, the jugular vein Hgated and the skin incision closed. The ferrets recover rapidly from the anaesthetic and are mobUe within 10-20 minutes. The animals are observed continuously during recovery from the anaesthetic and for 4 hours foUowing the cisplatin injection, after which time the animals are kiUed humanely. The numbers of retches and vomits occurring during the 4 hours after cisplatin administration are recorded by trained observers.
ASSAY 4: Separation-Induced VocaHsation
Male and female guinea-pigs pups are housed in family groups with their mothers and Httermates throughout the study. Experiments are commenced after weaning when the pups are 2 weeks old. Before entering an experiment, the pups are screened to ensure that a vigorous vocaHsation response is reproducibly eHcited foUowing maternal separation. The pups are placed individuaUy in an observation cage (55cm x 39cm x 19cm) in a room physically isolated from the home cage for 15 minutes and the duration of vocaHsation during this baseHne period is recorded. Only animals which vocaHse for longer than 5 minutes are employed for drug chaUenge studies (approximately 50% of available pups may faU to reach this criterion). On test days each pup receives an oral dose or an s.c. or i.p. injection of test compound or vehicle and is then immediately returned to the home cage with its mother and sibHngs for 30 to 60 minutes (or for up to 4 hours foUowing an oral dose, dependant upon the oral pharmacokinetics of the test compound) before social isolation for 15 minutes as described above. The duration of vocaHsation on drug treatment days is expressed as a percentage of the pre-treatment baseHne value for each animal. The same subjects are retested once weekly for up to 6 weeks. Between 6 and 8 animals receive each test compound at each dose tested.
As used herein, the term "CNS-penetrant" refers to NK-1 receptor antagonists which are able to inhibit NK-1 receptor antagonist-induced foot-tapping in the gerbU as hereinafter defined.
EssentiaUy, hind foot-tapping in the gerbil induced by infusion of the NK-1 receptor agonist, GR73632 (d Ala[L-Pro9,Me-Leu10]-substance P- (7-11)), under anaesthesia, directly into the central ventricles is inhibited when a CNS-penetrant NK-1 receptor antagonist is administered intravenously immediately prior to GR73632 chaUenge, wherein hind foot- tapping over a period of five minutes foUowing recovery from the anaesthesia is inhibited with an IDso<3mg/kg, and preferably with an
Figure imgf000013_0001
In an alternative method, the NK- 1 receptor antagonist is administered oraUy, 1 hour prior to GR73632 chaUenge, wherein the foot- tapping over a period of five minutes foUowing recovery from anaesthesia is inhibited with an IDso<30mg/kg, and preferably with an IDso≤lOmg/kg.
CNS-penetrant NK-1 receptor antagonists of use in the present invention are also effective in the attenuation of separation-induced vocaHsations by guinea-pig pups as hereinafter defined.
EssentiaUy, a vocaHsation response in guinea-pig pups is induced by isolation from their mothers and Httermates, which response is attenuated when a CNS-penetrant NK-1 receptor antagonist is administered subcutaneously 30 minutes prior to isolation, wherein vocaHsations during the first 15 minutes of isolation are attenuated with an ID5o<20mg/kg, preferably with an IDδo≤lOmg/kg, and especiaUy with an IDso≤δmg/kg.
In an alternative method, the NK-1 receptor antagonist is administered oraUy, 4 hours prior to isolation, wherein vocaHsations during the first 15 minutes of isolation are attenuated with an IDso<20mg/kg, preferably with an IDso≤lOmg/kg, and especially with an IDso≤δmg/kg.
A suitable selection cascade for NKi antagonists of use according to the present invention is as foUows: (i) Determine affinity for human NKi receptor in radioHgand binding studies (Assay 1); select compounds with ICεo < lOnM, preferably IC50 < 2nM, especiaUy ICso < InM.
(fi) Determine abihty of compounds to penetrate CNS by their abiHty to inhibit foot tapping in gerbUs induced by central injection of an NKi agonist (Assay 2); select compounds that inhibit foot tapping with IDso < 3mg/kg i.v., and preferably IDso < lmg/kg i.v. when administered immediately prior to central NKi agonist chaUenge, or IDso < 30mg/kg p.o., and preferably IDso < lOmg/kg p.o. 1 hour prior to chaUenge.
(Hi) Determine central duration of action of compounds in gerbU foot tapping assay foUowing intravenous administration 24 hours prior to central NKi agonist chaUenge; select compounds showing < 25-fold loss of potency compared with IDso determined in step (n) above with the proviso that IDso ≤ lOmg/kg i.v., and preferably < 5mg/kg i.v. after 24 hour pre-treatment. (iv) Determine oral bioavaUabiHty of compounds by pharmacokinetic analysis, activity in gerbU foot tapping assay foUowing oral administration and/or by abiHty to inhibit cisplatin-induced emesis in ferrets (Assay 3); select compounds with ID90 < 3mg/kg p.o., and preferably
Figure imgf000014_0001
Particularly preferred compounds of use in the present invention are identified using steps (i) to (iv) foUowed by step (v):
(v) Determine activity of compounds in assays sensitive to conventional antidepressant/anxiolytic drugs (inhibition of pharmacologicaUy evoked foot tapping in gerbUs and/or inhibition of distress vocaHsations in guinea-pig pups (Assay 4)). Select compounds with IDso < 20mg kg, and preferably IDso < lOmg/kg. Yet further preferred compounds of use in the present invention may be selected from those compounds which satisfy the NK-1 receptor binding criteria of step (i) which, in addition, have < 5-fold shift in affinity when incubated in the presence of human serum albumin (HSA) to show non-specific protein binding.
The NK- 1 receptor antagonist of use in the present invention is the compound 2-(R)-(l-(S)-(3,5-bis(trifl.uoromethyl)phenyl)-2-hydroxyethoxy)- 3-(S)-(4-fluorophenyl)-4-(l,2,4-triazol-3-yl)methylmorphoHne, the preparation of which is described in International Patent Specification No. WO 95/18124 and US Patent No. 5,612,337. In the aforementioned assays, this compound has the foUowing activity:
human NK- 1 receptor binding: ICso = 0.12 nM gerbU foot-tapping (5 mins.): IDso = 0.38 mg/kg i.v. gerbU foot-tapping (24 hrs.): IDso = 2.2 mg/kg i.v. ferret emesis: ID90 = 1 mg/kg p.o. guinea-pig vocaHsation
(4 hr. pre-treatment): IDso = 0.91 mg/kg p.o.
The foUowing example illustrates pharmaceutical compositions according to the invention.
EXAMPLE 1 Tablets containing 50-300mg of NK-1 antagonist
Amount mg NK-1 antagonist 50.0 100.0 300.0
MicrocrystaUine ceUulose 80.0 80.0 80.0
Modified food corn starch 80.0 80.0 80.0
Lactose 189.5 139.5 139.5
Magnesium Stearate 0.5 0.5 0.5 The active ingredient, ceUulose, lactose and a portion of the corn starch are mixed and granulated with 10% corn starch paste. The resulting granulation is sieved, dried and blended with the remainder of the corn starch and the magnesium stearate. The resulting granulation is then compressed into tablets containing 50mg, lOOmg and 300mg of the NK-1 receptor antagonist per tablet.

Claims

1. Use of 2-(R)-(l-(S)-(3,5-bis(trifluoromethyl)phenyl)-2- hydroxyethoxy)-3-(S)-(4-fluorophenyl)-4-(l,2,4-triazol-3- yl)methyhnorphoHne, or a pharmaceuticaUy acceptable salt thereof, for the manufacture of a medicament adapted for oral administration for the treatment or prevention of cognitive disorders.
2. Use of 2-(R)-(l-(S)-(3,5-bis(trifluoromethyl)phenyl)-2- hydroxyethoxy)-3-(S)-(4-fluorophenyl)-4-(l,2,4-triazol-3- yl)methylmorphoHne, or a pharmaceuticaUy acceptable salt thereof, for the manufacture of a medicament adapted for oral administration for the treatment or prevention of cognitive disorders in a patient who is non- responsive to heterocycHc antidepressants, SSRIs, serotonin agonists or antagonists, mixed serotonin and norepinephrine selective reuptake inhibitors, dopamine reuptake inhibitors or MAOIs, or for whom heterocycHc antidepressants, SSRIs, serotonin agonists or antagonists, mixed serotonin and norepinephrine selective reuptake inhibitors, dopamine reuptake inhibitors or MAOIs are contraindicated.
3. Use of 2-(R)-(l-(S)-(3,5-bis(trifluoromethyl)phenyl)-2- hydroxyethoxy)-3-(S)-(4-fluorophenyl)-4-(l,2,4-triazol-3- yl)methylmorphoHne, or a pharmaceuticaUy acceptable salt thereof, for the manufacture of a medicament adapted for oral administration for the treatment or prevention of cognitive disorders in a patient who is non- responsive to antipsychotic agents, or for whom antipsychotic agents are contraindicated.
4. An oral pharmaceutical composition for the treatment of cognitive disorders which comprises 2-(R)-(l-(S)-(3,5- bis(trifluoromethyl)phenyl)-2-hydroxyethoxy)-3-(S)-(4-fluorophenyl)-4- (l,2,4-triazol-3-yl)methylmorphoHne, or a pharmaceuticaUy acceptable salt thereof, together with a pharmaceuticaUy acceptable carrier or excipient.
5. A method for the treatment or prevention of cognitive disorders, which method comprises the oral administration to a patient in need of such treatment of an effective amount of 2-(R)-(l-(S)-(3,5- bis(trifluoromethyl)phenyl)-2-hydroxyethoxy)-3-(S)-(4-fluorophenyl)-4- (l,2,4-triazol-3-yl)methylmorphoHne, or a pharmaceuticaUy acceptable salt thereof.
6. A method for the treatment or prevention of cognitive disorders in a patient who is non-responsive to heterocycHc antidepressants, SSRIs, serotonin agents or antagonists, mixed serotonin and norepinephrine selective reuptake inhibitors, dopamine reuptake inhibitors or MAOIs, or for whom heterocycHc antidepressants, SSRIs, serotonin agents or antagonists, mixed serotonin and norepinephrine selective reuptake inhibitors, dopamine reuptake inhibitors or MAOIs are contraindicated, which method comprises oral administration to the patient in need of such treatment of an effective amount of 2-(R)-(l-(S)- (3,5-bis(trifluoromethyl)phenyl)-2-hydroxyethoxy)-3-(S)-(4-fluorophenyl)- 4-(l,2,4-triazol-3-yl)methylmorphoHne, or a pharmaceuticaUy acceptable salt thereof.
7. A method for the treatment or prevention of cognitive disorders in a patient who is non-responsive to antipsychotic agents, or for whom antipsychotic agents are contraindicated, which method comprises oral administration to the patient in need of such treatment of an effective amount of 2-(R)-(l-(S)-(3,5-bis(trifluoromethyl)phenyl)-2-hydroxyethoxy)- 3-(S)-(4-fluorophenyl)-4-(l,2,4-triazol-3-yl)methylmorphoHne, or a pharmaceuticaUy acceptable salt thereof.
8. A use according to claim 1, 2 or 3, or a composition according to claim 4 or a method according to claim 5, 6 or 7 wherein the cognitive disorders are selected from dementia, amnestic disorders and cognitive disorders not otherwise specified.
9. A use, composition or method according to claim 10 wherein the dementia is caused by degenerative disorders, lesions, trauma, infections, vascular disorders, toxins, anoxia, vitamin deficiency or endocrine disorders.
10. A use, composition or method according to claim 8 wherein the amnestic disorders are caused by: alcohol and other causes of thiamine deficiency; bUateral temporal lobe damage due to herpes simplex encephaHtis and other Hmbic encephaHtis, neuronal loss secondary to anoxia/hyp oglycaemia/severe convulsions, and surgery; degenerative disorders; vascular disorders; or pathology around ventricle III.
11. A use according to claim 1, 2 or 3, or a composition according to claim 4 or a method according to claim 5, 6 or 7 wherein the cognitive disorders are due to cognitive impairment resulting from other medical conditions.
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