WO1999064007A1 - Utilisation d'un antagoniste du recepteur nk-1 pour le traitement de troubles bipolaires - Google Patents

Utilisation d'un antagoniste du recepteur nk-1 pour le traitement de troubles bipolaires Download PDF

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Publication number
WO1999064007A1
WO1999064007A1 PCT/GB1999/001804 GB9901804W WO9964007A1 WO 1999064007 A1 WO1999064007 A1 WO 1999064007A1 GB 9901804 W GB9901804 W GB 9901804W WO 9964007 A1 WO9964007 A1 WO 9964007A1
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treatment
pharmaceutically acceptable
patient
reuptake inhibitors
bipolar disorder
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PCT/GB1999/001804
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English (en)
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Nadia Melanie Rupniak
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Merck Sharp & Dohme Limited
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Priority to AU42785/99A priority Critical patent/AU4278599A/en
Priority to CA002334580A priority patent/CA2334580A1/fr
Priority to EP99955394A priority patent/EP1087771A1/fr
Priority to JP2000553076A priority patent/JP2002517447A/ja
Publication of WO1999064007A1 publication Critical patent/WO1999064007A1/fr

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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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • This invention relates to the treatment or prevention of bipolar disorders by the administration of a NK-1 receptor antagonist, in particular, 2-(E)-(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-(E)-(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.
  • Bipolar disorder otherwise known as manic depressive disorder or bipolar affective disorder, is characterised by alternating conditions of mania and depression. The nature of the clinical course of the bipolar disorder may give rise to a diagnosis of bipolar I disorder, bipolar II disorder or cyclothymic disorder. Bipolar I disorder is generally considered to be the most severe, being an alternation of major depressive episodes and manic episodes. Bipolar II disorder refers to an alternation of major depressive episodes and hypomanic episodes, whilst cyclothymic disorder refers to an alternation of depressive symptoms and hypomanic symptoms.
  • Treatment regimens commonly include the use of tricyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOIs), some psychotropic drugs, lithium carbonate, and electroconvulsive therapy (ECT) (see R. J. Baldessarini in Goodman & Gilman's The Pharmacological Basis of Therapeutics, 9th Edition, Chapter 19, McGraw- Hill, 1996 for a review). More recently, new classes of antidepressant drugs are being developed including selective serotonin reuptake inhibitors (SSRIs), specific monoamine reuptake inhibitors and 5-HTIA receptor agonists and antagonists.
  • TCAs tricyclic antidepressants
  • MAOIs monoamine oxidase inhibitors
  • ECT electroconvulsive therapy
  • tricyclic antidepressants The most established drug treatment for the management of depressive episodes are the tricyclic antidepressants. For instance, depressed panents with prominent sleep disturbance and anxiety may be treated with a sedating tricyclic antidepressant such as amitriptyline; for other patients, less sedating compounds such as imipramine or desipramine can be used. As well as inhibiting the uptake of noradrenaline and 5-hydroxytriptamine, tricyclic antidepressants also possess antagonist properties at a variety of neurotransmitter receptors, including muscarinic cholinergic receptors, ⁇ i-adrenoceptors and Hi-histamine receptors.
  • receptor antagonist effects account for much of the side-effect profile of the tricyclic antidepressants, and in particular, their anticholinergic side-effects which are particularly troublesome in patients with prostatic enlargement or glaucoma.
  • Other side-effects include dry mouth, tachycardia, difficulty in visual accommodation, constipation, urinary retention, sexual dysfunction, cognitive impairment, postural hypotension, and weight gain.
  • Monoamine oxidase inhibitors are generally prescribed for patients who have failed to respond to tricyclic antidepressants or electroconvulsive therapy.
  • tricyclic antidepressants there are a number of side- effects associated with the use of MAOIs including dizziness, muscular twitching, insomnia, confusion, mania, tachycardia, postural hypotension, hypertension, dry mouth, blurred vision, impotence, peripheral oedema, hepatocellular damage and leucopenia.
  • SSRIs such as fluoxetine, fluvoxamine. sertraline and paroxetine are generally non-sedating. Furthermore, SSRIs do not stimulate appetite and may therefore be appropriate in patients in whom weight gain would be undesirable.
  • SSRIs are not without their own side-effects, including nausea, diarrhoea, dry mouth, reduced appetite, dyspepsia, vomiting, headache, nervousness, insomnia, anxiety, tremour, dizziness, fatigue, decreased libido, pharyngitis, dyspnoea, skin rash and sexual dysfunction.
  • drugs such as haloperidol or chlorpromazine may be used to control symptoms. After more than one episode of mania, lithium carbonate is often prescribed. Drugs such as haloperidol and chlorpromazine are typically associated with a number of side-effects, including extrapyramidal symptoms, acute dystonias or dyskinesias, akathesia, tremour, tachycardia, drowsiness, confusion, postural hypotension, blurring of vision, precipitation of glaucoma, dry mouth, constipation, urinary hesitance and impaired sexual function.
  • the therapeutic index of lithium is low and close control of plasma concentrations is required for its safe clinical application.
  • 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 implicated 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 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 bipolar disorder.
  • the compounds of this class advantageously exhibit a rapid onset of action and a reduced side-effect profile when compared against conventional mood-altering agents.
  • NK-1 receptor antagonist of use in the present invention enables the treatment of bipolar disorders, without the need for concomitant therapy using tricyclic antidepressants or monoamine oxidase inhibitors or, in particular, without the need for concomitant use of a serotonin agonist or an SSRI.
  • 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)-
  • the present invention also provides a method for the treatment or prevention of bipolar disorder without concomitant therapy with other antidepressant or anti-anxiety agents, 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)- - D
  • an oral pharmaceutical composition for the treatment of bipolar disorder which comprises essentially 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, together with a pharmaceutically acceptable carrier or excipient.
  • bipolar disorder is inadequately treated with lithium. Furthermore, some patients may be adversely affected by the side-effects of lithium.
  • the present invention accordingly provides the use of 2-(R)-(l-(S)- (3 , 5 -bis(trifluoromethyl)phenyl) - 2 -hy droxy ethoxy) - 3 - (S)- (4-fluorophenyl) - 4-(l,2,4-tr ⁇ azol-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 bipolar disorder, without concomitant therapy with other antidepressant or anti-anxiety agents, in a patient who is non-responsive to lithium or for whom lithium is contraindicated.
  • the present invention also provides a method for the treatment or prevention of bipolar disorder, without concomitant therapy with other antidepressant or anti-anxiety agents, in a patient who is non-responsive to lithium or for whom lithium is 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(trifiuoromethyl)phenyl)-2- hydroxyethoxy)-3-(S)-(4-fluorophenyl)-4-(l,2,4-triazol-3- yl)methylmorphohne, or a pharmaceutically acceptable salt thereof.
  • TCAs heterocyclic antidepressants
  • SSRIs mixed serotonin and norepinephrine reuptake inhibitors
  • MAOIs dopamine reuptake inhibitors
  • some patients may be adversely affected by the side-effects of antidepressants.
  • 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)methylmorpholine, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament adapted for oral administration for the treatment or prevention of bipolar disorder, without concomitant therapy with other antidepressant or anti-anxiety agents, in a patient who is non-responsive to heterocyclic antidepressants (TCAs, tetracyclics, and the like), SSRIs, mixed serotonin and norepinephrine reuptake inhibitors, dopamine reuptake inhibitors or MAOIs, or for whom heterocyclic antidepressants (TCAs, tetracyclics, and the like), SSRIs, mixed serotonin and norepinephrine reuptake
  • the present invention also provides a method for the treatment or prevention of bipolar disorder, without concomitant therapy with other antidepressant or anti-anxiety agents, in a patient who is non-responsive to heterocyclic antidepressants (TCAs, tetracyclics, and the like), SSRIs, mixed serotonin and norepinephrine reuptake inhibitors, dopamine reuptake inhibitors or MAOIs, or for whom heterocyclic antidepressants (TCAs, tetracyclics, and the like), SSRIs, mixed serotonin and norepinephrine 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(t ⁇ ifLuoromethyl)phenyl)-2-hydiOxyethoxy)-3-(S)-(4
  • non-responsive in relation to major depressive disorder means patients who have not had a reasonable chnical response (e.g. a 50% reduction in Hamilton Depression Scale (HAM-D) from a patient's baseline score after treatment with one or more chnical courses of conventional antidepressants).
  • HAM-D Hamilton Depression Scale
  • bipolar disorder includes bipolar I disorder, bipolar II disorder, cyclothymic disorder and bipolar disorder not otherwise specified.
  • Bipolar I disorder is an alternation of major depressive episodes and manic episodes.
  • Bipolar II disorder refers to an alternation of major depressive episodes and hypomanic episodes.
  • Cyclothymic disorder refers to an alternation of depressive symptoms and hypomanic symptoms.
  • a “major depressive episode” is defined as at least two weeks of depressed mood or loss of interest, which may be accompanied by other symptoms of depression. The symptoms must persist for most of the day (i.e. for at least two thirds of the patients' waking hours), nearly every day (i.e. for at least ten out of fourteen days) for at least two consecutive weeks.
  • a "depressed mood” is often described by the patient as feehng sad, hopeless, helpless or worthless. The patient may also appear sad to an observer, for example, through facial expression, posture, voice and tearfulness. In children and adolescents, the mood may be irritable.
  • a 'loss of interest is often described by the patient as feehng less interested in hobbies or not feeling any enjoyment in activities that were previously considered to be pleasurable.
  • a major depressive episode may be accompanied by other symptoms of depression including significant weight loss when not dieting or weight gain (e.g. a change of more than 5% body weight in one month), or decrease or increase in appetite; insomnia or hypersomnia; psychomotor agitation or retardation; fatigue or loss of energy; feelings of worthlessness or excessive or inappropriate guilt; diminished ability to think or concentrate; or indecisiveness; and recurrent thoughts of death, recurrent suicidal ideation with or without a specific plan, or a suicide attempt.
  • a "manic episode” is defined by a distinct period during which there is an abnormally and persistently elevated, expansive, or irritable mood. This period of abnormal mood must last at least 1 week (or less if hospitalization is required).
  • the mood disturbance must be accompanied by at least three additional symptoms from a list that includes inflated self-esteem or grandiosity, decreased need for sleep, pressure of speech, flight of ideas, distractibility, increased involvement in goal-directed activities or psych omotor agitation, and excessive involvement in pleasurable activities with a high potential of painful consequences. If the mood is irritable (rather than elevated or expansive), at least four of the above symptoms must be present.
  • the disturbance must be sufficiently severe to cause marked impairment in social or occupational functioning or to require hospitalization, or it is characterised by the presence of psychotic features.
  • a "hypomanic episode” is less severe than a manic episode.
  • the symptoms of a hypomanic episode are generally the same as those which define a manic episode, except that delusions and hallucinations are not present and the episode is not severe enough to cause marked impairment of social and occupational functioning or to require hospitalisation of the individual.
  • treatment refers both to the treatment and to the prevention or prophylactic therapy of the aforementioned conditions.
  • NK- 1 receptor antagonist for use in the present invention is described in International Patent Specification No. 95/18124. The preparation of this compound is fully described in this publication.
  • Suitable pharmaceutically 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 pharmaceutically 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, pills, capsules, wafers and the like.
  • 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.
  • the principal active ingredient is mixed with a pharmaceutical carrier, e.g.
  • a solid preformulation composition containing a homogeneous mixture of a compound of the present invention, or a non-toxic pharmaceutically acceptable salt thereof.
  • preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.
  • This solid 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 pill 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 shellac, cetyl alcohol and cellulose acetate.
  • liquid forms in which the novel compositions of the present invention may be incorporated for administration orally include aqueous solutions, suitably flavoured syrups, aqueous or oil suspensions, and flavoured emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil, peanut oil or soybean oil, as well as elixirs and similar pharmaceutical vehicles.
  • Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth. acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinyl-pyrrolidone 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, pills, 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 especially 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 especially about 500mg per day. The compounds are administered once a day.
  • NK-1 receptor antagonist required for use in the treatment or prevention of bipolar disorders will 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 will 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 following assays:
  • ASSAY 1 NK-1 Receptor binding
  • NK-1 receptor binding assays are performed in intact Chinese hamster ovary (CHO) cells 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. Typically, the receptor is expressed at a level of 3xl0 5 receptors per cell. Cells are grown in monolayer culture, detached from the plate with enzyme-free dissociation solution (Speciality Media Inc.), and washed prior to use in the assay. 125 I-Tyr 8 - substance P (O.
  • lnM 2000Ci/mmol; New England Nuclear
  • test compounds dissolved in 5 ⁇ l dimethylsulphoxide, DMSO
  • 5xl0 4 CHO cells Ligand binding is performed in 0.25ml of 50mM Tris-HCl, pH7.5, containing 5mM MnCl 2 , 150mM NaCl, 0.02% bovine serum albumin (Sigma), 50 ⁇ g/ml chymostatin (Peninsula), O.lnM phenylmethylsulphonyl fluoride, 2 ⁇ g/ml pepstatin, 2 ⁇ g/ml leupeptin and 2.8 ⁇ g/ml furoyl saccharine.
  • CNS-penetrant NK-1 receptor antagonists for use in the present invention can be identified by their ability to inhibit foot tapping in gerbils 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 & Williams, Eur. J. Pharmacol, 1994, 265, 179.
  • test compounds Male or female Mongolian gerbils (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 orally or by subcutaneous or intraperitoneal routes. A skin incision is then made in the midline of the scalp to expose the skull.
  • 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- 11)) 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 allowed 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.
  • ferrets Individually housed male ferrets (1.0 -2.5 kg) are dosed orally by gavage with test compound. Ten minutes later they are fed with approximately lOOg of tinned cat food. At 60 minutes following 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 ligated and the skin incision closed. The ferrets recover rapidly from the anaesthetic and are mobile within 10-20 minutes. The animals are observed continuously during recovery from the anaesthetic and for 4 hours following the cisplatin injection, after which time the animals are killed humanely. The numbers of retches and vomits occurring during the 4 hours after cisplatin administration are recorded by trained observers.
  • ASSAY 4 Separation-Induced Vocalisation
  • mice Male and female guinea-pigs pups are housed in family groups with their mothers and littermates 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 vocalisation response is reproducibly elicited following maternal separation. The pups are placed individually 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 vocalisation during this baseline period is recorded. Only animals which vocalise for longer than 5 minutes are employed for drug challenge studies (approximately 50%> of available pups may fail to reach this criterion). On test days each pup receives an oral dose or an s.c. or i.p.
  • CNS-penetrant refers to NK-1 receptor antagonists which are able to inhibit NK-1 receptor antagonist-induced foot-tapping in the gerbil as hereinafter defined.
  • hind foot-tapping in the gerbil induced by infusion of the NK-1 receptor agonist, GR73632 (d Ala[L-Pro 9 ,Me-Leu 10 ]-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 challenge, wherein hind foot- tapping over a period of five minutes following recovery from the anaesthesia is inhibited with an LD! ⁇ o ⁇ 3mg/kg, and preferably with an IDso ⁇ lmg/kg.
  • the NK-1 receptor antagonist is administered orally, 1 hour prior to GR73632 challenge, wherein the foot- tapping over a period of five minutes following recovery from anaesthesia is inhibited with an IDso ⁇ 30mg/kg, and preferably with an ID ⁇ o ⁇ lOmg/kg.
  • CNS-penetrant NK-1 receptor antagonists of use in the present invention are also effective in the attenuation of separation-induced vocalisations by guinea-pig pups as hereinafter defined.
  • a vocalisation response in guinea-pig pups is induced by isolation from their mothers and littermates, which response is attenuated when a CNS-penetrant NK-1 receptor antagonist is administered subcutaneously 30 minutes prior to isolation, wherein vocalisations during the first 15 minutes of isolation are attenuated with an ID5o ⁇ 20mg/kg, preferably with an IDso ⁇ lOmg/kg, and especially with an IDso ⁇ mg/kg.
  • the NK-1 receptor antagonist is administered orally, 4 hours prior to isolation, wherein vocalisations during the first 15 minutes of isolation are attenuated with an ID5o ⁇ 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 follows:
  • Particularly preferred compounds of use in the present invention are identified using steps (i) to (iv) followed by step (v): (v) Determine activity of compounds in assays sensitive to conventional antipsychotic drugs (inhibition of distress vocalisations 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.
  • 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(trifluoromethyl)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 following activity:
  • the active ingredient, cellulose, 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.

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Abstract

La présente invention concerne l'utilisation d'un antagoniste du récepteur NK-1 pour la fabrication d'un médicament, adapté à l'administration orale, destiné au traitement ou à la prévention de troubles bipolaires sans le besoin d'une thérapie simultanée à l'aide d'autres antidépresseurs ou d'anxiolytiques. L'invention concerne aussi des méthodes de traitement utilisant un tel antagoniste du récepteur NK-1 et des compositions pharmaceutiques le contenant.
PCT/GB1999/001804 1998-06-11 1999-06-08 Utilisation d'un antagoniste du recepteur nk-1 pour le traitement de troubles bipolaires WO1999064007A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
AU42785/99A AU4278599A (en) 1998-06-11 1999-06-08 Use of a nk-1 receptor antagonist for treating bipolar disorders
CA002334580A CA2334580A1 (fr) 1998-06-11 1999-06-08 Utilisation d'un antagoniste du recepteur nk-1 pour le traitement de troubles bipolaires
EP99955394A EP1087771A1 (fr) 1998-06-11 1999-06-08 Utilisation d'un antagoniste du recepteur nk-1 pour le traitement de troubles bipolaires
JP2000553076A JP2002517447A (ja) 1998-06-11 1999-06-08 双極性障害の治療のためのｎｋ−１受容体アンタゴニストの使用

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GBGB9812617.0A GB9812617D0 (en) 1998-06-11 1998-06-11 Therapeutic use
GB9812617.0 1998-06-11

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CA (1) CA2334580A1 (fr)
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WO (1) WO1999064007A1 (fr)

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995018124A1 (fr) * 1993-12-29 1995-07-06 Merck Sharp & Dohme Limited Derives de morpholine substitues et une utilisation en tant qu'agents therapeutiques
WO1996029328A1 (fr) * 1995-03-18 1996-09-26 Merck Sharp & Dohme Limited Derives de la morpholine, compositions les contenant et leur utilisation comme agents therapeutiques
WO1997049710A1 (fr) * 1996-06-21 1997-12-31 Merck Sharp & Dohme Limited Derives spiro-piperidine et leur utilisation comme agents therapeutiques
WO1998013369A1 (fr) * 1996-09-25 1998-04-02 Merck Sharp & Dohme Limited Derives spiro-azacycliques, preparation de ces derives et leur utilisation comme antagonistes de la tachykinine
WO1998015277A2 (fr) * 1996-10-07 1998-04-16 Merck Sharp & Dohme Limited Antagoniste du recepteur nk-1 utilise comme antidepresseur et/ou agent anxiolytique
WO1998024443A1 (fr) * 1996-12-02 1998-06-11 Merck Sharp & Dohme Limited Utilisation d'antagonistes du recepteur nk-1 dans le traitement des troubles bipolaires
WO1998054187A1 (fr) * 1997-05-29 1998-12-03 Merck Sharp & Dohme Limited Derives spiro-azacycliques et leur utilisation en tant qu'agents therapeutiques
WO1999025714A1 (fr) * 1997-11-19 1999-05-27 Pfizer Pharmaceuticals Inc. Composes ether cycliques du type piperidinylaminomethyltrifluoromethyle em tant qu'antagonistes de la substance p

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995018124A1 (fr) * 1993-12-29 1995-07-06 Merck Sharp & Dohme Limited Derives de morpholine substitues et une utilisation en tant qu'agents therapeutiques
WO1996029328A1 (fr) * 1995-03-18 1996-09-26 Merck Sharp & Dohme Limited Derives de la morpholine, compositions les contenant et leur utilisation comme agents therapeutiques
WO1997049710A1 (fr) * 1996-06-21 1997-12-31 Merck Sharp & Dohme Limited Derives spiro-piperidine et leur utilisation comme agents therapeutiques
WO1998013369A1 (fr) * 1996-09-25 1998-04-02 Merck Sharp & Dohme Limited Derives spiro-azacycliques, preparation de ces derives et leur utilisation comme antagonistes de la tachykinine
WO1998015277A2 (fr) * 1996-10-07 1998-04-16 Merck Sharp & Dohme Limited Antagoniste du recepteur nk-1 utilise comme antidepresseur et/ou agent anxiolytique
WO1998024443A1 (fr) * 1996-12-02 1998-06-11 Merck Sharp & Dohme Limited Utilisation d'antagonistes du recepteur nk-1 dans le traitement des troubles bipolaires
WO1998054187A1 (fr) * 1997-05-29 1998-12-03 Merck Sharp & Dohme Limited Derives spiro-azacycliques et leur utilisation en tant qu'agents therapeutiques
WO1999025714A1 (fr) * 1997-11-19 1999-05-27 Pfizer Pharmaceuticals Inc. Composes ether cycliques du type piperidinylaminomethyltrifluoromethyle em tant qu'antagonistes de la substance p

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GB9812617D0 (en) 1998-08-12
CA2334580A1 (fr) 1999-12-16
JP2002517447A (ja) 2002-06-18
AU4278599A (en) 1999-12-30

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