AU4278599A - Use of a nk-1 receptor antagonist for treating bipolar disorders - Google Patents

Description

WO 99/.64007 PCT/GB99/01804 USE OF A NK-1 RECEPTOR ANTAGONIST FOR TREATING BIPOLAR DISORDERS This invention relates to the treatment or prevention of bipolar 5 disorders by the administration of a NK-1 receptor antagonist, in particular, 2-(R )-(1-(S)-(3,5-bis(trifluoromethyl)phenyl)-2-hydroxyethoxy) 3-(S)-(4-fluorophenyl)-4-(1,2,4-triazol-3-yl)methylmorpholine, or a pharmaceutically acceptable salt thereof. Bipolar disorder, otherwise known as manic depressive disorder or 10 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 15 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 20 antidepressants (TCAs), monoamine oxidase inhibitors (MAOIs), some psychotropic drugs, lithium carbonate, and electroconvulsive therapy (ECT) (see R. J. Baldessarini in Goodman & Gilnan's The Pharmacological Basis of Therapeutics, 9th Edition, Chapter 19, McGraw Hill, 1996 for a review). More recently, new classes of antidepressant 25 drugs are being developed including selective serotonin reuptake inhibitors (SSRIs), specific monoamine reuptake inhibitors and 5-HTA receptor agonists and antagonists. The most established drug treatment for the management of depressive episodes are the tricyclic antidepressants. For instance, 30 depressed patients with prominent sleep disturbance and anxiety may be WO 99/64007 PCT/GB99/01804 -2 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 5 possess antagonist properties at a variety of neurotransmitter receptors, including muscarinic cholinergic receptors, oi-adrenoceptors and Hi-histamine receptors. These 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 10 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 15 who have failed to respond to tricyclic antidepressants or electroconvulsive therapy. As with 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, 20 hepatocellular damage and leucopenia. Of the new classes of antidepressant, selective serotonin reuptake inhibitors are increasingly prescribed, particularly in patients where the use of tricyclic antidepressants is contraindicated because of their anticholinergic and cardiotoxic effects. SSRIs such as fluoxetine, 25 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. However, SSRIs are not without their own side-effects, including nausea, diarrhoea, dry mouth, reduced appetite, dyspepsia, vomiting, headache, WO 99/64007 PCT/GB99/01804 -3 nervousness, insomnia, anxiety, tremour, dizziness, fatigue, decreased libido, pharyngitis, dyspnoea, skin rash and sexual dysfunction. Treatment of manic episodes is with drugs and psychological management. Typically, drugs such as haloperidol or chlorpromazine may 5 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 10 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. Side-effects of lithium include tremour, nausea, diarrhoea, thirst and polyuria. 15 Whatever drug is used, there is a delay of usually two, three or even four weeks before a therapeutic effect is observed. This period of delay may be particularly difficult for a patient suffering from a bipolar disorder. Neurokinin 1 (NK-1; substance P) receptor antagonists are being 20 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) 25 patent specification Nos. WO 95/16679, WO 95/18124 and WO 95/23798). More recently, International (PCT) patent specification No. WO 96/24353 (published 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 WO 99/64007 PCT/GB99/01804 -4 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 bipolar disorders. 5 The present invention provides the use of 2-(R)-(1-(S)-(3,5 bis(trifluoromethyl)phenyl)-2-hydroxyethoxy)-3-(S)-(4-fluorophenyl)-4 (1,2,4-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 10 onset of action and a reduced side-effect profile when compared against conventional mood-altering agents. The exceptional pharmacology of the 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 15 or monoamine oxidase inhibitors 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. 20 The present invention accordingly provides the use of 2-(R)-(1-(S) (3,5-bis(trifluoromethyl)phenyl)-2-hydroxyethoxy)-3-(S)-(4-fluorophenyl) 4-(1,2,4-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 25 concomitant therapy with other antidepressant or anti-anxiety agents. 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 30 amount of 2-(R)-(1-(S)-(3,5-bis(trifluoromethyl)phenyl)-2-hydroxyethoxy)- WO 99/64007 PCT/GB99/01804 3-(S)-(4-fluorophenyl)-4-(1,2,4-triazol-3-yl)methylmorpholine, 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 bipolar disorder 5 which comprises essentially 2-(R)-(1-(S)-(3,5-bis(trifluoromethyl)phenyl)-2 hydroxyethoxy)-3-(S)-(4-fluorophenyl)-4-(1,2,4-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 bipolar disorder is 10 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)-(1-(S) (3,5-bis(trifluoromethyl)phenyl)-2-hydroxyethoxy)-3-(S)-(4-fluorophenyl) 4-(1,2,4-triazol-3-yl)methylmorpholine, or a pharmaceutically acceptable 15 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. 20 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 25 an effective amount of 2-(R)-(l-(S)-(3,5-bis(trifluoromethyl)phenyl)-2 hydroxyethoxy)-3-(S)-(4-fluorophenyl)-4-(1,2,4-triazol-3 yl)methylmorpholine, or a pharmaceutically acceptable salt thereof. Furthermore, there exists a patient population in whom bipolar disorder is inadequately treated with heterocyclic antidepressants (TCAs, 30 tetracyclics. and the like), SSRIs, mixed serotonin and norepinephrine WO 99/64007 PCT/GB99/01804

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reuptake inhibitors, dopamine reuptake inhibitors or MAOIs. Furthermore, some patients may be adversely affected by the side-effects of antidepressants. The present invention accordingly provides the use of 2-(R)-(1-(S) 5 (3,5-bis(trifluoromethyl)phenyl)-2-hydroxyethoxy)-3-(S)-(4-fluorophenyl) 4-(1,2,4-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 10 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 15 reuptake inhibitors or MAOIs are 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 heterocyclic antidepressants (TCAs, tetracyclics, and the like), SSRIs, 20 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 25 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-(1,2,4-triazol-3-yl)methylmorpholine, or a pharmaceutically acceptable salt thereof. As used herein, the term "non-responsive" in relation to major 30 depressive disorder means patients who have not had a reasonable clinical WO 99/64007 PCT/GB99/01804 -7 response (e.g. a 50% reduction in Hamilton Depression Scale (HAM-D) from a patient's baseline score after treatment with one or more clinical courses of conventional antidepressants). As used herein, the term "bipolar disorder" includes bipolar I 5 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 10 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 15 (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 feeling 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 20 "loss of interest" is often described by the patient as feeling 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 25 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 30 suicidal ideation with or without a specific plan, or a suicide attempt.

WO 99/64007 PCT/GB99/01804 -8 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 5 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 psychomotor agitation, and excessive involvement in pleasurable activities with a high potential of painful consequences. If the 10 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. 15 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 20 individual. As used herein, the term "treatment" refers both to the treatment and to the prevention or prophylactic therapy of the aforementioned conditions. The NK- 1 receptor antagonist for use in the present invention is 25 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 30 with a solution of a pharmaceutically acceptable non-toxic acid such as W-O 99/64007 PCT/GB99/01804 -9 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 5 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, pills, capsules, wafers and the like. Additionally, the NK- 1 receptor antagonist of use according to the present invention 10 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. 15 For preparing solid 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 diluents, e.g. water, to form a solid preformulation 20 composition containing a homogeneous mixture of a compound of the present invention, or a non-toxic pharmaceutically 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 readily subdivided into 25 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 30 dosage form affording the advantage of prolonged action. For example, WO 99/64007 PCT/GB99/01804 - 10 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 5 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 shellac, cetyl alcohol and cellulose acetate. The liquid forms in which the novel compositions of the present 10 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 15 aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinyl-p yrrolidone or gelatin. Compositions of the present invention may also be administered via the buccal cavity using conventional technology, for example, absorption 20 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 1mg per day, preferably about 5mg per day and especially about 10mg per 25 day. A maximum dosage level for the NK- 1 receptor antagonist is about 1500mg per day, preferably about 1000mg per day and especially 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 bipolar 30 disorders will vary not only with the particular compounds or W 99/64007 PCT/GB99/01804 - 11 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. 5 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 10 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. Other , 1992, 42, 458. Typically, the receptor is expressed at a level of 3x10 5 receptors per cell. Cells are grown in monolayer culture, detached from the plate with enzyme-free dissociation solution 15 (Speciality Media Inc.), and washed prior to use in the assay. 125 1-Tyr 8 substance P (0. 1nM, 2000Ci/mmol; New England Nuclear) is incubated in the presence or absence of test compounds (dissolved in 5pl dimethylsulphoxide, DMSO) with 5x10 4 CHO cells. Ligand binding is performed in 0.25ml of 50mM Tris-HCl, pH7.5, containing 5mM MnCl2, 20 150mM NaCl, 0.02% bovine serum albumin (Sigma), 50tg/ml chymostatin (Peninsula), 0. nM phenylmethylsulphonyl fluoride, 2pg/ml pepstatin, 2 ig/ml leupeptin and 2.8ptg/ml furoyl saccharine. The incubation proceeds at room temperature until equilibrium is achieved (>40 minutes) and the receptor-ligand complex is harvested by filtration over GF/C filters pre 25 soaked in 0.1% polyethylenimine using a Tomtek 96-well harvester. Non specific binding is determined using excess substance P (1pM) and represents <10% of total binding.

WO 99/64007 PCT/GB99/01804 - 12 ASSAY 2: Gerbil Foot-Tapping 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 5 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. Male or female Mongolian gerbils (35-70g) are anaesthetised by inhalation of an isoflurane/oxygen mixture to permit exposure of the 10 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 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) or a selective NK- 1 receptor agonist 15 (e.g. GR73632 (d Ala[L-Pro9,Me-Leu1o]-substance P-(7-11)) is infused directly into the cerebral ventricles (e.g. 3pmol in 5ptl 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 20 (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. 25 ASSAY 3: Ferret Emesis 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 100g of tinned cat food. At 60 minutes following oral 30 dosing, cisplatin (10mg/kg) is given i.v. via a jugular vein catheter WO 99/64007 PCT/GB99/01804 - 13 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 5 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. 10 ASSAY 4: Sep aration-Induced Vocalisation 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 15 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 20 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. injection of test compound or vehicle and is then immediately returned to the home cage with its mother and siblings for 30 to 60 minutes (or for up to 4 hours following an oral dose, dependent upon 25 the oral pharmacokinetics of the test compound) before social isolation for 15 minutes as described above. The duration of vocalisation on drug treatment days is expressed as a percentage of the pre-treatment baseline 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 30 dose tested.

WO 99/64007 PCT/GB99/01804 - 14 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 gerbil as hereinafter defined. Essentially, hind foot-tapping in the gerbil induced by infusion of 5 the NK-1 receptor agonist, GR73632 (d Ala[L-Pro9,Me-Leu1 0 ]-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 10 anaesthesia is inhibited with an ID 5 o 3mg/kg, and preferably with an 1D 5 o 1mg/kg. In an alternative method, 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 15 is inhibited with an ID 5 o 30mg/kg, and preferably with an ID5o 10mg/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. Essentially, a vocalisation response in guinea-pig pups is induced 20 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 ID 5 o 20mg/kg, preferably with an IDso 10mg/kg, and especially with an 25 1D 50 5mg/kg. In an alternative method, 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 IDro20mg/kg. preferably with an ID 50 0mg/kg, and especially with an 30 IDo S5mg/kg.

WO 99/64007 PCT/GB99/01804 - 15 A suitable selection cascade for NKi antagonists of use according to the present invention is as follows: (i) Determine affinity for human NKi receptor in radioligand binding studies (Assay 1); select compounds with IC 50 1OnM, preferably 5 ICo 2nM, especially ICso lnM. (ii) Determine ability of compounds to penetrate CNS by their ability to inhibit foot tapping in gerbils induced by central injection of an NK1 agonist (Assay 2); select compounds that inhibit foot tapping with ID5o 3mg/kg i.v., and preferably IDso 1mg/kg i.v. when administered 10 immediately prior to central NK 1 agonist challenge, or ID 5 o 30mg/kg p.o., and preferably IDso 10mg/kg p.o. 1 hour prior to challenge. (iii) Determine central duration of action of compounds in gerbil foot tapping assay following intravenous administration 24 hours prior to central NK 1 agonist challenge; select compounds showing 25-fold loss of 15 potency compared with IDo determined in step (ii) above with the proviso that ID 5 o 10mg/kg i.v., and preferably 5mg/kg i.v. after 24 hour pre-treatment. (iv) Determine oral bioavailability of compounds by pharmacokinetic analysis, activity in gerbil foot tapping assay following 20 oral administration and/or by ability to inhibit cisplatin-induced emesis in ferrets (Assay 3); select compounds with ID9o 3mg/kg p.o., and preferably IDeo 1mg/kg p.o. Particularly preferred compounds of use in the present invention are identified using steps (i) to (iv) followed by step (v): 25 (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 IDoo 10mg/kg. Yet further preferred compounds of use in the present 30 invention may be selected from those compounds which satisfy the NK- 1 WO 99/64007 PCT/GB99/01804 - 16 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 5 compound 2-(R)-(1-(S)-(3,5-bis(trifluoromethyl)phenyl)-2-hydroxyethoxy) 3-(S)-(4-fluorophenyl)-4-(1,2,4-triazol-3-yl)methylmorpholine, 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: 10 human NK- 1 receptor binding: ICro= 0.12 nM gerbil foot-tapping (5 mins.): IDso = 0.38 mg/kg i.v. gerbil foot-tapping (24 hrs.): IDso= 2.2 mg/kg i.v. ferret emesis:

ID

9 o= 1 mg/kg p.o. guinea-pig vocalisation (4 hr. pre-treatment): IDo0= 0.91 mg/kg p.o. The following example illustrates pharmaceutical compositions according to the invention. 15 EXAMPLE 1 Tablets containing 50-300mg of NK- 1 antagonist Amount mg NK-1 antagonist 50.0 100.0 300.0 Microcrystalline cellulose 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, cellulose, lactose and a portion of the corn starch are mixed and granulated with 10% corn starch paste. The WO 99/64007 PCT/GB99/01804 - 17 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, 100mg and 300mg of the NK-1 receptor antagonist per tablet. 5

Claims (8)

1. Use of 2-(R)-(1-(S)-(3,5-bis(trifluoromethyl)phenyl)-2 hydroxyethoxy)-3-(S)-(4-fluorophenyl)- 4 -(1,2,4-triazol-3 5 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. 10

2. Use of 2-(R)-(-(S)-(3,5-bis(trifluoromethyl)phenyl)-2 hydroxyethoxy)-3-(S)-(4-fluorophenyl)-4-(1,2,4-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 15 with other antidepressant or anti-anxiety agents, in a patient who is non responsive to lithium or for whom lithium is contraindicated.

3. Use of 2-(R)-(1-(S)-(3,5-bis(trifluoromethyl)phenyl)-2 hydroxyethoxy)-3-(S)-(4-fluorophenyl)-4-(1,2 ,4-triazol-3 20 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, SSRIs, mixed serotonin and 25 norepinephrine reuptake inhibitors, dopamine reuptake inhibitors or MAOIs, or for whom heterocyclic antidepressants, SSRIs, mixed serotonin and norpinephrine reuptake inhibitors, dopamine reuptake inhibitors or MAOIs are contraindicated. WO 99/64007 PCT/GB99/01804 -19

4. An oral pharmaceutical composition for the treatment of bipolar disorder which comprises essentially 2-(R)-(1-(S)-(3,5 bis(trifluoromethyl)phenyl)-2-hydroxyethoxy)-3-(S)-(4-fluorophenyl)-4 (1,2,4-triazol-3-yl)methylmorpholine, or a pharmaceutically acceptable salt 5 thereof, together with a pharmaceutically acceptable carrier or excipient.

5. A method for the treatment or prevention of bipolar disorder without concomitant therapy with other anti-depressant or anti-anxiety agents, which method comprises the oral administration to a patient in 10 need of such treatment of 2-(R)-(1-(S)-(3,5-bis(trifluoromethyl)phenyl)- 2 hydroxyethoxy)-3-(S)-(4-fluorophenyl)-4-(1,2,4-triazol-3 yl)methylmorpholine, or a pharmaceutically acceptable salt thereof.

6. A method for the treatment or prevention of bipolar disorder 15 without concomitant therapy with other anti-depressant 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)-(1-(S) (3,5-bis(trifluoromethyl)phenyl)-2-hydroxyethoxy)-3-(S)-(4-fluorophenyl) 20 4-(1,2,4-triazol-3-yl)methylmorpholine, or a pharmaceutically acceptable salt thereof.

7. A method for the treatment or prevention of bipolar disorder without concomitant therapy with other anti-depressant or anti-anxiety 25 agents, in a patient who is non-responsive to heterocyclic antidepressants, SSRIs, mixed serotonin and norepinephrine reuptake inhibitors, dopamine reuptake inhibitors or MAOIs, or for whom heterocyclic antidepressants, SSRIs, mixed serotonin and norpinephrine reuptake inhibitors, dopamine reuptake inhibitors or MAOIs are contraindicated, 30 which method comprises oral administration to the patient in need of such WO 99/64007 PCT/GB99/01804 - 20 treatment of 2-(R)-(1-(S)-(3,5-bis(trifluoromethyl)phenyl)-2 hydroxyethoxy)-3-(S)-(4-fluorophenyl)-4-(1,2,4-triazol-3 yl)methylmorpholine, or a pharmaceutically acceptable salt thereof. 5

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 bipolar disorder is bipolar I disorder, bipolar II disorder, cyclothymic disorder or bipolar disorder not otherwise specified.