USE OF NK-1 RECEPTOR ANTAGONISTS FOR TREATING MOVEMENT DISORDERS

Abstract: The present invention provides the use of an orally active, long acting, CNS-penetrant NK-1 antagonist for the manufacture of a medicament for oral administration for the treatment or prevention of movement disorders, methods of treatment using such a NK-1 receptor antagonist and pharmaceutical compositions comprising it.

Description: USE OF NK-1 RECEPTOR ANTAGONISTS FOR TREATING MOVEMENT DISORDERS This invention relates to the treatment or prevention of movement disorders by the administration of a specific class of NK-1 receptor antagonists. Diseases of the extrapyramidal motor systems cause either a loss of movement (akinesia) accompanied by an increase in muscle tone (rigidity) or abnormal involuntary movements (dyskinesias) often accompanied by a reduction in muscle tone. The akinetic-rigid syndrome called parkinsonism, and the dyskinesias represent opposite ends of the spectrum of movement disorders (for review see C. D. Marsden in Oxford Textbook of Medicine, 3rd Edition, Oxford University Press, 1996, vol. 3, pages 3998-4022). Treatment of akinetic-rigid conditions such as parkinsonism typically involves the use of levodopa, anticholinergics or dopamine agonists. Levodopa is converted into dopamine in the brain by the enzyme dopa decarboxylase. However, this enzyme is also present in the gut wall, liver, kidney and cerebral capillaries, thus the peripheral formation of levodopa metabolites may give rise to side-effects such as nausea, vomiting, cardiac dysrhythmias and postural hypotension. This peripheral decarboxylation is largely prevented by the addition of a selective extracerebral decarboxylase inhibitor, such as carbidopa or benserazide, which themselves do not penetrate the brain. Levodopa combined with carbidopa (SINEMET ™ ) or benserazide (MADOPAR ™ ) is now the treatment of choice when levodopa is indicated. Even then, this combination therapy may be associated with side-effects such as dyskinesias and psychiatric disturbances. An anticholinergic such as benzhexol or orphenadrine may be used, however, anticholinergics cause peripheral parasympathetic blockade which may cause dry mouth, blurred vision and constipation, and they may also precipitate glaucoma, urinary retention and a toxic confusional state. Dopamine agonists such as bromocriptine (PARLODEL ™ ), lisuride and pergolide (CELANCE ) act directly on dopamine receptors and have a similar side-effect profile to levodopa. The dyskinesias, notably tremor, chorea, myoclonus, tics and dystonias, are treated with a variety of pharmacological agents. Thus, for example, tremor may be treated with benzodiazepines such as diazepam; chorea may be treated with diazepam, a phenothiazide or haloperidol, or tetrabenazine; tics may be controlled with neuroleptics such as haloperidol or pimozide; and dystonias tend to be treated with levodopa, benzodiazepines such as diazepam, anticholinergics such as benzhexol, phenothiazines and other neuroleptics such as haloperidol, and tetrabenazine. Treatment of psychotic disorders with neuroleptic agents, such as haloperidol may be at the expense of a number of side-effects, including extrapyramidal symptoms, acute dystonias, tardive dyskinesias, akathesia, tremor, tachycardia, drowsiness, confusion, postural hypotension, blurring of vision, precipitation of glaucoma, dry mouth, constipation, urinary hesitance and impaired sexual function. 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 (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 selective serotonin reuptake inhibitor (SSRI). NK-1 receptor antagonists are described in published European Patent Specification Nos. 0 360 390, 0 394 989, 0 429 366, 0 443 132, 0 482 539, 0 512 901, 0 512 902, 0 514 273, 0 514 275, 0 517 589, 0 520 555, 0 522 808, 0 528 495, 0 532 456, 0 533 280, 0 536 817, 0 545 478, 0 577 394, 0 590 152, 0 599 538, 0 610 793, 0 634 402, 0 686 629, 0 693 489, 0 694 535, 0 699 655, 0 699 674, 0 707 006, 0 708 101, 0 714 891, 0 723 959, 0 733 632 and 0 776 893; and in International Patent Specification Nos. 90/05525, 90/05729, 91/09844, 91/18899, 92/01688, 92/06079, 92/12151, 92/15585, 92/17449, 92/20661, 92/20676, 92/21677, 93/00330, 93/00331, 93/01159, 93/01165, 93/01169, 93/01170, 93/06099, 93/09116, 93/10073, 93/14113, 93/18023, 93/19064, 93/21155, 9321181, 93/23380, 93/24465, 94/01402, 94/02461, 94/03429, 94/03445, 94/04494, 94/04496, 94/05625, 94/07843, 94/10165, 94/10167, 94/10168, 94/10170, 94/11368, 94/13639, 94/13663, 94/14767, 94/15903, 94/19320, 94/19323, 94/20500, 94/26735, 94/26740, 94/29309, 95/02595, 95/04040, 95/04042, 95/06645, 95/07886, 95/07908, 95/08549, 95/11880, 95/14017, 95/15311, 95/16679, 95/17382, 95/18124, 95/18129, 95/19344, 95/20575, 95/21819, 96/22525, 95/23798, 95/26338, 95/28418, 95/30674, 95/30687, 96/05193, 96/05203, 96/06094, 96/07649, 96/10562, 96/16939, 96/18643, 96/20197, 96/21661, 96/29304, 96/29317, 96/29326, 96/29328, 96/31214, 96/32385, 96/37489, 97/01553, 97/01554, 97/03066, 97/08144, 97/14671, 97/17362, 97/18206, 97/19084, 97/19942 and 97/21702; and in British Patent Specification Nos. 2 266 529, 2 268 931, 2 269 170, 2 269 590, 2 271 774, 2 292 144, 2 293 168, 2 293 169, and 2 302 689. In view of the short-comings of existing therapy, there is a need for new, safe and effective treatment for movement disorders. The present invention provides the use of a CNS penetrant NK-1 receptor antagonist in an oral medicament for the treatment of movement disorders. The compounds of this class advantageously exhibit a rapid onset of action and a reduced side-effect profile when compared against conventional agents used for the treatment of extrapyramidal movement disorders and other types of movement disorders (e.g. idiopathic Parkinson's disease, secondary Parkinson's disease, Huntingdon's disease, dystonia, chorea, tics, myoclonus and athetosis). In particular, the present invention provides a means for the identification of NK-1 receptor antagonists which would be effective in an oral medicament for the treatment of movement disorders with or without combination with conventional agents currently in use. The aforementioned patent specifications which describe NK-1 receptor antagonists provide no reliable method for the identification of such compounds. The exceptional pharmacology of the class of NK-1 receptor antagonists of use in the present invention enables the treatment of movement disorders, without the need for concomitant therapy. Furthermore, the exceptional pharmacology of the class of NK-1 receptor antagonists of use in the present invention results in a rapid onset of action. The present invention accordingly provides the use of an orally active, long acting, CNS-penetrant NK-1 receptor antagonist (as hereinafter defined) for the manufacture of a medicament adapted for oral administration for the treatment or prevention of movement disorders. The present invention also provides a method for the treatment or prevention of movement disorders, which method comprises the oral administration to a patient in need of such treatment of an effective amount of an orally active, long acting, CNS-penetrant NK-1 receptor antagonist (as hereinafter defined). In a further aspect of the present invention, there is provided an oral pharmaceutical composition for the treatment of movement disorders which comprises an orally active, long acting, CNS-penetrant NK-1 receptor antagonist (as hereinafter defined), together with a pharmaceutically acceptable carrier or excipient. There exists a patient population in whom dyskinesias are inadequately treated with existing neuroleptic therapy. Furthermore, some patients may be adversely affected by the side-effects of neuroleptic drugs. The present invention accordingly provides the use of an orally active, long acting, CNS-penetrant NK-1 receptor antagonist for the manufacture of a medicament adapted for oral administration for the treatment or prevention of dyskinesias in a patient who is non-responsive to neuroleptic agents, or for whom neuroleptic agents are contraindicated. The present invention also provides a method for the treatment or prevention of dyskinesias in a patient who is non-responsive to neuroleptic agents, or for whom neuroleptic agents are contraindicated, which method comprises oral administration to the patient in need of such treatment of an effective amount of an orally active, long acting, CNS-penetrant NK-1 receptor antagonist. Whilst it is envisaged that an orally active, long acting, CNS- penetrant NK-1 receptor antagonist will be useful alone in the treatment of movement disorders, it will be appreciated that a combination of a conventional antiparkinsonian drug with a NK-1 receptor antagonist may provide an enhanced effect in the treatment of akinetic-rigid disorders such as parkinsonism. Such a combination may enable a lower dose of the antiparkinsonian agent to be used without compromising the efficacy of the antiparkinsonian agent, thereby minimising the risk of adverse side- effects. Thus, according to a further aspect of the present invention there is provided the use of a NK-1 receptor antagonist and an antiparkinsonian agent for the manufacture of a medicament for the treatment or prevention of akinetic-rigid disorders. The present invention also provides a method for the treatment or prevention of akinetic-rigid disorders, which method comprises administration to a patient in need of such treatment of an amount of a NK-1 receptor antagonist and an amount of an antiparkinsonian agent, such that together they give effective relief. In a further aspect of the present invention, there is provided a pharmaceutical composition comprising a NK-1 receptor antagonist and an antiparkinsonian agent, together with at least one pharmaceutically acceptable carrier or excipient. It will be appreciated that the NK-1 receptor antagonist and the antiparkinsonian agent may be present as a combined preparation for simultaneous, separate or sequential use for the treatment or prevention of akinetic-rigid disorders. Such combined preparations may be, for example, in the form of a twin pack. In a further or alternative aspect of the present invention, there is therefore provided a product comprising a NK-1 receptor antagonist and an antiparkinsonian agent as a combined preparation for simultaneous, separate or sequential use in the treatment or prevention of akinetic-rigid disorders. It will be further appreciated that a combination of a conventional neuroleptic drug with a NK-1 receptor antagonist may provide an enhanced effect in the treatment of dyskinesias. Such a combination may enable a lower dose of the neuroleptic agent to be used without compromising the efficacy of the neuroleptic agent, thereby minimising the risk of adverse side-effects. A yet further advantage of such a combination is that, due to the action of the NK-1 receptor antagonist, adverse side- effects caused by the neuroleptic agent such as acute dystonias, dyskinesias, akathesia and tremor may be reduced or prevented. Thus, according to a further aspect of the present invention there is provided the use of a NK-1 receptor antagonist and a neuroleptic agent for the manufacture of a medicament for the treatment or prevention of dyskinesias. The present invention also provides a method for the treatment or prevention of dyskinesias, which method comprises administration to a patient in need of such treatment of an amount of a NK-1 receptor antagonist and an amount of a neuroleptic agent, such that together they give effective relief. In a further aspect of the present invention, there is provided a pharmaceutical composition comprising a NK-1 receptor antagonist and a neuroleptic agent, together with at least one pharmaceutically acceptable carrier or excipient. It will be appreciated that the NK-1 receptor antagonist and the neuroleptic agent may be present as a combined preparation for simultaneous, separate or sequential use for the treatment or prevention of dyskinesias. Such combined preparations may be, for example, in the form of a twin pack. In a further or alternative aspect of the present invention, there is therefore provided a product comprising a NK-1 receptor antagonist and an neuroleptic agent as a combined preparation for simultaneous, separate or sequential use in the treatment or prevention of dyskinesias. It will be appreciated that when using a combination of the present invention, the NK-1 receptor antagonist and the antiparkinsonian or neuroleptic agent may be in the same pharmaceutically acceptable carrier and therefore administered simultaneously. They may be in separate pharmaceutical carriers such as conventional oral dosage forms which are taken simultaneously. The term "combination" also refers to the case where the compounds are provided in separate dosage forms and are administered sequentially. Therefore, by way of example, the antiparkinsonian or neuroleptic agent may be administered as a tablet and then, within a reasonable period of time, the NK-1 receptor antagonist may be administered either as an oral dosage form such as a tablet or a fast-dissolving oral dosage form. By a "fast-dissolving oral formulation" is meant, an oral delivery form which when placed on the tongue of a patient, dissolves within about 10 seconds. As used herein, the term "movement disorders" includes akinesias and akinetic-rigid syndromes, dyskinesias and medication-induced parkinsonism (such as neuroleptic-induced parkinsonism, neuroleptic malignant syndrome, neuroleptic-induced acute dystonia, neuroleptic- induced acute akathisia, neuroleptic-induced tardive dyskinesia and medication-induced postural tremor). Examples of "akinetic-rigid syndromes" include Parkinson's disease, drug-induced parkinsonism, postencephalitic parkinsonism, progressive supranuclear palsy, multiple system atrophy, corticobasal degeneration, parkinsonism-ALS dementia complex and basal ganglia calcification. Examples of "dyskinesias" include tremor (including rest tremor, postural tremor and intention tremor), chorea (such as Sydenham's chorea, Huntington's disease, benign hereditary chorea, neuroacanthocytosis, symptomatic chorea, drug- induced chorea and hemiballism), myoclonus (including generalised myoclonus and focal myoclonus), tics (including simple tics, complex tics and symptomatic tics), and dystonia (including generalised dystonia such as iodiopathic dystonia, drug-induced dystonia, symptomatic dystonia and paroxymal dystonia, and focal dystonia such as blepharospasm, oromandibular dystonia, spasmodic dysphonia, spasmodic torticollis, axial dystonia, dystonic writer's cramp and hemiplegic dystonia). Another "movement disorder" which may be treated according to the present invention is Gilles de la Tourette's syndrome, and the symptoms thereof. As used herein, the term "treatment" refers both to the treatment and to the prevention or prophylactic therapy of the aforementioned conditions. Preferred NK-1 receptor antagonists for use in the present invention are selected from the classes of compounds described in European Patent Specification No. 0 577 394, and International Patent Specification Nos. 95/08549, 95/18124, 95/23798 and 96/05181, and International Patent Application No. PCT/GB97/01630. The preparation of such compounds is fully described in the aforementioned publications. Particularly preferred NK-1 receptor antagonists of use in the present invention include: 2-(S)-(3,5-bιs(trifluoromethyl)benzyloxy)-3(S)-(4-fluorophenyl)-4-(3-(5-oxo- lH,4H-l,2,4-triazolo)methyl)morpholine; 2-(R)-(l-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(3-(5-oxo-lH,4H- l,2,4-triazolo)methyl)-3-(S)-phenyl-morpholine; 2-(S)-(3,5-bιs(trifluoromethyl)benzyloxy)-4-(3-(5-oxo-lH,4H-l,2,4- triazolo)methyl)-3-(S)-phenyl-morpholine; 2-(R)-(l-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)- 4-(3-(5-oxo-lH,4H-l,2,4-triazolo)methyl)morpholine; 2-(R)-(l-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(5-(N,N- dimethylamino)methyl-l, 2, 3-triazol-4-yl)methyl-3-(S)-phenylmorp holine; 2-(R)-(l-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(5-(N,N- dimethylamino)methyl-l,2,3-triazol-4-yl)methyl-3-(S)-(4- fluorophenyl)morpholine; 2-(R)-(l-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)- 4-(3-(4-monophosphoryl-5-oxo-lH-l,2,4-triazolo)methyl)morpholine; 2-(R)-(l-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)- 4-(3-(l-monophosphoryl-5-oxo-lH-l, 2, 4-triazolo)methyl)morp holine; 2-(R)-(l-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)- 4-(3-(2-monophosphoryl-5-oxo-lH-l,2,4-triazolo)methyl)morpholine; 2-(R)-(l-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)- 4-(3-(5-oxyphosphoryl-lH-l,2,4-triazolo)methyl)morpholine; 2-(S)-(l-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)- 4-(3-(l-monophosphoryl-5-oxo-4H-l,2,4-triazolo)methyl)morpholine; 2-(R)-(l-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(4-N,N- dimethylaminobut-2-yn-yl)-3-(S)-(4-fluorophenyl)morpholine; (3S,5R,6S)-3-[2-cyclopropoxy-5-(trifluoromethoxy)phenyl]-6-phenyl-l-oxa- 7-aza-spiro[4.5]decane; (3R,5R,6S)-3-[2-cyclopropoxy-5-(trifluoromethoxy)phenyl]-6-phenyl-l-oxa- 7-aza-spiro[4.5]decane; or a pharmaceutically acceptable salt thereof. Full descriptions of the preparation of the NK-1 receptor antagonists which may be employed in the present invention may be found in the references cited herein. Suitable antiparkinsonian agents of use in combination with a NK-1 receptor antagonist include levodopa (with or without a selective extracerebral decarboxylase inhibitor such as carbidopa or benserazide), anticholinergics such as biperiden (optionally as its hydrochloride or lactate salt) and trihexyphenidyl (benzhexol) hydrochloride, and dopamine agonists such as alentemol, bromocriptine, fenoldopam, lisuride, naxagoHde, pergolide and pramipexole. It will be appreciated that the dopamine agonist may be in the form of a pharmaceutically acceptable salt, for example, alentemol hydrobromide, bromocriptine mesylate, fenoldopam mesylate, naxagolide hydrochloride and pergolide mesylate. Lisuride and pramipexol are commonly used in a non-salt form. Suitable neuroleptic agents of use in combination with a NK-1 receptor antagonist include the phenothiazine, thioxanthene, heterocyclic dibenzazepine, butyrophenone, diphenylbutylpiperidine and indolone classes of neuroleptic agent. Suitable examples of phenothiazines include chlorpromazine, mesoridazine, thioridazine, acetophenazine, fluphenazine, perphenazine and trifluoperazine. Suitable examples of thioxanthenes include chlorprothixene and thiothixene. An example of a dibenzazepine is clozapine. An example of a butyrophenone is haloperidol. An example of a diphenylbutylpiperidine is pimozide. An example of an indolone is molindolone. Other neuroleptic agents include loxapine, sulpiride and risperidone. It will be appreciated that the neuroleptic agents when used in combination with a NK-1 receptor antagonist may be in the form of a pharmaceutically acceptable salt, for example, chlorpromazine hydrochloride, mesoridazine besylate, thioridazine hydrochloride, acetophenazine maleate, fluphenazine hydrochloride, flurphenazine enathate, fluphenazine decanoate, trifluoperazine hydrochloride, thiothixene hydrochloride, haloperidol decanoate, loxapine succinate and molindone hydrochloride. Perphenazine, chlorprothixene, clozapine, haloperidol, pimozide and risperidone are commonly used in a non-salt form. Suitable pharmaceutically acceptable salts of the NK-1 receptor antagonists 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. Where the compound carries an acidic group, for example a carboxylic acid group, the present invention also contemplates salts thereof, preferably non-toxic pharmaceutically acceptable salts thereof, such as the sodium, potassium and calcium salts thereof. Suitable pharmaceutically acceptable salts of the antiparkinsonian and neuroleptic agents used in combination with a NK-1 receptor antagonist according to the present invention include those salts described above in relation to the salts of NK-1 receptor antagonists. Preferably the compositions containing an 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 antagonists 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 antagonists 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 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 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 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.- For example, 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. 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 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. The present invention further provides a process for the preparation of a pharmaceutical composition comprising a NK-1 receptor antagonist and an antipsychotic agent, which process comprises bringing a NK-1 receptor antagonist and an antipsychotic agent, into association with a pharmaceutically acceptable carrier or excipient. When administered in combination, either as a single or as separate pharmaceutical composition(s), the NK-1 receptor antagonist and an antipsychotic agent are presented in a ratio which is consistent with the manifestation of the desired effect. In particular, the ratio by weight of the NK-1 receptor antagonist and the antipsychotic agent will suitably be between 0.001 to 1 and 1000 to 1, and especially between 0.01 to 1 and 100 to 1. 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 one to three times daily, preferably once or twice a day, and especially once a day. A minimum dosage level for the antiparkinsonian agent will vary depending upon the choice of agent, but is typically about 0.05mg per day for the most potent compounds or about 20mg per day for less potent compounds. A maximum dosage level for the antipsychotic agent is typically 30mg per day for the most potent compounds or 500mg per day for less potent compounds. The compounds are administered one to three times daily, preferably once or twice a day, and especially once a day. A minimum dosage level for the neuroleptic agent will vary depending upon the choice of agent, but is typically about 0.5mg per day for the most potent compounds or about 20mg per day for less potent compounds. A maximum dosage level for the neuroleptic agent is typically 30mg per day for the most potent compounds or 200mg per day for less potent compounds. The compounds are administered one to three times daily, preferably once or twice a day, and especially 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 movement diosrders 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. When used in combination, it will be appreciated that the amount of the NK-1 receptor antagonist and the antiparkinsonian or neuroleptic agent required for use in the treatment or prevention of movement 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. Two compounds of use in the present invention which are described in International Patent Application No. PCT/GB97/01630 may be prepared according to the following methods: PREPARATION 1 (2-S r )-l-ter^-Butoxycarbonyl-2-phenylpiperidin-3-one Dimethyl sulfoxide (20.80ml, 22.90g, 29.3mmol) in dichloromethane (75ml) was added dropwise to a cooled (-70°C) solution of oxalyl chloride (13.95ml, 20.30g, 160mmol) in dichloromethane (350ml). The mixture was stirred at -70°C for 15 minutes, then (25,35)- l-ter/:-butoxycarbonyl-3- hydroxy-2-phenylpiperidine (prepared by the method described in European Patent Specification number 0 528 495-A; 36.91g, 133mmol) in dichloromethane (150ml) was added dropwise. The mixture was stirred at -70 °C for 20 minutes, then allowed to warm to -30°C. The mixture was cooled to -50 °C and triethylamine (55.95ml, 40.45g, 400mmol) was added slowly. The mixture was allowed to warm to 0°C and diluted with ice- cooled dichloromethane (250ml). The mixture was washed with ice cold aqueous citric acid solution (5%, 2x300ml) and water (300ml), dried (MgSO ), and the solvent was evaporated under reduced pressure to give the title compound as a yellow oil (42.3g), which was used immediately without further purification. Η NMR (250MHz, CDCI3) δ 7.5-7.3 (5H, m), 5.8 (IH, br s), 4.2 (IH, br s), 3.4 (IH, m), 2.6 (2H, m), 2.0 (2H, m), and 1.54 (9H, s). PREPARATION 2 (2S,3 -l-fer£-Butoxycarbonyl-3-hvdroxy-3-(2-methylene-3- phenoxypropyl)-2-phenylpiperidine A solution of 3-(chloromagnesio)-2-(phenoxymethyl)-l-propene in THF (0.91M, 3ml) (Louw et. al, Tetrahedron, 48, 6087-6104, 1992, prepared from 2.74mmol of 3-chloro-2-(phenoxymethyl)-l-propene) was slowly added to a solution of (2S)-l-ferf-butoxycarbonyl-2-phenylpiperidin- 3-one (Preparation 1) in THF (3ml). The mixture was stirred at room temperature for 1 hours, then saturated aqueous ammonium chloride (20ml) was added and the mixture was extracted with ethyl acetate (20ml). The organic phase was washed with brine, dried (MgSO 4 ) and the solvent was evaporated under reduced pressure . The residue was purified by column chromatography on silica gel, eluting with hexane/ethyl acetate (100:0 increasing to 80:20) to give the title compound. *H NMR (360MHz, CDCls) δ 7.48 (2H, d, =6.9 Hz), 7.35-7.2 (6H, m), 6.9-6.88 (3H, m), 5.4 (IH, s), 5.15 (2H, d, =13.7 Hz), 4.61 (2H, s), 4.11 (2H, m), 3.17 (IH, m), 2.66 and 2.59 (2H, AB d, =14.0 Hz), 1.95 (2H, m), 1.79 (2H, m), and 1.36 (9H, s). m/z (ES + ) 424 (M+l). PREPARATION 3 (5i?.65 r )-3-Methylene-6-phenyl-l-oxa-7-(ter^-butoxycarbonyl)aza- spiro[4.51decane To a cooled(-80 °C) solution of (2S,3i2)-l-tert-butoxycarbonyl-3- hydroxy-3-(2-methylene-3-phenoxypropyl)-2-phenylpiperidine (Preparation 2, 1.53g, 3.62mmol) in THF (20ml) was added n-butyl lithium (2.5M in hexanes, 1.45ml, 3.62mmol) followed by a solution of zinc chloride (0.5M in THF, 7.24ml, 3.62mmol). The solution was allowed to warm to room temperature and tetrakis(triphenylphosphine)palladium (0) (0.23g, 0.2mmol) was added. The mixture was degassed with bubbling nitrogen and heated under reflux for 16 hours. The mixture was cooled and the solvent was evaporated under reduced pressure. The residue was partitioned between ethyl acetate and 2M sodium hydroxide. The organic phase was washed with saturated brine, dried (MgSO 4 ) and purified by chromatography on a column containing silica gel (eluting with hexane containing increasing proportions of ethyl acetate between 0% to 5%). Evaporation of the fractions gave (6S,5R)-3-methylene-6-phenyl-l-oxa-7- (tert-butoxycarbonyl)aza-spiro[4.5]decane. Η NMR (360MHz, CDCI 3 ) δ 7.58 (2H, d, =8.4 Hz), 7.32-7.21 (3H, m), 5.23 (IH, s), 5.06 (IH, m), 4.97 (IH, m), 4.39 (2H, AB d, =13.3 Hz), 3.99 (IH, dd, =13.3, 4.48 Hz), 2. 83 (IH, ABd =lo.5 Hz), 2.7 (lH.td J=12.5, 3.93 Hz), 2.5 (IH, ABd, J=15Λ Hz), 2.15 (2H, td, J=12., .4 Hz), 1.69 (2H, m), and 1.46 (9H,s). m/z (ES + ) 329 (M+2H- t BuOCO). PREPARATION 4 (5R..65 r )-3-Keto-6-phenyl-l-oxa-7-(ter^-butoxycarbonyl)aza-spiro[4.51decane Through a cooled (-80 °C) solution of (5i?,6S)-3-methylene-6-phenyl- 5 l-oxa-7-(£eri-butoxycarbonyl)aza-spiro[4.δ]decane (Preparation 3; 0.665g) in dichloromethane (δml) and methanol (δml) was bubbled a mixture of ozone and oxygen for 4δ minutes. After the solution had been purged with nitrogen, dimethyl sulphide (O.δml) was added and then stirred under nitrogen at room temperature for 16 hours. The solvent was removed in 0 υacuo and the residue partitioned between ethyl acetate and water. The organic phase was dried (MgSO ), evaporated and the residue purified by chromatography on a column containing silica gel (eluting with hexane containing increasing proportions of ethyl acetate between 0% to 10%). Evaporation of the fractions gave the title compound. Η NMR (250MHz, 5 CDC1 3 ) δ 7.δ8 (2H, d, =6.2 Hz), 7.37-7.26 (3H, m), 5.3 (IH, s), 4.15 and 4.09 (2H, AB d, =17.4 Hz), 3.97 (IH, m), 2.80 (IH, td, =12.9, 4.0 Hz), 2.74 and 2.48 (2H, ABd, =18.1 Hz), 2.29 (2H, m), 1.88-1.63 (2H, m), and 1.44 (9H, s). m/z (ES + ) 332 (M+l). 0 PREPARATION 5 (5J?,65 r )-3-Trifluoromethylsulfonyloxy-6-phenyl-l-oxa-7-(^βr - butoxycarbonyl)aza-spiro[4.δldec-3-ene To a cooled (-80 °C) solution of IM sodium hexamethyldisilazide (0.38ml, 0.38mmol) in THF was added a solution of (δi?,6S)-3-keto-6- δ phenyl-l-oxa-7-(ter^-butoxycarbonyl)aza-spiro[4.δ]decane (Preparation 4; O.lOδmg, 0.319mmol) in THF (3ml). The solution was stirred for 1 hours at -80°C then a solution of 2-[N,N-bis(trifluoromethylsulfonyl)amino]-δ- chloropyridine (0.163g, 0.41δmmol) in THF (3ml) was added. The solution was stirred at -80°C for 30 minutes then at room temperature for 30 0 minutes before being quenched by addition of saturated ammonium chloride solution and ethyl acetate. The dried (MgSO 4 ) organic phase was purified by chromatography on a column containing silica gel (eluting with hexane containing increasing proportions of ethyl acetate between 0% to 5%). Evaporation of the fractions gave the title compound. Η NMR (360MHz, CDCls) δ 7.4 (2H, d, =7.3 Hz), 7.3-7.22 (3H, m), 6.01 (IH, t, 5 =2.13 Hz), 5.13 (IH, s), 4.56 and 4.26 (2H, ABdd, =12.4, 1.97 Hz),4.10 (IH, dt, J=12.6, 4.22 Hz), 3.00 (IH, m), 2.28-2.04 (2H, m), 1.88-1.76 (2H, m), and 1.37 (9H, s). m/z (ES + ) 464 (M+l). PREPARATION 6 10 (δi?.6g)-3-Trimethylstannyl-6-phenyl-l-oxa-7-(Zer^-butoxycarbonyl)aza- spiro[4.51dec-3-ene To a degassed solution of (5R.,6S)-3-trifluoromethylsulfonyloxy-6- phenyl-l-oxa-7-(ieri-butoxycarbonyl)aza-spiro[4.δ]dec-3-ene (Preparation δ; 0.482g, 1.04mmol), lithium chloride (0.264g, 6.2δmmol), lithium lδ carbonate (0.076g) and hexamethyl distannane(0.96g, 2.9mmol) in THF (10ml) was added triphenylphosphine palladium (0) (0.06g). The solution was degassed and then heated at 60°C for δ hours under nitrogen. Water (20ml) and ethyl acetate (20ml) were added and the dried organic phase was purified by chromatography on a column containing silica gel (eluting 20 with hexane containing increasing proportions of ethyl acetate between 0% to δ%). Evaporation of the fractions gave the title compound as a crystalline solid. W NMR (360MHz, CDCI3) δ 7.2δ (2H, d, =7.3 Hz), 7.1- 7.0 (3H, m), δ.83 (IH, t, =2.δ Hz), 4.78 (IH, s), 4.48 and4.02 (2H, dd, J=12.9, 2.3 Hz), 3.96 (IH, dd, =6.16, 13.4 Hz), 2.9δ (IH, td, =13.3, 4.5 5 Hz), 1.84 (IH, m), 1.68 (IH, m), 1.60 (2H, m), 1.19 (9H, s), and 0.0 (6H, s). PREPARATION 7 (2g,3i?)-l-ter^-Butoxycarbonyl-3-(3-hvdroxy p ro p yn-l-yl)-2-phenylpiperidin- 3-ol 0 O-Trimethylsilylpropargyl alcohol (24.51ml, 20.47g, 160ml) was added slowly to a cooled (-10°C) solution of ethylmagnesium bromide (IM in tetrahydrofuran, 160ml, 160mmol). The mixture was stirred at 0°C for 20 minutes, then at room temperature for 2 hours. The mixture was cooled to -10°C and a solution of (2»S)-l-ter£-butoxycarbonyl-2- phenylpiperidin-3-one (Preparation 1; 42.3g) in tetrahydrofuran (200ml) δ was added dropwise over 30 minutes. (Internal temperature below -5°C). The mixture was stirred at room temperature for 14 hours, poured into water (300ml) and saturated aqueous ammonium chloride (300ml) and extracted with ethyl acetate (2x300ml). The combined organic fractions were washed with brine (300ml), dried (MgSO 4 ) and the solvent was 10 evaporated under reduced pressure. The residue was dissolved in ethyl acetate (δOOml) and a solution of tetrabutylammonium fluoride (IM in THF, 160ml, 160mmol) was added dropwise. The mixture was stirred at room temperature for 30 minutes, water (300ml) was added, and the layers were separated. The aqueous layer was extracted with ethyl lδ acetate (2x300ml) and the combined organic fractions were washed with water (300ml) and brine (300ml), dried (MgSO ) and the solvent was evaporated under reduced pressure to give the crude title compound as an orange oil (4δg). The crude material was purified by flash column chromatography on silica gel, eluting with hexane/ethyl acetate (90:10 0 increasing to 2δ:7δ) to give the title compound as an amber oil (32.2g). Η NMR (CDCla) δ 7.δ3-7.δδ (2H, m), 7.19-7.35 (3H, m), 5.δ6 (IH, s), 4.27 (2H, s), 3.99-4.03 (IH, m), 3.2δ (IH, br s), 2.77-2.81 (IH, m), 2.77 (IH, br s), 2.12-2.20 (IH, m), 1.91-1.99 (2H, m), 1.77-1.83 (IH, m), and 1.39 (9H, s). δ PREPARATION 8 2-Bromo-4-(trifluoromethoxy)phenol To a cooled (0 °C) solution of 4-trifluoromethoxyphenol (3δ.6g, 0.2mol) in chloroform (280ml) was added dropwise a solution of bromine (32g, 0.2mol) in chloroform (δOml). The solution was stirred at 0°C for 1 0 hour and at room temperature for 2 hours. Dichloromethane (200ml) and water (400ml) ware added and the organic phase was washed further with water(400ml), brine (200ml) and dried (MgSO ). The solvent was removed and the residue was purified by distillation at reduced pressure to give the title compound. Η NMR (2δOMHz, CDC1 3 ) δ 7.38 (1H, d, =2.1 Hz), 7.13 (IH, dd, =9.1, 2.1 Hz), 7.03 (IH, d, =9.1 Hz), and δ.δ3 (IH, s). δ PREPARATION 9 2-Benzyloxy-δ-(trifluoromethoxy)bromobenzene 2-Bromo-4-(trifluoromethoxy)phenol (Preparation 8; δg, 20mmol) was dissolved in N,N-dimethylformamide (60ml), and potassium carbonate 10 (5.4g, 40mmol) was added, followed by benzyl bromide (3.5ml, 30mmol), and the reaction was stirred at ambient temperature for 15 hours. The reaction was diluted with water (150ml) and extracted into ethyl acetate (3x60ml). The combined organic fractions were washed with water (100ml), brine (100ml), dried (MgSO ) and evaporated in vacuo. lδ Purification on silica, eluting with 2% and δ% ethyl acetate in hexane gave the title compound as a clear oil (6.7g, 96%). NMR (2δ0MHz, CDCI3) δ δ.47 (2H, s), 7.23 (IH, d, J=9 Hz), 7.43 (IH, dd J=8.2, 2.9 Hz), and 7.7δ (6H, m). 20 PREPARATION 10 -(2g , .3R)-l-^e^-Butoxycarbonyl-3-(3-hvdroxyρrop-l-en-l-yl)-2- phenylpiperidin-3-ol Palladium on calcium carbonate, poisoned with lead (Lindlar δ catalyst, 2g) was added to a solution of (2<S,3R)-l-ter£-butoxycarbonyl-3-(3- hydroxypropyn-lyl)-2-phenylpiperidin-3-ol (Preparation 7; 32g, 96.6mmol) in ethyl acetate (300ml) and the mixture was stirred under hydrogen (1 atmosphere) for 4 hours. The mixture was filtered and the solvent was evaporated under reduced pressure to give the title compound as an oil 0 (32g, 100%). i H NMR (360MHz, CDCI3) δ 7.42 (2H, d, J=1.6 Hz), 7.3δ-7.2δ (3H, m), δ.83 (IH, d, 12.3 Hz), 5.68 (IH, dt, =12.3, 6.0 Hz), 5.06 (IH, s), 4.27 (IH, m), 4.12 (2H, m), 3.32 (IH, m), 3.13 (IH, s), 2.28 (IH, t, =δ.9 Hz), 2.02 (IH, m), 1.92-1.78 (3H, m), and 1.32 (9H, s). m/z (ES + ) 334 (M+l). PREPARATION 11 δ (δ J R.6S r )-6-Phenyl-l-oxa-7-(terit-butoxycarbonyl)aza-spiro[4.δ1dec-3-ene Diethylazodicarboxylate (18.2ml, llδmmol) in THF (100ml) was added dropwise to a solution of -(2S,3i?)-l-ierf-butoxycarbonyl-3-(3- hydroxyprop-l-en-l-yl)-2-phenylpiperidin-3-ol (Preparation 10; 32g, 96mmol) and triphenylphosphine (30.2g, llδmmol) in THF (700ml). The 10 mixture was stirred at 0°C for 30 minutes then at room temperature for 1.5 hours. The solvent was evaporated under reduced pressure and the residue was purified by flash column chromatography on silica gel, eluting with hexane/ethyl acetate (95:5 increasing to 80:20) to give the title compound as a colorless solid (23.4g, 77%). Η NMR (CDC1 3 ) δ 7.45 (2H, d, lδ =7.4 Hz), 7.27 (2H, t, J=1Λ Hz), 7.20 (IH, t, =7.4 Hz), 6.03 (IH, dt, J=6.1, 2.0 Hz), δ.68 (IH, dt, J=6.1, 2.0 Hz), δ.06 (IH, s), 4.61 (IH, dt, =13.1, 2.0 Hz), 4.32 (IH, dt, =13.1, 2.0 Hz), 4.08 (IH, m), 3.0δ (IH, m), 2.0δ (IH, m), 1.75 (3H, m), and 1.37 (9H, s). m/z (ES + ) 316 (M+l). 20 PREPARATION 12 2-Benzyloxy-5-(trifluoromethoxy)benzene Benzyl bromide (66.17ml, 9δ.3δg, 0.56mol) was added to a mixture of 4-(trifluoromethoxy)phenol (90.26g, O.δlmol) and potassium carbonate (140.97g, 1.2mol) in dimethylformamide (160ml) and the mixture was 2δ stirred at room temperature for 72 hours. The mixture was poured into water (1.5 1) and extracted with ethyl acetate (3x500ml). The combined organic fractions were washed with aqueous sodium carbonate (saturated, δOOml), dried (MgSO 4 ) and the solvent was evaporated under reduced pressure to give the title compound as a colorless solid (133. δg, 99%). H 30 NMR (360MHz, CDCI3) δ 7.39 (5H, m), 7.14 (2H, d, J=9.0 Hz), 6.9δ (2H, d, =9.0 Hz), and δ.Oδ (2H, s). PREPARATION 13 2-Benzyloxy-δ-(trifluoromethoxy)iodobenzene Iodine (71.96g, 0.28mol) in chloroform was added dropwise to a δ mixture of 2-benzyloxy-δ-(trifluoromethoxy)benzene (Preparation 12, 73.06g, 0.27mol) and silver trifluoro acetate (71.δ7g, 0.32mol) in dichloromethane and the mixture was stirred at room temperature for 18 hours. The mixture was filtered through celite, washed with aqueous sodium thiosulfate (δ%, 2x2 1), dried (MgSO ) and the solvent was 10 evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with hexane/ethyl acetate, to give the title compound as a colorless oil (108.03g), containing 11% unreacted 2-benzyloxy-δ-(trifluoromethoxy)iodobenzene. Η NMR (360MHz, CDCls) δ 7.67 (IH, d, =2.8 Hz), 7.40 (δH, m), 7.16 (IH, dd, lδ =8.9, 2.8 Hz), 6.82 (IH, d, =8.9 Hz), and δ.14 (2H, s). PREPARATION 14 (δi?,65)-3-(2-Benzyloxy-δ-(trifluoromethoxy)phenyl)-6-phenyl-l-oxa-7-(^er^ butoxycarbonyl)aza-spiror4.δldec-3-ene 20 (δi?,6S)-3-Trimethylstannyl-6-phenyl-l-oxa-7-(ieri- butoxycarbonyl)aza-spiro[4.δ]dec-3-ene (Preparation 6; 6.43mmol), lithium chloride (0.163g), benzyloxy-δ-(trifluoromethoxy)phenol (Preparation 9; 7.7mmol) in toluene (2δml) was degassed before addition of triphenylphosphine palladium (0) (0.37g). The solution was degassed δ thoroughly before heating to 110°C for 14 hours. The solution was partitioned between water and ethyl acetate and the dried organic phase was purified by chromatography on a column containing silica gel (eluting with hexane containing increasing proportions of ethyl acetate between 0% to 4%) to give the title compound. J H NMR (360MHz, CDCI3) δ 1.33 (9H, 0 s), 1.65 (IH, m), 1.76 (2H, m), 2.08 (IH, m), 3.11 (IH, m), 4.08 (IH, m), 4.60 (IH, dd, J=12.2 Hz, J=2 Hz), 4.92 (IH, dd, J=12.1 Hz, =1.8 Hz), 5.08 (IH, s). δ. l (2H, q, =11.5 Hz), 6.6δ (IH, s), 6.94 (2H, d, J=8.9 Hz), 7.08 (IH, d, J=9 Hz), 7.18 (2H, t, J=8.1 Hz), 7.2δ (3H, m), 7.38 (δH, m). PREPARATION 15 δ (35,δ^.6g)-3-(2-Hvdroxy-δ-(trifluoromethoxy)phenyl)-6-phenyl-l-oxa-7- (ter^-butoxycarbonyl)aza-spiror4.δ1decane (5i?,6S -3-(2-Benzyloxy-δ-(trifluoromethoxy)phenyl)-6-phenyl-l-oxa- 7-(teri-butoxycarbonyl)aza-spiro[4.δ]dec-3-ene (Preparation 14) (3.88g) was dissolved in ethyl acetate (lδml) and methanol (lδml). Palladium 10 hydroxide on carbon (l.OOg) was added and the suspension was shaken under a hydrogen atmosphere (δO psi) for 72 hours. The mixture was filtered and the solvent was evaporated under reduced pressure. The residue was purified by medium pressure chromatography on silica gel, eluting with hexane/ethyl acetate (7δ:2δ) to give (3R,5R,6S)-3-(2-hydroxy- lδ 5-(trifluoromethoxy)phenyl)-6-phenyl-l-oxa- 7-(tert-butoxycarbonyl)aza- spiro[4.5]decane (191mg), Η NMR (2δOMHz, CDCI3) δ 7.70 (2H, d, =7.3 Hz), 7.33 (2H, t, =7.3 Hz), 7.26 (IH, d, =7.3 Hz), 7.0δ (IH, br s), 6.96 (2H, m), 6.82 (IH, d, =9.4 Hz), δ.43 (IH, s), 4.27 (IH, m), 4.01 (IH, m), 3.9δ (IH, m), 3.73 (IH, m), 2.73 (2H, m), 2.33 (IH, m), 1.87-1.68 (4H, m); 0 and l.δO (9H, s).and (3S,5R,6S)-3-(2-hydroxy-5-(trifluoromethoxy)phenyl)- 6-phenyl- 1-oxa- 7-(tert-butoxycarbonyl)aza-spiro[4.5]decane (2.3g), Η NMR (360MHz, CDCI3) δ 1.38 (9H, s), 1.73 (2H, m), 1.81 (IH, m), 2.18 (2H, m), 2.δ0 (IH, m), 2.81 (IH, m), 3.62 (IH, t, =7.2 Hz), 3.92 (IH, m), 3.98 (IH, d, =13.2 Hz), 4.23 (IH, m), δ.33 (IH, s), 6.7δ (IH, d, =8.5 Hz), 6.94 (2H, 5 m), 7.25 (IH, m), 7.31 (2H, m), and 7.5δ (2H, d, =7.8 Hz). PREPARATION 16 (3R.δ .65)-3-(2-Benzyloxy-δ- ( trifluoromethox y ) p henyl -6-phenyl-l-oxa-7- (fer£-butoxycarbonyl)aza-spiro[4.δldecane 0 A mixture of 2-benzyloxy-δ-(trifluoromethoxy)iodobenzene (Preparation 13, 21.8g, δδ.2mmol), (5-R,6S)-6-phenyl-l-oxa-7-(terf- butoxycarbonyl)aza-spiro[4.δ]dec-3-ene (Preparation 11, 7.0g, 22.1mmol), tetra-n-butylammonium chloride (6.18g, 22.2mmol), lithium chloride (9.3δg, 0.22mol) and potassium formate (δ.64g, 67.0mmol) in dimethylformamide (100ml) was degassed with a firestone valve (δ x). δ Palladium acetate (491mg, 2.2mmol) was added and the mixture was degassed with a firestone valve (5 x). The mixture was stirred at 60°C for 15 hours, then further 2-benzyloxy-5-(trifluoromethoxy)iodobenzene (Preparation 13, 4.32g, ll.Ommol), potassium formate (2.78g, 33.δmmol) and palladium acetate (260mg, l.lmmol) were added. The mixture was 10 stirred at 60°C for 22 hours, cooled and filtered. The solvent was evaporated under reduced pressure, water (600ml) was added and the mixture was extracted with ethyl acetate (2x300ml). The combined organic fractions were washed with brine (300ml), dried (MgSO ) and the solvent was evaporated under reduced pressure. The residue was purified lδ by flash column chromatography on silica gel, eluting with hexane/dichloromethane (7δ:25 increasing to 0:100) then dichloromethane/ethyl acetate (95:δ), to give the title compound (9.42g, 73%). i H NMR (360MHz, CDC1 3 ) δ 7.δ6 (2H, d, =7.7 Hz), 7.40-7.20 (8H, m), 7.14 (IH, d, =2.0 Hz), 7.00 (IH, dd, =8.9, 2.0 Hz), 6.88 (IH, d, =8.9 20 Hz), δ.30 (IH, s), δ.08 (2H, s), 4.27 (IH, m), 3.97 (IH, m), 3.87 (2H, m), 2.78 (IH, m), 2.δ6 (IH, m), 2.15 (IH, m), 1.96 (IH, m), 1.67 (3H, m), and 1.42 (9H, s). PREPARATION 17 2δ (37 .δ J R.65 , -3-(2-Hvdroxy-δ- ( trifluoromethoxy phenyl)-6-phenyl-l-oxa-7- ( β -butoxycarbonyl)aza-spiror4.δldecane Palladium on carbon (10%, 0.δ9g) was added to a solution of (3 J R,δi?,6S)-3-(2-benzyloxy-δ-(trifluoromethoxy)phenyl)-6-phenyl-l-oxa-7- (teri-butoxycarbonyl)aza-spiro[4.δ]decane (Preparation 16, 6.10g, 30 lO.δmmol) in methanol-water (99:1, 200ml) and the mixture was stirred under hydrogen (50 psi.) for 72 hours. The mixture was filtered, washing with ethanol, and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with dichloromethane/ethyl acetate (99:1 increasing to 90:10) to give the title compound. Η NMR (360MHz, CDC1 3 ) δ 7.70 (2H, d, =7.3 5 Hz), 7.33 (2H, t, =7.3 Hz), 7.26 (IH, d, =7.3 Hz), 7.0δ (IH, br s), 6.96 (2H, m), 6.82 (IH, d, =9.4 Hz), δ.43 (IH, s), 4.27 (IH, m), 4.01 (IH, m), 3.9δ (IH, m), 3.73 (IH, m), 2.73 (2H, m), 2.33 (IH, m), 1.87-1.58 (4H, m), and 1.50 (9H, s). 10 PREPARATION 18 (35.5i?,65 , )-3-r2-(l-Phenylthiocvcloprop-l-yl)oxy-δ- (trifluoromethoxy)phenyll-6-phenyl-l-oxa-7-(ter^-butoxycarbonyl)aza- spiro[4.δldecane (3S,δi?,6S)-3-(2-Hydroxy-δ-(trifluoromethoxy)phenyl)-6-phenyl-l- lδ oxa-7-(ieri-butoxycarbonyl)aza-spiro[4.δ]decane (Preparation lδ) (290mg, O.δθmmol) was dissolved in toluene (δml) and silver carbonate (179mg, O.βδmmol) was added in one portion. (l-Iodocycloprop-l-yl)phenylsulfide (Cohen T. and Matz J. R., J. Am. Chem. Soc. 1980, 102, 6902) (180mg, 0.6δmmol) was then added over one minute at room temperature. The 20 mixture was stirred at δδ°C for 4 hours, then further portions of silver carbonate (179mg, O.βδmmol) and (l-iodocycloprop-l-yl)phenylsulfide (180mg, O.βδmmol) were added. The mixture was stirred at δδ°C for a further 3 hours, cooled, filtered and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on δ silica gel, eluting with hexane/ethyl acetate (90:10 increasing to 80:20) to give the title compound as a colourless oil (120mg, 32%). H NMR (250MHz, CDC1 3 ) δ 7.5δ-7.44 (4H, m), 7.36-7.23 (7H, m), 7.13-7.02 (2H, m), 5.16 (IH, br s), 4.09 (IH, t, J=G Hz), 4.03-3.92 (IH, m), 3.67-3.49 (2H, m), 2.94-2.79 (IH, m), 2.26 (IH, dd, J=7.9, 12.9 Hz), 2.15-2.01 (2H, m), 1.76- 0 1.59 (3H, m), 1.53-1.45 (4H, m), and 1.36 (9H, s). m/z (ES + ) 642 (M+l). PREPARATION 19 (3i?.δi?.6S , )-3-r2-(l-Phenylthiocvcloprop-l-yl)oxy-δ- ( ' trifluoromethoxy)phenyll-6-phenyl-l-oxa-7-(ter^-butoxycarbonyl)aza- spiro[4.δ]decane δ Prepared from (3i?,δΛ,6S)-3-(2-hydroxy-δ- (trifluoromethoxy)phenyl)-6-phenyl-l-oxa-7-(ieri-butoxycarbonyl)aza- spiro[4.δ]decane (Preparation 17) according to the method of Preparation 18. m NMR (360MHz, CDC1 3 ) δ 7.δ7 (2H, app. d, =7.6 Hz), 7.4δ (2H, app. d, J=7.1 Hz), 7.36-7.19 (7H, m), 7.16-7.06 (2H, m), δ.28 (IH, br s), 0 4.13 (IH, app. t, =7.8 Hz), 3.96 (IH, br. d, =13 Hz), 3.80-3.60 (2H, m), 2.79 (IH, br. t, =13 Hz), 2.δ0 (IH, dd, .7=13, 7.9 Hz), 2.17 (IH, dt, J=13, 4.6 Hz), 1.80 (IH, dd, =12, 9.8 Hz), 1.75-1.38 (7H, m), and 1.44 (9H, s). m/z (ES + ) 642 (M+l). 5 PREPARATION 20 (35 , .5R,6g r )-3-f2-Cvclopropoxy-δ-(trifluoromethoxy)phenyl]-6-phenyl-l-oxa- 7-(fer^butoxycarbonyl)aza-spiro[4.δldecane Naphthalene (120mg, 0.936mmol) was dissolved in THF (1.5ml) under nitrogen and freshly cut lithium metal (7.0mg, 0.94mmol) was 0 added. The mixture was then sonicated at room temperature for 20 minutes to produce a dark green solution of lithium naphthalenide. This solution was cooled to -78 °C, then (3iS,5i?,6S)-3-[2-(l-phenylthiocycloprop- l-yl)oxy-δ-(trifluoromethoxy)phenyι]-6-phenyl-l-oxa-7-(ter£- butoxycarbonyl)aza-spiro[4.δ]decane (Preparation 18) (120mg, 0.187mmol) δ in THF (O.δml) was added over 1 minute. The reaction mixture was stirred for 30 minutes, then water (δml) and ether (10ml) were added. The layers were separated and the aqueous layer was extracted with ether (10ml). The combined organic fractions were dried (MgSO 4 ) and the solvent was evaporated under reduced pressure. The residue was purified 0 by column chromatography on silica gel, eluting with hexane/ethyl acetate (90:10 increasing to 80:20) to give the title compound as a colourless oil (68.6mg, 59%). Η NMR (250MHz, CDC1 ) δ 7.δ8-7.δ2 (2H, m), 7.36-7.17 (4H, m), 7.10-7.01 (2H, m), 5.18 (IH, br s), 4.20 (IH, t, =6.7 Hz), 4.05-3.9δ (IH, m), 3.76-3.δδ (3H, m), 2.92-2.79 (IH, m), 2.37 (IH, dd, J=12.9, 7.8 Hz), 2.18-2.06 (2H, m), 1.80-1.67 (3H, m), 1.38 (9H, s), and 0.86-0.73 (4H, δ m). m/z (ES + ) 634 (M+l). PREPARATION 21 (3 R.δ J R.65)-3-r2-Cvclopropoxy-5-(trifluoromethoxy)phenyll-6-phenyl-l-oxa- 7- (fer -butoxycarbonyl)aza-spiro [4.51 decane 0 Naphthalene (120mg, 0.936mmol) was dissolved in THF (1.5ml) under nitrogen and freshly cut lithium metal (7.0mg, 0.94mmol) was added. The mixture was then sonicated at room temperature for 20 minutes to produce a dark green solution of lithium naphthalenide. A solution of (3i?,5i?,6S)-3-[2-(l-phenylthiocycloprop-l-yl)oxy-δ- 6 (trifluoromethoxy)phenyl]-6-phenyl-l-oxa-7-(ieri-butoxycarbonyl)aza- spiro [4.5] decane (Preparation 19, 13δmg, 0.21mmol) in THF (2ml) under nitrogen was cooled to -78°C and the solution of lithium naphthalenide in THF was added dropwise until the intense green colour persisted. The reaction was then stirred for one minute, water (δml) was added and the 0 mixture was warmed to room temperature. Ether (10ml) was added and the layers were separated. The aqueous phase was extracted with a further portion of ether (10ml) and the combined organic phases were dried (MgSO ) and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting δ with hexane/ethyl acetate (60:60) to give the title compound as a colourless oil (87mg, 78%). Η NMR (360MHz, CDCI3) δ 7.69 (2H, app. d, =7=7.6 Hz), 7.32 (2H, app. t, =7.6 Hz), 7.27-7.18 (2H, m), 7.11-7.03 (2H, m), δ.32 (IH, br s), 4.29-4.21 (IH, m), 3.97 (IH, br. d, =13 Hz), 3.83-3.68 (3H, m), 2.76 (IH, dt, =13, 4.1 Hz), 2.5δ (IH, dd, =13, 7.2 Hz), 2.22 (IH, dt, =12, 5.2 0 Hz), 1.85 (IH, dd, =13, 9.9 Hz), 1.80-1.63 (3H, m), 1.46 (9H, s), and 0.82- 0.76 (4H, m). m/z (ES + ) 534 (M+l). COMPOUND A (3S',5.R.6S r )-3-r2-Cvclop Opoxy-5-(trifluoromethoxy)phenyll-6-phenyl-l-oxa- 7-aza-spiro[4.5]decane Hydrochloride Trifluoroacetic acid (2.5ml) was added dropwise to a stirred, cooled 0°C) solution of (3S,57?,6S)-3-[2-cyclopropoxy-5-(trifluoromethoxy)phenyl]- 6-phenyl-l-oxa-7-(teri-butoxycarbonyl)aza-spiro[4.5]decane (Preparation 20; 492mg, 0.92mmol) in dichloromethane (25ml) and the mixture was stirred at room temperature for 3 hours. The mixture was poured into water (50ml), the pH was adjusted to 10.0 with aqueous sodium hydroxide (4M) and the mixture was extracted with dichloromethane (3x50ml). The combined organic fractions were dried (MgSO ) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with dichloromethane/methanol/ammonia (aq.) (96:4:0.4 increasing to 94:6:0.6). The residue was dissolved in ethanol (20ml), cooled in ice and ethereal hydrogen chloride (IM, 1.8ml, l.δmmol) was added dropwise. The mixture was stirred at 0°C for 5 minutes, then the solvent was evaporated under reduced pressure. The residue was crystallized from ether (20ml)/ethanol (0.5ml) and the solid was collected and dried in vacuo to give the title compound as a colorless solid (354mg, 89%). m.p. 214-216 °C, Η NMR (500MHz, CD 3 OD) δ 7.59 (2H, m), 7.52 (3H, m), 7.26 (IH, d, =8.9 Hz), 7.03 (IH, dd, =8.9, 2.2 Hz), 6.20 (IH, d, =2.2 Hz), 4.85 (2H, br s), 4.43 (IH, s), 4.19 (IH, t, J=8.0 Hz), 3.87 (IH, quin, =8.0 Hz), 3.76 (IH, m), 3.44 (IH, m), 3.25 (2H, m) 2.29-1.78 (6H, m), 0.80 (2H, m), and 0.66 (2H, m). m/z (ES + ) 434 (M+l). Found: C, 61.41; H, 5.51; N, 3.08. C 24 H 26 F 3 NO 3 .HCI requires: C, 61.34; H, 5.79; N, 2.98%. COMPOUND B (3R.,5i?.6S r )-3-[2-Cvclopro p oxy-δ-(trifluoromethoxy)phenyll-6-phenyl-l-oxa- 7-aza-spiro[ " 4.51 decane Prepared from the compound of Preparation 21 according to the δ method used for Compound A. Η NMR (360MHz, CDC1 3 ) δ 7.50-7.42 (2H, m), 7.36-7.26 (3H, m), 7.03 (IH, d, =8.9 Hz), 6.95 (IH, br. d, =8.9 Hz), 6.81 (IH, br s), 3.92 (IH, t, Hz), 3.62-3.53 (2H, m), 3.50 (IH, s), 3.20 (IH, dd, =12, 4.2 Hz), 2.77 (IH, dt, =12, 2.8 Hz), 2.30-1.93 (4H, m), 1.87 (IH, br s), 1.71-1.49 (3H, m), 0.76-0.65 (2H, m), and 0.65-0.54 (2H, m). m/z 0 (ES + ) 434 (M+l). A further compound and diastereomers thereof of use in the present invention may be prepared according to the following method: DESCRIPTION 1 5 2-(l-Phenylthiocvcloprop-l-yl)oxy-5-(trifluoromethoxy)benzaldehvde Silver carbonate (1.2 g, 4.34 mmol) was added to a solution of 2-hydroxy-5-(trifluoromethoxy)benzaldehyde (0.5 g, 2.43 mmol) and (l-iodocycloprop-l-yl)phenylsulfide (Cohen T. and Matz J. R., J. Am. Chem. Soc. 1980, 102, 6902) (1.2 g, 4.34 mmol) in toluene (30 mL) and the mixture was stirred at 40 °C overnight. The mixture was cooled, diluted with ethyl acetate and filtered, washing well with ethyl acetate. The mixture was washed with aqueous sodium hydroxide, dried (MgSO 4 ) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with 5 hexane/Et 2 O (95:δ), to give the title compound as a yellow oil (191 mg, 27%). NMR (360MHz, CDCI3) δ 1.51-1.66 (2H, m), 1.44-1.48 (2H, m), 7.25-7.35 (7H, m), 7.69 (IH, d, 2.0 Hz), and 10.26 (IH, s). DESCRIPTION 2 2-Cvclopropoxy-5-(trifluoromethoxy)benzaldehvde Freshly cut lithium metal (97 mg, 13.9 mmol) was added to a solution of naphthalene (1.77 g, 13.9 mmol) in THF (20 mL) and the mixture was sonicated at room temperature for 30 min. to produce a dark green solution of lithium naphthalenide. A solution of 2-(l-phenylthiocycloprop-l-yl)oxy-δ-(trifluoromethoxy)benzaldehyde (Description 1, 96 mg, 0.27 mmol) in THF (2 mL) was cooled to -78 °C and the solution of lithium naphthalenide in THF (2 mL) was added dropwise until the intense green colour persisted. The reaction was then stirred for δ min., water (6 mL) was added and the mixture was warmed to room temperature. The mixture was extracted with ethyl acetate, the combined organic fractions were dried (MgSO 4 ) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with hexane/Et2θ (80:20), to give to give the title compound as a colourless oil (4 mg, 6%). Η NMR (360MHz, CDC1 3 ) δ 0.86 (4H, m), 3.82-3.9 (IH, m), 7.42 (2H, m), 7.62 (IH, d, 2.5 Hz), and 10.36 (IH, s). DESCRIPTION 3 2-Nitro-4-(trifluoromethoxy)phenol Iron(lll)nitrate nonahydrate (1.97 g, 4.87 mmol) was added to a solution of 4-(trifluoromethoxy)phenol (2 g, 11.24 mmol) in ethanol (20 mL) and the mixture was heated under reflux overnight. The mixture was allowed to cool to room temperature, acidified to pH 1 with aqueous hydrochloric acid (IM) and extracted with ethyl acetate. The combined organic fractions were dried (MgSO ), and the solvent was evaporated under reduced pressure. The residue was purified by short column chromatography on silica gel, eluting with hexane/EtOAc (70:30), to give the title compound as a yellow oil (2.25 g, 89%). Η NMR (360MHz, CDCI 3 ) δ 10.53 (IH, s), 8.01 (IH, d, J 3.0 Hz), 7.49 (IH, dd, J 9.1, 3.0 Hz), and 7.23 (IH, d, 9.1 Hz). DESCRIPTION 4 5 2-(l-Phenylthiocvcloprop-l-yl)oxy-5-(trifluoromethoxy)nitrobenzene Prepared from the compound of Description 3 according to the method of Description 1. Η NMR (360MHz, CDC1 3 ) δ 7.73 (IH, d, 2.7 Hz), 7.58 (IH, d, 9.2 Hz), 7.60-7.24 (6H, m), 1.57-1.53 (2H, m), and 1.44-1.40 (2H, m). 10 DESCRIPTION 5 2-Cvclopropoxy-5-(trifluoromethoxy)benzeneamine Prepared from the compound of Description 4 according to the method of Description 2. *H NMR (360MHz, CDCI3) δ 7.06 (IH, dd, 2.8, lδ 6.7 Hz), 6.66 (2H, m), 3.83 (2H, br s), 3.74 (IH, m), and 0.79 (4H, m). m/z (ES + ) 234 (M+l). DESCRIPTION 6 2-(l-Phenylthiocvcloprop-l-yl)oxy-5-(trifluoromethoxy)benzeneamine 20 Iron powder (13.5 g, 241 mmol) was added to a suspension of 2-(l-phenylthiocycloprop-l-yl)oxy-δ-(trifluoromethoxy)nitrobenzene (Description 4, 11.27 g, 30.1 mmol) in water (300 mL) and acetic acid (75 mL) and the mixture was stirred at 80 °C overnight. The mixture was cooled and filtered through celite, washing with ether. The filtrate was 5 extracted with ether, the combined organic fractions were washed with aqueous sodium hydroxide (IM), dried (MgSO 4 ), and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with hexane/Et2θ (90:10 increasing to 80:20), to give the title compound as a yellow solid (8 g, 78%). 30 i H NMR (360MHz, CDCI3) δ 7.48 (2H, m), 7.34-7.23 (3H, m), 7.15 (IH, d, J 8.74 Hz), 6.60-6.66 (2H, m), 3.78 (2H, br s), 1.49-1.46 (2H, m), and 1.39-1.35 (2H, m). DESCRIPTION 7 2-Cyclopropoxy-5-(trifluoromethoxy)benzeneamine Prepared from the compound of Description 6 according to the method of Description 2. Η NMR (360MHz, CDC1 3 ) δ 7.06 (IH, dd, 2.8, 6.7 Hz), 6.66 (2H, m), 3.83 (2H, br s), 3.74 (IH, m), and 0.79 (4H, m). m/z (ES + ) 234 (M+l). DESCRIPTION 8 2-Cvclopropoxy-δ-(trifluoromethoxy)iodobenzene An ice-cooled solution of sodium nitrite (3.56 g, 51 mmol) in water (10 mL) was added dropwise to a stirred, cooled (0 °C) solution of 2-cyclopropoxy-5-(trifluoromethoxy)benzeneamine (Description 7, 4.8 g, 20.6 mmol) in aqueous hydrochloric acid (δM, 300 mL), maintaining the internal temperature at 0 °C. The mixture was stirred at 0 °C for 30 min., then potassium iodide (8.65 g, 51.5 mmol) in water (10 mL) was added dropwise, maintaining the internal temperature at 0 °C. The mixture was stirred at 0 °C for 30 min., then allowed to warm up to room temperature and stirred until nitrogen evolution ceased. The mixture was extracted with ether, the organic fraction was washed with aqueous sodium thiosulfate (10%), dried (MgSO 4 ), and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with hexane/Et2θ (98:2 increasing to 95:5), to give the title compound as a colourless oil (6.23 g, 88%). *H NMR (360MHz, CDC1 3 ) δ 7.62 (IH, d, J 2Λ Hz), 7.20 (IH, dd, 9.1, 2.4 Hz), 7.15 (IH, d, J 9.1 Hz), 3.80 (IH, m), and 0.83 (4H, m). DESCRIPTION 9 2-Cyclopropoxy-5-(trifluoromethoxy)benzaldehyde A solution of 2-cyclopropoxy-5-(trifluoromethoxy)iodobenzene (Description 8, 0.344 g, 1 mmol) in toluene (2.5 mL) was degassed with bubbling nitrogen for 10 min. Tetrakis(triphenylphosphine)palladium (0) (15 mg) was added, the mixture was degassed with bubbling nitrogen for a further 5 min., then carbon monoxide was bubbled through the mixture for 10 min. The mixture was warmed to 50 °C and a solution of tributyl tin hydride (0.3 mL, 1.1 mmol) in toluene (5 mL) was added at a rate of 2 mL/h. via a syringe pump, maintaining carbon monoxide bubbling throughout. The mixture was cooled, diluted with ether (20 mL) and aqueous potassium fluoride solution (50%) was added. The mixture was stirred at room temperature overnight, filtered and the layers were separated. The organic layer was dried (MgSO 4 ), and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with hexane/Et2θ (80:20), to give the title compound as a colourless oil. Η NMR (360MHz, CDCI3) δ 0.86 (4H, m), 3.82-3.9 (IH, m), 7.42 (2H, m), 7.62 (IH, d, 2.5 Hz), and 10.36 (IH, s). DESCRIPTION 10 (±)-(2i?£ -l-fer^Butoxycarbonyl-2-phenylpiperidin-3-one Dimethyl sulfoxide (32.0 mL, 35.3 g, 0.45 mol) in dichloromethane (100 mL) was added dropwise to a cooled (-70 °C) solution of oxalyl chloride (18.7 mL, 27.5 g, 0.22 mol) in dichloromethane (1000 mL). The mixture was stirred at -70 °C for 15 min., then (2S,3S)-l-ierf-butoxycarbonyl-3-hydroxy-2-phenylpiperidine (prepared by the method described in European Patent Specification number 0 628 495-A; 50 g, 0.18 mol) in dichloromethane (150 mL) was added dropwise. The mixture was stirred at -70 °C for 1 h., then triethylamine (125.8 mL, 91.3 g, 0.9 mol) was added slowly. The mixture was stirred at room temperature for 1 h., water (250 mL) and aqueous sodium hydrogen carbonate (saturated, 250 mL) were added and the mixture was stirred at room temperature overnight. The layers were separated and the aqueous layer was extracted with dichloromethane (2 x 300 mL). The combined δ organic fractions were washed with brine, dried (MgSO 4 ) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with hexane/EtOAc (90:10), to give the title compound as a yellow oil (45.0 g, 91%). Η NMR (250MHz, CDCI3) δ 7.5-7.3 (5H, m), 5.8 (IH, br s), 4.2 (IH, br s), 3.4 (IH, m), 2.6 (2H, 0 m), 2.0 (2H, m), and 1.54 (9H, s). DESCRIPTION 11 (±V(2 3fi.2S3S)-l-(tert-Butoxycarbonyl)-2- p henyl p i p eridin-3-amine A solution of hydroxylamine hydrochloride (17 g, 0.24 mol) and 5 sodium acetate (55.67 g, 0.41 mol) in water (150 mL) was added to a solution of (±)-(2i?S)-l-ier^-butoxycarbonyl-2-phenylpiperidin-3-one (Description 10, 45 g, 0.16 mol) in ethanol (300 mL) and the mixture was stirred at room temperature for 1 h. The solvent was evaporated under reduced pressure, water was added and the mixture was extracted with ethyl acetate. The organic fraction was washed with brine, dried (MgSO 4 ) and the solvent was evaporated under reduced pressure. The residue was dissolved in ethanol (400 mL) and Raney nickel (50 g) was added. The mixture was shaken under hydrogen (40 psi) overnight, filtered and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with C^CL MeOH (100:0 increasing to 85:15), to give the title compound as a colorless oil (10.9 g, 24%). i H NMR (360MHz, CDCI3) δ 7.43 (2H, d, J 7.0 Hz), 7.30 (3H, m), 5.19 (IH, d, 6.2 Hz), 4.00 (IH, m), 3.17 (2H, m), 1.90-1.64 (4H, m), 1.36 (9H, s), and 1.26 (2H, br s). COMPOUND C (±)-(2J^3i?.2g3g)-N-{f2-Cvclopropoxy-5-(trifluoromethoxy)phenvnmethyl}-2 -phenylpiperidin-3-amine Dihydrochloride 2-Cyclopropoxy-5-(trifluoromethoxy)benzaldehyde (Description 9, 55 mg, 0.21 mmol) was added to (±)-(2i23i2,2S3S l-(ter«-b toxycarbonyl)-2- phenylpiperidin-3-amine (Description 11, 58 mg, 0.21 mmol), citric acid (89 mg, 0.42 mmol) and 3A molecular sieves in dry methanol (5 mL) and the mixture was stirred at room temperature for 1.5 h. Sodium borohydride (30 mg) was added and the mixture was stirred at room temperature for 2 h. Ethyl acetate was added and the mixture was washed with aqueous hydrochloric acid (O.lM, 2 x 25 mL) and brine (25 mL), dried (MgSO ) and the solvent was evaporated under reduced pressure. The residue was dissolved in dichloromethane (3 mL), cooled to 0 °C and trifluoroacetic acid (2 mL) was added slowly. The mixture was stirred at room temperature for 1 h., the solvent was evaporated under reduced pressure and ethyl acetate was added. The mixture was washed with aqueous sodium hydrogen carbonate (saturated, 2 x 25 mL) and brine (25 mL), dried (MgSO 4 ) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with CH 2 Cl2/MeOH/NH 3 (Aq.) (96:4:0.4). The residue was dissolved in ethanol (2 mL), cooled in ice and ethereal hydrogen chloride (IM, 0.24 mL, 0.24 mmol) was added. The solvent was evaporated under reduced pressure and the residue was recrystallised from ethanol to give the title compound as a colorless solid (20 mg, 20%). m.p. 169-171 °C. Η NMR (400MHz, CD3OD) δ 0.64 (IH, m), 0.80 (3H, m), 1.99 (IH, m), 2.24 (IH, m), 2.46 (2H, m), 3.30 (IH, m), 3.64 (IH, m), 3.76 (2H, m), 3.96 (IH, br s), 4.08 (IH, m), 4.95 (IH, s), 7.23 (IH, s), 7.31 (IH, d, 9.0 Hz), 7.37 (IH, d, J 9.0 Hz), 7.54 (3H, m), and 7.67 (2H, m). m/z (ES + ) 407 (M+l). Particularly preferred NK-1 receptor antagonists of use in the present invention are compounds which are potent NK-1 receptor antagonists, i.e. compounds with an NK-1 receptor affinity (IC 50 ) of less than lOnM, favourably less than 2nM and preferably less than InM. The class of orally active, long acting, CNS-penetrant NK-1 receptor antagonists of use in the present invention is identified using a combination of 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, 468. 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. ^i-Tyr 8 - substance P (O.lnM, 2000Ci/mmol; New England Nuclear) is incubated in the presence or absence of test compounds (dissolved in δμl dimethylsulphoxide, DMSO) with 5xl0 4 CHO cells. Ligand binding is performed in 0.2δml of 60mM Tris-HCl, pH7.5, containing δmM MnCL;, 150mM NaCl, 0.02% bovine serum albumin (Sigma), δOμg/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 until equilibrium is achieved (>40 minutes) and the receptor-ligand complex is harvested by filtration over GF/C filters pre- soaked in 0.1% polyethylenimine using a Tomtek 96-well harvester. Non- specific binding is determined using excess substance P (lμM) and represents <10% of total binding. 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 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 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 (e.g. GR73632 (d Ala [L-Pro 9 ,Me-Leu 10 ] -substance P-(7-ll)) is infused directly into the cerebral ventricles (e.g. 3pmol in δμl i.e. 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. ASSAY 3: Ferret Emesis Individually housed male ferrets (1.0 -2.6 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 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 (δδcm x 39cm x 19cm) in a room physically isolated from the home cage for 16 minutes and the duration of vocalisation during this baseline period is recorded. Only animals which vocalise for longer than δ minutes are employed for drug challenge studies (approximately 60% 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 the oral pharmacokinetics of the test compound) before social isolation for lδ 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 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 gerbil as hereinafter defined. Essentially, 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 IDso 3mg/kg, and preferably with an 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 is inhibited with an ID50≤30mg/kg, and preferably with an IDso≤lOmg/kg. CNS-penetrant NK-1 receptor antagonists of use in the present ivnention 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 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 vocaHsations during the first 15 minutes of isolation are attenuated with an ID5o≤20mg/kg, preferably with an IDso≤lOmg/kg, and especially with an ID δ o≤δmg/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 ID5o≤20mg/kg, preferably with an IDso≤lOmg/kg, and especially with an IDso<5mg/kg. 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 IC50 ≤ lOnM, preferably I Ceo ≤ 2nM, especially IC50 < InM. (ii) Determine ability of compounds to penetrate CNS by their ability to inhibit foot tapping in gerbils induced by central injection of an NKi agonist (Assay 2); select compounds that inhibit foot tapping with ID50 < 3mg/kg i.v., and preferably ID50 < lmg/kg i.v. when administered immediately prior to central NKi agonist challenge, or ID50 < 30mg/kg p.o., and preferably ID50 ≤ lOmg/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 NKi agonist challenge; select compounds showing < 25-fold loss of potency compared with ID50 determined in step (ii) above with the proviso that ID50 ≤ lOmg/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 oral administration and/or by ability 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) 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 ID50 ≤ 20mg/kg, and preferably ID50 ≤ 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. One example of a NK-1 receptor antagonist of use in the present invention is the compound 2-(R)-(l-(R)-(3,5-bis(trifluoromethyl)phenyl)- ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(5-oxo-lH,4H-l,2,4-triazolo)methyl)- morpholine, the preparation of which is described in International Patent Specification No. WO 95/16679. In the aforementioned assays, this compound has the following activity: human NK-1 receptor binding: IC5o=0.1nM gerbil foot-tapping (5 mins.): ID5o=0.36mg/kg i.v. gerbil foot-tapping (24 hrs.): ID5o=0.33mg/kg i.v. ferret emesis: ID9o<3mg/kg p.o. guinea-pig vocalisation (4 hr. pre-treatment): ID5o=0.73mg/kg p.o. The following 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 Microcrystalline cellulose 80.0 80.0 80.0 Modified food corn starch 80.0 80.0 80.0 Lactose 189.5 139.5 139.6 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 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 δOmg, lOOmg and 300mg of the NK-1 receptor antagonist per tablet. Pharmaceutical compositions comprising a combination of a NK-1 receptor antagonist and a neuroleptic agent may be prepared with separate active ingredients or with a combination of active ingredients in one composition. In such combined preparations, the ratio of the NK-1 receptor antagonist and the neuroleptic agent will depend upon the choice of active ingredients. EXAMPLE 2 Tablets containing 60-300mg of NK-1 antagonist and 5-10mg of haloperidol Amount mg NK-1 antagonist 60.0 50.0 100.0 100.0 300.0 300.0 haloperidol δ.O 10.0 5.0 10.0 5.0 10.0 Microcrystalline cellulose 80.0 80.0 80.0 80.0 80.0 80.0 Modified food corn starch 80.0 80.0 80.0 80.0 80.0 80.0 Lactose 184.5 179.5 134.5 129.5 134.5 129.5 Magnesium Stearate 0.5 0.5 0.5 0.5 0.5 0.5 The active ingredients, 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 CNS-penetrant NK-1 receptor antagonist per tablet.

Claims: CLAIMS 1. Use of an orally active, long acting, CNS-penetrant NK-1 5 receptor antagonist for the manufacture of a medicament for oral administration for the treatment or prevention of movement disorders. 2. Use of an orally active, long acting, CNS-penetrant NK-1 receptor antagonist for the manufacture of a medicament for oral 10 administration for the treatment or prevention dyskinesias in a patient who is non-responsive to neuroleptic agents, or for whom neuroleptic agents are contraindicated. 3. Use of a NK-1 receptor antagonist and an antiparkinsonian Iδ agent for simultaneous, separate or sequential administration for the manufacture of a medicament for the treatment or prevention of akinetic- rigid disorders. 4. Use of a NK-1 receptor antagonist and a neuroleptic agent for 0 simultaneous, separate or sequential administration for the manufacture of a medicament for the treatment or prevention of dyskinesias. δ. An oral pharmaceutical composition for the treatment of movement disorders which comprises an orally active, long acting, CNS- 5 penetrant NK-1 receptor antagonist, together with a pharmaceutically acceptable carrier or excipient. 6. A pharmaceutical composition comprising a NK-1 receptor antagonist and an antiparkinsonian agent, together with at least one 0 pharmaceutically acceptable carrier or excipient. 7. A pharmaceutical composition comprising a NK-1 receptor antagonist and a neuroleptic agent, together with at least one pharmaceutically acceptable carrier or excipient. 5 8. A product comprising a NK-1 receptor antagonist and an antiparkinsonian agent as a combined preparation for simultaneous, separate or sequential use for the treatment or prevention of akinetic-rigid disorders. 10 9. A product comprising a NK-1 receptor antagonist and an antiparkinsonian agent as a combined preparation for simultaneous, separate or sequential use for the treatment or prevention of dyskinesias. 10. A method for the treatment or prevention of movement lδ disorders, which method comprises the oral administration to a patient in need of such treatment of an effective amount of an orally active, long acting, CNS-penetrant NK-1 receptor antagonist. 11. A method for the treatment or prevention of dyskinesias in a 20 patient who is non-responsive to neuroleptic agents or for whom neuroleptic agents are contraindicated, which method comprises oral administration to the patient in need of such treatment of an effective amount of an orally active, long acting, CNS-penetrant NK-1 receptor antagonist. 6 12. A method for the treatment or prevention of akinetic-rigid disorders, which method comprises administration to a patient in need of such treatment of an amount of a NK-1 receptor antagonist and an amount of an antiparkinsonian agent, such that together they give 0 effective relief. 13. A method for the treatment or prevention of dyskinesias, which method comprises administration to a patient in need of such treatment of an amount of a NK-1 receptor antagonist and an amount of a neuroleptic agent, such that together they give effective relief. 14. A use according to claim 1, 2, 3 or 4, or a composition according to claim δ, 6 or 7, or a product according to claim 8 or 9 or a method according to claim 10, 11, 12 or 13 wherein the NK-1 receptor antagonist is selected from the classes of compounds described in EP-A- 0577394, WO-A-9508549, WO-A-9518124, WO-A-9523798, WO-A-9605181 and International Patent Application No. PCT/GB97/01630. 15. A use according to claim 1, 2, 3 or 4, or a composition according to claim 5, 6 or 7, or a product according to claim 8 or 9 or a method according to claim 10, 11, 12 or 13 wherein the NK-1 receptor antagonist is: 2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3(S)-(4-fluorophenyl)-4-(3-(5-oxo- lH,4H-l,2,4-triazolo)methyl)morpholine; 2-(R)-(l-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(3-(5-oxo-lH,4H- l,2,4-triazolo)methyl)-3-(S)-phenyl-morpholine; 2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-4-(3-(5-oxo-lH,4H-l,2,4- triazolo)methyl)-3-(S)-phenyl-morpholine; 2-(R)-(l-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)- 4-(3-(5-oxo-lH,4H-l,2,4-triazolo)methyl)morpholine; 2-(R)-(l-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(5-(N,N- dimethylamino)methyl-l,2,3-triazol-4-yl)methyl-3-(S)-phenylmorpholine; 2-(R)-(l-(R)-(3,δ-bis(trifluoromethyl)phenyl)ethoxy)-4-(δ-(N,N- dimethylamino)methyl-l,2,3-triazol-4-yl)methyl-3-(S)-(4- fluorophenyl)morpholine; 2-(R)-(l-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)- 4-(3-(4-monophosphoryl-5-oxo-lH-l,2,4-triazolo)methyl)morpholine; 2-(R)-(l-(R)-(3,δ-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)- 4-(3-(l-monophosphoryl-5-oxo-lH-l, 2, 4-triazolo)methyl)morp holine; 2-(R)-(l-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)- 4-(3-(2-monophosphoryl-5-oxo-lH-l, 2, 4-triazolo)methyl)morp holine; 5 2-(R)-(l-(R)-(3,δ-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)- 4-(3-(δ-oxyphosphoryl-lH-l,2,4-triazolo)methyl)morpholine; 2-(S)-(l-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)- 4-(3-(l-monophosphoryl-5-oxo-4H- 1,2, 4-triazolo)methyl)morp holine; 2-(R)-(l-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(4-N,N- 10 dimethylaminobut-2-yn-yl)-3-(S)-(4-fluorophenyl)morpholine; (3S,δR,6S)-3-[2-cyclopropoxy-5-(trifluoromethoxy)phenyl]-6-phenyl-l-oxa- 7-aza-spiro[4.5]decane; (3R,5R,6S)-3-[2-cyclopropoxy-5-(trifluoromethoxy)phenyl]-6-phenyl-l-oxa- 7-aza-spiro [4. δ] deca rή e," lδ (±)-(2iJ3iJ,2S3S N-{[2-(yclopropoxy-5-(trifluoromethoxy)phenyl]methyl}-2- phenylpiperidin-3-amine; or a pharmaceutically acceptable salt thereof. 16. A use according to claim 1, or a composition according to 20 claim 5 or a method according to claim 10 wherein the movement disorders are selected from akinesias and akinetic-rigid syndromes, dyskinesias and medication-induced parkinsonian. 17. A use according to claim 1, or a composition according to 5 claim 6 or a method according to claim 10 wherein the movement disorder is Gilles de la Tourette syndrome, and the symptoms thereof. 18. A use according to claim 2 or 4, or a composition according to claim 7, or a product according to claim 9, or a method according to claim 0 11 or 13 or a use, composition or method according to claim 16 wherein the dyskinesias are selected from tremor, chorea, myoclonus, tics, and dystonia. 19. A use according to claim 3, or a composition according to δ claim 6, or a product according to claim 8, or a method according to claim 12 or a use, composition or method according to claim 16 wherein the akinetic-rigid disorders or syndromes are selected from Parkinson's disease, drug-induced parkinsonism, postencephalitic parkinsonism, progressive supranuclear palsy, multiple system atrophy, corticobasal 0 degeneration, parkinsonian-ALS dementia complex and basal ganglia calcification.

Inventors: BAKER RAYMOND, CURTIS NEIL ROY, ELLIOTT JASON MATTHEW, HARRISON TIMOTHY, HOLLINGWORTH GREGORY JOHN, JACKSON PHILIP STEPHEN, KULAGOWSKI JANUSZ JOZEF, RUPNIAK NADIA MELANIE, SEWARD EILEEN MARY, SWAIN CHRISTOPHER JOHN, WILLIAMS BRIAN JOHN, BAKER, RAYMOND, CURTIS, NEIL, ROY, ELLIOTT, JASON, MATTHEW, HARRISON, TIMOTHY, HOLLINGWORTH, GREGORY, JOHN, JACKSON, PHILIP, STEPHEN, KULAGOWSKI, JANUSZ, JOZEF, RUPNIAK, NADIA, MELANIE, SEWARD, EILEEN, MARY, SWAIN, CHRISTOPHER, JOHN, WILLIAMS, BRIAN, JOHN
Applicants: BAKER RAYMOND, CURTIS NEIL ROY, ELLIOTT JASON MATTHEW, HARRISON TIMOTHY, HOLLINGWORTH GREGORY JOHN, JACKSON PHILIP STEPHEN, KULAGOWSKI JANUSZ JOZEF, MERCK SHARP & DOHME, RUPNIAK NADIA MELANIE, SEWARD EILEEN MARY, SWAIN CHRISTOPHER JOHN, WILLIAMS BRIAN JOHN, BAKER, RAYMOND, CURTIS, NEIL, ROY, ELLIOTT, JASON, MATTHEW, HARRISON, TIMOTHY, HOLLINGWORTH, GREGORY, JOHN, JACKSON, PHILIP, STEPHEN, KULAGOWSKI, JANUSZ, JOZEF, MERCK SHARP & DOHME LIMITED, RUPNIAK, NADIA, MELANIE, SEWARD, EILEEN, MARY, SWAIN, CHRISTOPHER, JOHN, WILLIAMS, BRIAN, JOHN
Application year: 1997
Main classification: A61K31
IPC codes: A61K31, A61K45, A61P25, A61P43, C07D211, C07D413, C07D491