AU5753098A

AU5753098A - Use of nk-1 receptor antagonists for treating schizophrenic disorders

Info

Publication number: AU5753098A
Application number: AU57530/98A
Authority: AU
Inventors: Raymond Baker; Neil Roy Curtis; Jason Matthew Elliott; Timothy Harrison; Gregory John Hollingworth; Philip Stephen Jackson; Janusz Jozef Kulagowski; Nadia Melanie Rupniak; Eileen Mary Seward; Christopher John Swain; Brian John Williams
Original assignee: Merck Sharp and Dohme Ltd
Current assignee: Organon Pharma UK Ltd
Priority date: 1996-12-02
Filing date: 1997-11-25
Publication date: 1998-06-29
Anticipated expiration: 2017-11-25
Also published as: EP0942735A1; AU732633B2; WO1998024445A1; JP2001505881A; CA2273807A1

Description

USE OF NK-1 RECEPTOR ANTAGONISTS FOR TREATING SCHIZOPHRENIC DISORDERS

This invention relates to the treatment or prevention of certain schizophrenic disorders by the administration of a specific class of NK-1 receptor antagonists.

The essential features of schizophrenia are a mixture of characteristic signs and symptoms (both positive and negative) which are present in an individual for a significant portion of time over at least one month. The so-called "active-phase" symptoms include delusions, hallucinations, disorganised speech, disorganised or catatonic behaviour and negative symptoms (e.g. affective flattening, alogia and avolition). Some patients have only a single episode of the illness, but most have either recurrent episodes or chronic illness. The care of schizophrenic patients is a major part of the work of psychiatrists. The long-term care of schizophrenic patients is complicated, however, generally symptoms can at least be kept under control if patients with chronic schizophrenia receive long-term treatment with an antipsychotic drug. Frequently, schizophrenic symptoms cannot be controlled without invoking extrapyramidal side-effects. Consequently, antiparkinsonian drugs may also be prescribed to reduce these side-effects, however, the use of anticholinergic drugs may actually increase the risk of tardive dyskinesia (a late and sometimes irreversible side-effect of prolonged treatment with antipyschotic drugs). Treatment of schizophrenia with antipsychotic (or neuroleptic) agents, such as haloperidol and chlorpromazine, is typically associated with 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. Such side-effects are often debilitating and contribute considerably to a patient's non-compliance with prescribed treatment. They may also hinder a patient's social rehabilitation.

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). On the other hand, European Patent Specification No. 0 286 928 describes inhibitors of the enzyme prolyl-endopeptidase, which enzyme degrades neuropeptides such as substance P, the enzyme inhibitors having an antipsychotic, anxiolytic and antidepressant action. Thus, degrading substance P or reducing the action of substance P in some other way (e.g. antagonism at its preferred NK-1 receptor) might be expected to be detrimental to the treatment of psychoses such as schizophrenic disorders.

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 antipsychotic therapy, there is a need for new, safe and effective treatment for schizophrenic disorders.

The present invention provides the use of a CNS penetrant NK-1 receptor antagonist in an oral, once-a-day medicament for the treatment of schizophrenic disorders. The compounds of this class advantageously exhibit a rapid onset of action and a reduced side-effect profile when compared against conventional antipsychotic agents.

In particular, the present invention provides a means for the identification of NK-1 receptor antagonists which would be effective in an oral once-a-day medicament for the treatment of schizophrenic disorders. 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 schizophrenic disorders, without the need for concomitant therapy and in particular, without the need for concomitant use of a antipsychotic agents. 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 schizophrenic disorders.

The present invention also provides a method for the treatment or prevention of schizophrenic 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 schizophrenic 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 schizophrenic disorders are inadequately treated with existing antipsychotic therapy. Furthermore, some patients may be adversely affected by the side-effects of antipsychotic drugs.

The present invention accordingly provides the use of 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 schizophrenic disorders in a patient who is non- responsive to antipsychotic agents, or for whom antipsychotic agents are contraindicated.

The present invention also provides a method for the treatment or prevention of schizophrenic disorders in a patient who is non-responsive to antipsychotic agents, or for whom antipsychotic agents are contraindicated, which method comprises oral administration to the patient in need of such treatment of an effective amount of 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 schizophrenic disorders, it will be appreciated that a combination of a conventional antipsychotic drug with a NK-1 receptor antagonist may provide an enhanced effect in the treatment of schizophrenic disorders. Such a combination would be expected to provide for a rapid onset of action to treat schizophrenic symptoms thereby enabling prescription on an "as needed basis". Furthermore, such a combination may enable a lower dose of the CNS agent to be used without compromising the efficacy of the antipsychotic 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 antipsychotic 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 an antipsychotic agent for the manufacture of a medicament for the treatment or prevention of schizophrenic disorders.

The present invention also provides a method for the treatment or prevention of schizophrenic 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 antipsychotic 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 antipsychotic agent, together with at least one pharmaceutically acceptable carrier or excipient. It will be appreciated that the NK-1 receptor antagonist and the antipsychotic agent may be present as a combined preparation for simultaneous, separate or sequential use for the treatment or prevention of schizophrenic 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 antipsychotic agent as a combined preparation for simultaneous, separate or sequential use in the treatment or prevention of schizophrenic disorders.

It will be appreciated that when using a combination of the present invention, the NK-1 receptor antagonist and the antipsychotic 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 antipsychotic 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 "schizophrenic disorders" includes paranoid, disorganised, catatonic, undifferentiated and residual schizophrenia; schizophreniform disorder; schizoaffective disorder; delusional disorder; brief psychotic disorder; shared psychotic disorder; substance-induced psychotic disorder; and psychotic disorder not otherwise specified.

Other conditions commonly associated with schizophrenic disorders include self-injurious behaviour (e.g. Lesch-Nyhan syndrome) and suicidal gestures. 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-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-bιs(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(trιfluoromethyl)phenyl)ethoxy)-4-(5-(N,N- dimethylamino)methyl-l,2,3-triazol-4-yl)methyl-3-(S)-phenylmorpholine;

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-bιs(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-bιs(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-

4-(3-(l-monophosphoryl-5-oxo-lH-l,2,4-triazolo)methyl)morpholine;

2-(R)-(l-(R)-(3,5-bis(tnfluoromethyl)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-bιs(trιfluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)- 4-(3-(5-oxyphosphoryl-lH-l,2,4-triazolo)methyl)morpholine; 2-(S)-(l-(R)-(3,5-bis(tπfluoromethyl)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(tιτfluoromethyl)phenyl)ethoxy)-4-(4-N,N- dimethylaminobut-2-yn-yl)-3-(S)-(4-fluorophenyl)morpholine; (3S,5R,6S)-3-[2-cyclopiOpoxy-5-(trifluoromethoxy)phenyl]-6-phenyl-l-oxa- 7-aza-spiro[4.5]decane; (3R,5R,6S)-3-[2-cyclopiOpoxy-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 antipsychotic agents of use in combination with a NK-1 receptor antagonist include the phenothiazine, thioxanthene, heterocyclic dibenzazepine, butyrophenone, diphenylbutylpiperidine and indolone classes of antipsychotic 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 antipsychotic agents include loxapine, sulpiride and risperidone. It will be appreciated that the antipsychotic 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.

Other classes of antipsychotic agnet of use in combination with a NK-1 receptor antagonist include dopamine receptor antagonists, especially D2, D3 and D4 dopamine receptor antagonists, and muscarinic ml receptor agonists. An example of a D3 dopamine receptor antagonist is the compound PNU-99194A. An example of a D4 dopamine receptor antagonist is PNU-101387. An example of a muscarinic ml receptor agonist is xanomeline.

Another class of antipsychotic agent of use in combination with a NK-1 receptor antagonist is the 5-HT₂A receptor antagonists, examples of which include MDL100907 and fananserin. Also of use in combination with a NK-1 receptor antagonist are the serotonin dopamine antagonists (SDAs) which are believed to combine 5-HT₂A and dopamine receptor antagonist activity, examples of which include olanzapine and ziperasidone.

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 antipsychotic 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 a day.

A minimum dosage level for the antipsychotic 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 antipsychotic 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 a day.

It will be appreciated that the amount of the NK-1 receptor antagonist required for use in the treatment or prevention of schizophrenic 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 antipsychotic agent required for use in the treatment or prevention of schizophrenic 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-tβrt-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 (2S',3S)-l-teri-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, CDC1₃) δ 7.5-7.3 (5H, m), 5.8 (1H, br s), 4.2 (1H, br s), 3.4 (1H, m), 2.6 (2H, m), 2.0 (2H, m), and 1.54 (9H, s).

PREPARATION 2

(2g,3i?)-l-fert-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-^eri-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 ) 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. Η NMR (360MHz, CDCls) δ 7.48 (2H, d, J=6.9 Hz), 7.35-7.2 (6H, m), 6.9-6.88 (3H, m), 5.4 (1H, s), 5.15 (2H, d, =13.7 Hz), 4.61 (2H, s), 4.11 (2H, m), 3.17 (1H, 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?,6S^r)-3-Methylene-6-phenyl-l-oxa-7-(tβrt.-butoxycarbonyl)aza- spiro[4.51decane

To a cooled(-80 °C) solution of (2S,3#)-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 ) 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-methyleιιe-6-phenyl-l-oxa-7- (tert-butoxycarbonyl)aza-spiro[4.5]decane. Η NMR (360MHz, CDCI₃) δ 7.58 (2H, d, =8.4 Hz), 7.32-7.21 (3H, m), 5.23 (1H, s), 5.06 (1H, m), 4.97 (1H, m), 4.39 (2H, AB d, =13.3 Hz), 3.99 (1H, dd, =13.3, 4.48 Hz), 2. 83 (1H, ABd =15.5 Hz), 2.7 (lH.td =12.5, 3.93 Hz), 2.5 (1H, ABd, =15.4 Hz), 2.15 (2H, td, =12., .4 Hz), 1.69 (2H, m), and 1.46 (9H,s). m/z (ES⁺) 329 (M+2H-^tBuOCO). PREPARATION 4

(5i?,65^f)-3-Keto-6-phenyl-l-oxa-7-(fert-bυtoxycarbonyl aza-spiro 4.51decane Through a cooled (-80 °C) solution of (5i?,6S)-3-methylene-6-phenyl- l-oxa-7-(tert-butoxycarbonyl)aza-spiro[4.5]decane (Preparation 3; 0.665g) in dichloromethane (5ml) and methanol (5ml) was bubbled a mixture of ozone and oxygen for 45 minutes. After the solution had been purged with nitrogen, dimethyl sulphide (0.5ml) was added and then stirred under nitrogen at room temperature for 16 hours. The solvent was removed in υacuo and the residue partitioned between ethyl acetate and water. The organic phase was dried (MgSO₄), 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, CDCla) δ 7.58 (2H, d, =6.2 Hz), 7.37-7.26 (3H, m), 5.3 (1H, s), 4.15 and 4.09 (2H, AB d, =17.4 Hz), 3.97 (1H, m), 2.80 (1H, td, J=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).

PREPARATION 5

(5J^,65^r)-3-Trifluoromethylsulfonyloxy-6-phenvI-l-oxa-7-(t-βrf- butoxycarbonyl)aza-spiiO[4.5]dec-3-ene

To a cooled (-80 °C) solution of 1M sodium hexamethyldisilazide (0.38ml, 0.38mmol) in THF was added a solution of (5#,6S)-3-keto-6- phenyl-l-oxa-7-(tert-butoxycarbonyl)aza-spiro[4.5]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]-5- chloropyridine (0.163g, 0.415mmol) in THF (3ml) was added. The solution was stirred at -80°C for 30 minutes then at room temperature for 30 minutes before being quenched by addition of saturated ammonium chloride solution and ethyl acetate. The dried (MgSO ) 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, CDC ) δ 7.4 (2H, d, -7.3 Hz), 7.3-7.22 (3H, m), 6.01 (IH, t, =2.13 Hz), 5.13 (IH, s), 4.56 and 4.26 (2H, ABdd, =12.4, 1.97 Hz),4.10 (IH, dt, =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 (5-R,6S^r)-3-Trimethylstannyl-6-phenyl-l-oxa-7-(t.6rt.-butoxycarbonyl)aza- spiro[4.5]dec-3-ene

To a degassed solution of (5Λ,6S)-3-trifluoromethylsulfonyloxy-6- phenyl-l-oxa-7-(teri-butoxycarbonyl)aza-spiro[4.5]dec-3-ene (Preparation 5; 0.482g, 1.04mmol), lithium chloride (0.264g, 6.25mmol), lithium 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 5 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 with hexane containing increasing proportions of ethyl acetate between 0% to 5%). Evaporation of the fractions gave the title compound as a crystalline solid. Η NMR (360MHz, CDCI3) δ 7.25 (2H, d, =7.3 Hz), 7.1- 7.0 (3H, m), 5.83 (IH, t, =2.5 Hz), 4.78 (IH, s), 4.48 and4.02 (2H, dd, =12.9, 2.3 Hz), 3.96 (IH, dd, =6.16, 13.4 Hz), 2.95 (IH, td, J=13.3, 4.5 Hz), 1.84 (IH, m), 1.68 (IH, m), 1.60 (2H, m), 1.19 (9H, s), and 0.0 (6H, s).

PREPARATION 7

(25^,,3i?)-l-tert-Butoxycarbonyl-3-(3-hydroxypropyn-l-yl)-2-phenylpiperidin- 3-ol O-TrimethylsilylpiOpargyl alcohol (24.51ml, 20.47g, 160ml) was added slowly to a cooled (-10°C) solution of ethylmagnesium bromide (1M 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 (2S)-l-tert-butoxycarbonyl-2- phenylpiperidin-3-one (Preparation 1; 42.3g) in tetrahydrofuran (200ml) 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 ) and the solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate (500ml) and a solution of tetrabutylammonium fluoride (1M 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 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 (45g). The crude material was purified by flash column chromatography on silica gel, eluting with hexane/ethyl acetate (90:10 increasing to 25:75) to give the title compound as an amber oil (32.2g). Η NMR (CDC1₃) δ 7.53-7.55 (2H, m), 7.19-7.35 (3H, m), 5.56 (IH, s), 4.27 (2H, s), 3.99-4.03 (IH, m), 3.25 (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).

PREPARATION 8

2-Bromo-4-(trifluoromethoxy)phenol

To a cooled (0 °C) solution of 4-trifluoromethoxyphenol (35.6g, 0.2mol) in chloroform (280ml) was added dropwise a solution of bromine (32g, 0.2mol) in chloroform (50ml). The solution was stirred at 0°C for 1 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 (MgSO₄). The solvent was removed and the residue was purified by distillation at reduced pressure to give the title compound. Η NMR (250MHz, CDC1 ) δ 7.38 (IH, d, =2.1 Hz), 7.13 (IH, dd, =9.1, 2.1 Hz), 7.03 (IH, d, J=9.1 Hz), and 5.53 (IH, s).

PREPARATION 9 2-Benzyloxy-5-(τrifluoromethoxy)bromobenzene

2-Bromo-4-(trifluoromethoxy)phenol (Preparation 8; 5g, 20mmol) was dissolved in N,N-dimethylformamide (60ml), and potassium carbonate (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 υacuo. Purification on silica, eluting with 2% and 5% ethyl acetate in hexane gave the title compound as a clear oil (6.7g, 96%). Η NMR (250MHz, CDCI3) δ 5.47 (2H, s), 7.23 (IH, d, J=9 Hz), 7.43 (IH, dd =8.2, 2.9 Hz), and 7.75 (6H, m).

PREPARATION 10 -(2S.3Jg -l-terf-Butoxycarbonyl-3-(3-hvdroxyprop-l-en-l-yl)-2- phenylpiperidin-3-ol

Palladium on calcium carbonate, poisoned with lead (Lindlar catalyst, 2g) was added to a solution of (2-S,3i )-l-tert.-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 (32g, 100%). NMR (360MHz, CDCI3) δ 7.42 (2H, d, =7.6 Hz), 7.35-7.25 (3H, m), 5.83 (IH, d. -J12.3 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, =5.9 Hz), 2.02 (IH, m), 1.92-1.78 (3H, m), and 1.32 (9H, s). m/z (ES+) 334 (M+l).

PREPARATION 11

5 (5i?,6g)-6-Phenyl-l-oxa-7-(?:βri-butoxycarbonyl)aza-spiror4.51dec-3-ene Diethylazodicarboxylate (18.2ml, llδmmol) in THF (100ml) was added dropwise to a solution of -(2iS',3i?)-l-tert-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 0 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 (CDC1₃) δ 7.45 (2H, d, 5 =7.4 Hz), 7.27 (2H, t, =7.4 Hz), 7.20 (IH, t, =7.4 Hz), 6.03 (IH, dt, .7=6.1, 2.0 Hz), 5.68 (IH, dt, J=6.1, 2.0 Hz), 5.06 (IH, s), 4.61 (IH, dt, =13.1, 2.0 Hz), 4.32 (IH, dt, =13.1, 2.0 Hz), 4.08 (IH, m), 3.05 (IH, m), 2.05 (IH, m), 1.75 (3H, m), and 1.37 (9H, s). m/z (ES⁺) 316 (M+l).

0 PREPARATION 12

2-BenzyIoxy-5-(trifluoromethoxy)benzene

Benzyl bromide (66.17ml, 9δ.3δg, O.δβmol) 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 δ 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, 500ml), dried (MgS0₄) and the solvent was evaporated under reduced pressure to give the title compound as a colorless solid (133. δg, 99%). *H 0 NMR (360MHz, CDCI3) δ 7.39 (δH, 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-5-(trifluoromethoxy)benzene (Preparation 12, 73.06g, 0.27mol) and silver trifluoroacetate (71.57g, 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 (MgSO₄) 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, CDC1₃) δ 7.67 (IH, d, =7=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^r)-3-(2-Benzyloxy-δ-(trifluoromethoxy)phenyl)-6-phenyl-l-oxa-7-(t.βr^- butoxycarbonyl)aza-spiro[4.δ]dec-3-ene 0 (δi?,6»S)-3-Trimethylstannyl-6-phenyl-l-oxa-7-(iert- 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. Η 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, =12.2 Hz, =2 Hz), 4.92 (IH, dd, =12.1 Hz, =1.8 Hz), δ.08 (IH, s), δ. l (2H. q, =ll.δ Hz), 6.6δ (IH, s), 6.94 (2H, d, =8.9 Hz), 7.08 (IH, d, J=9 Hz). 7.18 (2H, t, =8.1 Hz), 7.2δ (3H, m), 7.38 (δH, m).

PREPARATION 15 δ (3g,δ .65^,)-3-(2-Hvdi XV-δ-⁽trifluoromethoxy⁾phenyl⁾-6-phenyl-l-oxa-7- (tβr^-butoxycarbonyl)aza-spiro[4.δldecane

(δi?,6S)-3-(2-Benzyloxy-δ-(trifluoromethoxy)phenyl)-6-phenyl-l-oxa- 7-(f.eri-butoxycarbonyl)aza-spiro[4.δ]dec-3-ene (Preparation 14) (3.88g) was dissolved in ethyl acetate (15ml) and methanol (15ml). Palladium

10 hydroxide on carbon (l.OOg) was added and the suspension was shaken under a hydrogen atmosphere (50 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)pheιιyl)-6-phenyl-l-oxa- 7-(tert-butoxycarbonyl)aza- spiro[4.5]decane (191mg), ^lH NMR (2δ0MHz, CDCI3) δ 7.70 (2H, d, =7.3 Hz), 7.33 (2H, t, =7.3 Hz), .7.26 (IH, d, =7.3 Hz), 7.05 (IH, br s), 6.96 (2H, m), 6.82 (IH, d, =9.4 Hz), 5.43 (IH, s), 4.27 (IH, m), 4.01 (IH, m), 3.95 (IH, m), 3.73 (IH, m), 2.73 (2H, m), 2.33 (IH, m), 1.87-1.58 (4H, m); 0 and 1.50 (9H, s).and (3S,5R,6S)-3-(2-hydroxy-5-(trifluoromethoxy)phenyl)- 6-phenyl-l-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), 2.50 (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), 5.33 (IH, s), 6.75 (IH, d, =8.5 Hz), 6.94 (2H, δ m), 7.2δ (IH, m), 7.31 (2H, m), and 7.δδ (2H, d, =7.8 Hz).

PREPARATION 16

(3J?.δJ?.6g)-3-(2-Benzyloxy-δ-(trifluoromethoxy)phenyl)-6-phenyl-l-oxa-7- (fert butoxycarbonyl)aza-spiro[4.δldecane 0 A mixture of 2-benzyloxy-δ-(trifluoromethoxy)iodobenzene

(Preparation 13, 21.8g, 55.2mmol), (δ7?,6S)-6-phenyl-l-oxa-7-(tert- 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 (5 x). 5 Palladium acetate (491mg, 2.2mmol) was added and the mixture was degassed with a firestone valve (δ x). The mixture was stirred at 60°C for lδ hours, then further 2-benzyloxy-δ-(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:2δ increasing to 0:100) then dichloromethane/ethyl acetate (9δ:δ), to give the title compound (9.42g, 73%). Ή NMR (360MHz, CDC1₃) δ 7.δ6 (2H, d, J=7.7 Hz), 7.40-7.20 (8H, m), 7.14 (IH, d, =2.0 Hz), 7.00 (IH, dd, J=8.9, 2.0 Hz), 6.88 (IH, d, =8.9 0 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), 2.1δ (IH, m), 1.96 (IH, m), 1.67 (3H, m), and 1.42 (9H, s).

PREPARATION 17 δ (3 ,δi?.6g)-3-(2-Hvdroxy-δ-(trifluoromethoxy)phenyl)-6-phenyl-l-oxa-7-

( er -butoxycarbonyl)aza-spiro [4. δl decane

Palladium on carbon (10%, 0.δ9g) was added to a solution of

(3i?,δi?,6iS)-3-(2-benzyloxy-δ-(trifluoromethoxy)phenyl)-6-phenyl-l-oxa-7-

(tert-butoxycarbonyl)aza-spiro[4.δ]decane (Preparation 16, 6.10g, 0 lO.δmmol) in methanol-water (99:1, 200ml) and the mixture was stirred under hydrogen (δO 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, CDC1₃) 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, .7=9.4 Hz), δ.43 (IH, s), 4.27 (IH, m), 4.01 (IH, ), 3.9δ (IH, m), 3.73 (IH, m), 2.73 (2H, m), 2.33 (IH, m), 1.87-l.δ8 (4H, m), and l.δO (9H, s).

10 PREPARATION 18

(35.δi?.6g)-3-r2-(l-Phenylthiocvcloprop-l-yl)oxy-δ- (trifluoromethoxy)phenyll-6-phenyl-l-oxa-7-(t^gr^-butoxycarbonyl)aza- spiro [4. δ] decane

(3S,δi?,6S)-3-(2-Hydroxy-δ-(trifluoromethoxy)phenyl)-6-phenyl-l- lδ oxa-7-(ter^-butoxycarbonyl)aza-spiro[4.δ]decane (Preparation lδ) (290mg, O.δ9mmol) 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, 0.65mmol) was then added over one minute at room temperature. The

20 mixture was stirred at 5δ°C for 4 hours, then further portions of silver carbonate (179mg, 0.6δmmol) 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 5 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, CDCI3) δ 7.δδ-7.44 (4H, m), 7.36-7.23 (7H, m), 7.13-7.02 (2H, m), δ.16 (IH, br s), 4.09 (IH, t, =6 Hz), 4.03-3.92 (IH, m), 3.67-3.49 (2H, m), 2.94-2.79 (IH, m), 2.26 (IH, dd, =7.9, 12.9 Hz), 2.1δ-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

(37 .δ7 ,65^l -3-[2-(l-Phenylthiocvcloprop-l-yl)oxy-δ- (trifluoromethoxy)phenyll-6-phenyl-l-oxa-7-(tβrt-butoxycarbonyl)aza- spiro [4.5] decane 5 Prepared from (3Λ,δΛ,6S)-3-(2-hydroxy-δ-

(trifluoromethoxy)phen} )-6-phenyl-l-oxa-7-(teri-butoxycarbonyl)aza- spiro [4. δ] decane (Preparation 17) according to the method of Preparation 18. Η NMR (360MHz, CDC1₃) δ 7.δ7 (2H, app. d, =7.6 Hz), 7.4δ (2H, app. d, =7.7 Hz), 7.36-7.19 (7H, m), 7.16-7.06 (2H, m), δ.28 (IH, br s), 0 4.13 (IH, app. t, J=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, =13, 7.9 Hz), 2.17 (IH, dt, =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

(35,57?,65^l)-3-|^"2-Cvclopropoxy-δ-(trifluoromethoxy)phenyll-6-phenyl-l-oxa- 7-(fβrf:-butoxycarbonyl)aza-spiro[^"4.5]decane

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 (3S,δi?,6S)-3-[2-(l-phenylthiocycloprop- l-yl)oxy-δ-(trifluoromethoxy)phenyl]-6-phenyl-l-oxa-7-(teri- 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 (MgSO₄) 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 (58.6mg, 59%). Η NMR (250MHz, CDC1₃) δ 7.58-7.δ2 (2H, m), 7.36-7.17 (4H, m), 7.10-7.01 (2H, m), 5.18 (IH, br s), 4.20 (IH, t, ,7=6.7 Hz), 4.05-3.9δ (IH, m), 3.76-3.5δ (3H, m), 2.92-2.79 (IH, m), 2.37 (IH, dd, .7=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⁺) δ34 (M+l).

PREPARATION 21

(3i?.5ig,6<S)-3-r2-Cvclopropoxy-5-(trifluoromethoxy)phenvn-6-phenyl-l-oxa- 7-(tβrt-butoxycarbonyl)aza-spirof4.51decane

10 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 (37?,5i?,6S')-3-[2-(l-phenylthiocycloprop-l-yl)oxy-5- lδ (trifluoromethoxy)phenyl]-6-phenyl-l-oxa-7-(ier^-butoxycarbonyl)aza- spiro[4.5]decane (Preparation 19, 135mg, 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 (MgSO₄) and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting δ with hexane/ethyl acetate (δ0:δ0) to give the title compound as a colourless oil (87mg, 78%). Η NMR (360MHz, CDCI3) δ 7.δ9 (2H, app. d, J=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), 2.55 (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

(35'.57?,65 -3-[2-Cvclopro^poxy-δ-(trifluoromethoxy)^phenyll-6-phenyl-l-oxa- 7-aza-spiro [4. δ] decane Hydrochloride δ Trifluoroacetic acid (2. ml) was added dropwise to a stirred, cooled

0°C) solution of (3S',δi?,6S)-3-[2-cyclopropoxy-δ-(trifluoromethoxy)phenyl]- 6-phenyl-l-oxa-7-(ter^-butoxycarbonyl)aza-spiro[4.δ]decane (Preparation 20; 492mg, 0.92mmol) in dichloromethane (2δml) and the mixture was stirred at room temperature for 3 hours! The mixture was poured into

10 water (δOml), the pH was adjusted to 10.0 with aqueous sodium hydroxide (4M) and the mixture was extracted with dichloromethane (3xδ0ml). 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 lδ 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 (1M, 1.8ml, 1.8mmol) was added dropwise. The mixture was stirred at 0°C for δ minutes, then the solvent was evaporated under reduced pressure. The residue was crystallized from ether (20ml)/ethanol 0 (O.δml) and the solid was collected and dried in υacuo to give the title compound as a colorless solid (3δ4mg, 89%). m.p. 214-216 °C, Η NMR (δOOMHz, CD₃OD) δ 7.59 (2H, m), 7.δ2 (3H, m), 7.26 (IH, d, =8.9 Hz), 7.03 (IH, dd, Hz), 4.85 (2H, br s), 4.43 (IH, s), 4.19 (IH, t, =8.0 Hz), 3.87 (IH, quin, =8.0 Hz), 3.76 (IH, m), 5 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. C₂₄H₂₆F₃NO₃.HCI requires: C, 61.34; H, 5.79; N, 2.98%. COMPOUND B

(37 ,δ7?,6ι$^r)-3-r2-Cyclopropox^y-δ-(trifluoromethoxy)^phenyll-6-phenyl-l-oxa- 7-aza-spiro[4.δ]decane

Prepared from the compound of Preparation 21 according to the δ method used for Compound A. Η NMR (360MHz, CDC1₃) δ 7.δ0-7.42 (2H, m), 7.36-7.26 (3H, m), 7.03 (IH, d, =8.9 Hz), 6.9δ (IH, br. d, =8.9 Hz), 6.81 (IH, br s), 3.92 (IH, t, =7.4 Hz), 3.62-3.δ3 (2H, m), 3.δ0 (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), 0.76-0.6δ (2H, ), and 0.6δ-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-δ-(trifluoromethoxy)benzaldehyde 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 0 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 (MgSO₄) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with 5 hexane/Et2θ (95:δ), to give the title compound as a yellow oil (191 mg, 27%). NMR (360MHz, CDCI3) δ 1.51-1.56 (2H, m), 1.44-1.48 (2H, m), 7.25-7.3δ (7H, m), 7.69 (IH, d, 2.0 Hz), and 10.26 (IH, s). DESCRIPTION 2

2-Cvclopropoxy-δ-(trifluoromethoxy)benzaldehyde

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 δ 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

10 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 (MgSO₄) and the solvent was evaporated under reduced pressure. The residue was purified by flash column

Iδ chromatography on silica gel, eluting with hexane/Et2θ (80:20), to give to give the title compound as a colourless oil (4 mg, 6%). *H NMR (360MHz, CDC1₃) 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).

0 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 δ allowed to cool to room temperature, acidified to pH 1 with aqueous hydrochloric acid (1M) and extracted with ethyl acetate. The combined organic fractions were dried (MgSO₄), 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 0 the title compound as a yellow oil (2.25 g, 89%). Η NMR (360MHz, CDCI₃) δ 10.53 (IH, s), 8.01 (IH, d, 3.0 Hz), 7.49 (IH, dd, 9.1, 3.0 Hz), and 7.23 (IH, d, 9.1 Hz).

DESCRIPTION 4

2-(l-Phenylthiocvcloprop-l-^yl)oxy-δ-(trifluoromethoxy)nitrobenzene Prepared from the compound of Description 3 according to the method of Description 1. Η NMR (360MHz, CDC1₃) δ 7.73 (IH, d, 2.7 Hz), 7.δ8 (IH, d, 9.2 Hz), 7.δ0-7.24 (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.δ6 (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-Phenylthiocycloprop-l-yl)oxy-δ-(trifluoromethoxy)benzeneamine 20 Iron powder (13. δ 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 (7δ mL) and the mixture was stirred at 80 °C overnight. The mixture was cooled and filtered through celite, washing with ether. The filtrate was 2δ extracted with ether, the combined organic fractions were washed with aqueous sodium hydroxide (1M), dried (MgSO₄), 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 iH NMR (360MHz, CDCI3) δ 7.48 (2H, m), 7.34-7.23 (3H, m), 7.15 (IH, d, J - oU "

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-Cvclopropoxy-5-(trifluoromethoxy)benzeneamine

Prepared from the compound of Description 6 according to the method of Description 2. *H NMR (360MHz, CDC1₃) δ 7.06 (IH, dd, 2.8, 6.7 Hz), 6.δ6 (2H, m), 3.83 (2H, br s), 3.74 (IH, m), and 0.79 (4H, m). m/z (ES⁺) 234 (M+l).

10

DESCRIPTION 8

2-Cyclopropoxy-δ-(trifluoromethoxy)iodobenzene

An ice-cooled solution of sodium nitrite (3.δδ g, δl mmol) in water (10 mL) was added dropwise to a stirred, cooled (0 °C) solution of lδ 2-cyclopropoxy-δ-(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.δ5 g, 51. δ mmol) in water (10 mL) was added dropwise, maintaining the internal temperature at 0 °C. The mixture was

20 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 (MgSO₄), and the solvent was evaporated under reduced pressure. The residue was purified by flash column δ chromatography on silica gel, eluting with hexane/Et2θ (98:2 increasing to 9δ:δ), to give the title compound as a colourless oil (6.23 g, 88%). Η NMR (360MHz, CDCI3) δ 7.62 (IH, d, J 2.4 Hz), 7.20 (IH, dd, J 9.1, 2.4 Hz), 7.15 (IH, d, 9.1 Hz), 3.80 (IH, m), and 0.83 (4H, m). - o JL ~

DESCRIPTION 9

2-Cvciopropoxy-δ-(trifluoromethoxy)benzaldehyde

A solution of 2-cyclopropoxy-δ-(trifluoromethoxy)iodobenzene (Description 8, 0.344 g, 1 mmol) in toluene (2.δ mL) was degassed with δ bubbling nitrogen for 10 min. Tetrakis(triphenylphosphine)palladium (0) (lδ mg) was added, the mixture was degassed with bubbling nitrogen for a further δ min., then carbon monoxide was bubbled through the mixture for 10 min. The mixture was warmed to δO °C and a solution of tributyl tin hydride (0.3 mL, 1.1 mmol) in toluene (δ mL) was added at a rate of 2

10 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 (δ0%) was added. The mixture was stirred at room temperature overnight, filtered and the layers were separated. The organic layer was dried (MgSO₄), and the solvent was lδ evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with hexane/Et₂O (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). 0

DESCRIPTION 10

(±)-(2it'g)-l-tβr^-Butoxycarbonyl-2-phenylpiperidin-3-one

Dimethyl sulfoxide (32.0 mL, 35.3 g, 0.4δ mol) in dichloromethane

(100 mL) was added dropwise to a cooled (-70 °C) solution of oxalyl 2δ chloride (18.7 mL, 27. δ g, 0.22 mol) in dichloromethane (1000 mL). The mixture was stirred at -70 °C for lδ min., then

(2S,3S)-l-^ert-butoxycarbonyl-3-hydroxy-2-phenylpiperidine (prepared by the method described in European Patent Specification number 0 δ28

49δ-A; δO g, 0.18 mol) in dichloromethane (lδO mL) was added dropwise. 30 The mixture was stirred at -70 °C for 1 h., then triethylamine (12δ.8 mL,

91.3 g, 0.9 mol) was added slowly. The mixture was stirred at room temperature for 1 h., water (2δ0 mL) and aqueous sodium hydrogen carbonate (saturated, 2δ0 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 (MgSO₄) 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, CDC1₃) 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

(± -(27^37 .2S^l3_lS)-l-(t6rt-Butoxycarbonyl -2-phenylpiperidin-3-amine A solution of hydroxylamine hydrochloride (17 g, 0.24 mol) and 5 sodium acetate (5δ.67 g, 0.41 mol) in water (lδO mL) was added to a solution of (±)-(272S)-l-^βrt-butoxycarbonyl-2-phenylpiperidin-3-one (Description 10, 4δ 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 0 ethyl acetate. The organic fraction was washed with brine, dried (MgSO₄) and the solvent was evaporated under reduced pressure. The residue was dissolved in ethanol (400 mL) and Raney nickel (δO 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 δ by flash column chromatography on silica gel, eluting with CH2Ci2/MeOH (100:0 increasing to 85:15), to give the title compound as a colorless oil (10.9 g, 24%). Η NMR (360MHz, CDCI3) δ 7.43 (2H, d, 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). 0 COMPQUND C

(±)-(27^37?.2g3g)-N-{r2-Cvclopropoxy-δ-(trifluoromethoxy)phenvnmethyll-2 -phenylpiperidin-3-amine Dihydrochloride

2-Cyclopropoxy-δ-(trifluoromethoxy)benzaldehyde (Description 9, δδ δ mg, 0.21 mmol) was added to (±)-(2i23i?,2S3S l-(ter«-butoxycarbonyl)-2- phenylpiperidin-3-amine (Description 11, δ8 mg, 0.21 mmol), citric acid

(89 mg, 0.42 mmol) and 3A molecular sieves in dry methanol (δ 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

10 temperature for 2 h. Ethyl acetate was added and the mixture was washed with aqueous hydrochloric acid (0.1M, 2 x 25 mL) and brine (25 mL), dried (MgSO₄) 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 lδ 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 2δ mL) and brine (2δ mL), dried (MgSO₄) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on

20 silica gel, eluting with CH₂Cl2/MeOH/NH₃(Aq.) (96:4:0.4). The residue was dissolved in ethanol (2 mL), cooled in ice and ethereal hydrogen chloride (1M, 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. *H

2δ 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), 3.75 (2H, m), 3.96 (IH, br s), 4.08 (IH, m), 4.9δ (IH, s), 7.23 (IH, s), 7.31 (IH, d, 9.0 Hz), 7.37 (IH, d, J 9.0 Hz), 7.δ4 (3H, m), and 7.67 (2H, m). m/z (ES⁺) 407 (M+l).

30 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 (IC₅₀) 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 δ combination of 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. Ther., 1992, 42, 4δ8. Typically, the receptor is expressed at a level of 3xl0⁵ receptors per cell. Cells are grown in monolayer culture, detached from the plate with enzyme-free dissociation solution lδ (Speciality Media Inc.), and washed prior to use in the assay. ^^l- yr⁸- 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 δxlO⁴ CHO cells. Ligand binding is performed in 0.2δml of δOmM Tris-HCl, pH7.δ, containing δmM MnCl₂, 0 lδOmM 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- δ soaked in 0.1% polyethylenimine using a Tomtek 96-well harvester. Nonspecific binding is determined using excess substance P (lμM) and represents <10% of total binding.

ASSAY 2: Gerbil Foot-Tapping 30 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. δ Male or female Mongolian gerbils (3δ-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 δml/kg i.v. Alternatively, test compounds may be administered orally or by subcutaneous or intraperitoneal routes. A skin

10 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-Pro⁹,Me-Leu¹⁰]-substance P-(7-ll)) is infused directly into the cerebral ventricles (e.g. 3pmol in δμl i.c.v., depending on test substance) by vertical insertion of a cuffed 27 gauge needle to a depth lδ of 4.5mm below bregma. The scalp incision is closed and the animal allowed to recover from anaesthesia in a clear perspex observation box (2δcm x 20cm x 20cm). The duration and/or intensity of hind foot tapping is then recorded continuously for approximately δ minutes. Alternatively, the ability of test compounds to inhibit foot tapping evoked by aversive

20 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.δ kg) are dosed orally by

2δ 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

30 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, δ

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

10 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 lδ minutes and the duration of vocalisation during this baseline period is lδ recorded. Only animals which vocalise for longer than δ minutes are employed for drug challenge studies (approximately δ0% 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

20 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

2δ 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.

30 Essentially, hind foot-tapping in the gerbil induced by infusion of the NK-1 receptor agonist, GR73632 (d Ala[L-Pro⁹,Me-Leu¹⁰]-substance P- (7-11)), under anaesthesia, directly into the central ventricles is inhibited when a CNS-penetrant NK-1 receptor antagonist is administered intravenously immediately prior to GR73632 challenge, wherein hind foot- tapping over a period of five minutes following recovery from the δ 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 0 is inhibited with an ID5o≤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 δ 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 lδ minutes of isolation are attenuated with an IDso<20mg/kg, preferably with an IDso≤lOmg/kg, and especially with an IDso≤δmg/kg. In an alternative method, the NK-1 receptor antagonist is administered orally, 4 hours prior to isolation, wherein vocalisations during the first lδ minutes of isolation are attenuated with an IDso 20mg/kg, preferably with an IDso≤lOmg/kg, and especially with an IDso≤δmg/kg. A suitable selection cascade for NKi antagonists of use according to the present invention is as follows:

(i) Determine affinity for human NKi receptor in radioligand binding studies (Assay 1); select compounds with IC50 ≤ lOnM, preferably IC50 < 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 IDso < 3mg/kg i.v., and preferably IDso < 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 < 2δ-fold loss of potency compared with ID50 determined in step (ii) above with the proviso that ID50 ≤ lOmg/kg i.v., and preferably < δmg/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 IDso < lOmg/kg.

Yet further preferred compounds of use in the present invention may be selected from those compounds which satisfy the NK-1 receptor binding criteria of step (i) which, in addition, have < 5-fold shift in affinity when incubated in the presence of human serum albumin (HSA) to show non-specific protein binding.

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-(δ-oxo-lH,4H-l,2,4-triazolo)methyl)- morpholine, the preparation of which is described in International Patent Specification No. WO 96/16679. In the aforementioned assays, this compound has the following activity:

human NK-1 receptor binding: IC5o=0.1nM gerbil foot-tapping (δ mins.): IDso=0.36mg/kg i.v. gerbil foot-tapping (24 hrs.): IDso=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.

δ The following example illustrates pharmaceutical compositions according to the invention.

EXAMPLE 1 Tablets containing δ0-300mg of NK-1 antagonist

Amount mg NK-1 antagonist 60.0 100.0 300.0

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

0 The active ingredient, cellulose, lactose and a portion of the corn starch are mixed and granulated with 10% corn starch paste. The resulting granulation is sieved, dried and blended with the remainder of the corn starch and the magnesium stearate. The resulting granulation is then compressed into tablets containing 50mg, lOOmg and 300mg of the δ NK-1 receptor antagonist per tablet.

Pharmaceutical compositions comprising a combination of a NK-1 receptor antagonist and an antipsychotic 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 antipsychotic agent will depend upon the choice of active ingredients.

EXAMPLE 2 Tablets containing δ0-300mg of NK-1 antagonist and δ-lOmg 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 184.5 179.5 134.5 129.5 134.5 129.6

Magnesium Stearate 0.5 0.5 0.5 0.5 O.δ 0.5

EXAMPLE 3 Tablets containing 60-300mg of NK-1 antagonist and 2δmg of chlorpromazine hvdrochloride

Amount mg

NK-1 antagonist δθ.0 100.0 300.0 chlorpromazine hydrochloride 25.0 2δ.O 25.0

Microcrystalline cellulose 80.0 80.0 80.0

Modified food corn starch 80.0 80.0 80.0

Lactose 164.5 114.5 114.6

Magnesium Stearate 0.5 0.5 O.δ

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

1. Use of an orally active, long acting, CNS-penetrant NK-1 receptor antagonist for the manufacture of a medicament adapted for oral

5 administration for the treatment or prevention of schizophrenic disorders.

2. 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 schizophrenic disorders

10 in a patient who is non-responsive to antipsychotic agents, or for whom antipsychotic agents are contraindicated.

3. Use of a NK-1 receptor antagonist and an antipsychotic agent for simultaneous, separate or sequential administration for the lδ manufacture of a medicament for the treatment or prevention of schizophrenic disorders.

4. An oral pharmaceutical composition for the treatment of schizophrenic disorders which comprises an orally active, long acting,

20 CNS-penetrant NK-1 receptor antagonist, together with a pharmaceutically acceptable carrier or excipient.

δ. A pharmaceutical composition comprising a NK-1 antagonist and an antipsychotic agent, together with at least one pharmaceutically δ acceptable carrier or excipient.

6. A product comprising a NK-1 receptor antagonist and an antipsychotic agent as a combined preparation for simultaneous, separate or sequential use in the treatment or prevention of schizophrenic 0 disorders.

7. A method for the treatment or prevention of schizophrenic 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. δ

8. A method for the treatment or prevention of psychotic disorders in a patent who is non-responsive to antipsychotic agents, or for whom antipsychotic agents are contraindicated, which method comprises oral administration to the patient in need of such treatment of an effective

10 amount of an orally active, long acting, CNS-penetrant NK-1 receptor antagonist.

9. A method for the treatment or prevention of schizophrenic disorders, which method comprises administration to a patient in need of lδ such treatment of an amount of a NK-1 receptor antagonist and an amount of an antipsychotic agent, such that together they give effective relief.

10. A use according to claim 1, 2 or 3, or a composition according 20 to claim 4 or δ, or a product according to claim 6 or a method according to claim 7, 8 or 9 wherein the NK-1 receptor antagonist is selected from the classes of compounds described in EP-A-677394, WO-A-9508549, WO-A-9518124, WO-A-9623798, WO-A-9605181 and International Patent Application No. PCT/GB97/01630. 25

11. A use according to claim 1, 2 or 3, or a composition according to claim 4 or 5, or a product according to claim 6 or a method according to claim 7, 8 or 9 wherein the NK-1 receptor antagonist is: 2-(S)-(3,δ-bis(trifluoromethyl)benzyloxy)-3(S)-(4-fluorophenyl)-4-(3-(5-oxo-

30 lH,4H-l,2,4-triazolo)methyl)morpholine; 2-(R)-(l-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(3-(δ-oxo-lH,4H- l,2,4-triazolo)methyl)-3-(S)-phenyl-morpholine;

2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-4-(3-(δ-oxo-lH,4H-l,2,4- triazolo)methyl)-3-(S)-phenyl-morpholine; δ 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,δ-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-(5-(N,N- 0 dime thylamino)methyl- 1,2, 3 -triazol-4-yl)methyl- 3 - (S) - (4- fluorophenyl)morpholine;

2-(R)-(l-(R)-(3,δ-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-

4-(3-(4-monophosphoryl-δ-oxo-lH-l ,2,4-triazolo)methyl)morpholine;

2-(R)-(l-(R)-(3,δ-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)- 5 4-(3-(l-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-(2-monophosphoryl-δ-oxo-lH-l,2,4-triazolo)methyl)morpholine;

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; 0 2-(S)-(l-(R)-(3,δ-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-

4-(3-(l-monophosphoryl-δ-oxo-4H-l,2,4-triazolo)methyl)morpholine;

2-(R)-(l-(R)-(3,δ-bis(trifluoromethyl)phenyl)ethoxy)-4-(4-N,N- dimethylaminobut-2-yn-yl)-3-(S)-(4-fluorophenyl)morpholine;

(3S,δR,6S)-3-[2-cyclopropoxy-δ-(trifluoromethoxy)phenyl]-6-phenyl-l-oxa- δ 7-aza-spiro[4.δ]decane;

(3R,δR,6S)-3-[2-cyclopropoxy-δ-(trifluoromethoxy)phenyl]-6-phenyl-l-oxa-

7-aza-spiro[4.δ]decane;

(±)-(2i?3J?,2S3S N-{[2-cyclopropoxy-δ-(trifluoromethoxy)phenyl]methyl}-2- phenylpiperidin-3-amine; 0 or a pharmaceutically acceptable salt thereof.

12. A use according to claim 1, 2 or 3, or a composition according to claim 4 or δ, or a product according to claim 6 or a method according to claim 7, 8 or 9 wherein the schizophrenic disorders are selected from: paranoid, disorganised, catatonic, undifferentiated and residual schizophrenia; schizophreniform disorder; schizoaffective disorder; delusional disorder; brief psychotic disorder; shared psychotic disorder; substance-induced psychotic disorder; and psychotic disorder not otherwise specified.