CA2298779A1 - Use of nk-1 receptor antagonists for treating aggressive behaviour disorders - Google Patents

Abstract

The present invention provides the use of an NK-1 receptor antagonist, and optionally an antipsychotic agent, for the manufacture of a medicament for the treatment or prevention of aggressive behaviour, methods of treatment using such an NK-1 receptor antagonist and pharmaceutical compositions and products comprising it.

Description

AGGRESSIVE BEHAVIOUR DISORDERS
This invention relates to the treatment or prevention of aggressive behaviour by the administration of a NK-1 receptor antagonist.
Aggressive behaviour when uncontrolled or out of proportion to any provocation may give rise to a condition which requires medication.
Individuals with narcissistic, obsessive, paranoid or schizoid traits may be especially prone to outbursts of aggressive behaviour, especially when under stress. When particularly severe, aggressive behaviour may lead to job loss, difficulties with marriage and interpersonal relationships, school suspension, accidents, hospitalization or incarceration.
Treatment of aggressive behaviour is with drugs and psychological management. Typically, antipsychotic drugs such as haloperidol or chlorpromazine may be used to control symptoms. However, antipsychotic drugs are 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.
Studies into the possible CNS site for aggressive behaviour have focused upon the amygdala. In cats, electrical stimulation of the amygdala facilitates the emergence of "defensive rage" syndrome elicited by stimulation of the hypothalamus. This syndrome comprises attack behaviour and vocalisation which is accompanied by marked sympathetic arousal. The antidepressants imipramine, desmethylimipramine and chlorimipramine have been found to block attack behaviour caused by hypothalamic stimulation in cats (B. Dubinsky & M.E. Goldberg, Neuropharmacology (1971) 10:537). The neurochemical mechanisms underlying amydaloid modulation of aggressive behaviour in the cat have been investigated by Allan Siegel and his co-workers (Aggressive Behaviour (1995) 21:49-62). Whilst it is clear that substance P has a role as a principle neurotransmitter in the pathway between the medial nucleus of the amygdala to the medial hypothalamus, the apparent organisation of pathways from the amydala which modulate defensive rage behaviour at the level of the medial hypothalamus and the midbrain periaqueductal gray (PAG) sites, suggests that substance P is one of many neurotransmitters which are intimately involved in the aggressive behaviour response.
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 95123798).
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). However, such as regimen would not be free of side-effects due to the serotonin agonist or SSRI.
There is no disclosure in WO 96/24353 that would lead one to conclude that an NK-1 receptor antagonist alone would be effective in the treatment of aggressive behaviour disorders. Furthermore, there is no direction in 3 that would lead the skilled reader to the identification of any NK-1 receptor antagonist that would be effective in the treatment of aggressive behaviour disorders. Also, it will be appreciated that agonism of the 5-HT1A receptor and inhibition of serotonin reuptake are not generally recognised as mechanisms associated with the action of antipsychotic drugs.

In view of the short-comings of existing agents for the treatment of aggressive behaviour, there is a need for new, safe and effective treatment of aggressive behaviour.
The present invention accordingly provides the use of a NK-1 receptor antagonist for the manufacture of a medicament for the treatment or prevention of aggressive behaviour.
The present invention also provides a method for the treatment or prevention of aggressive behaviour, which method comprises administration to a patient in need of such treatment of an effective amount of a NK-1 receptor antagonist.
In a further aspect of the present invention, there is provided a pharmaceutical composition for the treatment or prevention of aggressive behaviour comprising a NK-1 receptor antagonist, together with at least one pharmaceutically acceptable carrier or excipient.
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 aggressive behaviour. Such a combination would be expected to provide for a rapid onset of action to treat an aggressive outburst thereby enabling use on an "as needed basis".
Furthermore, such a combination may enable a lower dose of the antispychotic 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 aggressive behaviour.

The present invention also provides a method for the treatment or prevention of aggressive behaviour, 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 aggressive behaviour. 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 aggressive behaviour.
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 "aggressive behaviour" includes explosive personality disorder, intermittent explosive disorder, aggressive personality, aggressive nature, aggressiveness, excessive emotional instability, pathological emotionality, quarrelsomeness, dementia with behavioural disturbance, and personality change of the aggressive type due to a general medical condition.
Aggressive behaviour may also be associated with substance intoxication, substance withdrawal, oppositional defiant disorder, conduct disorder, antisocial personality disorder, borderline personality disorder, a manic episode and schizophrenia.
As used herein, the term "treatment" refers both to the treatment and to the prevention or prophylactic therapy of aggressive behaviour.
NK-1 receptor antagonists of use in the present invention 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.
90105525, 90105729, 91/09844, 91118899, 92/01688, 92/06079, 92/12151, 92/15585, 92/17449, 92/20661, 92/20676, 92/21677, 93/00330, 93/00331, 93101159, 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, 94110167, 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//7382, 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, 97103066, 97/08144, 97/14671, 97/17362, 97/18206, 97/19084, 97/19942, 97/21702, 97/30055, 97/38692, 97/49710 and 98/01450 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, 2 302 689, and 2 309 458.
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. Suitable examples of dibenzazepines include clozapine and olanzapine. 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, ffuphenazine hydrochloride, flurphenazine enathate, fluphenazine decanoate, trifluoperazine hydrochloride, thiothixene hydrochloride, haloperidol decanoate, loxapine succinate and molindone hydrochloride. Perphenazine, chlorprothixene, clozapine, olanzapine, haloperidol, pimozide and risperidone are commonly used in a non-salt form.

WO 99/0?375 PCT/EP98/04933 _7_ Particularly preferred NK-1 receptor antagonists are those described in European Patent Specification No. 0 577 394, i.e. compounds of formula (I):

R2 wN Rs R~
or a pharmaceutically acceptable salt thereof, wherein:
Rl is selected from the group consisting of:
(1) hydrogen;
(2) C1-salkyl, unsubstituted or substituted with one or more of the substituents selected from:
(a) hydroxy, (b) oxo, (c) C i-salkoxy, (d) phenyl-C1-salkoxy, (e) phenyl, (fj -CN, (g) halo, (h) -NR9R1~, wherein R9 and Rl~ are independently selected from:
(i) hydrogen, (ii) C1-salkyl, (iii) hydroxy-C1-salkyl, and (iv) phenyl, (i) -NR9COR1~, wherein R9 and Rl~ are as defined above, (j) -NR9C02R1~, wherein R9 and R1~ are as defined above, (k) -CONR9R1~, wherein R9 and Rl~ are as defined above, (1) -COR9, wherein R9 is as defined above, (m) -COzR9, wherein R9 is as defined above, _g_ (n) heterocycle, wherein the heterocycle is selected from the group consisting of:

(A) benzimidazolyl, (B) benzofuranyl, (C) benzthiophenyl, (D) benzoxazolyl, (E) furanyl, (F) imidazolyl, (G) indolyl, (H) isoxazolyl, (I) isothiazolyl, (J) oxadiazolyl, (K) oxazolyl, (L) pyrazinyl, (1VI) pyrazolyl, (I~ pyridyl, (O) pyrimidyi, (P) pyrrolyl, (fa) quinoiyl, (R.) tetrazolyl, (S) thiadiazolyl, (T) thiazolyl, (U) thienyl, triazolyl, (V~ azetidinyl, (X) 1,4-dioxanyl, {~ hexahydroazepinyl, (Z) oxanyl, (AA) piperazinyl, (AB) piperidinyl, (AC) pyrrolidinyl, _g-(AD) tetrahydrofuranyl, and (AE) tetrahydrothienyl, and wherein the heterocylcle is unsubstituted or substituted with one or more substituent(s) selected from:
(i) C1-salkyl, unsubstituted or substituted with halo, -CFs, -OCHs, or phenyl, (ii) C1-salkoxy, (lll) OXO, (iv) hydroxy,-(v) thioxo, (vi) -SR9, wherein R9 is as defined above, (vii) halo, (viii) cyano, (ix) phenyl, (x) trifluoromethyl, (xi) -(CH2)m-NR9R1, wherein m is 0, 1 or 2, and R9 and Rlo are as defined above, (xii) -NR9COR1~, wherein R9 and Rlo are as defined above, (xiii) -CONR9Rlo, wherein R9 and Rlo are as defined above, (xiv) -COZR9, wherein R9 is as defined above, and (xv) -(CH2)m-OR9, wherein m and R9 are as defined above;

(3) Ca-salke nyl, unsubstituted or substituted with one or more of the substituent(s) selected from:

(a) hydroxy, (b) oxo, (c) Cl.salkoxy, (d) phenyl-Ci-salkoxy, (e) phenyl, (f) -CN, (g) halo, (h) -CONR9R1~, wherein R9 and Rlo are as defined above, (i) -COR9, wherein Rs is as defined above, (j) -CO2R9~ wherein Rs is as defined above, {k) heterocycle, wherein the heterocycle is as defined above;
(4) Cz-salkynyl;

(5) phenyl, unsubstitued or substituted with one or more of the substituent(s) selected from:

(a) hydroxy, (b) Ca-salkoxy, (c) Ci-salkyl, (d) Cz-salkenyl, (e) halo, (f) -CN, (g) -NOz, (h) -CFs, (i) -(CH2)m-NR9R~~, wherein m, R9 and Rl~
are as defined above, {j) -NR9COR1~, wherein R9 and Rl~ are as defined above, (k) -NR9C02R1~, wherein R9 and Rl~ are as defined above, (1) -CONR9R1~, wherein R9 and Rl~ are as defined above, (m) -C02NR9R1~, wherein R9 and Rl~ are as defined above, (n) -COR9, wherein R9 is as defined above, (o) -COzR9, wherein R9 is as defined above;

Rz and R3 are independently selected from the group consisting of:
(1) hydrogen;
(2) C1-salkyl, unsubstituted or substituted with one or more of the substituents selected from:
(a) hydroxy, (b) oxo, (c) Ci-salkoxy, (d) phenyl-Ci-salkoxy, (e) phenyl, (f) -CN, (g) halo, (h) -NR9R1, wherein R9 and Rl are independently selected from:
(i) -NR9COR1, wherein R9 and Rl are as defined above, (j) -NR9COaR1, wherein R9 and Rl are as defined above, (k) -CONR9R1, wherein R9 and Rl are as defined above, (1) -COR9, wherein R9 is as defined above, and (m) -C02R9, wherein R9 is as defined above;

(3) Cz-salkenyl, unsubstituted or substituted with one or more of the substituent(s) selected from:

(a) hydroxy, (b) oxo, (c) C 1-salkoxy, (d) phenyl-C1-salkoxy, (e) phenyl, (fj -CN, (g) halo, (h) -CONR9R1 wherein R9 and Rl are as defined above, (i) -COR9, wherein R9 is as defined above, (j) -COzR9, wherein R9 is as defined above;

(4) Ca.salkynyl;

(5) phenyl, unsubstituted or substituted with one or more of the substituent(s) selected from:

(a) hydroxy, (b) Cl.salkoxy, (c) Ci-salkyl, (d) Cz-salkenyl, (e) halo, (fj -CN, (g) -N02, (h) -CFs, (i) -(CH2)m-NR9Rls, wherein m, Rs and Rl~ are as defined above, (j) -NR9COR1~, wherein R9 and Rl~ are as defined above, (k) -NR9C02R1~, wherein R9 and Rl~ are as defined above, (1) -CONR9R1~, wherein R9 and Rl~ are as defined above, (m) -COzNR9Rl~, wherein R9 and Rl~ are as defined above, (n) -COR9, wherein R9 is as defined above, (o) -COzR9, wherein R9 is as defined above;
and the groups Rl and RZ may be joined together to form a heterocyclic ring selected from the group consisting of:
(a) pyrrolidinyl, (b) piperidinyl, (c) pyrrolyl, (d) pyridinyl, (e) imidazolyl, (f) oxazolyl, and (g) thiazolyl, and wherein the heterocyclic ring is unsubstituted or substituted with one or more substituent(s) selected from:
(i) C1-salkyl, (ii) oxo, (iii) C1-salkoxy, (iv) -NR9R1~, wherein R9 and Rl~ are as defined above, (v) halo, and (vi) triffuoromethyl;

and the groups R2 and R3 may be joined together to form a carbocyclic ring selected from the group consisting o~
(a) cyclopentyl, (b) cyclohexyl, (c) phenyl, and wherein the carbocyclic ring is unsubstituted or substituted with one or more substituents selected from:
(i) Ci.salkyl, (ii) Cl.salkoxy, (iii) -NR9R1°, wherein R° and Rl° are as defined above, (iv) halo, and (v) trifluoromethyl;
and the groups RZ and R3 may be joined together to form a heterocyclic ring selected from the group consisting o~
(a) pyrrolidinyl, (b) piperidinyl, (c) pyrrolyl, (d) pyridinyl, (e) imidazolyl, (f) furanyl, (g) oxazolyl, (h) thienyl, and (i) thiazolyl, and wherein the heterocyclic ring is unsubstituted or substituted with one or more substituent(s) selected from:
(i) Cl.salkyl, (ii) oxo, (iii) Ci.salkoxy, (iv) -NR9R1°, wherein R° and Rl° are as defined above, (v) halo, and (vi) trifluoromethyl;
X is selected from the group consisting of (1) -O-, (2) (3) -SO-, and {4) -S02-;

R4 is selected from the group consisting of:
{1) Rs R
,Y
Rs (2) -Y-Ci-salkyl, wherein alkyl is unsubstituted or substituted with one or more of substituents selected from:
the (a) hydroxy, (b) oxo, (c) C i-salkoxy, (d) phenyl-C1-salkoxy, (e) phenyl, (f) -CN, (g) halo, (h) -NR9R10, wherein R9 and R10 are as defined above, (i) -NR9COR1~, wherein R9 and Rl~ are as defined above, (j) -NR9COzRl~, wherein R9 and Rl~ are as defined above, (k) -CONR9R1~, wherein R9 and Rl~ are as defined above, (1) -COR9, wherein R9 is as defined above, (m) -COzR9, wherein R9 is as defined above;

(3) -Y-C2-salkenyl, wherein the alkenyl is unsubstituted or substituted with one or more of the substituent(s) selected from:

(a) hydroxy, (b) oxo, (c) C i-salkoxy, (d) phenyl-Ci-salkoxy, (e) phenyl, (f) -CN, (g) halo, (h) -CONR9R1, wherein R9 and Rl are as defined above, (i} -COR9, wherein R9 is as defined above, (j) -COzR9, wherein R9 is as defined above, (4) -O(CO)-phenyl, wherein the phenyl is unsubstituted or substituted with one or more of Rs, R~and Rs;
R5 is selected from the group consisting of:
(1) phenyl, unsubstituted or substituted with one or more of Rll, R12 and Rla ;
(2) C1-salkyl, unsubstituted or substituted with one or more of the substituent(s) selected from:
(a) hydroxy, (b) oxo, (c) C1-salkoxy, (d) phenyl-Ci-salkoxy, (e) phenyl, (f) -CN, (g) halo, (h) -NR9R1, wherein R9 and Rl are as defined above, (i) -NR9COR1, wherein R9 and Rl are as defined above, (j) -NR9COZR1, wherein R9 and Rl are as defined above, (k) -CONR9R1, wherein R9 and Rl are as defined above, (1) -COR9, wherein R9 is as defined above, (m) -COzR9, wherein R9 is as defined above;

(3) CZ-salkenyl, unsubstituted or substituted with one or more of the substituent(s) selected from:

(a) hydroxy, (b) oxo, (c) C1-salkoxy, (d) phenyl-Ci-salkoxy, (e) phenyl, (fj -CN, (g) halo, (h) -CONR9R1, wherein R9 and Rl are as defined above, (i) -COR9, wherein R9 is as defined above, (j) -C02R9, wherein R9 is as defined above;

(4) heterocycle, wherein the heterocycle is as defined above;

Rs, R7 and R8 are independently selected from the group consisting of:
(1) hydrogen;

(2) C1-salkyl, unsubstituted or substituted with one or more of the substituents selected from:

{a) hydroxy, (b) oxo, (c) Ci-salkoxy, (d) phenyl-Cl-aalkoxy, (e) phenyl, (fj -CN, (g) halo, (h) -NR9R1, wherein R9 and Rl are as defined above, (i) -NR9COR1, wherein R9 and Rl are as defined above, (j) -NR9COzR1, wherein R9 and Rl are as defined above, (k) -CONR9R1, wherein R9 and Rl axe as defined above, (1) -COR9, wherein R9 is as defined above, and (m) -COzR9, wherein R9 is as defined above;

(3) C2-salkenyl, unsubstituted or substituted with one or more of the substituent(s) selected from:

{a) hydroxy, (b) oxo, (c) Ci-salkoxy, (d} phenyl-Ci-salkoxy, (e) phenyl, -CN, (g) halo, -(h) -CONR9R1 wherein R9 and Rl are as defined above, (i) -COR9 wherein R9 is as defined above, (j) -C02R9, wherein R9 is as defined above;

(4) Cz-salkynyl;

(5} phenyl, unsubstituted or substituted with one or more of the substituent(s) selected from:

(a) hydroxy, (b) Ci-salkoxy, (c) C1-salkyl, (d) Ca-salkenyl, (e) halo, (f) -CN, (g) -NO2, (h) -CFs, (i) -(CHs)m-NR9R1, wherein m, R9 and Rl are as defined above, (j) -NR9COR1, wherein R9 and Rl are as defined above, (k) -NR9C02R1, wherein R9 and Rl are as defined above, (1) -CONR9R1, wherein Rg and Rl are as defined above, (m) -C02NR9R1, wherein R9 and Rl are as defined above, (n) -COR9, wherein R9 is as defined above;

(o) -COzR9, wherein R9 is as defined above;

(6) halo, (7) -CN, (8) -CFs, (9) -NOz, (10) -SRI4, wherein Rl~ is hydrogen or CI-salkyl, (11) -SORI4, wherein RI4 is as defined above, (12) -SO2R14, wherein RI4 is as defined above, (13) NR9COR1~, wherein R9 and Rl~ are as defined above, (14) CONR9COR1~, wherein R9 and Rl~ are as defined above, (15) NR9R1~, wherein R9 and Rl~ are as defined above, (16) NR9C02R1~, wherein R9 and Rl~ are as defined above, (17) hydroxy, (18) C1-salkoxy, (19) COR9, wherein R9 is as defined above, (20) COzR9, wherein R9 is as defined above, RII, RI2 and RI3 are independently selected from the definitions of Rs, R%
and R8, or -OX;
Y is selected from the group consisting of:
(1) a single bond, (2) -O-, (3) -S-, (4) -CO-, (5) -CHz-, (6) -CHRIS-, and {7) -CRlsRls_, wherein RIS and Rls are independently selected from the group consisting of-.
(a) C1-salkyl, unsubstituted or substituted with one or more of the substituents selected from:
(i) hydroxy, (ii) oxo, (iii) C1-salkoxy, (iv) phenyl-C1-salkoxy, (v) phenyl, (vi) -CN, (vii) halo, (viii) -NR9R1, wherein R9 and Rl are as defined above, (ix) -NR9COR1, wherein R9 and Rl are as defined above, (x) -NR9COzR1, wherein R9 and Rl are as defined above, (xi) . -CONR9R1, wherein R9 and Rl are as defined above, (xii) -COR9, wherein R9 is as defined above, and (xiii) -CO2R9, wherein R9 is as defined above;

(b) phenyl, unsubstituted or substituted with one or more of the substituent(s) selected from:

(i) hydroxy, (ii) Ci-salkoxy, (iii) C 1-salkyl, (iv) Cz-salkenyl, (v) halo, (vi) -CN, (vii) -N02, (viii) -CFs, (ix) -(CHz)m-NR9R1, wherein m, R9 and Rl are as defined above, (x) -NR9COR1°, wherein R9 and Rl° are as defined above, (xi) -NR9C02R1°, wherein R9 and Rl° are as defined above, (xii) -CONR9R1°, wherein R9 and Rl° are as defined above, (xiii) -C02NR9R1°, wherein R9 and Rl° are as defined above, (xiv) -COR9, wherein R9 is as defined above, and (xv) -C02R9, wherein R9 is as defined above;

Z is selected from:
(1) hydrogen, (2) C1-4alkyl, and (3) hydroxy, with the proviso that if Y is -O-, Z is other than hydroxy, or if Y is -CHR15-, then Z and R15 may be joined together to form a double bond.
Particularly preferred compounds of formula (I) are those wherein:
Rl is selected from the group consisting o~
(1) Ci-salkyl, substituted with one or more of the substituents selected from:
(a) heterocycle, wherein the heterocycle is selected from the group consisting of:
(A) benzimidazolyl, (B) imidazolyl, (C) isoxazolyl, (D) isothiazolyl, (E) oxadiazolyl, (F) pyrazinyl, (G) pyrazolyl, (H) pyridyl, (I) pyrrolyl, (J) tetrazolyl, (K) thiadiazolyl, (L) triazolyl, and (M) piperidinyl, and wherein the heterocycle is unsubstituted or substituted with one or more substituent(s) selected from:
(i) Ci-salkyl, unsubstituted or substituted with halo, -CFs, -OCHs, or phenyl, (ii) C1-salkoxy, (iii) oxo, (iv) thioxo, (v) cyano, (vi) -SCHs, (vii) phenyl, (viii) hydroxy, (ix) trifluoromethyl, (x) -(CH2)m-NR9Rlo, wherein m is 0, 1 or 2, and R9 and Rlo areindependently selected from:

(I) hydrogen, (II) C1-salkyl, (III) hydroxyCl.salkyl, and (I~ phenyl, (xi) -NR9CORlo, wherein R9 and Rlo are as defined above, and (xii) -CONR9Rlo, wherein R9 and Rlo are as defined above, RZ and R3 are independently selected from the group consisting o~
(1) hydrogen;

(2) C1-salkyl (3) Cz-salkenyl, and (5) phenyl;

X is -O-;
R4 is Rs i R
,Y ~ ' Ra R5 is phenyl, unsubstituted or substituted with halo;
Rs, R7 and R8 are independently selected from the group consisting of:
(1) hydrogen, (2) C1-salkyl, (3) halo, and (4) -CFs;
Y is -O-; and Z is hydrogen or C1-4alkyl;
and pharmaceutically acceptable salts thereof.
Particularly preferred compounds of formula (I) are:
4-(3-(1,2,4-triazolo)methyl)-2(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3(S)-phenyl-morpholine;
4-(3-(1,2,4-triazolo)methyl)-2(S)-(3,5-bis(triffuoromethyl)benzyloxy)-3(R)-phenyl-morpholine;
4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)-2(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3(S)-phenyl-morpholine; and 2-(R)-(1-(R)-(3,5-bis(triouoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)morpholine; or a pharmaceutically acceptable salt thereof.
Further preferred NK-1 receptor antagonists are those described in International (PCT) Patent Specification No. WO 95!18124, i.e. compounds of formula (II):
R~
Y I ,_ R2 R9a O O
Rs (II) R9b N / 4 R
,X
Rs Rs or a pharmaceutically acceptable salt or prodrug thereof, wherein Rl is hydrogen, halogen, Ci-salkyl, Ci-salkoxy, CFs, NOz, CN, SRe, SORa, S02Ra, C02Ra, CONRaRb, Ca-salkenyl, Ca.salkynyl or Ci-4alkyl substituted by Ci-4alkoxy, where Ra and Rb each independently represent hydrogen or Ci-aalkyl;
R2 is hydrogen, halogen, C1-salkyl, C1-salkoxy substituted by C1-4alkoxy or CFa;

R3 is hydrogen, halogen or CFs;
R4 is hydrogen, halogen, C1-salkyl, C1-salkoxy, CFs, NO2, CN, SRa, SORa, SOaRa, COzRa, CONRaRb, C2-salkenyl, C2-salkynyl or Ci_4alkyl substituted by C1-4alkoxy, where Ra and Rb each independently represent hydrogen or C1-4alkyl;
R5 is hydrogen, halogen, Ci-salkyl, Ci.salkoxy substituted by C1-4alkoxy or CFs;
Rs is a 5-membered or 6-membered heterocyclic ring containing 2 or 3 nitrogen atoms optionally substituted by =O, =S or a Ci-4alkyl group, and optionally substituted by a group of the formula ZNR7R8 where Z is C1-salkylene or Cs-scycloalkylene;
R7 is hydrogen, C1-4alkyl, Cs-7cycloalkyi or Cs-7cyc1oa1kylCi-4alkyl, or C2-4alkyl substituted by Ci-4alkoxy or hydroxyl;
R8 is hydrogen, C1-4alkyl, Cs-7cycloalkyl or Cs-7cycloalkylCi-4alkyl, or Ca-4alkyl substituted by one or two substituents selected from C1-4alkoxy, hydroxyl or a 4, 5 or 6 membered heteroaliphatic ring containing one or two heteroatoms selected from N, O and S;
or R~, R8 and the nitrogen atom to which they are attached form a heteroaliphatic ring of 4 to 7 ring atoms, optionally substituted by a hydroxy group, and optionally containing a double bond, which ring may optionally contain an oxygen or sulphur ring atom, a group S(O) or S(O)z or a second nitrogen atom which will be part of a NH or NR~ moiety where R~ is C1-4alkyl optionally substituted by hydroxy or C1-4alkoxy;
or R7, R8 and the nitrogen atom to which they are attached form a non-aromatic azabicyclic ring system of 6 to 12 ring atoms;
or Z, R7 and the nitrogen atom to which they are attached form a heteroaliphatic ring of 4 to 7 ring atoms which may optionally contain an oxygen ring atom;
R9a and R9b are each independently hydrogen or C1-4alkyl, or R9$ and R9b are joined so, together with the carbon atoms to which they are attached, there is formed a Cs-~ ring;

X is an alkylene chain of 1 to 4 carbon atoms optionally substituted by oxo; and Y is a C1-4alkyl group optionally substituted by a hydroxyl group;
with the proviso that if Y is C1-4alkyl, R~ is susbstituted at least by a group of formula ZNR7R$ as defined above.
Particularly preferred compounds of formula (II) are those of formula (IIa) and pharmaceutically acceptable salts thereof:
Ai Y
O 0 I i A2 c N
t RsiX ~ As (IIa) wherein:
A1 is fluorine or CFs;
A2 is fluorine or CFs;
A3 is fluorine or hydrogen;
and X, Y and Rs are as defined in relation to formula (II).
Particularly preferred compounds of formula (II) include:
2-{R,)-(1-(R,)-(3,5-bis(triffuoromethyl)phenyl)ethoxy)-4-(5-(dimethylamino) methyl-1,2,3-triazol-4-yl)methyl-3-(S)-phenylmorpholine;
2-(R,)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(5-(dimethylamino) methyl-1,2,3-triazol-4-yl)methyl-3-(S)-(4-fluorophenyl)morpholine;
and pharmaceutically acceptable salts thereof.
Further preferred NK-1 receptor antagonists are those described in European Patent Specification No. WO 95/23798, i.e. compounds of formula (III):

Rs R3 X Y \ R~
Z Rs (III) g2 /N i Rll (~)p A

or a pharmaceutically acceptable salt thereof, wherein:
RZ and R3 are independently selected from the group consisting of (1) hydrogen, (2) C1-salkyl, unsubstituted or substituted with one or more of the substituents selected from:
(a) hydroxy, (b) oxo, (c) C1-salkoxy, (d) phenyl-C1-3alkoxy, (e) phenyl, (fj -CN, (g) halo, (h) -NR9R1~, wherein R9 and Rl~ are independently selected from:
(i) hydrogen, (ii) C1_salkyl, (iii) hydroxy-C1-salkyl, and (iv) phenyl, (i) -NR9CORls, wherein R9 and Rl~ are as defined above, (j) -NR9C02R1°, wherein R9 and Rl~ are as defined above, (k) -CONR9R1~, wherein R9 and Rl~ are as defined above, (1) -COR9, wherein R9 is as defined above, and (m) -C02R9, wherein R9 is as defined above;
*rB

(3) Cz-salkenyl, unsubstituted or substituted with one or more of the substituent(s) selected from:

(a) hydroxy, (b) oxo, (c) Ci-salkoxy, (d) phenyl-Ci-salkoxy, (e) phenyl, (fj -CN, (g) halo, (h) -CONR9R1~ wherein R9 and Rl~ are as defined above, (i) -COR9 wherein R9 is as defined above, (j) -C02R9, wherein R9 is as defined above;

(4) Ca-salkynyl;

(5) phenyl, unsubstituted or substituted with one or more of the substituent(s) selected from:

(a) hydroxy, (b) C1-salkoxy, (c) Ci.salkyl, (d) Cz-salkenyl, (e) halo, (f) -CN, (g) -NOa, (h) -CFs, (i) -(CHz)m-NR9R1, wherein m, R9 and Rl~ are as defined above, (j) -NR9CORlfl, wherein R9 and Rl~ are as defined above, (k) -NR9COzRl~, wherein R9 and Rl~ are as defined above, (1) -CONR9R1~, wherein R9 and RIB are as defined above, (m) -C02NR9R1~, wherein R9 and Rl~ are as defined above, (n) -COR9, wherein R9 is as defined above, (o) -C02R9, wherein R~ is as defined above;

and the groups R2 and R3 may be joined together to form a carbocyclic ring selected from the group consisting of:
(a) cyclopentyl, (b) cyclohexyl, (c) phenyl, and wherein the carbocyciic ring is unsubstituted or substituted with one or more substituents selected from:
(i) Ci-salkyl,-(ii) C1-salkoxy, (iii) -NR9R1°, wherein R9 and Rl° are as defined above, (iv) halo, and (v) trifluoromethyl;
I5 and the groups R2 and R3 may be joined together to form a heterocyclic ring selected from the group consisting o~
(a) pyrrolidinyl, {b) piperidinyl, (c) pyrrolyl, (d) pyridinyl, (e) imidazolyl, (f) furanyl, (g) oxazolyl, (h) thienyl, and (i) thiazolyl, and wherein the heterocyclic ring is unsubstituted or substituted with one or more substituent(s) selected from:
(i) C1-salkyl, (ii) oxo, (iii) C1-salkoxy, (iv) -NR9R1°, wherein Rs and Rl° are as defined above, (v) halo, and (vi) trifluoromethyl;
R6, R~ and R8 are independently selected from the group consisting o~
(1) hydrogen;
(2) Ci-salkyl, unsubstituted or substituted with one or more of the substituents selected from:
(a) hydroxy, (b) oxo, (c) Cl.ealkoxy, (d) phenyl-C1-salkoxy, (e) phenyl, (f) -CN, (g) halo, (h) -NR9R1~, wherein R9 and Rl~ are as defined above, (i) -NR9COR1~, wherein R9 and Rl~ are as defined above, (j) -NR9C02R1~, wherein R9 and Rl~ are as defined above, (k) -CONR9R1~, wherein R9 and Rl~ are as defined above, (1) -COR9, wherein R9 is as defined above, and (m) -COzR9, wherein R9 is as defined above;

(3) Ca-salkenyl, unsubstituted or substituted with one or more of the substituent(s) selected from:

(a) hydroxy, (b) oxo, (c) C1-salkoxy, (d) phenyl-Cl.aalkoxy, (e) phenyl, (fj -CN, (g) halo, (h) -CONR9R1~ wherein R9 and Rl~ are as defined above, (i) -COR9 wherein R~ is as defined above, (j) -C02R9, wherein R~ is as defined above;
(4) Cz-salkynyl;

(5) phenyl, unsubstituted or substituted with one or more of the substituent(s) selected from:

(a) hydroxy, (b) Ci-salkoxy, (c) C1-salkyl, (d) Ca-salkenyl, {e) halo, (fj -CN, (g) -NO2, (h) -CFs, (i) -(CH2)m-NR9R1, wherein m, R9 and Rl are as defined above, (j) -NR9COR1°, wherein R9 and Rl° are as defined above, (k) -NR9C02R1°, wherein R9 and Rl° are as defined above, (1) -CONR9R1°, wherein R9 and Rl° are as defined above, (m) -COzNR9R1°, wherein R9 and Rl° are as defined above, (n) -COR9, wherein R9 is as defined above, {o) -C02R9, wherein R9 is as defined above;
(6) halo, (7) -CN, {8) -CFs, (9) -NOz, (10) -SR14, wherein Rl4 is hydrogen or C1-salkyl, (11) -SOR14, wherein R14 is as defined above, (12) -SO2R14, wherein R14 is as defined above, (13) NR9COR1°, wherein R9 and Rl° are as defined above, (14) CONR9COR1°, wherein R9 and Rl° are as defined above, (15) NR9R1°, wherein R9 and Rl° are as defined above, (16) NR9C02R1°, wherein R9 and Rl° are as defined above, {17) hydroxy, (18) C1-salkoxy, (19) COR9, wherein R9 is as defined above, (20) COzRs, wherein R9 is as defined above, (21) 2-pyridyl, (22) 3-pyridyl, (23) 4-pyridyl, (24) 5-tetrazolyl, (25) 2-oxazolyl, and (26) 2-thiazolyl;

Rl y Ri2 and R13 are independently selected from the definitions of Rs, R7 and R8, or -OX;
A is selected from the group consisting of:
(1) Ci-salkyl, unsubstituted or substituted with one or more of the substituents selected from:
(a) hydroxy, (b) oxo, (c) C1-salkoxy, (d) phenyl-Cl-aalkoxy, (e) phenyl, (f) -CN, (g) halo, wherein halo is fluoro, chloro, bromo or iodo, (h) -NR9R1~, wherein R9 and Rl~ are as defined above, (i) -NR9COR1~, wherein R9 and Rl~ are as defined above, (j) -NR9COzRl~, wherein R9 and Rl~ are as defined above, (k) -CONR9R1~, wherein R9 and Rl~ are as defined above, (1) -COR9, wherein Rs is as defined above, and (m) -COzR9, wherein R9 is as defined above;

*rB

(2) Cz-salkenyl, unsubstituted or substituted with one or more of the substituent(s) selected from:

(a) hydroxy, (b) oxo, (c) C i-salkoxy, (d) phenyl-Cl.salkoxy, (e) phenyl, (f) -CN, (g) halo, (h) -CONR9R1~ wherein R9 and Rl~ are as defined above, {i) -COR9 wherein R9 is as defined above, and (j) -COzR9, wherein R9 is as defined above;
and (3) C2.salkynyl;
I5 B is a heterocycle, wherein the heterocycle is selected from the group consisting o~
_ X X X
N ~ N-N N-~ N-N
~N~O ~ ~ S
i N O N O N
X H
X
N-~ N-N N-~ N-N X
~N~S ~ ~ ~p'X ~ ~ ,X
X S N N S
X N-N N~ N-N
N-N ~ ~ ,N ~ ,N
N N N
N X X X
*rB

X ~ X
N=N
w N. ~ N ~~O ~ N
~N~ X ~~p N
H X H
/\
S ~ ~ ~X ~~ 'X N
N ~ ~p S
N N X
X
,~N..X N ~ N
X N X
i \ ~ i \ ~ ~ \
X X
and wherein the heterocycle may be substituted in addition to -X with one or more substituent(s) selected from:
(i) Ci.salkyl, unsubstituted or substituted with halo, -CFa, -OCHa, or phenyl, (ii) Ci-salkoxy, (iii) oxo, (iv) hydroxy, (v) thioxo, (vi) -SR9, wherein R9 is as defined above, (vii) halo, (viii) cyano, (ix) phenyl, {x) trifluoromethyl, (xi) -(CH2)m-NR9R1~, wherein m is 0, 1 or 2, and R9 and R1~

are as defined above, *rB

(xii) -NR9COR1°, wherein R° and Rl° are as defined above, (xiii) -CONR9R1°, wherein R9 and Rl° are as defined above, (xiv) -COzR9, wherein R9 is as defined above, and (xv) -(CH2)m-OR9, wherein m and R° are as defined above;
pisOorl;
X is selected from:
(a) -PO(OH)O' ~ M+, wherein M+ is a pharmaceutically acceptable monovalent counterion, (b) -PO(O')2 ~ 2M+, (c) -PO(0')z ~ DZ+, wherein DZ+ is a pharmaceutically acceptable divalent counterion, (d) -CH(R4)-PO(OH)O' ~ M+, wherein R4 is hydrogen or Ci-salkyl, (e) -CH(R4)-PO(O')z ~ 2M+, (fj -CH(R4)-PO(O')2 ~ Dz+~
(g) -SOa' ~ M+, (h) -CH(R.4)-SOs- ~ M+, (i) -CO-CHzCH2-COZ' ~ M+, (j) -CH(CHs)-0-CO-R5, wherein R5 is selected from the group consisting of:

(i) ~O~NH3+M.
HZ+ M.
(ii) wO~N.Rs {iii) w O ~. CO2. M+
COZ M+
) \O C02~M+
(v) C02 M+
(~i) -O C02 M+
C02 M+
COZ M+
(vii) ~O ~ ; and (k) hydrogen, with the proviso that if p is 0 and none of Rll, Riz or R13 are -OX, then X is other than hydrogen;
Y is selected from the group consisting o~
{1) a single bond, (2) -O-, (3) -S-, (4) -CO-, (5) -CH2-, (6) -CHR15-, and (7) -CRl$Rls- , wherein R15 and Rls are independently selected from the group consisting of:

(a) C1-salkyl, unsubstituted or substituted with one or more of the substituents selected from:

(i) hydroxy, (ii) oxo, (iii) C1-salkoxy, (iv) phenyl-Ci-salkoxy, (v) phenyl, (vi) -CN, (vii) halo, (viii) -NR9R1, wherein R~ and Rl are as defined above, (ix) -NR9COR1, wherein R9 and R1 are as defined above, {x) -NR9COaR1, wherein R9 and Rl are as defined above, (xi) -CONR9R1, wherein R9 and Rl are as defined above, (xii) -COR9, wherein R9 is as defined above, and (xiii) -COzR9, wherein Rs is as defined above;

(b) phenyl, unsubstituted or substituted with one or more of the substituent(s) selected from:

(i) hydroxy, (ii) C1-salkoxy, (iii) C1-salkyl, (iv) C2-salkenyl, (v) halo, (vi) -CN, (vii) -NOa, (viii) -CFs, (ix) -(CH2)m-NR9R1, wherein m, R and Rl are as defined above, (x) -NR9COR1, wherein R9 and Rlo are as defined above, (xi) -NR9COzRlo, wherein R9 and Rlo are as defined above, (xii) -CONR9Rlo, wherein R9 and Rlo are as defined above, (xiii) -COaNR9Rlo, wherein R and Rlo are as defined above, (xiv) -COR9, wherein R9 is as defined above, and (xv) -COzR9, wherein R9 is as defined above;

Z is selected from:
(1) hydrogen, (2) C1-salkyl, and (3) hydroxy, with the proviso that if Y is -O-, Z is other than hydroxy, or if Y is -CHR15-, then Z and Ri5 may be joined together to form a double bond.
Particularly preferred compounds of formula (III) are those wherein:
Rz and R3 are independently selected from the group consisting of:
(1) hydrogen, (2) Ci-salkyl, (3) Cz-salkenyl, and (4) phenyl;

Rs, R7 and R$ are independently selected from the group consisting of:

(1) hydrogen, (2) C1-salkyl, (3) ffuoro, (4) chloro, (5) bromo, (6) iodo, and (7) -CFs~

Rll, R12 nd R13 are independently selected from the group a consisting of:

(1) fluoro, (2) chloro, (3) bromo, and (4) iodo;
A is unsubstituted i.salkyl;
B is selected from the group consisting of X
N-~ ~ xN_~ XN-N
~N~O ~ ~~ /\O ~~ ~S
i N ~ N N
X H
N-~ X X
N-N N-~\ N-N
N S ~ S ~ ~O'X ~ ~~ ,X
N N N S
X H
N-NX ~ , ~ N
N N
N X X
X X
/ N O / N
O N S
H x H
x / ~ ,x N ~ D' S , i N N
X
pis0orl;
X is selected from:
(a) -PO(OH)O- ~ M+, wherein M+ is a pharmaceutically acceptable monovalent counterion, (b) -PO(O-)z ~ 2M+, (c) -PO(O-)2 ' D2+, wherein DZ+ is a pharmaceutically acceptable divalent counterion, (d) -CH(R4)-PO(OH)O- ~ M+, wherein R4 is hydrogen or C1-salkyl, _g8_ (e) -CH(R4)-PO(O-)2 ~ 2M+, (fj -CH(R.4)-PO(O-)2 ~ D2+, (i) -CO-CHzCHz-COa' ~ M+, (j) -CH(CH3)-O-CO-R5, wherein R5 is selected from the group consisting o~
(i) ~O~NH3+M-HZ+ M_ (u) ~O~N~OH
( 1) \O~C02 M+ , C02 M+
(iv) W ~ +

/ C02.
(v) O

COZ M+
(vi) -'O COZ M+ , C02 M+
COZ M+
(vii) ~0 ~ I ; and Y is -O-;
Z is hydrogen or C1-salkyl;
and pharmaceutically acceptable salts thereof.

Particularly preferred compounds of formula (III) include:
(1) 2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)morpholine N-oxide;
(2) 2-(S)-(3,5-bis(triffuoromethyl)benzyloxy)-3-(S)-phenyl-4-(3-(4-(ethoxycarbonyloxy-1-ethyl)-5-oxo-1H-1,2,4-triazolo)methyl)morpholine;
(3) 2-(R)-(1-(R)-(3,5-bis(triffuoromethyl)phenyl)ethoxy)-3-(S)-(4 fluorophenyl)-4-(3-(4-monophosphoryl-5-oxo-1H-1,2,4 triazolo)methyl)morpholine;
(4) 2-(R,)-(1-(R)-(3,5-bis(triffuoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(1-monophosphoryl-5-oxo-1H-1,2,4-triazolo)methyl)morpholine;
(5) 2-{R)-(1-(R)-(3,5-bis(trilluoromethyl)phenyl)ethoxy)-3-(S)-(4 fluorophenyl)-4-(3-(2-monophosphoryl-5-oxo-1H-1,2,4 triazolo)methyl)morpholine;
(6) 2-(R,)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(5-oxyphosphoryl-1H-1, 2, 4-triazolo)methyl)morpholine;
(7) 2-(S)-(1-(R)-(3,5-bis(triffuoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(1-monophosphoryl-5-oxo-4H-1,2,4-triazolo)methyl)morpholine;
and pharmaceutically acceptable salts thereof.
Further preferred NK-1 receptor antagonists are those described in European Patent Specification No. WO 96/05181, i.e. compounds of formula (I~:

R' i/

Y
R9a O O Rs 9~
R' X
wherein X is a group of the formula NRsR7 or a C- or N-linked imidazolyl ring;
Y is hydrogen or C1-aalkyl optionally substituted by a hydroxy group;
Rl is hydrogen, halogen, C1-salkyl, Cl.salkoxy, CFs, NOz, CN, SRa, SORa, SOzRa, COzRa, CONRaRb, Cz-salkenyl, Cz-salkynyl or Ci-4alkyl substituted by Ci-4alkoxy, wherein Ra and Rb each independently represent hydrogen or C1-4alkyl;
Rz is hydrogen, halogen, Ci-salkyl, Ci-salkoxy substituted by Ci-4alkoxy or CFs;
R3 is hydrogen, halogen or CFs;
R4 is hydrogen, halogen, Ci-salkyl, C1-salkoxy, hydroxy, CFs, NOz, CN, SRa, SORa, SOzRa, COzRa, CONR$Rb, Cz-salkenyl, Cz-salkynyl or C1-4alkyl substituted by C1-4alkoxy, wherein Ra and Rb are as previously defined;
R5 is hydrogen, halogen, Cl.salkyl, Ci-salkoxy substituted by C1-4alkoxy or CFa;
Rs is hydrogen, C1-salkyl, Cs-7cycloalkyl, Cs-7cycloalkylCi-4alkyl, phenyl, or Cz-4alkyl substituted by Ci-4alkoxy or hydroxy;
R7 is hydrogen, C1-salkyl, Cs.~cycloalkyl, Cs-7cycloalkylCi-4alkyl, phenyl, or Cz-4alkyl substituted by one or two substituents selected from C1-4alkoxy, hydroxy or a 4, 5 or 6 membered heteroaliphatic ring containing one or two heteroatoms selected from N, O and S;
or R~ and R7, together with the nitrogen atom to which they are attached, form a saturated or partially saturated heterocyclic ring of 4 to 7 ring atoms, which ring may optionally contain in the ring one oxygen or sulphur atom or a group selected from NR8, S(O) or S(O)2 and which ring may be optionally substituted by one or two groups selected from hydroxyCi-4alkyl, Cl-4alkoxyCl-4alkyl, oxo, CORa or COzR$ where Ra is as previously defined;
or Rs and R~ together with the nitrogen atom to which they are attached, form a non-aromatic azabicyclic ring system of 6 to 12 ring atoms;
R$ is hydrogen, C1-4alkyl, hydroxyCl-4alkyl or Ci.4alkoxyCi-4alkyl;
and R9a and R9b are each independently hydrogen or C1-4alkyl, or R9a and R9b are joined so, together with the carbon atoms to which they are attached, there is formed a Cs-~ ring;
and pharmaceutically acceptable salts thereof.
Particularly preferred compounds of formula (IV) are those of formula (IVa) and pharmaceutically acceptable salts thereof:
Ai Y ~ Aa O O
(IVa) N
~ A
X
wherein A1 is fluorine or CFa;

AZ is fluorine or CFs;
A3 is fluorine or hydrogen;
and X and Y are as defined in relation to formula {I).
Specific compounds of formula (I~ of use in the present invention include:
2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-ffuorophenyl)-4-(4-morpholinobut-2-yn-yl)morpholine;
2-(R)-(1-(R.)-(3,5-bis(triffuoromethyl)phenyl)ethoxy)-4-(4-N,N-dimethylaminobut-2-yn-yl)-3-(S)-(4-fluorophenyl)morpholine;
4-(4-azetidinylbut-2-yn-yl)-2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl) ethoxy)-3-(S)-(4-fluorophenyl)morpholine;
2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-ffuorophenyl)-4-(4-imidazolylbut-2-yn-yl)morpholine;
2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-{4-fluorophenyl)-4-(4-(N-methylpiperazinyl)but-2-yn-yl)morpholine;
4-(4-bis(2-methoxyethyl)aminobut-2-yn-yl)-2-(R)-(1-(R)-(3,5-bis(triffuoromethyl)phenyl)ethoxy)-3-(S)-(4-ffuorophenyl)morpholine;
2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-ffuorophenyl)-4-(4-pyrrolidinobut-2-yn-yl)morpholine;
3-(S)-(4-fluorophenyl)-2-(R)-{1-(R)-(3-fluoro-5-(trifluoromethyl)phenyl) ethoxy)-4-(4-morpholinobut-2-yn-yl)morpholine;
3-(S)-(4-fluorophenyl)-4-(4-morpholinobut-2-yn-yl)-2-(R)-(1-(R)-(3-(triffuoromethyl)phenyl)ethoxy)morpholine;
4-(4-azetidinylbut-2-yn-yl)-3-(S)-(4-ffuorophenyl)-2-(R)-(1-(R)-(3-(trifluoromethyl)phenyl)ethoxy)morpholine;
2-(R)-(1-(R)-(3, 5-bis(triffuoromethyl)phenyl)ethoxy)-4-(4-(N-(2-methoxyethyl)-N-methyl)aminobut-2-yn-yI)-3-(S)-phenylmorpholine;
2-(R,)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(4-(N-cyclopropyl-N-(2-methoxyethyl)amino)but-2-yn-yl)-3-(S)-phenylmorpholine;
2-(R,)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(4-(N-isopropyl-N-(2-methoxyethyl)amino)but-2-yn-yl)-3-(S)-phenylmorpholine;

4-(4-(N,N-dimethylamino)but-2-yn-yl)-3-(S)-(4-ffuorophenyl)-2-(R)-(1-(S)-(3-ffuoro-5-(triffuoromethyl)phenyl-2-hydroxyethoxy)morpholine;
4-(4-azetidinylbut-2yn-yl)-3-(S)-(4-ffuorophenyl)-2-(R)-(1-(S)-(3-ffuoro-5-(triffuoromethyl)phenyl)-2-hydroxyethoxy)morpholine;
2-(R)-(1-(S)-(3,5-bis(trifluoromethyl)phenyl)-2-hydroxyethoxy)-4-(4-(N,N-dimethylamino)but-2-yn-yl)-3-(S)-(4-ffuorophenyl)morpholine;
4-{4-azetidinylbut-2-yn-yl)-2-(R)-(1-(S)-(3, 5-bis(triffuoromethyl)phenyl-2-hydroxyethoxy)-3-(S)-(4-ffuorophenyl)morpholine;
4-(4-N-bis(2-methoxy)ethyl-N-methylamino)but-2-yn-yl)-2-(R)-(1-(R.)-(3,5-bis(triffuoromethyl)phenyl)ethoxy)-3-(S)-(4-ffuorophenyl)morpholine;
2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-ffuorophenyl)-4-(4-(2-(S)-(methoxymethyl)pyrrolidino)but-2-yn-yl)morpholine;
4-(4-(7-azabicyclo [2.2.1]heptano)but-2-yn-yl)-2-(R)-(1-(R,)-(3, 5-bis(triffuoromethyl)phenyl)ethoxy)-3-(S)-(4-ffuorophenyl)morpholine;
2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(4-diisopropylaminobut-2-yn-yl)-3-(S)-(4-ffuorophenyl)morpholine;
2-(R)-(1-(R,)-(3-ffuoro-5-(triffuoromethyl)phenyl)ethoxy)-4-(4-(2-(S)-(methoxymethyl)pyrrolidino)but-2-yn-yl)-3-(S)-phenylmorpholine;
2-(R.)-{1-(R)-(3, 5-bis(triffuoromethyl)phenyl)ethoxy)-3-(S)-(4-ffuorophenyl)-4-(4-(2-(S)-(hydroxymethyl)pyrroiidino)but-2-yn-yl)morpholine;
and pharmaceutically acceptable salts thereof.
,Another class of NK-1 receptor antagonists of use in the present invention is that described in European Patent Specification No.
0 436 334, i.e. compounds of formula (~:
R' Ra Ri ERs RZ (V) R8-(~) ~6 or a pharmaceutically acceptable salt thereof, wherein Y is (CHa)n wherein n is an integer from 1 to 4, and wherein any one of the carbon-carbon single bonds in said (CH2)~ may optionally be replaced by a carbon-carbon double bond, and wherein any one of the carbon atoms of said (CH2)n may optionally be substituted with R4, and wherein any one of the carbon atoms of said (CH2)n may optionally be substituted with R7;
Z is (CHa)m wherein m is an integer from 0 to 6, and wherein any one of the carbon-carbon single bonds of (CHz)m may optionally be replaced by a carbon-carbon double bond or a carbon-carbon triple bond, and any one of the carbon atoms of said (CH2)m may optionally be substituted with R8.
Rl is hydrogen or Ci-salkyl optionally substituted with hydroxy, Cl.4alkoxy or fluoro;
RZ is a radical selected from hydrogen, Ci-s straight or branched alkyl, Cs-7cycloalkyl wherein one of the CHz groups in said cycloalkyl may optionally be replaced by NH, oxygen or sulphur; aryl selected from phenyl and naphthyl; heteroaryl selected from indanyl, thienyl, furyl, pyridyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl and quinolyl; phenyl-CZ-salkyl, benzhydryl and benzyl, wherein each of said aryl and heteroaryl groups and the phenyl moieties of said benzyl, phenyl -CZ-salkyl and benzhydryl may optionally be substituted with one or more substituents independently selected from halo, nitro, C1-s alkyl, C1-salkoxy, triffuoromethyl, amino, C1-salkylamino, Ci-salkyl-O-CO, Ci-salkyl-O-CO-C1-salkyl, C1-salkyl-CO-O, C1-salkyl-CO-C1-salkyl-O-, C1-salkyl-CO, Ci-salkyl-CO-C1-salkyl-, di-C1-salkylamino, -CONH-C1-salkyl, C1-salkyl-CO-NH-C1-salkyl, -NHCOH and -NHCO-Cl.salkyl; and wherein one of the phenyl moieties of said benzhydryl may optionally be replaced by naphthyl, thienyl, furyl or pyridyl;
Rs is hydrogen, phenyl or Ci-salkyl;

or R2 and Rg together with the carbon to which they are attached, form a saturated ring having from 3 to 7 carbon atoms wherein one of the CHZ groups in said ring may optionally be replaced by oxygen, NH or sulfur;
R3 is aryl selected from phenyl and naphthyl; heteroaryl selected from indanyl, thienyl, furyl, pyridyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl and quinolyl; and cycloalkyl having 3 to 7 carbon atoms wherein one of the {CHz) groups in said cycloalkyl may optionally be replaced by NH, oxygen or sulphur;
wherein each of said aryl and heteroaryl groups may optionally be substituted with one or more substituents, and said Cs-7cycloalkyl may optionally be substituted with one or two substituents, each of said substituents being independently selected from halo, nitro, C1-salkyl, C1-salkoxy, trifluoromethyl, amino, C1-salkylamino, -CO-NH- C1-salkyl, Ci-salkyl-CO-NH-C1-salkyl, -NHCOH and -NHCO-Ci-salkyl;
R4 and R7 are each independently selected from hydroxy, halogen, halo, amino, oxo, cyano, methylene, hydroxymethyl, halomethyl, C1-salkylamino, di-C1-salkylamino, Ci-salkoxy, C1-salkyl-O-CO, C1-salkyl-O-CO-C1-salkyl, Ci-salkyl-CO-O, C1-salkyl-CO-Ci-salkyl-O-, Ci-salkyl-CO-, Ci-salkyl-CO-C1-salkyl, and the radicals set forth in the definition of R2;
Rs is -NHCOR9, -NHCH2R9, S02R$ or one of the radicals set forth in any of the definitions of R2, R4 and R~;
R8 is oximino (=NOH) or one of the radicals set forth in any of the definitions of R2, R4 and R7;
R9 is Cl-salkyl, hydrogen, phenyl or phenylCl-salkyl;
with the proviso that (a) when m is 0, R$ is absent, (b) when R4, Rs, R7 or R8 is as defined in R2, it cannot form together with the carbon to which it is attached ,a ring with R6, and (c) when R4 and R7 are attached to the same carbon atom, then either each of R4 and R7 is independently selected from hydrogen, fluoro and Cl.salkyl, or R4 and R7, together with the carbon to which they are attached, for a Ca-s saturated carbocyclic ring that forms a spiro compound with the nitrogen-containing ring to which they are attached.
A particularly preferred compound of formula (~ is (2S,3S)-cis-3-(2-methoxybenzylamino)-2-phenylpiperidine; or a pharmaceutically acceptable salt thereof.
Another class of NK-1 receptor antagonists of use in the present invention is that described in International Patent Specification No. WO
93/21155, i.e. compounds of formula (VI):

~CH-R1 (VI) z or a pharmaceutically acceptable salt thereof, wherein radicals R are phenyl radicals optionally 2- or 3-substituted by a halogen atom or a methyl radical;
Rl is optionally substituted phenyl, cyclohexadienyl, naphthyl, indenyl or optionally substituted heterocycle;
R2 is H, halogen, OH, alkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkyloxy, alkylthio, acyloxy, carboxy, optionally substituted alkyloxycarbonyl, benzyloxycarbonyl, amino or acylamino;
R3 is optionally 2-substituted phenyl;
R4 is OH or fluorine when Rb is H;
or R4 and R5 are OH ;
or R4 and RS together form a bond.
A particularly preferred compound of formula (VI) is (3aS, 4S, 7aS)-7,7-diphenyl-4-(2-methoxyphenyl)-2-[(2S)-(2-methoxyphenyl)propionyl]
perhydroisoindol-4-0l; or a pharmaceutically acceptable salt thereof.

WO 99/07375 PCTlEP98/04933 Another class of NK-1 receptor antagonists of use in the present invention is that described in European Patent Specification No.
0 591 040, i.e. compounds of formula (VII):
R Q
Ar-T-CO-NI-CH2-~-CH2-CHZ-Am +, A
~r' wherein Ar represents an optionally substituted mono-, di- or tricyclic aromatic or heteroaromatic group;
T represents a bond, a hydroxymethylene group, a C1-4alkoxymethylene group or a Ci-salkylene group;
Ar' represents a phenyl group which is unsubstituted or substituted by one or more substituents selected from halogen, preferably chlorine or fluorine, trifluoromethyl, C1-4alkoxy, C1-4alkyl where the said substituents may be the same or different; a thienyl group; a benzothienyl group; a naphthyl group; or an indolyl group;
R represents hydrogen, C1-4alkyl, u~-C1-4alkoxyCl-4alkyl, or ~-Cz-4alkanoyloxyCz-4alkyl;
Q represents hydrogen;
or Q and R together form a 1,2-ethylene, 1,3-propylene or 1,4-butylene group;
Am+ represents the radical ~c--N , in which Xl, Xz and Xs, together with the nitrogen atom to which they are attached, form an azabicyclic or azatricyclic ring system optionally substituted by a phenyl or benzyl group; and A- represents a pharmaceutically acceptable anion.

A particularly preferred compound of formula (VII) is (+) 1-[2-[3-(3,4-dichlorophenyl)-1-[(3-isopropoxyphenyl)acetyl]-3-piperidinyl]ethyl]-4-phenyl-1-azabicyclo[2,2,2]octane; or a pharmaceutically acceptable salt, especially the chloride, thereof.
Another class of NK-1 receptor antagonists of use in the present invention is that described in European Patent Specification No.
0 532 456, i.e. compounds of formula (VIII):

R1- X2 ~--X3-R~ (VIII) RZ--i or a pharmaceutically acceptable salt thereof, wherein Rl represents an optionally substituted aralkyl, aryloxyalykl, heteroaralkyl, aroyl, heteroaroyl, cycloalkylcarbonyi, aralkanoyl, heteroarylalkanoyl, aralkoxycarbonyl or arylcarbamoyl group or the acyl group of an a-amino acid optionally N-substituted by a lower alkanoyi or carbamoyl-lower alkanoyl group;
R2 represents cycloalkyl or an optionally substituted aryl or heteroaryl group;
R3 represents hydrogen, alkyl, carbamoyl or an alkanoyl or alkenoyl group optionally substituted by carboxy or esterified or amidated carboxy;
R4 represents an optionally substituted aryl group or an optionally partially saturated heteroaryl group;
Xi represents methylene, ethylene, a bond, an optionally ketalised carbonyl group or an optionally etherified hydroxymethylene group;
Xz represents alkylene, carbonyl or a bond; and Xs represents carbonyl, oxo-lower alkyl, oxo(aza)-lower alkyl, or an alkyl group optionally substituted by phenyl, hydroxymethyl, optionally esterified or amidated carboxy, or (in other than the a-position) hydroxy.
A particularly preferred compound of formula (VIII) is (2R*, 4S*)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-(4-quinolinylmethyl)-4-piperidineamine;
or a pharmaceutically acceptable salt thereof.

Another class of NK-1 receptor antagonists of use in the present invention is that described in European Patent Specification No.
0 443 132, i.e. compounds of formula (IX) / \
z /
CHZ
R~
R1-Y-A- N~CONH~HCON / (IX) Ra or a pharmaceutically acceptable salt thereof, wherein Rl is aryl, or a group of the formula:
/
\I
z X is CH or N; and Z is O or N-R5, in which R5 is hydrogen or lower alkyl;
R2 is hydroxy or lower alkoxy;
R3 is hydrogen or optionally substituted lower alkyl;
R4 is optionally substituted ar(lower)alkyl;
A is carbonyl or sulfonyl; and Y is a bond or lower alkenylene.
A particularly preferred compound of formula (IX) is the compound of formula (IXa) HO

\ N ~I~N /
(IXa) H3 \
'0 H~C~ j or a pharmaceutically acceptable salt thereof.
Another class of NK-1 receptor antagonists of use in the present invention is that described in International Patent Specification No. WO
92/17449, i.e. compounds of the formula (X) N J.,.~ Rz H
or a pharmaceutically acceptable salt thereof, wherein Rl is aryl selected from indanyl, phenyl and naphthyl; heteroaryl selected from thienyl, furyl, pyridyl and quinolyl; and cycloalkyl having 3 to 7 carbon atoms, wherein one of said carbon atoms may optionally be replaced by nitrogen, oxygen or sulfur; wherein each of said aryl and heteroaryl groups may optionally be substituted with one or more substituents, and said Cs-7cycloalkyl may optionally be substituted with one or two substituents, said substituents being independently selected from chloro, fluoro, bromo, iodo, nitro, Ci-ioalkyl optionally substituted with from one to three fluoro groups, C1-loalkoxy optionally substituted with from one to three fluoro groups, amino, C1-ioalkyl-S-, Ci-loalkyl-S(O)-, C1-loalkyl-S02-, phenyl, phenoxy, Ci-ioalkyl-SOzNH-, C1-loalkyl-SOzNH-C1-loakyl-, C1-loalkylamino-diCi-loalkyl-, cyano, hydroxy, cycloalkoxy having 3 to 7 carbon atoms, Ci-salkylamino, Ci-sdialkylamino, HC(O)NH- and C1-ioalkyl-C(O)NH-; and R2 is thienyl, benzhydryl, naphthyl or phenyl optionally substituted with from one to three substituents independently selected from chloro, bromo, ffuoro, iodo, cycloalkoxy having 3 to 7 carbon atoms, C1-ioalkyl optionally substituted with from one to three fluoro groups and C1-ioalkoxy optionally substituted with from one to three fluoro groups.
A particularly preferred compound of formula (X) is (2S,3S~-3-(2-methoxy-5-trifluoromethoxybenzyl)-amino-2-phenylpiperidine; or a pharmaceutically acceptable salt thereof.

Another class of NK-1 receptor antagonists of use in the present invention is that described in International Patent Specification No. WO
95/08549, i.e. compounds of formula (XI) (CH2)X
R
R' H

(XI) or a pharmaceutically acceptable salt thereof, wherein Rl is a Ci-4alkoxy group;
Rz is s N
N
i N-N ' R3 is a hydrogen or halogen atom;
R4 and R~ may each independently represent a hydrogen or halogen atom, or a C1-4alkyl, C1-4alkoxy or triffuoromethyl group;
Rs is a hydrogen atom, a C1-4alkyl, (CHz)mcyclopropyl, -S(O)"C1-4alkyl, phenyl, NR7R8, CH2C{0)CFs or triffuoromethyl group;
R7 and R$ may each independently represent a hydrogen atom, or a I5 Ci-4alkyl or acyl group;
x represents zero or 1;
n represents zero, 1 or 2; and m represents zero or 1.
Particularly preferred compounds of formula (XI) are (2-methoxy-5-tetrazol-1-yl-benzyl)-([2S,3S]-2-phenyl-piperidin-3-yl)-amine; and [2-methoxy-5-(5-trifluoromethyl-tetrazol-1-yl)-benzyl]-([2S,3S]-2-phenyl-piperidin-3-yl)-amine; or a pharmaceutically acceptable salt thereof.

Another class of tachykinin antagonists of use in the present invention is that described in International Patent Specification No. WO
95/14017, i.e. compounds of formula (XII) R$ R' R-(CH2)n C-CHZ N-(CHZ)o-R3 (CO)P
(CH~~
Rl (XII) or a pharmaceutically acceptable salt thereof, wherein m is zero, 1, 2 or 3;
n is zero or l;
o is zero, 1 or 2;
p is zero or 1;
R is phenyl, 2- or 3-indolyl, 2- or 3-indolinyl, benzothienyl, benzofuranyl, or naphthyl;
which R groups may be substituted with one or two halo, Ci.salkoxy, trifluoromethyl, C1-4alkyl, phenyl-Ci-salkoxy, or Ci-4alkanoyl groups;
Rl is trityl, phenyl, diphenylmethyl, phenoxy, phenylthio, piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, indolinyl, indolyl, benzothienyl, hexamethyleneiminyl, benzofuranyl, tetrahydropyridinyl, quinolinyl, isoquinolinyl, reduced quinolinyl, reduced isoquinolinyl, phenyl-(C1-4alkyl)-, phenyl-(C1-4alkoxy)-, quinolinyl-(Ci-4alkyl)-, isoquinolinyl-(C1-4alkyl)-, reduced quniolinyl-(Ci-4alkyl)-, reduced isoquinolinyl-(Cl.4alkyl)-, benzoyl-(Cl.salkyl)-, Ci-4alkyl, or -NH-CH2-R5;
any one of which Rl groups may be substituted with halo, C1-4alkyl, Ci-4alkoxy, trifluoromethyl, amino, Cl.4alkylamino, di(Cl.4alkyl)amino, or Cz-4alkanoylamino;
or any one of which Rl groups may be substituted with phenyl, piperazinyl, Cs-scycloalkyl, benzyl, C1-4alkyl, piperidinyl, pyridinyl, pyrimidinyl, C2-salkanoylamino, pyrrolidinyl, Cz-salkanoyl, or Ci-4alkoxycarbonyl;
any one of which groups may be substituted with halo, C1-4alkyl, C1-4alkoxy, trifluoromethyl, amino, Cl.4alkylamino, di(Cl.4alkyl)amino, or C2-aalkanoylamino;
or Rl is amino, a leaving group, hydrogen, C1-4alkylamino, or di(C 1-4alkyl)amino;
R5 is pyridyl, anilino-(Cl-salkyl)-, or anilinocarbonyl;
RZ is hydrogen, C1-4alkyl, Cl.4alkylsulfonyl, carboxy-(Ci-salkyl)-, Ci-salkoxycarbonyl-(C1-salkyl)-, or -CO-Rs;
Rs is hydrogen, Ci-4alkyl, Cl.shaloalkyl, phenyl, Ci.aalkoxy, Cl.shydroxyalkyl, amino, Cl.4alkylamino, di(C1-4alkyl)amino, or -(CH2)q-R~;
q is zero to 3;
R7 is carboxy, C1-4alkoxycarbonyl, Cl.4alkylcarbonyloxy, amino, C1-4alkylamino, di(C1-4alkyl)amino, C1-salkoxycarbonylamino, or phenoxy, phenylthio, piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, indolinyl, indolyl, benzothienyl, benzofuranyl, quinolinyl, phenyl-(Ci-4alkyl)-, quinolinyl-(C1-4alkyl)-, isoquinolinyl-(C1-4alkyl)-, reduced quinolinyl-(Ci-4alkyl)-, reduced isoquinolinyl-(Ci-4alkyl)-, benzoyl-Cl-salkyl;
any one of which aryl or heterocyclic R~ groups may be substituted with halo, trifluoromethyl, Cl.~alkoxy, C1-4alkyl, amino, C1-4alkylamino, di(Ci-4alkyl)amino, or Ca-4alkanoylamino;
or any one of which R7 groups may be substituted with phenyl, piperazinyl, Ca-8cycloalkyl, benzyl, piperidinyl, pyridinyl, pyrimidinyl, pyrrolidinyl, Cz-salkanoyl, or Ci.4alkoxycarbonyl;
any of which groups may be substituted with halo, trifluoromethyl, amino, C1-4alkoxy, C1-4alkyl, C1-4alkylamino, di(Ci.4alkyl)amino, or C2-4alkanoylamino;
Rs is hydrogen or Cl.salkyl;
R3 is phenyl, phenyl-(C1-salkyl)-, Cs-scycloalkyl, Cs-scycloalkenyl, Ci-salkyl, naphthyl, Cz-salkenyl, or hydrogen;

WO 99!07375 PCT/EP98/04933 any one or which groups except hydrogen may be substituted with one or two halo, C1-salkoxy, C1-salkylthio, nitro, triffuoromethyl, or C1-salkyl groups; and R4 is hydrogen or Ci-salkyl;
with the proviso that if Rl is hydrogen or halo, R3 is phenyl, phenyl-(C1-salkyl)-, Cs-scycloalkyl, Cs-scYcloalkenyl, or naphthyl.
A particularly preferred compound of formula (XII) is [N-(2-methoxybenzyl)acetylamino]-3-(1H-indol-3-yl)-2-[N-(2-(4-piperidin-1-yl)piperidin-1-yl)acetylaminQ]propane; or a pharmaceutically acceptable salt thereof.
The above compounds are only illustrative of NK-1 receptor antagonists which are currently under investigation. As this listing of compounds is not meant to be comprehensive, the use and methods of the present invention may employ any NK-1 receptor antagonist, in particular a NK-1 receptor antagonist which is orally active, long acting and CNS-penetrant. Accordingly the present invention is not strictly limited to any particular structural class of compound.
The preferred compounds of formulae (I), (II), (III) and (I~ will have the 2- and 3-substituents on the morpholine ring in the cis arrangement, the preferred stereochemistry being as shown in the following general formula:
i O ,,.v O w '2 3 '~i i R
Where the benzyloxy moiety is a-substituted, the preferred stereochemistry of the a-carbon is either (R) when the substituent is an _ 5~ -alkyl (e.g. methyl) group or (S'~ when the substituent is a hydroxyalkyl (e.g. hydroxymethyl) group.
Unless otherwise defined herein, suitable alkyl groups include straight-chained and branched alkyl groups containing from 1 to 6 carbon atoms. Typical examples include methyl and ethyl groups, and straight-chained or branched propyl and butyl groups. Particular alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl and tert-butyl.
Unless otherwise defined herein, suitable alkenyl groups include straight-chained and branched alkenyl groups containing from 2 to 6 carbon atoms. Typical examples include vinyl and allyl groups.
Unless otherwise defined herein, suitable alkynyl groups include straight-chained and branched alkynyl groups containing from 2 to 6 carbon atoms. Typical examples include ethynyl and propargyl groups.
Unless otherwise defined herein, suitable cycloalkyl groups include groups containing from 3 to 7 carbon atoms. Particular cycloalkyl groups are cyclopropyl and cyclohexyl.
Unless otherwise defined herein, suitable aryl groups include phenyl and naphthyl groups.
A particular aryl-C1-salkyl, e.g. phenyl-C1-salkyl, group is benzyl.
Unless otherwise defined herein, suitable heteroaryl groups include pyridyl, quinolyl, isoquinolyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyranyl, furyl, benzofuryl, thienyi, benzthienyl, imidazolyl, oxadiazolyl and thiadiazolyl groups.
The term "halogen" as used herein includes fluorine, chlorine, bromine and iodine.
The compounds of use in this invention may have one or more asymmetric centres and can therefore exist as enantiomers and possibly as diastereoisomers. It is to be understood that the present invention relates to the use of all such isomers and mixtures thereof.
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, malefic 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.
The present invention accordingly provides the use of a NK-1 receptor antagonist selected from the compounds of formulae (I), (II), (III), (IV), (~, (VI), (VII), (VIII), (IX), (X), (XI) and (XII) for the manufacture of a medicament for the treatment or prevention of aggressive behaviour.
The present invention also provides a method for the treatment or prevention of aggressive behaviour, which method comprises administration to a patient in need of such treatment of an effective amount of a NK-1 receptor antagonist selected from the compounds of formulae (I), (II), (III), {IV), (V), (VI), (VII), (VIII), (IX), (X), (XI) and (XII).
In a further aspect of the present invention, there is provided a pharmaceutical composition for the treatment or prevention of aggressive behaviour comprising a NK-1 receptor antagonist selected from the compounds of formulae (I), (II), (III), (IV), (V), (VI), (VII), {VIII), (IX), (X), (XI) and (XII), together with at least one pharmaceutically acceptable carrier or excipient.
Preferably the compositions according to the present invention are in unit dosage forms such as tablets, pills, capsules, powders, granules, _57_ solutions or suspensions, or suppositories, for oral, parenteral or rectal administration, by inhalation or insufflation or administration by trans-dermal patches or by buccal cavity absorption wafers.
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 or by injection 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.
Preferred compositions for administration by injection include those comprising a NK-1 receptor antagonist as the active ingredient, in association with a surface-active agent (or wetting agent or surfactant) or in the form of an emulsion (as a water-in-oil or oil-in-water emulsion).
Suitable surface-active agents include, in particular, non-ionic agents, such as polyoxyethylenesorbitans (e.g. TweenT"" 20, 40, 60, 80 or 85) and other sorbitans (e.g. SpanT"" 20, 40, 60, 80 or 85). Compositions with a surface-active agent will conveniently comprise between 0.05 and 5% surface-active agent, and preferably between 0.1 and 2.5%. It will be appreciated that other ingredients may be added, for example mannitol or other pharmaceutically acceptable vehicles, if necessary.
Suitable emulsions may be prepared using commercially available fat emulsions, such as IntralipidT"", LiposynT"', InfonutrolT"", LipofundinT""
and LipiphysanT"". The active ingredient may be either dissolved in a pre-mixed emulsion composition or alternatively it may be dissolved in an oil (e.g. soybean oil, safflower oil, cottonseed oil, sesame oil, corn oil or almond oil) and an emulsion formed upan mixing with a phospholipid (e.g. egg phospholipids, soybean phospholipids or soybean lecithin) and water. It will be appreciated that other ingredients may be added, for example glycerol or glucose, to adjust the tonicity of the emulsion. Suitable emulsions will typically contain up to 20% oil, for example, between 5 and 20%. The fat emulsion will preferably comprise fat droplets between O.I
and 1.O~,m, particularly 0.1 and 0.5~,m, and have a pH in the range of 5.5 to 8Ø
Compositions for inhalation or insufffation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as set out above.
Preferably the compositions are administered by the oral or nasal respiratory route for local or systemic effect. Compositions in preferably sterile pharmaceutically acceptable solvents may be nebulised by use of inert gases. Nebulised solutions may be breathed directly from the nebulising device or the nebulising device may be attached to a face mask, tent or intermittent positive pressure breathing machine. Solution, suspension or powder compositions may be administered, preferably orally or nasally, from devices which deliver the formulation in an appropriate manner.
Compositions of the present invention may also be presented for administration in the form of trans-dermal patches using conventional technology. The compositions may also be administered via the buccal cavity using, 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 5mg per day, preferably about lOmg per day and especially about 20mg per day. A maximum dosage level for the NK-1 receptor antagonist is about 1500mg per day, preferably about 1000mg per day and especially about 500mg per day. The compounds are administered 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 aggressive behaviour 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 aggressive behaviour will vary not only with the particular compounds or compositions selected but also with the route of administration, the nature of the condition being treated, and the age and condition of the patient, and will ultimately be at the discretion of the patient's physician or pharmacist.
The compounds of formulae (I), (II), (III), (IV), (~, (VI), (VII), (VIII), (IX), (X), (XI) and (XII) maybe prepared by the methods described in EP-A-0 577 394 (or WO 95/16679), WO 95/18124, WO 95/23798, WO 96/05181, EP-A-0 436 334, WO 93/21155, EP-A-0 591 040, EP-A-0 532 456, EP-A-0 443 132, WO 92/17449, WO 95/08549 and WO 95/14017, respectively.

Particularly preferred NK-1 receptor antagonists of the formulae {I), (II), (III), (I~, (~, (VI), (VII), (VIII), (IX), (X), (XI) and (XII) for use in the present invention are compounds which are potent NK-1 receptor antagonists, i.e. compounds with an NK-1 receptor affinity (ICso) of less than lOnM.
A particularly preferred class of NK-1 receptor antagonist of use in the present invention are those compounds which are orally active, long acting and CNS-penetrant. Such compounds may be identified using the pharmacological assays described hereinafter. The use of this sub-class of NK-1 antagonists in the treatment or prevention of aggressive behaviour represents a further aspect of the present invention.
Thus, 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 aggressive behaviour. The compounds of this class advantageously exhibit a rapid onset of action and a reduced side-effect profile when compared against conventional treatments of aggressive behaviour.
In particular, the present invention provides a means for the identification of NK-1 receptor antagonists which would be especially effective in an oral once-a-day medicament for the treatment of aggressive behaviour.
The exceptional pharmacology of the class of orally active, long acting, CNS-penetrant NK-1 receptor antagonists (as hereinafter defined) of use in the present invention enables the treatment of aggressive behaviour, without the need for concomitant therapy and in particular, without the need for concomitant use of 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 *rB

hereinafter defined) for the manufacture of a medicament adapted for oral administration for the treatment or prevention of aggressive behaviour.
The present invention also provides a method for the treatment or prevention of aggressive behaviour, 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 aggressive behaviour 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 aggressive behaviour is inadequately treated with antipsychotic agents. Furthermore, some patients may be adversely affected by the side-effects of antipsychotic agents such that the use of an antipsychotic agent, alone or in combination with a NK-1 receptor antagonist, would be undesirable.
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 aggressive behaviour in a patient who is non-responsive to antipsychotic agents or for whom antipsychotic agents are is contraindicated.
The present invention also provides a method for the treatment or prevention of aggressive behaviour in a patient who is non-responsive to antipsychotic agents or for whom antipsychotic agents are is contraindicated, which method comprises 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.
Preferred NK-1 receptor antagonists for use in the present invention as orally active, long acting, CNS-penetrant NK-1 receptor antagonists 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, 96/05181, and 97/49710 (Application No. PCTIGB97/01630). The preparation of such compounds is fully described in the aforementioned publications.
Thus, further particularly preferred NK-1 receptor antagonists of use in the present invention include:
(3S, 5R, 6S)-3-[2-cyclopropoxy-5-(trifluoromethoxy)phenyl-1-oxa-7-aza-spiro[4.5]decane;
(3R,5R,6S)-3-[2-cyclopropoxy-5-(trifluoromethoxy)phenyl-1-oxa-7-aza-sp iro [4. 5] decane;
2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3(S)-(4-fluorophenyl)-4-(3-(5-oxo-1 H, 4H-1, 2, 4-triazolo) methyl)morpholine;
2-(R)-(1-(R,)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)-3-(S)-phenyl-morpholine;
2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)-3-(S)-phenyl-morpholine;
2-(R)-(1-(R,)-(3, 5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)morpholine;
2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(5-(N,N-dimethylamino)methyl-1, 2, 3-triazol-4-yl)methyl-3-(S)-phenylmorpholine;
2-(R,)-(1-(R)-(3, 5-bis(trifluoromethyl)phenyl)ethoxy)-4-(5-(N, N-dimethylamino)methyl-1,2,3-triazol-4-yl)methyl-3-(S)-(4-fluorophenyl)morpholine;
2-(R.)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(4-monophosphoryl-5-oxo-1H-1,2,4-triazolo)methyl)morpholine;
2-(R.)-(1-(R.)-(3, 5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(1-monophosphoryl-5-oxo-1H-1,2,4-triazolo)methyl)morpholine;
2-(R,)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(2-monophosphoryl-5-oxo-1H-1,2,4-triazolo)methyl)morpholine;

2-(R)-(1-(R,)-(3,5-bis(triffuoromethyl)phenyl)ethoxy)-3-(S)-(4-ffuorophenyl)-4-(3-(5-oxyphosphoryl-1H-1,2,4-triazolo)methyl)morpholine;
2-(S)-(1-(R)-(3,5-bis(triffuoromethyl)phenyl)ethoxy)-3-(S)-(4-ffuorophenyl)-4-(3-(1-monophosphoryl-5-oxo-4H-1,2,4-triazolo)methyl)morpholine;
2-(R)-(1-(R)-(3,5-bis(triffuoromethyl}phenyl)ethoxy)-4-(4-N,N-dimethylaminobut-2-yn-yl)-3-{S)-(4-ffuorophenyl)morpholine;
2-(R)-(1-{S)-(3,5-bis{trifluoromethyl)phenyl)-2-hydroxyethoxy)-3-{S)-(4-ffuorophenyl)-4-(1,2,4-triazol-3-yl)methylmorpholine;
or a pharmaceutically acceptable salt thereof.
Full descriptions of the preparation of the NK-1 receptor antagonists may be found in the references cited herein.
Two compounds of use as orally active, long acting, CNS penetrant NK-1 receptor antagonists in the present invention which are described in International Patent Specification No. WO 97/49710 (Application No.
PCT/GB97/01630) may be prepared according to the following methods:

~2S)-1-tert-ButoxycarbonYl-2-,phenylQiperidin-3-one Dimethyl sulfoxide (20.80m1, 22.90g, 29.3mmol) in dichloromethane (75m1) was added dropwise to a cooled (-70°C} solution of oxalyl chloride (13.95m1, 20.30g, 160mmol) in dichloromethane (350m1). The mixture was stirred at -70°C for 15 minutes, then (2S,3S)-1-tert-butoxycarbonyl-3-hydroxy-2-phenylpiperidine (prepared by the method described in European Patent Specification number 0 528 495-A; 3fi.91g, 133mmol) in dichloromethane (150m1) 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 (55.95m1, 40.45g, 400mmo1) was added slowly. The mixture was allowed to warm to 0°C and diluted with ice-cooled dichloromethane (250m1). The mixture was washed with ice cold aqueous citric acid solution (5%, 2x300m1) and water (300m1), dried (MgS04), 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. 1H NMR (250MHz, CDCls) 8 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).

(2S 3R)-1-tert-Butox~icarbonyl-3-hydroxy-3-(2-methvlene-3-phenoxvnropyl)-2-phen~piperidine A solution of 3-(chloromagnesio)-2-(phenoxymethyl)-1-propene in THF (0.91M, 3m1) (Louw et. al., Tetrahedron, 48, 6087-6104, 1992, prepared from 2.74mmo1 of 3-chloro-2-(phenoxymethyl)-1-propene) was slowly added to a solution of (2S)-1-tert-butoxycarbonyl-2-phenylpiperidin-3-one (Preparation 1) in THF (3m1). The mixture was stirred at room temperature for 1 hours, then saturated aqueous ammonium chloride (20m1) was added and the mixture was extracted with ethyl acetate (20m1). The organic phase was washed with brine, dried (MgS04) 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. 1H NMR (360MHz, CDCls) 8 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, J=13.7 Hz), 4.61 (2H, s), 4.11 (2H, m), 3.17 (1H, m), 2.66 and 2.59 (2H, AB d, J=14.0 Hz), 1.95 (2H, m), 1.79 (2H, m), and 1.36 (9H, s). m/z (ES+) 424 (M+1).

(5Rs65~-3-Methylene-6-phenyl-1-oxa-7-(tert-butoxycarbonvDaza-spiro [4. 5] decane To a cooled(-80 °C) solution of (2S,3R)-1-tert-butoxycarbonyl-3-hydroxy-3-(2-methylene-3-phenoxypropyl)-2-phenylpiperidine (Preparation 2, 1.53g, 3.62mmo1) in THF (20m1) was added n-butyl lithium (2.5M in hexanes, 1.45m1, 3.62mmo1) followed by a solution of zinc chloride (0.5M in *rB

THF, 7.24m1, 3.62mmo1). The solution was allowed to warm to room temperature and tetrakis(triphenylphosphine)palladium (0) (0.23g, 0.2mmo1) 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 (MgS04) 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-1-oxa-~-(tert-butoxycarbonyl)aza-spiro~4.5Jdecane. 1H NMR (360MHz, CDCIs) b 7.58 (2H, d, J=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, J=13.3 Hz), 3.99 (1H, dd, J=13.3, 4.48 Hz), 2. 83 (1H, ABd J=15.5 Hz), 2.7 (lH,td J=12.5, 3.93 Hz), 2.5 (1H, ABd, J=15.4 Hz), 2.15 (2H, td, J=12., .4 Hz), 1.69 {2H, m), and 1.46 (9H,s). m/z (ES+) 329 (M+2H-tBuOCO).

(5R 6S)-3-Keto-6-phenyl-1-oxa-7-(tert-butoxycarbonyl)aza-spiro(4.5 decane Through a cooled (-80 °C) solution of {5R,6S)-3-methylene-6-phenyl-1-oxa-7-(tert-butoxycarbonyl)aza-spiro[4.5]decane (Preparation 3; 0.665g) in dichloromethane (5m1) and methanol (5m1) was bubbled a mixture of ozone and oxygen for 45 minutes. After the solution had been purged with nitrogen, dimethyl sulphide (0.5m1) was added and then stirred under nitrogen at room temperature for 16 hours. The solvent was removed in uacuo and the residue partitioned between ethyl acetate and water. The organic phase was dried (MgS04), 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. 1H NMR (250MHz, CDC13) 8 7.5$ (2H, d, J=6.2 Hz), 7.37-7.26 (3H, m), 5.3 (1H, s), 4.15 and 4.09 (2H, AB d, J=17.4 Hz), 3.97 (1H, m), 2.80 (1H, td, J=I2.9, 4.0 Hz), 2.74 and 2.48 (2H, ABd, J=18.1 Hz), 2.29 (2H, m), 1.88-1.63 (2H, m), and 1.44 (9H, s). m/z (ES+) 332 (M+1).

(5R 65'7-3-Triffuoromethylsulfonvloxy-6-phenyl-1-oxa-7-(tert-butoxycarbonyDaza-spirof 4.51 dec-3-ene To a cooled (-80 °C) solution of 1M sodium hexamethyldisilazide (0.38m1, 0.38mmo1) in THF was added a solution of (5R,6S~-3-keto-6-phenyl-1-oxa-7-(tent-butoxycarbonyl)aza-spiro[4.5]decane (Preparation 4;
0.105mg, 0.319mmol) in THF (3m1). The solution was stirred for 1 hours at -80°C then a solution of 2-[N,N-bis(trifluoromethylsulfonyl)amino]-5-chloropyridine (0.1638, 0.415mmo1) in THF (3m1) 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 (MgS04) 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. 1H NMR
(360MHz, CDCIs) 8 7.4 (2H, d, J=7.3 Hz), 7.3-7.22 (3H, m), 6.01 (1H, t, J=2.13 Hz), 5.13 (1H, s), 4.56 and 4.26 (2H, ABdd, J=12.4, 1.97 Hz),4.10 (1H, dt, J=12.6, 4.22 Hz), 3.00 (1H, m), 2.28-2.04 (2H, m), 1.88-1.76 {2H, m), and 1.37 (9H, s). m/z (ES+) 464 (M+1).

f5R 6S~-3-Trimethylstannyl-6-phenyl-1-oxa-7-(tert-butoxycarbonvl)aza-spiro f 4.51 dec-3-ene To a degassed solution of (5R,6,f~-3-trifluoromethylsulfonyloxy-6-phenyl-1-oxa-7-(tert-butoxycarbonyl)aza-spiro[4.5]dec-3-ene (Preparation 5; 0.4828, 1.04mmo1), lithium chloride (0.2648, 6.25mmo1), lithium carbonate (0.0768) and hexamethyl distannane(0.96g, 2.9mmo1) in THF

- 68 _ (lOml) was added triphenylphosphine palladium (0) (0.06g). The solution was degassed and then heated at 60°C for 5 hours under nitrogen. Water (20m1) and ethyl acetate (20m1) 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. 1H NMR (360MHz, CDCIs) b 7.25 (2H, d, J=7.3 Hz), 7.1-7.0 (3H, m), 5.83 (1H, t, J=2.5 Hz), 4.78 (1H, s), 4.48 and4.02 (2H, dd, J=12.9, 2.3 Hz), 3.96 (1H, dd, J=6.16, 13.4 Hz), 2.95 (1H, td, J=13.3, 4.5 Hz), 1.84 (1H, m), 1.68 (1H, m), 1.60 (2H, m), 1.19 (9H, s), and 0.0 (6H, s).
PREPARATION ?
(2S 3R)-1-tert-Butoxycarbonyl-3-(3-hvdroxynropyn-1-yl)-2-phenylpiperidin-3-0l O-Trimethylsilylpropargyl alcohol (24.51m1, 20.47g, 160m1) was added slowly to a cooled (-10°C) solution of ethylmagnesium bromide (1M
in tetrahydrofuran, 160m1, 160mmo1). The mixture was stirred at 0°C for minutes, then at room temperature for 2 hours. The mixture was cooled to -10°C and a solution of (2S)-1-tert-butoxycarbonyl-2-20 phenylpiperidin-3-one (Preparation 1; 42.3g) in tetrahydrofuran (200m1) was added dropwise over 30 minutes. (Internal temperature below -5°C).
The mixture was stirred at room temperature for 14 hours, poured into water (300m1) and saturated aqueous ammonium chloride {300m1) and extracted with ethyl acetate (2x300m1). The combined organic fractions were washed with brine (300m1), dried (MgS04) and the solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate {500m1) and a solution of tetrabutylammonium fluoride (1M in THF, 160m1, 160mmo1) was added dropwise. The mixture was stirred at room temperature for 30 minutes, water (300m1) was added, and the layers were separated. The aqueous layer was extracted with ethyl acetate (2x300m1) and the combined organic fractions were washed with water (300m1) and brine (300m1), dried (MgS04) 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). 1H
NMR (CDCIa) b 7.53-7.55 (2H, m), 7.19-7.35 (3H, m), 5.56 {1H, s), 4.27 (2H, s), 3.99-4.03 (1H, m), 3.25 (1H, br s), 2.77-2.81 (1H, m), 2.77 (1H, br s), 2.12-2.20 (1H, m), 1.91-1.99 (2H, m), 1.77-1.83 (1H, m), and 1.39 (9H, s).

2-Bromo-4-(trifluoromethoxy)phenol To a cooled (0 °C) solution of 4-trifluoromethoxyphenol (35.6g, 0.2mo1) in chloroform (280m1) was added dropwise a solution of bromine (32g, 0.2mo1) in chloroform (50m1). The solution was stirred at 0°C for hour and at room temperature for 2 hours. Dichloromethane {200m1) and water (400m1) ware added and the organic phase was washed further with water(400m1), brine (200m1) and dried (MgS04). The solvent was removed and the residue was purified by distillation at reduced pressure to give the title compound. 1H NMR (250MHz, CDCIs) 8 7.38 (1H, d, J=2.1 Hz), 7.13 (1H, dd, J=9.1, 2.1 Hz), 7.03 (1H, d, J=9.1 Hz), and 5.53 (1H, s).

2-Benzyloxy-5-(trifluoromethoxy)bromobenzene 2-Bromo-4-(trifluoromethoxy)phenol (Preparation 8; 5g, 20mmo1) was dissolved in N,N-dimethylformamide (60m1), and potassium carbonate (5.4g, 40mmol) was added, followed by benzyl bromide (3.5m1, 30mmo1), and the reaction was stirred at ambient temperature for 15 hours. The reaction was diluted with water (150m1) and extracted into ethyl acetate (3x60m1). The combined organic fractions were washed with water (100m1), brine (100m1), dried (MgS04) and evaporated in vacuo.
Purification on silica, eluting with 2% and 5% ethyl acetate in hexane gave -?0-the title compound as a clear oil (6.7g, 96%). 1H NMR (250MHz, CDCls) 8 5.47 (2H, s), 7.23 (1H, d, J=9 Hz), 7.43 (1H, dd J=8.2, 2.9 Hz), and 7.75 (6H, m).

Z-(2S 3R)-1-tert-Butoxycarbonyl-3-(3-hydroxynrop-1-en-1-yl)-2-phenylpiperidin-3-of Palladium on calcium -carbonate, poisoned with lead (Lindlar catalyst, 2g) was added to a solution of (2S,3R)-1-tent-butoxycarbonyl-3-(3-hydroxypropyn-lyl)-2-phenylpiperidin-3-of (Preparation 7; 32g, 96.6mmo1) in ethyl acetate (300m1) 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%). 1H NMR (360MHz, CDCIs) 8 7.42 (2H, d, J=7.6 Hz), 7.35-7.25 (3H, m), 5.83 (1H, d, J12.3 Hz), 5.68 (1H, dt, J=12.3, 6.0 Hz), 5.06 (1H, s), 4.27 (1H, m), 4.12 (2H, m), 3.32 (1H, m), 3.13 (1H, s), 2.28 (1H, t, J=5.9 Hz), 2.02 (1H, m), 1.92-1.78 (3H, m), and 1.32 (9H, s). m/z (ES+) 334 (M+1).

(5R 6S)-6-Phenyl-1-oxa-'7-(tert-butoxycarbonyl)aza-spirof4.51dec-3-ene Diethylazodicarboxylate (18.2m1, 115mmo1) in THF (100m1) was added dropwise to a solution of Z-(2S,3R)-1-tert-butoxycarbonyl-3-(3-hydroxyprop-1-en-1-yl)-2-phenylpiperidin-3-of (Preparation 10; 32g, 96mmo1) and triphenylphosphine (30.28, 115mmol) in THF (700m1). The 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%). 1H NMR (CDC13) 8 7.45 (2H, d, J=7.4 Hz), 7.27 (2H, t, J=7.4 Hz), 7.20 (1H, t, J=7.4 Hz), 6.03 (1H, dt, J=6.1, 2.0 Hz), 5.68 (1H, dt, J=6.1, 2.0 Hz), 5.06 (1H, s), 4.61 (1H, dt, J=13.1, 2.0 Hz), 4.32 (1H, dt, J=13.1, 2.0 Hz), 4.08 (1H, m), 3.05 (1H, m), 2.05 (1H, m), 1.75 (3H, m), and 1.37 (9H, s). m/z (ES+) 316 (M+1).

2-Benzyloxy-5-(trifluoromethoxv)benzene Benzyl bromide (66.17m1, 95.358, 0.56mo1) was added to a mixture of 4-(trifluoromethoxy)phenol (90.268, 0.51mo1) and potassium carbonate (140.978, l.2mo1) in dimethylformamide (160m1) and the mixture was stirred at room temperature for 72 hours. The mixture was poured into water (1.51) and extracted with ethyl acetate (3x500m1). The combined organic fractions were washed with aqueous sodium carbonate (saturated, 500m1), dried (MgS04) and the solvent was evaporated under reduced pressure to give the title compound as a colorless solid (133.58, 99%). 1H
NMR (360MHz, CDCIs) 8 7.39 (5H, m), 7.14 (2H, d, J=9.0 Hz), 6.95 (2H, d, J=9.0 Hz), and 5.05 (2H, s).

2-Benzvloxy-5- trifluoromethoxy)iodobenzene Iodine (71.968, 0.28mo1) in chloroform was added dropwise to a mixture of 2-benzyloxy-5-(trifluoromethoxy)benzene (Preparation 12, 73.068, 0.27mo1) and silver trifluoroacetate (71.578, 0.32mo1) in dichloromethane and the mixture was stirred at room temperature for 18 hours. The mixture was filtered through celite, washed with aqueous sodium thiosulfate (5%, 2x21), dried (MgS04) and the solvent was 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 (108.038), containing 11%
unreacted 2-benzyloxy-5-(trifluoromethoxy)iodobenzene. 1H NMR
(360MHz, CDCls) b 7.67 (1H, d, J=2.8 Hz), 7.40 (5H, m), 7.16 (1H, dd, J=8.9, 2.8 Hz), 6.82 (1H, d, J=8.9 Hz), and 5.14 (2H, s).

(5R 6S)-3-(2-Benzyloxy-5-(trifluoromethoxy)nhenyl)-6-nhenyl-1-oxa-7-(tert-butoxycarbonyl)aza-spirof4.51dec-3-ene (5R,6S)-3-Trimethylstannyl-6-phenyl-1-oxa-7-(tert-butoxycarbonyl)aza-spiro[4.5]dec-3-ene (Preparation 6; 6.43mmol), lithium chloride (0.163g), benzyloxy-5-(triffuoromethoxy)phenol (Preparation 9;
7.7mmol) in toluene (25m1) was degassed before addition of triphenylphosphine palladium (0) (0.37g). The solution was degassed 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. 1H NMR (360MHz, CDCls) 8 1.33 {9H, s), 1.65 (1H, m), 1.76 (2H, m), 2.08 (1H, m), 3.11 (1H, m}, 4.08 (1H, m), 4.60 (1H, dd, J=12.2 Hz, J=2 Hz), 4.92 (1H, dd, J=12.1 Hz, J=1.8 Hz), 5.08 (1H, s), 5.1 (2H, q, J=11.5 Hz), 6.65 (1H, s), 6.94 (2H, d, J=8.9 Hz), 7.08 (1H, d, J=9 Hz), 7.18 (2H, t, J=8.1 Hz}, 7.25 (3H, m), 7.38 (5H, m).

(3S 5R 6S)-3-(2-Hydroxy-5-(trifluoromethoxy)phenyl)-6-phenyl-1-oxa-7-(tert-butoxycarbonyl)aza-spirof4.51decane (5R,6S)-3-(2-Benzyloxy-5-(triffuoromethoxy)phenyl)-6-phenyl-1-oxa-7-(tert-butoxycarbonyl)aza-spiro[4.5]dec-3-ene (Preparation I4) (3.88g) was dissolved in ethyl acetate (l5ml) and methanol (15m1). Palladium hydroxide on carbon (I.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 (75:25) to give (3R, 5R, 6S)-3-(2-hydroxy-5-(trifluoromethoxy)phenyl)-6-phenyl-1-oxcz-7-(tert-butoxycarbonyl)aza-spiro(4.5Jdecane (191mg), 1H NMR (250MHz, CDC13) 8 7.70 (2H, d, J=7.3 Hz), 7.33 (2H, t, J=7.3 Hz), 7.26 (1H, d, J=7.3 Hz), 7.05 (1H, br s), 6.96 (2H, m), 6.82 (1H, d, J=9.4 Hz), 5.43 (1H, s), 4.27 (1H, m), 4.01 {1H, m), 3.95 (1H, m), 3.73 (1H, m), 2.73 (2H, m), 2.33 (1H, m), 1.87-1.58 {4H, m);
and 1.50 (9H, s).and (3S,5R,6S)-3-(2-hydroxy-5-(trifluoromethoxy)phenyl)-6-phenyl-1-oxa-7-(tert-butoxycarbonyl)aza-spiro(4.5Jdecane (2.3g), 1H NMR
(360MHz, CDCls) 8 1.38 (9H, s), 1.73 (2H, m), 1.81 (1H, m), 2.18 (2H, m), 2.50 (1H, m), 2.81 (1H, m), 3.62 (1H, t, J=7.2 Hz), 3.92 (1H, m), 3.98 (1H, d, J=13.2 Hz), 4.23 (1H, m), 5.33 (1H, s), 6.75 (1H, d, J=8.5 Hz), 6.94 (2H, m), 7.25 (1H, m), 7.31 {2H, m), and 7.55 (2H, d, J=7.8 Hz).

(3R 5R 6S)-3-(2-Benzyloxy-5-(trifluoromethoxv)phenyD-6-phenvl-1-oxa-7-(tert-b utoxycarbonyl) aza-spiro f 4.51 decane A mixture of 2-benzyloxy-5-(trifluoromethoxy)iodobenzene (Preparation 13, 21.88, 55.2mmo1), (5R,6S)-6-phenyl-1-oxa-7-(tert-butoxycarbonyl)aza-spiro[4.5]dec-3-ene (Preparation 11, 7.Og, 22.1mmol), tetra-n-butylammonium chloride (6.188, 22.2mmo1), lithium chloride (9.35g, 0.22mo1) and potassium formate (5.64g, 67.Ommol) in dimethylformamide (100m1) was degassed with a firestone valve (5 x).
Palladium acetate (491mg, 2.2mmo1) 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-(triffuoromethoxy)iodobenzene (Preparation 13, 4.32g, ll.Ommo1), potassium formate (2.78g, 33.5mmo1) and palladium acetate (260mg, l.lmmol) were added. The mixture was stirred at 60°C for 22 hours, cooled and filtered. The solvent was evaporated under reduced pressure, water (600m1) was added and the mixture was extracted with ethyl acetate (2x300m1). The combined organic fractions were washed with brine (300mI), dried {MgS04) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with hexane/dichloromethane (75:25 increasing'to 0:100) then dichloromethane/ethyl acetate (95:5), to give the title compound (9.42g, 73%). 1H NMR (360MHz, CDCIs) 8 7.56 (2H, d, J=7.7 Hz), 7.40-7.20 (8H, m), 7.14 (1H, d, J=2.0 Hz), 7.00 (1H, dd, J=8.9, 2.0 Hz), 6.88 (1H, d, J=8.9 Hz), 5.30 (1H, s), 5.08 (2H, s), 4.27 (1H, m), 3.97 (1H, m), 3.87 (2H, m), 2.78 (1H, m), 2.56 (1H, m), 2.15 (1H, m), 1.96 (1H, m), 1.67 (3H, m), and 1.42 (9H, s).

(3R 5R 6S~ 3-(2-Hydroxv-5-~rifluoromethoxy)phenvl)-6-phenyl-I-oxa-7-(tent-butoxycarbonyl)aza-spirof4.51decane Palladium on carbon (10%, 0.59g) was added to a solution of (3R,5R,6S~-3-(2-benzyloxy-5-(trifluoromethoxy)phenyl)-6-phenyl-1-oxa-7-(tert-butoxycarbonyl)aza-spiro[4.5]decane (Preparation 16, 6.lOg, 10.5mmo1) in methanol-water (99:1, 200m1) 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. 1H NMR (360MHz, CDCls) 8 7.70 (2H, d, J=7.3 Hz), 7.33 (2H, t, J=7.3 Hz), 7.26 (1H, d, J=7.3 Hz), 7.05 (1H, br s), 6.96 (2H, m), 6.82 (IH, d, J=9.4 Hz), 5.43 (1H, s), 4.27 (1H, m), 4.01 (1H, m), 3.95 (1H, m), 3.73 (1H, m), 2.73 (2H, m), 2.33 (1H, m), 1.87-1.58 (4H, m), and 1.50 (9H, s).

(3S 5R 6S~-3-[2-(1-Phen~lthiocycloprop-1-yl)oxy-5-(trifluoromethoxy)phenylj-6-phen~~l-1-oxa-7-(tent-butoxvcarbonyl)aza-s~irof 4.51 decane (3S,5R,6S~-3-(2-Hydroxy-5-(trifluoromethoxy)phenyl)-G-phenyl-1-oxa-7-(tert-butoxycarbonyl)aza-spiro[4.5]decane (Preparation 15) (290mg, 0.59mmo1) was dissolved in toluene (5m1) and silver carbonate (179mg, 0.65mmo1) was added in one portion. (1-Iodocycloprop-1-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 mixture was stirred at 55°C for 4 hours, then further portions of silver carbonate (179mg, 0.65mmo1) and (1-iodocycloprop-1-yl)phenylsulfide (180mg, 0.65mmo1) were added. The mixture was stirred at 55°C for a further 3 hours, cooled, filtered and the solvent was evaporated under reduced pressure. The residue was purified 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 (120mg, 32%). 1H NMR
(250MHz, CDCls) 8 7.55-7.44 (4H, m), 7.36-7.23 (7H, m), 7.13-7.02 (2H, m), 5.16 (1H, br s), 4.09 (1H, t, J=6 Hz), 4.03-3.92 (1H, m), 3.67-3.49 (2H, m), 2.94-2.79 (1H, m), 2.26 (1H, dd, J=7.9, 12.9 Hz), 2.15-2.01 (2H, m), 1.76-1.59 (3H, m), 1.53-1.45 (4H, m), and 1.36 (9H, s). m/z (ES+) 642 (M+1).

(3R 5R.6f~-3-f2-(I-Phen lt~ycloprop-1-vl)oxy-5-(trifluoromethoxy)phenyl]-6-phenyl-1-oxa-7-(tert-butoxycarbonyl)aza-spiro~4.51decane Prepared from (3R,5R,65~-3-(2-hydroxy-5-(trifluoromethoxy)phenyl)-6-phenyl-1-oxa-7-(tent-butoxycarbonyl)aza-spiro[4.5]decane (Preparation 17) according to the method of Preparation 18. 1H NMR (360MHz, CDCIs) 8 7.57 (2H, app. d, J=7.6 Hz), 7.45 (2H, app. d, J=7.7 Hz), 7.36-7.19 (7H, m), 7.16-7.06 (2H, m), 5.28 (1H, br s), 4.13 (1H, app. t, J=7.8 Hz), 3.96 (1H, br. d, J=13 Hz), 3.80-3.60 (2H, m), 2.79 (1H, br. t, J=I3 Hz), 2.50 (1H, dd, J=13, 7.9 Hz), 2.17 (1H, dt, J=13, 4.6 Hz), 1.80 (1H, dd, J=12, 9.8 Hz), 1.75-1.38 (7H, m), and 1.44 (9H, s).
m/z (ES+) 642 (M+1).

(3S,5R 6S'7-3-L2-Cyclopropoxy-5-(trifluoromethoxv)phenyl]-6-phenyl-1-oxa-7-(tent-butoxycarbonyl)aza-spirof4.51decane Naphthalene (120mg, 0.936mmol) was dissolved in THF (1.5m1) under nitrogen and freshly cut lithium metal (7.Omg, 0.94mmol) was 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,5R,6S~-3-[2-(1-phenylthiocycloprop-1-yl)oxy-5-(trifluoromethoxy)phenyl]-6-phenyl-1-oxa-7-(tert-butoxycarbonyl)aza-spiro[4.5]decane (Preparation 18) (120mg, 0.187mmo1) in THF (0.5m1) was added over 1 minute. The reaction mixture was stirred for 30 minutes, then water (5ml) and ether (10m1) were added. The layers were separated and the aqueous layer was extracted with ether (lOml). The combined organic fractions were dried (MgS04) and the solvent was evaporated under reduced pressure. The residue was purified 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%). 1H NMR (250MHz, CDCls) 8 7.58-7.52 (2H, m), 7.36-7.17 (4H, m), 7.10-7.01 (2H, m), 5.18 (1H, br s), 4.20 (1H, t, J=6.7 Hz), 4.05-3.95 (1H, m), 3.76-3.55 (3H, m), 2.92-2.79 (1H, m), 2.37 (1H, 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, m). m/z (ES+) 534 (M+1).

(3R.5R,6S~-3-f2-Cvclo~rOnoxv-5-(trifluoromethoxy)phenyll-6-phenyl-1-oxa-7-(tert-butoxycarbonyl) aza-spiro [4. 51 decane Naphthalene (120mg, 0.936mmo1) was dissolved in THF (1.5m1) under nitrogen and freshly cut lithium metal (7.Omg, 0.94mmo1) 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 (3R,5R,6S)-3-(2-(1-phenylthiocycloprop-1-yl)oxy-5-_ 77 -(trifluoromethoxy)phenyl]-6-phenyl-1-oxa-7-(tent-butoxycarbonyl)aza-spiro[4.5]decane (Preparation 19, 135mg, 0.21mmo1) in THF (2m1) 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 {5ml) was added and the mixture was warmed to room temperature. Ether (lOml) was added and the layers were separated. The aqueous phase was extracted with a further portion of ether (10m1) and the combined organic phases were dried (MgS04) and the solvent was evaporated under reduced pressure.
The residue was purified by column chromatography on silica gel, eluting with hexane/ethyl acetate (50:50) to give the title compound as a colourless oil (87mg, 78%). 1H NMR (360MHz, CDCl8) 8 7.59 (2H, app. d, J=7.6 Hz), 7.32 (2H, app. t, J=7.6 Hz), 7.27-7.18 (2H, m), 7.11-7.03 (2H, m), 5.32 (1H, br s), 4.29-4.21 (1H, m), 3.97 (1H, br. d, J=13 Hz), 3.83-3.68 (3H, m), 2.76 (1H, dt, J=13; 4.1 Hz), 2.55 (1H, dd, J=13, 7.2 Hz), 2.22 (1H, dt, J=12, 5.2 Hz), 1.85 (1H, dd, J=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+1).
COMPOUND A
(3S 5R 6S)-3-[2-Cyclopropoxy-5-(trifluoromethox~phenyll-6-phenyl-1-oxa-7-aza-spirof4 5ldecane Hydrochloride Trifluoroacetic acid (2.5m1) was added dropwise to a stirred, cooled 0°C) solution of (3S,5R,6S)-3-[2-cyclopropoxy-5-(triffuoromethoxy)phenyl]
6-phenyl-1-oxa-7-(tert-butoxycarbonyl)aza-spiro[4.5]decane (Preparation 20; 492mg, 0.92mmo1) in dichloromethane (25m1) and the mixture was stirred at room temperature for 3 hours. The mixture was poured into water (50m1), the pH was adjusted to 10.0 with aqueous sodium hydroxide (4M) and the mixture was extracted with dichloromethane (3x50m1). The combined organic fractions were dried (MgS04) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with *rB

-78_ dichloromethane/methanol/ammonia (aq.) (96:4:0.4 increasing to 94:6:0.6).
The residue was dissolved in ethanol (20m1), cooled in ice and ethereal hydrogen chloride (1M, l.8ml, l.8mmo1) 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 (20m1)/ethanol (0.5m1) and the solid was collected and dried in uacuo to give the title compound as a colorless solid (354mg, 89%). m.p. 214-216 °C, iH NMR
(500MHz, CDsOD) 8 7.59 (2H, m), 7.52 (3H, m), 7.26 (1H, d, J=8.9 Hz), 7.03 (1H, dd, J=8.9, 2.2 Hz), 6.20 (1H, d, J=2.2 Hz), 4.85 (2H, br s), 4.43 (1H, s), 4.19 (1H, t, J=8.0 Hz), 3.87 (1H, quin, J=8.0 Hz), 3.76 (1H, m), 3.44 (1H, 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+1). Found: C, 61.41; H, 5.51; N, 3.08.
C24H2sFsNOs.HCI requires: C, 61.34; H, 5.79; N, 2.98%.
COMPOUND B
(3R 5R 6S~-3-f2-Cyclopro~oxy-5-(trifluoromethoxy)phenyll-6-phenyl-1-oxa-7-aza-spiro(4.5]decane Prepared from the compound of Preparation 21 according to the method used for Compound A. 1H NMR (360MHz, CDCIs) 8 7.50-7.42 (2H, m), 7.36-7.26 (3H, m), 7.03 (1H, d, J=8.9 Hz), 6.95 (1H, br. d, J=8.9 Hz), 6.81 (1H, br s), 3.92 (1H, t, J=7.4 Hz), 3.62-3.53 (2H, m), 3.50 (1H, s), 3.20 (1H, dd, J=12, 4.2 Hz), 2.77 (1H, dt, J=12, 2.8 Hz), 2.30-1.93 (4H, m), 1.87 (1H, br s), 1.71-1.49 (3H, m), 0.76-0.65 (2H, m), and 0.65-0.54 (2H, m). m/z {ES+) 434 (M+1).
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 (ICso) of less than lOnM, favourably less than 2nM and preferably less than lnM.

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, 458. The receptor is expressed at a level of 3x105 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. 125I_Tyr8-substance P (O.lnM, 2000Ci/mmol; New England Nuclear) is incubated in the presence or absence of test compounds (dissolved in 5~1 dimethylsulphoxide, DMSO) with 5x104 CHO cells. Ligand binding is performed in 0.25m1 of 50mM
Tris-HCl, pH7.5, containing 5mM MnClz, 150mM NaCI, 0.02% bovine serum albumin (Sigma), 50~,g/ml chymostatin (Peninsula), O.lnM
phenylmethylsulphonyl fluoride, 2~,g/ml pepstatin, 2pg/ml leupeptin and 2.8~,g/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 (1~.M) 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 central infusion of NK-1 receptor agonists such as GR73632 based on the method of Rupniak & Williams, Eur. J. Pharmacol., 1994, 265, 179.

Briefly, male or female Mongolian gerbils (35-70g) are anaesthetised by inhalation of an isoffurane/oxygen mixture to permit exposure of the jugular vein in order to permit administration of test compounds or vehicle in an injection volume of 5m1/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. A selective NK-1 receptor agonist (e.g. GR73632 (d Ala[L-Pro9,Me-Leul~]-substance P-(7-11)) is infused directly into the cerebral ventricles (e.g. 3pmol in 5~1 i.c.v., depending on test substance) by vertical insertion of a cuffed 27 gauge needle to a depth of 4.5mm below bregma. The scalp incision is closed and the animal allowed to recover from anaesthesia in a clear perspex observation box (25cm x 20cm x 20cm). The duration of hind foot tapping is then recorded continuously for approximately 5 minutes.
ASSAY 3: Ferret Emesis Individually housed male ferrets {1.0 -2.5 kg) are dosed orally by gavage with test compound. Ten minutes later they are fed with approximately 100g of tinned cat food. At 60 minutes following oral dosing, cisplatin (l0mg/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. 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 axe screened to ensure that a vigorous vocalisation response is reproducibly elicited following maternal separation. The pups are placed individually in an observation cage (55cm x 39cm x l9cm) in a room physically isolated from the home cage for 15 minutes and the duration of vocalisation during this baseline period is recorded. Only animals which vocalise for longer than 5 minutes are employed for drug challenge studies (approximately 50% of available pups may fail to reach this criterion). On test days each pup receives an oral dose or an s.c. or i.p. injection of test compound or vehicle and is then immediately returned to the home cage with its mother and siblings for 30 to FO minutes before social isolation for 15 minutes as described above.
The duration of vocalisation on drug treatment days is expressed as a percentage of the pre-treatment baseline value for each animal. The same subjects are retested once weekly for up to 6 weeks. Between 6 and 8 animals receive each test compound.
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-Pro9,Me-Leul°]-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 IDso<_lmg/kg.
In an alternative method, the NK-1 receptor antagonist is administered orally, 1 hour prior to GR73632 challenge, wherein the foot-tapping over a period of five minutes following recovery from anaesthesia is inhibited with an IDso<_30mg/kg, and preferably with an IDso<_lOmg/kg.

CNS-penetrant NK-1 receptor antagonists of use in the present 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 vocalisations during the first 15 minutes of isolation are attenuated with an IDso<-20mg/kg, preferably with an IDso<_lOmg/kg, and especially with an IDso<_5mg/kg.
In an alternative method, the NK-1 receptor antagonist is administered orally, 4 hours prior to isolation, wherein vocalisations during the first 15 minutes of isolation are attenuated with an IDso<20mg/kg, preferably with an IDso<lOmg/kg, and especially with an ipso<_5mg/kg.
A suitable selection cascade for NKl antagonists of use according to the present invention is as follows:
(i) Determine affinity for human NKl receptor in radioligand binding studies (Assay 1); select compounds with IC~o <_ lOnM, preferably ICso _< 2nM, especially ICso <_ lnM.
(ii) Determine ability of compounds to penetrate CNS by their ability to inhibit foot tapping in gerbils induced by central injection of an NKl agonist (Assay 2); select compounds that inhibit foot tapping with IDso <_ 3mg/kg i.v., and preferably IDso < 1mg/kg i.v. when administered immediately prior to central NKl agonist challenge, or IDso < 30mglkg p.o., and preferably IDso <_ 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 NKl agonist challenge; select compounds showing <_ 25-fold loss of potency compared with IDso determined in step (ii) above with the proviso that IDso _< l0mg/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 IDso <_ 3mg/kg p.o., and preferably IDso _< lmg/kg p.o.
Particularly preferred compounds of use in the present invention are identified using steps (i) to (iv) followed by step (v):
(v) Determine activity of compounds in assays sensitive to conventional antipsychotic drugs (inhibition of distress vocalisations in guinea-pig pups (Assay 4)). Select compounds with IDso <_ 20mg/kg, and preferably IDso <_ lOmg/kg.
Yet further preferred compounds of use in the present invention may be selected from those compounds which satisfy the NK-1 receptor binding criteria of step (i) which, in addition, have <_ 5-fold shift in affinity when incubated in the presence of human serum albumin (HSA) to show non-specific protein binding.
One example of a NK-1 receptor antagonist of use in the present invention is the compound 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)-ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(5-oxo-1H,4H-1,2,4-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: ICso=O.lnM
gerbil foot-tapping (5 wins.): IDso=0.36mg/kg i.v.
gerbil foot-tapping (24 hrs.): IDso=0.33mg/kg i.v.
ferret emesis: IDso<3mg/kg p.o.
guinea pig vocalisation (4 hr. pre-treatment): ID~o=0.73mg/kg p.o.

A further example of a NK-1 receptor antagonist of use in the present invention is the compound 2-(R)-(1-(S)-(3,5-bis(trifluoromethyl)phenyl)-2-hydroxyethoxy)-3-(S)-(4-ffuorophenyl)-4-(1,2,4-triazol-3-yl)methylmorpholine, the preparation of which is described in International Patent Specification No. WO 95/18124 and US Patent No.
5,612,337. In the aforementioned assays, this compound has the following activity:
human NK-1 receptor binding: ICso = 0.12 nM
gerbil foot-tapping (5 mins.): IDso = 0.38 mg/kg i.v.
gerbil foot-tapping {24 hrs.): IDso = 2.2 mg/kg i.v.
ferret emesis: IDso = 1 mg/kg p.o.
guinea-pig vocalisation {4 hr. pre-treatment): IDso = 0.91 mglkg 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 cellulose80.0 80.0 80.0 Modified food corn 80.0 80.0 80.0 starch Lactose 189.5 139.5 139.5 Magnesium Stearate 0.5 0.5 0.5 The active ingredient, cellulose, lactose and a portion of the corn starch are mixed and granulated with 10% corn starch paste. The resulting granulation is sieved, dried and blended with the remainder of the corn starch and the magnesium stearate. The resulting granulation is _ g5 -then compressed into tablets containing 50mg, 100mg and 300mg of the NK-1 receptor antagonist per tablet.
EXAMPLE 2 Parenteral infection Amount Active Ingredient 10 to 300mg Citric Acid Monohydrate 0.75mg Sodium Phosphate 4.5mg Sodium Chloride 9mg Water for injection to 10m1 The sodium phosphate, citric acid monohydrate and sodium chloride are dissolved in a portion of the water. The active ingredient is dissolved or suspended in the solution and made up to volume.
I5 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 3 Tablets containing 50-300mg of NK-1 antagonist and 5-lOmg of haloperidol Amount mg NK-1 antagonist 50.0 50.0 100.0 100.0 300.0 300.0 haloperidol 5.0 10.0 5.0 10.0 5.0 10.0 Microcrystalline cellulose80.0 80.0 80.0 80.0 80.0 80.0 Modified food corn 80.0 80.0 80.0 80.0 80.0 80.0 starch 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 EXAMPLE 4 Tablets containing 50-300m~ of NK-1 antagonist and 25m~
of chlorpromazine hydrochloride Amount ma NK-1 antagonist 50.0 100.0 300.0 chlorpromazine hydrochloride25.0 25.0 25.0 Microcrystalline cellulose80.0 80.0 80.0 Modified food corn starch80.0 80.0 80.0 Lactose 164.5 114.5 114.5 Magnesium Stearate 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, 100mg and 300mg of the CNS-penetrant NK-1 receptor antagonist per tablet.

Claims (10)

1. Use of an orally active, long acting, CNS-penetrant NK-1 receptor antagonist for the manufacture of a medicament for the treatment or prevention of aggressive behaviour.

2. Use of an orally active, long acting, CNS-penetrant NK-1 receptor antagonist and an antipsychotic agent for the manufacture of a medicament for the treatment or prevention of aggressive behaviour.

3. A pharmaceutical composition adapted for oral administration for the treatment or prevention of aggressive behaviour comprising an orally active, long acting, CNS-penetrant NK-1 receptor antagonist, together with at least one pharmaceutically acceptable carrier or excipient.

4. A composition according to claim 3 which further comprises an antipsychotic agent.

5. A product comprising an orally active, long acting, CNS-penetrant NK-1 receptor antagonist and an antipsychotic agent as a combined preparation for simultaneous, separate or sequential use in the treatment or prevention of aggressive behaviour.

6. A method for the treatment or prevention of aggressive behaviour, which method comprises 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.

7. A method for the treatment or prevention of aggressive behaviour, which method comprises administration to a patient in need of such treatment of an amount of an orally active, long acting, CNS-penetrant NK-1 receptor antagonist and an amount of an antipsychotic agent, such that together they give effective relief.

8. A use according to claim 1 or 2, a composition according to claim 3 or 4, a product according to claim 5 or a method according to claim 6 or 7 wherein the orally active, long acting, CNS-penetrant 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 WO-A-9749710.

9. A use according to claim 1 or 2, a composition according to claim 3 or 4, a product according to claim 5 or a method according to claim 6 or 7 wherein the NK-1 receptor antagonist is selected from:
(3S,5R,6S)-3-[2-cyclopropoxy-6-(trifluoromethoxy)phenyl-1-oxo-7-aza-spiro[4.5]decane;
(3R,5R,6S)-3-[2-cyclopropoxy-5-(trifluoromethoxy)phenyl-1-oxo-7-aza-spiro[4.5]decane;
2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3(S)-(4-fluorophenyl)-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)morpholine;
2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)-3-(S)-phenyl-morpholine;
2-(S)-(3, 5-bis(trifluoromethyl)benzyloxy)-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)-3-(S)-phenyl-morpholine;
2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)morpholine;
2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(5-(N,N-dimethylamino)methyl-1,2,3-triazol-4-yl)methyl-3-(S)-phenylmorpholine;
2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(5-(N,N-dimethylamino) methyl-1,2, 3-triazol-4-yl)methyl-3-(S)-(4-fluorophenyl)morpholine;

2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(4-monophosphoryl-5-oxo-1H-1,2,4-triazolo)methyl)morpholine;
2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(1-monophosphoryl-5-oxo-1H-1,2,4-triazolo)methyl)morpholine;
2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(2-monophosphoryl-5-oxo-1H-1,2,4-triazolo)methyl)morpholine;
2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(5-oxyphosphoryl-1H-1,2,4-triazolo)methyl)morpholine;
2-(S)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(1-monophosphoryl-5-oxo-4H-1,2,4-triazolo)methyl)morpholine;
2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(4-N,N-dimethylaminobut-2-yn-yl)-3-(S)-(4-fluorophenyl)morpholine;
2-(R)-(1-(S)-(3,5-bis(trifluoromethyl)phenyl)-2-hydroxyethoxy)-3-(S)-(4-fluorophenyl)-4-(1,2,4-triazol-3-yl)methylmorpholine;
or a pharmaceutically acceptable salt thereof.

10. A use according to claim 1 or 2, a composition according to claim 3 or 4, a product according to claim 5 or a method according to claim 6 or 7 wherein the aggressive behaviour is explosive personality disorder, intermittent explosive disorder, aggressive personality, aggressive nature, aggressiveness, excessive emotional instability, pathological emotionality, quarrelsomeness, dementia with behavioural disturbances, and personality change of the aggressive type due to a general medical condition.