Use of NK-1 receptor antagonists for treating mania

The present invention provides methods for the treatment or prevention of mania or hypomania which comprises administration of a NK-1 receptor antagonist, optionally with an antipsychotic agent, and pharmaceutical compositions containing a NK-1 receptor antagonist.

This invention relates to the treatment or prevention of mania by the 
administration of a NK-1 receptor antagonist. 
A Manic Episode is defined by a distinct period during which there is an 
abnormally and persistently elevated, expansive, or irritable mood. This 
period of abnormal mood must last at least 1 week (or less if 
hospitalization is required). The mood disturbance must be accompanied by 
at least three additional symptoms from a list that includes inflated 
self-esteem or grandiosity, decreased need for sleep, pressure of speech, 
flight of ideas, distractibility, increased involvement in goal-directed 
activities or psychomotor agitation, and excessive involvement in 
pleasurable activities with a high potential of painful consequences. If 
the mood is irritable (rather than elevated or expansive), at least four 
of the above symptoms must be present. The disturbance must be 
sufficiently severe to cause marked impairment in social or occupational 
functioning or to require hospitalization, or it is characterised by the 
presence of psychotic features. The episode must not be due to the direct 
physiological effects of a drug of abuse, a medication, other somatic 
treatments for depression (e.g., electroconvulsive therapy or light 
therapy) or toxin exposure. The episode must also not be due to the direct 
physiological effects of a general medical condition (e.g., multiple 
sclerosis, brain tumour). (Diagnostic and Statistical Manual of Mental 
Disorders, Fourth Edition, American Psychiatric Association, 1994). 
The elevated mood of a Manic Episode may be described as euphoric, 
unusually good, cheerful, or high. Although the person's mood may 
initially have an infectious quality for the uninvolved observer, it is 
recognized as excessive by those who know the person well. The expansive 
quality of the mood is characterised by unceasing and indiscriminate 
enthusiasm for interpersonal, sexual or occupational interactions. 
Although the elevated mood is considered the prototypical symptom, the 
predominant mood disturbance may be irritability, particularly when the 
person's wishes are thwarted. Lability of mood (e.g. the alternation 
between euphoria and irritability) is frequently seen. 
Treatment of mania is with drugs and psychological management. Typically, 
drugs such as haloperidol or chlorpromazine may be used to control 
symptoms. After more than one episode of mania, lithium carbonate is often 
prescribed. Drugs such as haloperidol and chlorpromazine are typically 
associated with a number of side-effects, including extrapyramidal 
symptoms, acute dystonias, tardive dyskinesias, akathesia, tremor, 
tachycardia, drowsiness, confusion, postural hypotension, blurring of 
vision, precipitation of glaucoma, dry mouth, constipation, urinary 
hesitance and impaired sexual function. The therapeutic index of lithium 
is low and close control of plasma concentrations is required for its safe 
clinical application. Side-effects of lithium include tremor, nausea, 
diarrhoea, thirst and polyuria. 
Neurokinin 1 (NK-1; substance P) receptor antagonists are being developed 
for the treatment of a number of physiological disorders associated with 
an excess or imbalance of tachykinins, and in particular substance P. 
Examples of conditions in which substance P has been implicated include 
disorders of the central nervous system such as anxiety, depression and 
psychosis (see, for instance, International (PCT) patent specification 
Nos. WO 95/16679, WO 95/18124 and WO 95/23798). 
In view of the short-comings of existing agents for the treatment of mania, 
there is a need for new, safe and effective treatment of mania. 
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 mania. 
The present invention also provides a method for the treatment or 
prevention of mania, 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 mania 
comprising a NK-1 receptor antagonist, together with at least one 
pharmaceutically acceptable carrier or excipient. 
Included within the scope of the present invention is the use of NK-1 
receptor antagonists in the treatment or prevention of hypomania. A 
hypomanic episode is distinguished from a manic episode in that it is not 
severe enough to cause marked impairment in social and occupational 
functioning or to require hospitalization, and there are no psychotic 
features. 
Thus, in a further aspect of the present invention, there is provided the 
use of a NK-1 receptor antagonist for the manufacture of a medicament for 
the treatment or prevention of hypomania. 
The present invention also provides a method for the treatment or 
prevention of hypomania, which method comprises adminstration 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 hypomania 
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 mania. Such a combination would be expected to provide for a 
rapid onset of action to treat a manic episode thereby enabling 
prescription 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 
mania. 
The present invention also provides a method for the treatment or 
prevention of mania, 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 mania. 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 mania. 
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. 
Included within the scope of the present invention is the use of NK-1 
receptor antagonists in combination with an antipsychotic agent in the 
treatment or prevention of hypomania. 
As used herein, the term "treatment" refers both to the treatment and to 
the prevention or prophylactic therapy of mania or hypomania. 
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. 90/05525, 90/05729, 91/09844, 91/18899, 92/01688, 
92/06079, 92/12151, 92/15585, 92/17449, 92/20661, 92/20676, 92/21677, 
93/00330, 93/00331, 93/01159, 93/01165, 93/01169, 93/01170, 93/06099, 
93/09116, 93/10073, 93/14113, 93/18023, 93/19064, 93/21155, 9321181, 
93/23380, 93/24465, 94/01402, 94/02461, 94/03429, 94/03445, 94/04494, 
94/04496, 94/05625, 94/07843, 94/10165, 94/10167, 94/10168, 94/10170, 
94/11368, 94/13639, 94/13663, 94/14767, 94/15903, 94/19320, 94/19323, 
94/20500, 94/26735, 94/26740, 94/29309, 95/02595, 95/04040, 95/04042, 
95/06645, 95/07886, 95/07908, 95/08549, 95/11880, 95/14017, 95/15311, 
95/16679, 95/17382, 95/18124, 95/18129, 95/19344, 95/20575, 95/21819, 
96/22525, 95/23798, 95/26338, 95/28418, 95/30674, 95/30687, 96/05193, 
96/05203, 96/06094, 96/07649, 96/10562, 96/16939, 96/18643, 96/20197, 
96/21661, 96/29304, 96/29317, 96/29326, 96/29328, 96/31214, 96/32385, 
96/37489, 97/01553, 97/01554, 97/03066, 97/08144, 97/14671, 97/17362, 
97/18206, 97/19084, 97/19942 and 97/21702; and in British Patent 
Specification Nos. 2 266 529, 2 268 931, 2 269 170, 2 269 590, 2 271 774, 
2 292 144, 2 293 168, 2 293 169, and 2 302 689. 
Suitable antipsychotic agents of use in combination with a NK-1 receptor 
antagonist include the phenothiazine, thioxanthene, heterocyclic 
dibenzazepine, butyrophenone, diphenylbutylpiperidine and indolone classes 
of antipsychotic agent. Suitable examples of phenothiazines include 
chlorpromazine, mesoridazine, thioridazine, acetophenazine, fluphenazine, 
perphenazine and trifluoperazine. Suitable examples of thioxanthenes 
include chlorprothixene and thiothixene. An example of a dibenzazepine is 
clozapine. An example of a butyrophenone is haloperidol. An example of a 
diphenylbutylpiperidine is pimozide. An example of an indolone is 
molindolone. Other antipsychotic agents include loxapine, sulpiride and 
risperidone. It will be appreciated that the antipsychotic agents when 
used in combination with a NK-1 receptor antagonist may be in the form of 
a pharmaceutically acceptable salt, for example, chlorpromazine 
hydrochloride, mesoridazine besylate, thioridazine hydrochloride, 
acetophenazine maleate, fluphenazine hydrochloride, flurphenazine 
enathate, fluphenazine decanoate, trifluoperazine hydrochloride, 
thiothixene hydrochloride, haloperidol decanoate, loxapine succinate and 
molindone hydrochloride. Perphenazine, chlorprothixene, clozapine, 
haloperidol, pimozide and risperidone are commonly used in a non-salt 
form. 
Particularly preferred NK-1 receptor antagonists are those described in 
European Patent Specification No. 0 577 394, i.e. compounds of formula 
(I): 
##STR1## 
or a pharmaceutically acceptable salt thereof, wherein: 
R.sup.1 is selected from the group consisting of: 
(1) hydrogen; 
(2) C.sub.1-6 alkyl, unsubstituted or substituted with one or more of the 
substituents selected from: 
(a) hydroxy, 
(b) oxo, 
(c) C.sub.1-6 alkoxy, 
(d) phenyl-C.sub.1-3 alkoxy, 
(e) phenyl, 
(f) --CN, 
(g) halo, 
(h) --NR.sup.9 R.sup.10, wherein R.sup.9 and R.sup.10 are independently 
selected from: 
(i) hydrogen, 
(ii) C.sub.1-6 alkyl, 
(iii) hydroxy-C.sub.1-6 alkyl, and 
(iv) phenyl, 
(i) --NR.sup.9 COR.sup.10, wherein R.sup.9 and R.sup.10 are as defined 
above, 
(j) --NR.sup.9 CO.sub.2 R.sup.10, wherein R.sup.9 and R.sup.10 are as 
defined above, 
(k) --CONR.sup.9 R.sup.10, wherein R.sup.9 and R.sup.10 are as defined 
above, 
(l) --COR.sup.9, wherein R.sup.9 is as defined above, 
(m) --CO.sub.2 R.sup.9, wherein R.sup.9 is as defined above, 
(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, 
(M) pyrazolyl, 
(N) pyridyl, 
(O) pyrimidyl, 
(P) pyrrolyl, 
(Q) quinolyl, 
(R) tetrazolyl, 
(S) thiadiazolyl, 
(T) thiazolyl, 
(U) thienyl, 
(V) triazolyl, 
(W) azetidinyl, 
(X) 1,4-dioxanyl, 
(Y) hexahydroazepinyl, 
(Z) oxanyl, 
(AA) piperazinyl, 
(AB) piperidinyl, 
(AC) pyrrolidinyl, 
(AD) tetrahydrofuranyl, and 
(AE) tetrahydrothienyl, 
and wherein the heterocylcle is unsubstituted or substituted with one or 
more substituent(s) selected from: 
(i) C.sub.1-6 alkyl, unsubstituted or substituted with halo, --CF.sub.3, 
--OCH.sub.3, or phenyl, 
(ii) C.sub.1-6 alkoxy, 
(iii) oxo, 
(iv) hydroxy, 
(v) thioxo, 
(vi) --SR.sup.9, wherein R.sup.9 is as defined above, 
(vii) halo, 
(viii) cyano, 
(ix) phenyl, 
(x) trifluoromethyl, 
(xi) --(CH.sub.2).sub.m --NR.sup.9 R.sup.10, wherein m is 0, 1 or 2, and 
R.sup.9 and R.sup.10 are as defined above, 
(xii) --NR.sup.9 COR.sup.10, wherein R.sup.9 and R.sup.10 are as defined 
above, 
(xiii) --CONR.sup.9 R.sup.10, wherein R.sup.9 and R.sup.10 are as defined 
above, 
(xiv) --CO.sub.2 R.sup.9, wherein R.sup.9 is as defined above, and 
(xv) --(CH.sub.2).sub.m --OR.sup.9, wherein m and R.sup.9 are as defined 
above; 
(3) C.sub.2-6 alkenyl, unsubstituted or substituted with one or more of the 
substituent(s) selected from: 
(a) hydroxy, 
(b) oxo, 
(c) C.sub.1-6 alkoxy, 
(d) phenyl-C.sub.1-3 alkoxy, 
(e) phenyl, 
(f) --CN, 
(g) halo, 
(h) --CONR.sup.9 R.sup.10, wherein R.sup.9 and R.sup.10 are as defined 
above, 
(i) --COR.sup.9, wherein R.sup.9 is as defined above, 
(j) --CO.sub.2 R.sup.9, wherein R.sup.9 is as defined above, 
(k) heterocycle, wherein the heterocycle is as defined above; 
(4) C.sub.2-6 alkynyl; 
(5) phenyl, unsubstitued or substituted with one or more of the 
substituent(s) selected from: 
(a) hydroxy, 
(b) C.sub.1-6 alkoxy, 
(c) C.sub.1-6 alkyl, 
(d) C.sub.2-5 alkenyl, 
(e) halo, 
(f) --CN, 
(g) --NO.sub.2, 
(h) --CF.sub.3, 
(i) --(CH.sub.2).sub.m --NR.sup.9 R.sup.10, wherein m, R.sup.9 and R.sup.10 
are as defined above, 
(j) --NR.sup.9 COR.sup.10, wherein R.sup.9 and R.sup.10 are as defined 
above, 
(k) --NR.sup.9 CO.sub.2 R.sup.10, wherein R.sup.9 and R.sup.10 are as 
defined above, 
(l) --CONR.sup.9 R.sup.10, wherein R.sup.9 and R.sup.10 are as defined 
above, 
(m) --CO.sub.2 NR.sup.9 R.sup.10, wherein R.sup.9 and R.sup.10 are as 
defined above, 
(n) --COR.sup.9, wherein R.sup.9 is as defined above, 
(o) --CO.sub.2 R.sup.9, wherein R.sup.9 is as defined above; 
R.sup.2 and R.sup.3 are independently selected from the group consisting 
of: 
(1) hydrogen; 
(2) C.sub.1-6 alkyl, unsubstituted or substituted with one or more of the 
substituents selected from: 
(a) hydroxy, 
(b) oxo, 
(c) C.sub.1-6 alkoxy, 
(d) phenyl-C.sub.1-3 alkoxy, 
(e) phenyl, 
(f) --CN, 
(g) halo, 
(h) --NR.sup.9 R.sup.10, wherein R.sup.9 and R.sup.10 are independently 
selected from: 
(i) --NR.sup.9 COR.sup.10, wherein R.sup.9 and R.sup.10 are as defined 
above, 
(j) --NR.sup.9 CO.sub.2 R.sup.10, wherein R.sup.9 and R.sup.10 are as 
defined above, 
(k) --CONR.sup.9 R.sup.10, wherein R.sup.9 and R.sup.10 are as defined 
above, 
(l) --COR.sup.9, wherein R.sup.9 is as defined above, and 
(m) --CO.sub.2 R.sup.9, wherein R.sup.9 is as defined above; 
(3) C.sub.2-6 alkenyl, unsubstituted or substituted with one or more of the 
substituent(s) selected from: 
(a) hydroxy, 
(b) oxo, 
(c) C.sub.1-6 alkoxy, 
(d) phenyl-C.sub.1-3 alkoxy, 
(e) phenyl, 
(o) --CN, 
(g) halo, 
(h) --CONR.sup.9 R.sup.10 wherein R.sup.9 and R.sup.10 are as defined 
above, 
(i) --COR.sup.9, wherein R.sup.9 is as defined above, 
(j) --CO.sub.2 R.sup.9, wherein R.sup.9 is as defined above; 
(4) C.sub.2-6 alkynyl; 
(5) phenyl, unsubstituted or substituted with one or more of the 
substituent(s) selected from: 
(a) hydroxy, 
(b) C.sub.1-6 alkoxy, 
(c) C.sub.1-6 alkyl, 
(d) C.sub.2-5 alkenyl, 
(e) halo, 
(f) --CN, 
(g) --NO.sub.2, 
(h) --CF.sub.3, 
(i) --(CH.sub.2).sub.m --NR.sup.9 R.sup.10, wherein m, R.sup.9 and R.sup.10 
are as defined above, 
(j) --NR.sup.9 COR.sup.10, wherein R.sup.9 and R.sup.10 are as defined 
above, 
(k) --NR.sup.9 CO.sub.2 R.sup.10, wherein R.sup.9 and R.sup.10 are as 
defined above, 
(l) --CONR.sup.9 R.sup.10, wherein R.sup.9 and R.sup.10 are as defined 
above, 
(m) --CO.sub.2 NR.sup.9 R.sup.10, wherein R.sup.9 and R.sup.10 are as 
defined above, 
(n) --COR.sup.9, wherein R.sup.9 is as defined above, 
(o) --CO.sub.2 R.sup.9, wherein R.sup.9 is as defined above; 
and the groups R.sup.1 and R.sup.2 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) C.sub.1-6 alkyl, 
(ii) oxo, 
(iii) C.sub.1-6 alkoxy, 
(iv) --NR.sup.9 R.sup.10, wherein R.sup.9 and R.sup.10 are as defined 
above, 
(v) halo, and 
(vi) trifluoromethyl; 
and the groups R.sup.2 and R.sup.3 may be joined together to form a 
carbocyclic ring selected from the group consisting of: 
(a) cyclopentyl, 
(b) cyclohexyl, 
(c) phenyl, 
and wherein the carbocyclic ring is unsubstituted or substituted with one 
or more substituents selected from: 
(i) C.sub.1-6 alkyl, 
(ii) C.sub.1-6 alkoxy, 
(iii) --NR.sup.9 R.sup.10, wherein R.sup.9 and R.sup.10 are as defined 
above, 
(iv) halo, and 
(v) trifluoromethyl; 
and the groups R.sup.2 and R.sup.3 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) 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) C.sub.1-6 alkyl, 
(ii) oxo, 
(iii) C.sub.1-6 alkoxy, 
(iv) --NR.sup.9 R.sup.10, wherein R.sup.9 and R.sup.10 are as defined 
above, 
(v) halo, and 
(vi) trifluoromethyl; 
X is selected from the group consisting of: 
(1) --O--, 
(2) --S--, 
(3) --SO--, and 
(4) --SO.sub.2 --; 
R.sup.4 is selected from the group consisting of: 
(1) 
##STR2## 
(2) --Y--C.sub.1-8 alkyl, wherein alkyl is unsubstituted or substituted 
with one or more of the substituents selected from: 
(a) hydroxy, 
(b) oxo, 
(c) C.sub.1-6 alkoxy, 
(d) phenyl-C.sub.1-3 alkoxy, 
(e) phenyl, 
(f) --CN, 
(g) halo, 
(h) --NR.sup.9 R.sup.10, wherein R.sup.9 and R.sup.10 are as defined above, 
(i) --NR.sup.9 COR.sup.10, wherein R.sup.9 and R.sup.10 are as defined 
above, 
(j) --NR.sup.9 CO.sub.2 R.sup.10, wherein R.sup.9 and R.sup.10 are as 
defined above, 
(k) --CONR.sup.9 R.sup.10, wherein R.sup.9 and R.sup.10 are as defined 
above, 
(l) --COR.sup.9, wherein R.sup.9 is as defined above, 
(m) --CO.sub.2 R.sup.9, wherein R.sup.9 is as defined above; 
(3) --Y--C.sub.2-6 alkenyl, wherein the alkenyl is unsubstituted or 
substituted with one or more of the substituent(s) selected from: 
(a) hydroxy, 
(b) oxo, 
(c) C.sub.1-6 alkoxy, 
(d) phenyl-C.sub.1-6 alkoxy, 
(e) phenyl, 
(f) --CN, 
(g) halo, 
(h) --CONR.sup.9 R.sup.10, wherein R.sup.9 and R.sup.10 are as defined 
above, 
(i) --COR.sup.9, wherein R.sup.9 is as defined above, 
(j) --CO.sub.2 R.sup.9, wherein R.sup.9 is as defined above, 
(4) --O(CO)-phenyl, wherein the phenyl is unsubstituted or substituted with 
one or more of R.sup.6, R.sup.7 and R.sup.8 ; 
R.sup.5 is selected from the group consisting of: 
(1) phenyl, unsubstituted or substituted with one or more of R.sup.11, 
R.sup.12 and R.sup.13 ; 
(2) C.sub.1-8 alkyl, unsubstituted or substituted with one or more of the 
substituent(s) selected from: 
(a) hydroxy, 
(b) oxo, 
(c) C.sub.1-6 alkoxy, 
(d) phenyl-C.sub.1-3 alkoxy, 
(e) phenyl, 
(f) --CN, 
(g) halo, 
(h) --NR.sup.9 R.sup.10, wherein R.sup.9 and R.sup.10 are as defined above, 
(i) --NR.sup.9 COR.sup.10, wherein R.sup.9 and R.sup.10 are as defined 
above, 
(j) --NR.sup.9 CO.sub.2 R.sup.10, wherein R.sup.9 and R.sup.10 are as 
defined above, 
(k) --CONR.sup.9 R.sup.10, wherein R.sup.9 and R.sup.10 are as defined 
above, 
(l) --COR.sup.9, wherein R.sup.9 is as defined above, 
(m) --CO.sub.2 R.sup.9, wherein R.sup.9 is as defined above; 
(3) C.sub.2-6 alkenyl, unsubstituted or substituted with one or more of the 
substituent(s) selected from: 
(a) hydroxy, 
(b) oxo, 
(c) C.sub.1-6 alkoxy, 
(d) phenyl-C.sub.1-3 alkoxy, 
(e) phenyl, 
(f) --CN, 
(g) halo, 
(h) --CONR.sup.9 R.sup.10, wherein R.sup.9 and R.sup.10 are as defined 
above, 
(i) --COR.sup.9, wherein R.sup.9 is as defined above, 
(j) --CO.sub.2 R.sup.9, wherein R.sup.9 is as defined above; 
(4) heterocycle, wherein the heterocycle is as defined above; 
R.sup.6, R.sup.7 and R.sup.8 are independently selected from the group 
consisting of: 
(1) hydrogen; 
(2) C.sub.1-6 alkyl, unsubstituted or substituted with one or more of the 
substituents selected from: 
(a) hydroxy, 
(b) oxo, 
(c) C.sub.1-6 alkoxy, 
(d) phenyl-C.sub.1-3 alkoxy, 
(e) phenyl, 
(f) --CN, 
(g) halo, 
(h) --NR.sup.9 R.sup.10, wherein R.sup.9 and R.sup.10 are as defined above, 
(i) --NR.sup.9 COR.sup.10, wherein R.sup.9 and R.sup.10 are as defined 
above, 
(j) --NR.sup.9 CO.sub.2 R.sup.10, wherein R.sup.9 and R.sup.10 are as 
defined above, 
(k) --CONR.sup.9 R.sup.10, wherein R.sup.9 and R.sup.10 are as defined 
above, 
(l) --COR.sup.9, wherein R.sup.9 is as defined above, and 
(m) --CO.sub.2 R.sup.9, wherein R.sup.9 is as defined above; 
(3) C.sub.2-6 alkenyl, unsubstituted or substituted with one or more of the 
substituent(s) selected from: 
(a) hydroxy, 
(b) oxo, 
(c) C.sub.1-6 alkoxy, 
(d) phenyl-C.sub.1-3 alkoxy, 
(e) phenyl, 
(f) --CN, 
(g) halo, 
(h) --CONR.sup.9 R.sup.10 wherein R.sup.9 and R.sup.10 are as defined 
above, 
(i) --COR.sup.9 wherein R.sup.9 is as defined above, 
(j) --CO.sub.2 R.sup.9, wherein R.sup.9 is as defined above; 
(4) C.sub.2-6 alkynyl; 
(5) phenyl, unsubstituted or substituted with one or more of the 
substituent(s) selected from: 
(a) hydroxy, 
(b) C.sub.1-6 alkoxy, 
(c) C.sub.1-6 alkyl, 
(d) C.sub.2-5 alkenyl, 
(e) halo, 
(f) --CN, 
(g) --NO.sub.2, 
(h) --CF.sub.3, 
(i) --(CH.sub.2).sub.m --NR.sup.9 R.sup.10, wherein m, R.sup.9 and R.sup.10 
are as defined above, 
(j) --NR.sup.9 COR.sup.10, wherein R.sup.9 and R.sup.10 are as defined 
above, 
(k) --NR.sup.9 CO.sub.2 R.sup.10, wherein R.sup.9 and R.sup.10 are as 
defined above, 
(l) --CONR.sup.9 R.sup.10, wherein R.sup.9 and R.sup.10 are as defined 
above, 
(m) --CO.sub.2 NR.sup.9 R.sup.10, wherein R.sup.9 and R.sup.10 are as 
defined above, 
(n) --COR.sup.9, wherein R.sup.9 is as defined above; 
(o) --CO.sub.2 R.sup.9, wherein R.sup.9 is as defined above; 
(6) halo, 
(7) --CN, 
(8) --CF.sub.3, 
(9) --NO.sub.2, 
(10) --SR.sup.14, wherein R.sup.14 is hydrogen or C.sub.1-5 alkyl, 
(11) --SOR.sup.14, wherein R.sup.14 is as defined above, 
(12) --SO.sub.2 R.sup.14, wherein R.sup.14 is as defined above, 
(13) NR.sup.9 COR.sup.10, wherein R.sup.9 and R.sup.10 are as defined 
above, 
(14) CONR.sup.9 COR.sup.10, wherein R.sup.9 and R.sup.10 are as defined 
above, 
(15) NR.sup.9 R.sup.10, wherein R.sup.9 and R.sup.10 are as defined above, 
(16) NR.sup.9 CO.sub.2 R.sup.10, wherein R.sup.9 and R.sup.10 are as 
defined above, 
(17) hydroxy, 
(18) C.sub.1-6 alkoxy, 
(19) COR.sup.9, wherein R.sup.9 is as defined above, 
(20) CO.sub.2 R.sup.9, wherein R.sup.9 is as defined above, 
R.sup.11, R.sup.12 and R.sup.13 are independently selected from the 
definitions of R.sup.6, R.sup.7 and R.sup.8, or --OX; 
Y is selected from the group consisting of: 
(1) a single bond, 
(2) --O--, 
(3) --S--, 
(4) --CO--, 
(5) --CH.sub.2 --, 
(6) --CHR.sup.15 --, and 
(7) --CR.sup.15 R.sup.16 --, wherein R.sup.15 and R.sup.16 are 
independently selected from the group consisting of: 
(a) C.sub.1-6 alkyl, unsubstituted or substituted with one or more of the 
substituents selected from: 
(i) hydroxy, 
(ii) oxo, 
(iii) C.sub.1-6 alkoxy, 
(iv) phenyl-C.sub.1-3 alkoxy, 
(v) phenyl, 
(vi) --CN, 
(vii) halo, 
(viii) --NR.sup.9 R.sup.10, wherein R.sup.9 and R.sup.10 are as defined 
above, 
(ix) --NR.sup.9 COR.sup.10, wherein R.sup.9 and R.sup.10 are as defined 
above, 
(x) --NR.sup.9 CO.sub.2 R.sup.10, wherein R.sup.9 and R.sup.10 are as 
defined above, 
(xi) --CONR.sup.9 R.sup.10, wherein R.sup.9 and R.sup.10 are as defined 
above, 
(xii) --COR.sup.9, wherein R.sup.9 is as defined above, and 
(xiii) --CO.sub.2 R.sup.9, wherein R.sup.9 is as defined above; 
(b) phenyl, unsubstituted or substituted with one or more of the 
substituent(s) selected from: 
(i) hydroxy, 
(ii) C.sub.1-6 alkoxy, 
(iii) C.sub.1-6 alkyl, 
(iv) C.sub.2-5 alkenyl, 
(v) halo, 
(vi) --CN, 
(vii) --NO.sub.2, 
(viii) --CF.sub.3, 
(ix) --(CH.sub.2).sub.m --NR.sup.9 R.sup.10, wherein m, R.sup.9 and 
R.sup.10 are as defined above, 
(x) --NR.sup.9 COR.sup.10, wherein R.sup.9 and R.sup.10 are as defined 
above, 
(xi) --NR.sup.9 CO.sub.2 R.sup.10, wherein R.sup.9 and R.sup.10 are as 
defined above, 
(xii) --CONR.sup.9 R.sup.10, wherein R.sup.9 and R.sup.10 are as defined 
above, 
(xiii) --CO.sub.2 NR.sup.9 R.sup.10, wherein R.sup.9 and R.sup.10 are as 
defined above, 
(xiv) --COR.sup.9, wherein R.sup.9 is as defined above, and 
(xv) --CO.sub.2 R.sup.9, wherein R.sup.9 is as defined above; 
Z is selected from: 
(1) hydrogen, 
(2) C.sub.1-4 alkyl, and 
(3) hydroxy, with the proviso that if Y is --O--, Z is other than hydroxy, 
or if Y is --CHR.sup.15 --, then Z and R.sup.15 may be joined together to 
form a double bond. 
Particularly preferred compounds of formula (I) are those wherein: 
R.sup.1 is selected from the group consisting of: 
(1) C.sub.1-6 alkyl, 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) C.sub.1-6 alkyl, unsubstituted or substituted with halo, --CF.sub.3, 
--OCH.sub.3, or phenyl, 
(ii) C.sub.1-6 alkoxy, 
(iii) oxo, 
(iv) thioxo, 
(v) cyano, 
(vi) --SCH.sub.3, 
(vii) phenyl, 
(viii) hydroxy, 
(ix) trifluoromethyl, 
(x) --(CH.sub.2).sub.m --NR.sup.9 R.sup.10, wherein m is 0, 1 or 2, and 
R.sup.9 and R.sup.10 are independently selected from: 
(I) hydrogen, 
(II) C.sub.1-6 alkyl, 
(III) hydroxyC.sub.1-6 alkyl, and 
(IV) phenyl, 
(xi) --NR.sup.9 COR.sup.10, wherein R.sup.9 and R.sup.10 are as defined 
above, and 
(xii) --CONR.sup.9 R.sup.10, wherein R.sup.9 and R.sup.10 are as defined 
above, R.sup.2 and R.sup.3 are independently selected from the group 
consisting of: 
(1) hydrogen; 
(2) C.sub.1-6 alkyl 
(3) C.sub.2-6 alkenyl, and 
(5) phenyl; 
X is --O--; 
R.sup.4 is 
##STR3## 
R.sup.5 is phenyl, unsubstituted or substituted with halo; 
R.sup.6, R.sup.7 and R.sup.8 are independently selected from the group 
consisting of: 
(1) hydrogen, 
(2) C.sub.1-6 alkyl, 
(3) halo, and 
(4) --CF.sub.3 ; 
Y is --O--; and 
Z is hydrogen or C.sub.1-4 alkyl; 
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(trifluoromethyl)benzyloxy)-3(R)- 
phenyl-morpholine; 
4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)-2(S)-(3,5-bis(trifluoromethyl)benz 
yloxy)-3(S)-phenyl-morpholine; and 
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; 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): 
##STR4## 
or a pharmaceutically acceptable salt or prodrug thereof, wherein R.sup.1 
is hydrogen, halogen, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, CF.sub.3, 
NO.sub.2, CN, SR.sup.a, SOR.sup.a, SO.sub.2 R.sup.a, CO.sub.2 R.sup.a, 
CONR.sup.a R.sup.b, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl or C.sub.1-4 
alkyl substituted by C.sub.1-4 alkoxy, where R.sup.a and R.sup.b each 
independently represent hydrogen or C.sub.1-4 alkyl; 
R.sup.2 is hydrogen, halogen, C.sub.1-6 alkyl, C.sub.1-6 alkoxy substituted 
by C.sub.1-4 alkoxy or CF.sub.3 ; 
R.sup.3 is hydrogen, halogen or CF.sub.3 ; 
R.sup.4 is hydrogen, halogen, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, CF.sub.3, 
NO.sub.2, CN, SR.sup.a, SOR.sup.a, SO.sub.2 R.sup.a, CO.sub.2 R.sup.a, 
CONR.sup.a R.sup.b, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl or C.sub.1-4 
alkyl substituted by C.sub.1-4 alkoxy, where R.sup.a and R.sup.b each 
independently represent hydrogen or C.sub.1-4 alkyl; 
R.sup.5 is hydrogen, halogen, C.sub.1-6 alkyl, C.sub.1-6 alkoxy substituted 
by C.sub.1-4 alkoxy or CF.sub.3 ; 
R.sup.6 is a 5-membered or 6-membered heterocyclic ring containing 2 or 3 
nitrogen atoms optionally substituted by .dbd.O, .dbd.S or a C.sub.1-4 
alkyl group, and optionally substituted by a group of the formula 
ZNR.sup.7 R.sup.8 where 
Z is C.sub.1-6 alkylene or C.sub.3-6 cycloalkylene; 
R.sup.7 is hydrogen, C.sub.1-4 alkyl, C.sub.3-7 cycloalkyl or C.sub.3-7 
cycloalkylC.sub.1-4 alkyl, or C.sub.2-4 alkyl substituted by C.sub.1-4 
alkoxy or hydroxyl; 
R.sup.8 is hydrogen, C.sub.1-4 alkyl, C.sub.3-7 cycloalkyl or C.sub.3-7 
cycloalkylC.sub.1-4 alkyl, or C.sub.2-4 alkyl 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.sup.7, R.sup.8 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).sub.2 or a second nitrogen atom which will be part of a NH or 
NR.sup.c moiety where R.sup.c is C.sub.1-4 alkyl optionally substituted by 
hydroxy or C.sub.1-4 alkoxy; 
or R.sup.7, R.sup.8 and the nitrogen atom to which they are attached form a 
non-aromatic azabicyclic ring system of 6 to 12 ring atoms; 
or Z, R.sup.7 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; 
R.sup.9a and R.sup.9b are each independently hydrogen or C.sub.1-4 alkyl, 
or R.sup.9a and R.sup.9b are joined so, together with the carbon atoms to 
which they are attached, there is formed a C.sub.5-7 ring; 
X is an alkylene chain of 1 to 4 carbon atoms optionally substituted by 
oxo; and 
Y is a C.sub.1-4 alkyl group optionally substituted by a hydroxyl group; 
with the proviso that if Y is C.sub.1-4 alkyl, R.sup.6 is substituted at 
least by a roup of formula ZNR.sup.7 R8 as defined above. 
Particularly preferred compounds of formula (II) are those of formula (IIa) 
and pharmaceutically acceptable salts thereof: 
##STR5## 
wherein: A.sup.1 is fluorine or CF.sub.3 ; 
A.sup.2 is fluorine or CF.sub.3 ; 
A.sup.3 is fluorine or hydrogen; 
and X, Y and R.sup.6 are as defined in relation to formula (II). 
Particularly preferred compounds of formula (II) include: 
2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)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): 
##STR6## 
or a pharmaceutically acceptable salt thereof, wherein: 
R.sup.2 and R.sup.3 are independently selected from the group consisting 
of: 
(1) hydrogen, 
(2) C.sub.1-6 alkyl, unsubstituted or substituted with one or more of the 
substituents selected from: 
(a) hydroxy, 
(b) oxo, 
(c) C.sub.1-6 alkoxy, 
(d) phenyl-C.sub.1-3 alkoxy, 
(e) phenyl, 
(f) --CN, 
(g) halo, 
(h) --NR.sup.9 R.sup.10, wherein R.sup.9 and R.sup.10 are independently 
selected from: 
(i) hydrogen, 
(ii) C.sub.1-6 alkyl, 
(iii) hydroxy-C.sub.1-6 alkyl, and 
(iv) phenyl, 
(i) --NR.sup.9 COR.sup.10, wherein R.sup.9 and R.sup.10 are as defined 
above, 
(j) --NR.sup.9 CO.sub.2 R.sup.10, wherein R.sup.9 and R.sup.10 are as 
defined above, 
(k) --CONR.sup.9 R.sup.10, wherein R.sup.9 and R.sup.10 are as defined 
above, 
(l) --COR.sup.9, wherein R.sup.9 is as defined above, and 
(m) --CO.sub.2 R.sup.9, wherein R.sup.9 is as defined above; 
(3) C.sub.2-6 alkenyl, unsubstituted or substituted with one or more of the 
substituent(s) selected from: 
(a) hydroxy, 
(b) oxo, 
(c) C.sub.1-6 alkoxy, 
(d) phenyl-C.sub.1-3 alkoxy, 
(e) phenyl, 
(f) --CN, 
(g) halo, 
(h) --CONR.sup.9 R.sup.10 wherein R9 and R.sup.10 are as defined above, 
(i) --COR.sup.9 wherein R.sup.9 is as defined above, 
(j) --CO.sub.2 R.sup.9, wherein R.sup.9 is as defined above; 
(4) C.sub.2-6 alkynyl; 
(5) phenyl, unsubstituted or substituted with one or more of the 
substituent(s) selected from: 
(a) hydroxy, 
(b) C.sub.1-6 alkoxy, 
(c) C.sub.1-6 alkyl, 
(d) C.sub.2-5 alkenyl, 
(e) halo, 
(f) --CN, 
(g) --NO.sub.2, 
(h) --CF.sub.3, 
(i) --(CH.sub.2).sub.m --NR.sup.9 R.sup.10, wherein m, R.sup.9 and R.sup.10 
are as defined above, 
(j) --NR.sup.9 COR.sup.10, wherein R.sup.9 and R.sup.10 are as defined 
above, 
(k) --NR.sup.9 CO.sub.2 R.sup.10, wherein R.sup.9 and R.sup.10 are as 
defined above, 
(l) --CONR.sup.9 R.sup.10, wherein R.sup.9 and R.sup.10 are as defined 
above, 
(m) --CO.sub.2 NR.sup.9 R.sup.10, wherein R.sup.9 and R.sup.10 are as 
defined above, 
(n) --COR.sup.9, wherein R.sup.9 is as defined above, 
(o) --CO.sub.2 R.sup.9, wherein R.sup.9 is as defined above; 
the groups R.sup.2 and R.sup.3 may be joined together to form a carbocyclic 
ring elected from the group consisting of: 
(a) cyclopentyl, 
(b) cyclohexyl, 
(c) phenyl, 
and wherein the carbocyclic ring is unsubstituted or substituted with one 
or more substituents selected from: 
(i) C.sub.1-6 alkyl, 
(ii) C.sub.1-6 alkoxy, 
(iii) --NR.sup.9 R.sup.10, wherein R.sup.9 and R.sup.10 are as defined 
above, 
(iv) halo, and 
(v) trifluoromethyl; 
and the groups R.sup.2 and R.sup.3 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) 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) C.sub.1-6 alkyl, 
(ii) oxo, 
(iii) C.sub.1-6 alkoxy, 
(iv) --NR.sup.9 R.sup.10, wherein R.sup.9 and R.sup.10 are as defined 
above, 
(v) halo, and p2 (vi) trifluoromethyl; 
R.sup.6, R.sup.7 and R.sup.8 are independently selected from the group 
consisting of: 
(1) hydrogen; 
(2) C.sub.1-6 alkyl, unsubstituted or substituted with one or more of the 
substituents selected from: 
(a) hydroxy, 
(b) oxo, 
(c) C.sub.1-6 alkoxy, 
(d) phenyl-C.sub.1-3 alkoxy, 
(e) phenyl, 
(f) --CN, 
(g) halo, 
(h) --NR.sup.9 R.sup.10, wherein R.sup.9 and R.sup.10 are as defined above, 
(i) --NR.sup.9 COR.sup.10, wherein R.sup.9 and R.sup.10 are as defined 
above, 
(j) --NR.sup.9 CO.sub.2 R.sup.10, wherein R.sup.9 and R.sup.10 are as 
defined above, 
(k) --CONR.sup.9 R.sup.10, wherein R.sup.9 and R.sup.10 are as defined 
above, 
(l) --COR.sup.9, wherein R.sup.9 is as defined above, and 
(m) --CO.sub.2 R.sup.9, wherein R.sup.9 is as defined above; 
(3) C.sub.2-6 alkenyl, unsubstituted or substituted with one or more of the 
substituent(s) selected from: 
(a) hydroxy, 
(b) oxo, 
(c) C.sub.1-6 alkoxy, 
(d) phenyl-C.sub.1-3 alkoxy, 
(e) phenyl, 
(f) --CN, 
(g) halo, 
(h) --CONR.sup.9 R.sup.10 wherein R.sup.9 and R.sup.10 are as defined 
above, 
(i) --COR.sup.9 wherein R.sup.9 is as defined above, 
(j) --CO2R.sup.9, wherein R.sup.9 is as defined above; 
(4) C.sub.2-6 alkynyl; 
(5) phenyl, unsubstituted or substituted with one or more of the 
substituent(s) selected from: 
(a) hydroxy, 
(b) C.sub.1-6 alkoxy, 
(c) C.sub.1-6 alkyl, 
(d) C.sub.2-5 alkenyl, 
(e) halo, 
(f) --CN, 
(g) --NO.sub.2, 
(h) --CF.sub.3, 
(i) --(CH.sub.2).sub.m --NR.sup.9 R.sup.10, wherein m, R.sup.9 and R.sup.10 
are as defined above, 
(j) --NR.sup.9 COR.sup.10, wherein R.sup.9 and R.sup.10 are as defined 
above, 
(k) --NR.sup.9 CO.sub.2 R.sup.10, wherein R.sup.9 and R.sup.10 are as 
defined above, 
(l) --CONR.sup.9 R.sup.10, wherein R.sup.9 and R.sup.10 are as defined 
above, 
(m) --CO.sub.2 NR.sup.9 R.sup.10, wherein R.sup.9 and R.sup.10 are as 
defined above, 
(n) --COR.sup.9, wherein R.sup.9 is as defined above, 
(o) --CO.sub.2 R.sup.9, wherein R.sup.9 is as defined above; 
(6) halo, 
(7) --CN, 
(8) --CF.sub.3, 
(9) --NO.sub.2, 
(10) --SR.sup.14, wherein R.sup.14 is hydrogen or C.sub.1-5 alkyl, 
(11) --SOR.sup.14, wherein R.sup.14 is as defined above, 
(12) --SO.sub.2 R.sup.14, wherein R.sup.14 is as defined above, 
(13) NR.sup.9 COR.sup.10, wherein R.sup.9 and R.sup.10 are as defined 
above, 
(14) CONR.sup.9 COR.sup.10, wherein R.sup.9 and R.sup.10 are as defined 
above, 
(15) NR.sup.9 R.sup.10, wherein R.sup.9 and R.sup.10 are as defined above, 
(16) NR.sup.9 CO.sub.2 R.sup.10, wherein R.sup.9 and R.sup.10 are as 
defined above, 
(17) hydroxy, 
(18) C.sub.1-6 alkoxy, 
(19) COR.sup.9, wherein R.sup.9 is as defined above, 
(20) CO.sub.2 R.sup.9, wherein R.sup.9 is as defined above, 
(21) 2-pyridyl, 
(22) 3-pyridyl, 
(23) 4-pyridyl, 
(24) 5-tetrazolyl, 
(25) 2-oxazolyl, and 
(26) 2-thiazolyl; 
R.sup.11, R.sup.12 and R.sup.13 are independently selected from the 
definitions of R.sup.6, R.sup.7 and R.sup.8, or --OX; 
A is selected from the group consisting of: 
(1) C.sub.1-6 alkyl, unsubstituted or substituted with one or more of the 
substituents selected from: 
(a) hydroxy, 
(b) oxo, 
(c) C.sub.1-6 alkoxy, 
(d) phenyl-C.sub.1-3 alkoxy, 
(e) phenyl, 
(f) --CN, 
(g) halo, wherein halo is fluoro, chloro, bromo or iodo, 
(h) --NR.sup.9 R.sup.10, wherein R.sup.9 and R.sup.10 are as defined above, 
(i) --NR.sup.9 COR.sup.10, wherein R.sup.9 and R.sup.10 are as defined 
above, 
(j) --NR.sup.9 CO.sub.2 R.sup.10, wherein R.sup.9 and R.sup.10 are as 
defined above, 
(k) --CONR.sup.9 R.sup.10, wherein R.sup.9 and R.sup.10 are as defined 
above, 
(l) --COR.sup.9, wherein R.sup.9 is as defined above, and 
(m) --CO.sub.2 R.sup.9, wherein R.sup.9 is as defined above; 
(2) C.sub.2-6 alkenyl, unsubstituted or substituted with one or more of the 
substituent(s) selected from: 
(a) hydroxy, 
(b) oxo, 
(c) C.sub.1-6 alkoxy, 
(d) phenyl-C.sub.1-3 alkoxy, 
(e) phenyl, 
(f) --CN, 
(g) halo, 
(h) --CONR.sup.9 R.sup.10 wherein R.sup.9 and R.sup.10 are as defined 
above, 
(i) --COR.sup.9 wherein R.sup.9 is as defined above, and 
(j) --CO.sub.2 R.sup.9, wherein R.sup.9 is as defined above; and 
(3) C.sub.2-6 alkynyl; 
B is a heterocycle, wherein the heterocycle is selected from the group 
consisting of: 
##STR7## 
and wherein the heterocycle may be substituted in addition to --X with one 
or more substituent(s) selected from: 
(i) C.sub.1-6 alkyl, unsubstituted or substituted with halo, --CF.sub.3, 
--OCH.sub.3, or phenyl, 
(ii) C.sub.1-6 alkoxy, 
(iii) oxo, 
(iv) hydroxy, 
(v) thioxo, 
(vi) --SR.sup.9, wherein R.sup.9 is as defined above, 
(vii) halo, 
(viii) cyano, 
(ix) phenyl, 
(x) trifluoromethyl, 
(xi) --(CH.sub.2).sub.m --NR.sup.9 R.sup.10, wherein m is 0, 1 or 2, and 
R.sup.9 and R.sup.10 are as defined above, 
(xii) --NR.sup.9 COR.sup.10, wherein R.sup.9 and R.sup.10 are as defined 
above, 
(xiii) --CONR.sup.9 R.sup.10, wherein R.sup.9 and R.sup.10 are as defined 
above, 
(xiv) --CO.sub.2 R.sup.9, wherein R.sup.9 is as defined above, and 
(xv) --(CH.sub.2).sub.m --OR.sup.9, wherein m and R.sup.9 are as defined 
above; 
p is 0 or 1; 
X is selected from: 
(a) --PO(OH)O.sup.-.M.sup.+, wherein M.sup.+ is a pharmaceutically 
acceptable monovalent counterion, 
(b) --PO(O.sup.-).sub.2.2M.sup.+, 
(c) --PO(O.sup.-).sub.2.D.sup.2+, wherein D.sup.2+ is a pharmaceutically 
acceptable divalent counterion, 
(d) --CH(R.sup.4)--PO(OH)O.sup.-.M.sup.+, wherein R.sup.4 is hydrogen or 
C.sub.1-3 alkyl, 
(e) --CH(R.sup.4)--PO(O.sup.-).sub.2.2M.sup.+, 
(f) --CH(R.sup.4)--PO(O.sup.-).sub.2.D.sup.2+, 
(g) --SO.sub.3.sup.-.M.sup.+, 
(h) --CH(R.sup.4)--SO.sub.3.M.sup.+, 
(i) --CO--CH.sub.2 CH.sub.2 --CO.sub.2.sup.-.M.sup.+, 
(j) --CH(CH.sub.3)--O--CO--R.sup.5, wherein R.sup.5 is selected from the 
group consisting of: 
##STR8## 
(k) hydrogen, with the proviso that if p is 0 and none of R.sup.11, 
R.sup.12 or R.sup.13 are --OX, then X is other than hydrogen; 
Y is selected from the group consisting of: 
(1) a single bond, 
(2) --O--, 
(3) --S--, 
(4) --CO--, 
(5) --CH.sub.2 --, 
(6) --CHR.sup.15 --, and 
(7) --CR.sup.15 R.sup.16 --, wherein R.sup.15 and R.sup.16 are 
independently selected from the group consisting of: 
(a) C.sub.1-6 alkyl, unsubstituted or substituted with one or more of the 
substituents selected from: 
(i) hydroxy, 
(ii) oxo, 
(iii) C.sub.1-6 alkoxy, 
(iv) phenyl-C.sub.1-3 alkoxy, 
(v) phenyl, 
(vi) --CN, 
(vii) halo, 
(viii) --NR.sup.9 R.sup.10, wherein R.sup.9 and R.sup.10 are as defined 
above, 
(ix) --NR.sup.9 COR.sup.10, wherein R.sup.9 and R.sup.10 are as defined 
above, 
(x) --NR.sup.9 CO.sub.2 R.sup.10, wherein R.sup.9 and R.sup.10 are as 
defined above, 
(xi) --CONR.sup.9 R.sup.10, wherein R.sup.9 and R.sup.10 are as defined 
above, 
(xii) --COR.sup.9, wherein R.sup.9 is as defined above, and 
(xiii) --CO.sub.2 R.sup.9, wherein R.sup.9 is as defined above; 
(b) phenyl, unsubstituted or substituted with one or more of the 
substituent(s) selected from: 
(i) hydroxy, 
(ii) C.sub.1-6 alkoxy, 
(iii) C.sub.1-6 alkyl, 
(iv) C.sub.2-5 alkenyl, 
(v) halo, 
(vi) --CN, 
(vii) --NO.sub.2, 
(viii) --CF.sub.3, 
(ix) --(CH.sub.2).sub.m --NR.sup.9 R.sup.10, wherein m, R.sup.9 and 
R.sup.10 are as defined above, 
(x) --NR.sup.9 COR.sup.10, wherein R.sup.9 and R.sup.10 are as defined 
above, 
(xi) --NR.sup.9 CO.sub.2 R.sup.10, wherein R.sup.9 and R.sup.10 are as 
defined above, 
(xii) --CONR.sup.9 R.sup.10, wherein R.sup.9 and R.sup.10 are as defined 
above, 
(xiii) --CO.sub.2 NR.sup.9 R.sup.10, wherein R.sup.9 and R.sup.10 are as 
defined above, 
(xiv) --COR.sup.9, wherein R.sup.9 is as defined above, and 
(xv) --CO.sub.2 R.sup.9, wherein R.sup.9 is as defined above; 
Z is selected from: 
(1) hydrogen, 
(2) C.sub.1-6 alkyl, and 
(3) hydroxy, with the proviso that if Y is --O--, Z is other than hydroxy, 
or if Y is --CHR.sup.15 --, then Z and R.sup.15 may be joined together to 
form a double bond. 
Particularly preferred compounds of formula (III) are those wherein: 
R.sup.2 and R.sup.3 are independently selected from the group consisting 
of: 
(1) hydrogen, 
(2) C.sub.1-6 alkyl, 
(3) C.sub.2-6 alkenyl, and 
(4) phenyl; 
R.sup.6, R.sup.7 and R.sup.8 are independently selected from the group 
consisting of: 
(1) hydrogen, 
(2) C.sub.1-6 alkyl, 
(3) fluoro, 
(4) chloro, 
(5) bromo, 
(6) iodo, and 
(7) --CF.sub.3 ; 
R.sup.11, R.sup.12 and R.sup.13 are independently selected from the group 
consisting of: 
(1) fluoro, 
(2) chloro, 
(3) bromo, and 
(4) iodo; 
A is unsubstituted .sub.1-6 alkyl; 
B is selected from the group consisting of: 
##STR9## 
p is 0 or 1; X is selected from: 
(a) --PO(OH)O.sup.-.M.sup.+, wherein M.sup.+ is a pharmaceutically 
acceptable monovalent counterion, 
(b) --PO(O.sup.-).sub.2.2M.sup.+, 
(c) --PO(O.sup.-).sub.2.D.sup.2+, wherein D.sup.2+ is a pharmaceutically 
acceptable divalent counterion, 
(d) --CH(R.sup.4)--PO(OH)O.sup.-.M.sup.+, wherein R.sup.4 is hydrogen or 
C.sub.1-3 alkyl, 
(e) --CH(R.sup.4)--PO(O.sup.-).sub.2.2M.sup.+, 
(f) --CH(R.sup.4)--PO(O.sup.-).sub.2.D.sup.2+, 
(i) --CO--CH.sub.2 CH.sub.2 --CO.sub.2 --.M.sup.+, 
(j) --CH(CH.sub.3)--O--CO--R.sup.5, wherein R.sup.5 is selected from the 
group consisting of: 
##STR10## 
Y is --O--; Z is hydrogen or C.sub.1-6 alkyl; and pharmaceutically 
acceptable salts thereof. 
Particularly preferred compounds of formula (III) include: 
(1) 2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-.sup.4 
-(3-(5-oxo-1H, 4H-1,2,4-triazolo)methyl)morpholine N-oxide; 
(2) 
2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-4-(3-(4-(ethoxycarb 
onyloxy-1-ethyl)-5-oxo-1H-1,2,4-triazolo)methyl)morpholine; 
(3) 
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; 
(4) 
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; 
(5) 
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; 
(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(trifluoromethyl)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 (IV): 
##STR11## 
wherein X is a group of the formula NR.sup.6 R.sup.7 or a C- or N-linked 
imidazolyl ring; 
Y is hydrogen or C.sub.1-4 alkyl optionally substituted by a hydroxy group; 
R.sup.1 is hydrogen, halogen, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, CF.sub.3, 
NO.sub.2, CN, SR.sup.a, SOR.sup.a, SO.sub.2 R.sup.a, CO.sub.2 R.sup.a, 
CONR.sup.a R.sup.b, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl or C.sub.1-4 
alkyl substituted by C.sub.1-4 alkoxy, wherein R.sup.a and R.sup.b each 
independently represent hydrogen or C.sub.1-4 alkyl; 
R.sup.2 is hydrogen, halogen, C.sub.1-6 alkyl, C.sub.1-6 alkoxy substituted 
by C.sub.1-4 alkoxy or CF.sub.3 ; 
R.sup.3 is hydrogen, halogen or CF.sub.3 ; 
R.sup.4 is hydrogen, halogen, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, hydroxy, 
CF.sub.3, NO.sub.2, CN, SR.sup.a, SOR.sup.a, SO.sub.2 R.sup.a, CO.sub.2 
R.sup.a, CONR.sup.a R.sup.b, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl or 
C.sub.1-4 alkyl substituted by C.sub.1-4 alkoxy, wherein R.sup.a and 
R.sup.b are as previously defined; 
R.sup.5 is hydrogen, halogen, C.sub.1-6 alkyl, C.sub.1-6 alkoxy substituted 
by C.sub.1-4 alkoxy or CF.sub.3 ; 
R.sup.6 is hydrogen, C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl, C.sub.3-7 
cycloalkylC.sub.1-4 alkyl, phenyl, or C.sub.2-4 alkyl substituted by 
C.sub.1-4 alkoxy or hydroxy; 
R.sup.7 is hydrogen, C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl, C.sub.3-7 
cycloalkylC.sub.1-4 alkyl, phenyl, or C.sub.2-4 alkyl substituted by one 
or two substituents selected from C.sub.1-4 alkoxy, hydroxy or a 4, 5 or 6 
membered heteroaliphatic ring containing one or two heteroatoms selected 
from N, O and S; 
or R.sup.6 and R.sup.7, 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 NR.sup.8, S(O) or S(O).sub.2 and 
which ring may be optionally substituted by one or two groups selected 
from hydroxyC.sub.1-4 alkyl, C.sub.1-4 alkoxyC.sub.1-4 alkyl, oxo, 
COR.sup.a or CO.sub.2 R.sup.a where R.sup.a is as previously defined; 
or R.sup.6 and R.sup.7 together with the nitrogen atom to which they are 
attached, form a non-aromatic azabicyclic ring system of 6 to 12 ring 
atoms; 
R.sup.8 is hydrogen, C.sub.1-4 alkyl, hydroxyC.sub.1-4 alkyl or C.sub.1-4 
alkoxyC.sub.1-4 alkyl; and 
R.sup.9a and R.sup.9b are each independently hydrogen or C.sub.1-4 alkyl, 
or R.sup.9a and R.sup.9b are joined so, together with the carbon atoms to 
which they are attached, there is formed a C.sub.5-7 ring; 
and pharmaceutically acceptable salts thereof. 
Particularly preferred compounds of formula (IV) are those of formula (IVa) 
and pharmaceutically acceptable salts thereof: 
##STR12## 
wherein A.sup.1 is fluorine or CF.sub.3 ; 
A.sup.2 is fluorine or CF.sub.3 ; 
A.sup.3 is fluorine or hydrogen; 
and X and Y are as defined in relation to formula (I). 
Specific compounds of formula (IV) of use in the present invention include: 
2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl) 
-4-(4-morpholinobut-2-yn-yl)morpholine; 
2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(4-N,N-dimethylamino 
but-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-fluorophenyl) 
-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(trifluorome 
thyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)morpholine; 
2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl) 
-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-(trifluo 
romethyl)phenyl)ethoxy)morpholine; 
4-(4-azetidinylbut-2-yn-yl)-3-(S)-(4-fluorophenyl)-2-(R)-(1-(R)-(3-(trifluo 
romethyl)phenyl)ethoxy)morpholine; 
2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(4-(N-(2-methoxyethy 
l)-N-methyl)aminobut-2-yn-yl)-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-fluorophenyl)-2-(R)-(1-(S)-(3 
-fluoro-5-(trifluoromethyl)phenyl-2-hydroxyethoxy)morpholine; 
4-(4-azetidinylbut-2yn-yl)-3-(S)-(4-fluorophenyl)-2-(R)-(1-(S)-(3-fluoro-5- 
(trifluoromethyl)phenyl)-2-hydroxyethoxy)morpholine; 
2-(R)-(1-(S)-(3,5-bis(trifluoromethyl)phenyl)-2-hydroxyethoxy)-4-(4-(N,N-di 
methylamino)but-2-yn-yl)-3-(S)-(4-fluorophenyl)morpholine; 
4-(4-azetidinylbut-2-yn-yl)-2-(R)-(1-(S)-(3,5-bis(trifluoromethyl)phenyl-2- 
hydroxyethoxy)-3-(S)-(4-fluorophenyl)morpholine; 
4-(4-N-bis(2-methoxy)ethyl-N-methylamino)but-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-fluorophenyl) 
-4-(4-(2-(S)-(methoxymethyl)pyrrolidino)but-2-yn-yl)morpholine; 
4-(4-(7-azabicyclo2.2.1!heptano)but-2-yn-yl)-2-(R)-(1-(R)-(3,5-bis(trifluo 
romethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)morpholine; 
2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(4-diisopropylaminob 
ut-2-yn-yl)-3-(S)-(4-fluorophenyl)morpholine; 
2-(R)-(1-(R)-(3-fluoro-5-(trifluoromethyl)phenyl)ethoxy)-4-(4-(2-(S)-(metho 
xymethyl)pyrrolidino)but-2-yn-yl)-3-(S)-phenylmorpholine; 
2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl) 
-4-(4-(2-(S)-(hydroxymethyl)pyrrolidino)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 (V): 
##STR13## 
or a pharmaceutically acceptable salt thereof, wherein Y is 
(CH.sub.2).sub.n wherein n is an integer from 1 to 4, and wherein any one 
of the carbon-carbon single bonds in said (CH.sub.2).sub.n may optionally 
be replaced by a carbon-carbon double bond, and wherein any one of the 
carbon atoms of said (CH.sub.2).sub.n may optionally be substituted with 
R.sup.4, and wherein any one of the carbon atoms of said (CH.sub.2).sub.n 
may optionally be substituted with R.sup.7 ; 
Z is (CH.sub.2).sub.m wherein m is an integer from 0 to 6, and wherein any 
one of the carbon-carbon single bonds of (CH.sub.2).sub.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 (CH.sub.2).sub.m may optionally be 
substituted with R.sup.8 ; 
R.sup.1 is hydrogen or C.sub.1-8 alkyl optionally substituted with hydroxy, 
C.sub.1-4 alkoxy or fluoro; 
R.sup.2 is a radical selected from hydrogen, C.sub.1-6 straight or branched 
alkyl, C.sub.3-7 cycloalkyl wherein one of the CH.sub.2 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-C.sub.2-6 alkyl, benzhydryl and 
benzyl, wherein each of said aryl and heteroaryl groups and the phenyl 
moieties of said benzyl, phenyl C.sub.2-6 alkyl and benzhydryl may 
optionally be substituted with one or more substituents independently 
selected from halo, nitro, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, 
trifluoromethyl, amino, C.sub.1-6 alkylamino, C.sub.1-6 alkyl-O--CO, 
C.sub.1-6 alkyl-O--CO--C.sub.1-6 alkyl, C.sub.1-6 alkyl-CO--O, C.sub.1-6 
alkyl-CO--C.sub.1-6 alkyl-O--, C.sub.1-6 alkyl-CO, C.sub.1-6 
alkyl-CO--C.sub.1-6 alkyl-, di-C.sub.1-6 alkylamino, --CONH--C.sub.1-6 
alkyl, C.sub.1-6 alkyl-CO--NH--C.sub.1-6 alkyl, --NHCOH and 
--NHCO--C.sub.1-6 alkyl; and wherein one of the phenyl moieties of said 
benzhydryl may optionally be replaced by naphthyl, thienyl, furyl or 
pyridyl; 
R.sup.5 is hydrogen, phenyl or C.sub.1-6 alkyl; 
or R.sup.2 and R.sup.5 together with the carbon to which they are attached, 
form a saturated ring having from 3 to 7 carbon atoms wherein one of the 
CH.sub.2 groups in said ring may optionally be replaced by oxygen, NH or 
sulfur; 
R.sup.3 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 (CH.sub.2) 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 C.sub.3-7 cycloalkyl 
may optionally be substituted with one or two substituents, each of said 
substituents being independently selected from halo, nitro, C.sub.1-6 
alkyl, C.sub.1-6 alkoxy, trifluoromethyl, amino, C.sub.1-6 alkylamino, 
--CO--NH--C.sub.1-6 alkyl, C.sub.1-6 alkyl-CO--NH--C.sub.1-6 alkyl, 
--NHCOH and --NHCO-C.sub.1-6 alkyl; 
R.sup.4 and R.sup.7 are each independently selected from hydroxy, halogen, 
halo, amino, oxo, cyano, methylene, hydroxymethyl, halomethyl, C.sub.1-6 
alkylamino, di-C.sub.1-6 alkylamino, C.sub.1-6 alkoxy, C.sub.1-6 
alkyl-O--CO, C.sub.1-6 alkyl-O--CO--C.sub.1-6 alkyl, C.sub.1-6 
alkyl-CO--O, C.sub.1-6 alkyl-CO--C.sub.1-6 alkyl-O--, C.sub.1-6 
alkyl-CO--, C.sub.1-6 alkyl-CO--C.sub.1-6 alkyl, and the radicals set 
forth in the definition of R.sup.2 ; 
R.sup.6 is --NHCOR.sup.9, --NHCH.sub.2 R.sup.9, SO.sub.2 R.sup.8 or one of 
the radicals set forth in any of the definitions of R.sup.2, R.sup.4 and 
R.sup.7 ; 
R.sup.8 is oximino (.dbd.NOH) or one of the radicals set forth in any of 
the definitions of R.sup.2, R.sup.4 and R.sup.7 ; 
R.sup.9 is C.sub.1-6 alkyl, hydrogen, phenyl or phenylC.sub.1-6 alkyl; with 
the proviso that (a) when m is 0, R.sup.8 is absent, (b) when R.sup.4, 
R.sup.6, R.sup.7 or R.sup.8 is as defined in R.sup.2, it cannot form 
together with the carbon to which it is attached ,a ring with R.sup.5, and 
(c) when R.sup.4 and R.sup.7 are attached to the same carbon atom, then 
either each of R.sup.4 and R.sup.7 is independently selected from 
hydrogen, fluoro and C.sub.1-6 alkyl, or R.sup.4 and R.sup.7, together 
with the carbon to which they are attached, for a C.sub.3-6 saturated 
carbocyclic ring that forms a spiro compound with the nitrogen-containing 
ring to which they are attached. 
A particularly preferred compound of formula (V) is 
(2S,3S)-cis-3-(2methoxybenzylamino)-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): 
##STR14## 
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; 
R.sup.1 is optionally substituted phenyl, cyclohexadienyl, naphthyl, 
indenyl or optionally substituted heterocycle; 
R.sup.2 is H, halogen, OH, alkyl, aminoalkyl, alkylaminoalkyl, 
dialkylaminoalkyl, alkyloxy, alkylthio, acyloxy, carboxy, optionally 
substituted alkyloxycarbonyl, benzyloxycarbonyl, amino or acylamino; 
R.sup.3 is optionally 2-substituted phenyl; 
R.sup.4 is OH or fluorine when R.sup.5 is H; 
or R.sup.4 and R.sup.5 are OH; 
or R.sup.4 and R.sup.5 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-ol; 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. 0 591 040, i.e. 
compounds of formula (VII): 
##STR15## 
wherein Ar represents an optionally substituted mono-, di- or tricyclic 
aromatic or heteroaromatic group; 
T represents a bond, a hydroxymethylene group, a C.sub.1-4 alkoxymethylene 
group or a C.sub.1-5 alkylene group; 
Ar' represents a phenyl group which is unsubstituted or substituted by one 
or more substituents selected from halogen, preferably chlorine or 
fluorine, trifluoromethyl, C.sub.1-4 alkoxy, C.sub.1-4 alkyl 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, C.sub.1-4 alkyl, .omega.-C.sub.1-4 alkoxyC.sub.1-4 
alkyl, or .omega.-C.sub.2-4 alkanoyloxyC.sub.2-4 alkyl; 
Q represents hydrogen; 
or Q and R together form a 1,2-ethylene, 1,3-propylene or 1,4-butylene 
group; 
Am.sup.+ represents the radical 
##STR16## 
in which X.sub.1, X.sub.2 and X.sub.3, 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-azabicyclo2,2,2!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): 
##STR17## 
or a pharmaceutically acceptable salt thereof, wherein R.sup.1 represents 
an optionally substituted aralkyl, aryloxyalykl, heteroaralkyl, aroyl, 
heteroaroyl, cycloalkylcarbonyl, aralkanoyl, heteroarylalkanoyl, 
aralkoxycarbonyl or arylcarbamoyl group or the acyl group of an 
.alpha.-amino acid optionally N-substituted by a lower alkanoyl or 
carbamoyl-lower alkanoyl group; 
R.sup.2 represents cycloalkyl or an optionally substituted aryl or 
heteroaryl group; 
R.sup.3 represents hydrogen, alkyl, carbamoyl or an alkanoyl or alkenoyl 
group optionally substituted by carboxy or esterified or amidated carboxy; 
R.sup.4 represents an optionally substituted aryl group or an optionally 
partially saturated heteroaryl group; 
X.sub.1 represents methylene, ethylene, a bond, an optionally ketalised 
carbonyl group or an optionally etherified hydroxymethylene group; 
X.sub.2 represents alkylene, carbonyl or a bond; and 
X.sub.3 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 .alpha.-position) 
hydroxy. 
A particularly preferred compound of formula (VIII) is (2R*, 
4S*)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-(4-quinolinylmethyl)-4-piperidinea 
mine; 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) 
##STR18## 
or a pharmaceutically acceptable salt thereof, wherein R.sup.1 is aryl, or 
a group of the formula: 
##STR19## 
X is CH or N; and Z is O or N--R.sup.5, in which R.sup.5 is hydrogen or 
lower alkyl; 
R.sup.2 is hydroxy or lower alkoxy; 
R.sup.3 is hydrogen or optionally substituted lower alkyl; 
R.sup.4 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) 
##STR20## 
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) 
##STR21## 
or a pharmaceutically acceptable salt thereof, wherein R.sup.1 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 C.sub.3-7 cycloalkyl may optionally be substituted with one or two 
substituents, said substituents being independently selected from chloro, 
fluoro, bromo, iodo, nitro, C.sub.1-10 alkyl optionally substituted with 
from one to three fluoro groups, C.sub.1-10 alkoxy optionally substituted 
with from one to three fluoro groups, amino, C.sub.1-10 alkyl-S--, 
C.sub.1-10 alkyl-S(O)--, C.sub.1-10 alkyl-SO.sub.2 --, phenyl, phenoxy, 
C.sub.1-10 alkyl-SO.sub.2 NH--, C.sub.1-10 alkyl-SO.sub.2 NH--C.sub.1-10 
alkyl-, C.sub.1-10 alkylamino-diC.sub.1-10 alkyl-, cyano, hydroxy, 
cycloalkoxy having 3 to 7 carbon atoms, C.sub.1-6 alkylamino, C.sub.1-6 
dialkylamino, HC(O)NH-- and C.sub.1-10 alkyl-C(O)NH--; and 
R.sup.2 is thienyl, benzhydryl, naphthyl or phenyl optionally substituted 
with from one to three substituents independently selected from chloro, 
bromo, fluoro, iodo, cycloalkoxy having 3 to 7 carbon atoms, C.sub.1-10 
alkyl optionally substituted with from one to three fluoro groups and 
C.sub.1-10 alkoxy 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) 
##STR22## 
or a pharmaceutically acceptable salt thereof, wherein R.sup.1 is a 
C.sub.1-4 alkoxy group; 
R.sup.2 is 
##STR23## 
R.sup.3 is a hydrogen or halogen atom; R.sup.4 and R.sup.5 may each 
independently represent a hydrogen or halogen atom, or a C.sub.1-4 alkyl, 
C.sub.1-4 alkoxy or trifluoromethyl group; 
R.sup.6 is a hydrogen atom, a C.sub.1-4 alkyl, (CH.sub.2).sub.m 
cyclopropyl, --S(O).sub.n C.sub.1-4 alkyl, phenyl, NR.sup.7 R.sup.8, 
CH.sub.2 C(O)CF.sub.3 or trifluoromethyl group; 
R.sup.7 and R.sup.8 may each independently represent a hydrogen atom, or a 
C.sub.1-4 alkyl 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-phenylpiperidin-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) 
##STR24## 
or a pharmaceutically acceptable salt thereof, wherein m is zero, 1, 2 or 
3; 
n is zero or 1; 
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, C.sub.1-3 alkoxy, 
trifluoromethyl, C.sub.1-4 alkyl, phenyl-C.sub.1-3 alkoxy, or C.sub.1-4 
alkanoyl groups; 
R.sup.1 is trityl, phenyl, diphenylmethyl, phenoxy, phenylthio, 
piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, indolinyl, indolyl, 
benzothienyl, hexamethyleneiminyl, benzofuranyl, tetrahydropyridinyl, 
quinolinyl, isoquinolinyl, reduced quinolinyl, reduced isoquinolinyl, 
phenyl-(C.sub.1-4 alkyl)-, phenyl-(C.sub.1-4 alkoxy)-, 
quinolinyl-(C.sub.1-4 alkyl)-, isoquinolinyl-(C.sub.1-4 alkyl)-, reduced 
quniolinyl-(C.sub.1-4 alkyl)-, reduced isoquinolinyl-(C.sub.1-4 alkyl)-, 
benzoyl-(C.sub.1-3 alkyl)-, C.sub.1-4 alkyl, or --NH--CH.sub.2 --R.sup.5 ; 
any one of which R.sup.1 groups may be substituted with halo, C.sub.1-4 
alkyl, C.sub.1-4 alkoxy, trifluoromethyl, amino, C.sub.1-4 alkylamino, 
di(C.sub.1-4 alkyl)amino, or C.sub.2-4 alkanoylamino; 
or any one of which R.sup.1 groups may be substituted with phenyl, 
piperazinyl, C.sub.3-8 cycloalkyl, benzyl, C.sub.1-4 alkyl, piperidinyl, 
pyridinyl, pyrimidinyl, C.sub.2-6 alkanoylamino, pyrrolidinyl, C.sub.2-6 
alkanoyl, or C.sub.1-4 alkoxycarbonyl; 
any one of which groups may be substituted with halo, C.sub.1-4 alkyl, 
C.sub.1-4 alkoxy, trifluoromethyl, amino, C.sub.1-4 alkylamino, 
di(C.sub.1-4 alkyl)amino, or C.sub.2-4 alkanoylamino; 
or R.sup.1 is amino, a leaving group, hydrogen, C.sub.1-4 alkylamino, or 
di(C.sub.1-4 alkyl)amino; 
R.sup.5 is pyridyl, anilino-(C.sub.1-3 alkyl)-, or anilinocarbonyl; 
R.sup.2 is hydrogen, C.sub.1-4 alkyl, C.sub.1-4 alkylsulfonyl, 
carboxy-(C.sub.1-3 alkyl)-, C.sub.1-3 alkoxycarbonyl-(C.sub.1-3 alkyl)-, 
or --CO--R.sup.6 ; 
R.sup.6 is hydrogen, C.sub.1-4 alkyl, C.sub.1-3 haloalkyl, phenyl, 
C.sub.1-3 alkoxy, C.sub.1-3 hydroxyalkyl, amino, C.sub.1-4 alkylamino, 
di(C.sub.1-4 alkyl)amino, or --(CH.sub.2).sub.q --R.sup.7 ; 
q is zero to 3; 
R.sup.7 is carboxy, C.sub.1-4 alkoxycarbonyl, C.sub.1-4 alkylcarbonyloxy, 
amino, C.sub.1-4 alkylamino, di(C.sub.1-4 alkyl)amino, C.sub.1-6 
alkoxycarbonylamino, or phenoxy, phenylthio, piperazinyl, piperidinyl, 
pyrrolidinyl, morpholinyl, indolinyl, indolyl, benzothienyl, benzofuranyl, 
quinolinyl, phenyl-(C.sub.1-4 alkyl)-, quinolinyl-(C.sub.1-4 alkyl)-, 
isoquinolinyl-(C.sub.1-4 alkyl)-, reduced quinolinyl(C.sub.1-4 alkyl)-, 
reduced isoquinolinyl-(C.sub.1-4 alkyl)-, benzoyl-C.sub.1-3 alkyl; 
any one of which aryl or heterocyclic R.sup.7 groups may be substituted 
with halo, trifluoromethyl, C.sub.1-4 alkoxy, C.sub.1-4 alkyl, amino, 
C.sub.1-4 alkylamino, di(C.sub.1-4 alkyl)amino, or C.sub.2-4 
alkanoylamino; 
or any one of which R.sup.7 groups may be substituted with phenyl, 
piperazinyl, C.sub.3-8 cycloalkyl, benzyl, piperidinyl, pyridinyl, 
pyrimidinyl, pyrrolidinyl, C.sub.2-6 alkanoyl, or C.sub.1-4 
alkoxycarbonyl; 
any of which groups may be substituted with halo, trifluoromethyl, amino, 
C.sub.1-4 alkoxy, C.sub.1-4 alkyl, C.sub.1-4 alkylamino, di(C.sub.1-4 
alkyl)amino, or C.sub.2-4 alkanoylamino; 
R.sup.8 is hydrogen or C.sub.1-6 alkyl; 
R.sup.3 is phenyl, phenyl-(C.sub.1-6 alkyl)-, C.sub.3-8 cycloalkyl, 
C.sub.5-8 cycloalkenyl, C.sub.1-8 alkyl, naphthyl, C.sub.2-8 alkenyl, or 
hydrogen; 
any one or which groups except hydrogen may be substituted with one or two 
halo, C.sub.1-3 alkoxy, C.sub.1-3 alkylthio, nitro, trifluoromethyl, or 
C.sub.1-3 alkyl groups; and 
R.sup.4 is hydrogen or C.sub.1-3 alkyl; 
with the proviso that if R.sup.2 is hydrogen or halo, R.sup.3 is phenyl, 
phenyl-(C.sub.1-6 alkyl)-, C.sub.3-8 cycloalkyl, C.sub.5-8 cycloalkenyl, 
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)acetylamino!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 CNSpenetrant. 
Accordingly the present invention is not strictly limited to any 
particular structural class of compound. 
The preferred compounds of formulae (I), (II), (III) and (IV) 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: 
##STR25## 
Where the benzyloxy moiety is a-substituted, the preferred stereochemistry 
of the .alpha.-carbon is either (R) when the substituent is an 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-C.sub.1-6 alkyl, e.g. phenyl-C.sub.1-6 alkyl, group is 
benzyl. 
Unless otherwise defined herein, suitable heteroaryl groups include 
pyridyl, quinolyl, isoquinolyl, pyridazinyl, pyrimidinyl, pyrazinyl, 
pyranyl, furyl, benzofuryl, thienyl, 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, maleic acid, succinic acid, acetic acid, citric acid, 
tartaric acid, carbonic acid, phosphoric acid or sulphuric acid. Salts of 
amine groups may also comprise the quaternary ammonium salts in which the 
amino nitrogen atom carries an alkyl, alkenyl, alkynyl or aralkyl group. 
Where the compound carries an acidic group, for example a carboxylic acid 
group, the present invention also contemplates salts thereof, preferably 
non-toxic pharmaceutically acceptable salts thereof, such as the sodium, 
potassium and calcium salts thereof. 
Suitable pharmaceutically acceptable salts of the antipsychotic agents used 
in combination with a NK-1 receptor antagonist according to the present 
invention include those salts described above in relation to the salts of 
NK-1 receptor antagonists. 
The present invention accordingly provides the use 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) for the manufacture of 
a medicament for the treatment or prevention of mania. 
The present invention also provides a method for the treatment or 
prevention of mania, 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 mania 
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, 
solutions or suspensions, or suppositories, for oral, parenteral or rectal 
administration, by inhalation or insufflation or administration by 
transdermal 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. Tween.TM. 20, 40, 60, 80 or 85) and 
other sorbitans (e.g. Span.TM. 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 Intralipid.TM., Liposyn.TM., Infonutrol.TM., 
Lipofundin.TM. and Lipiphysan.TM.. The active ingredient may be either 
dissolved in a premixed 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 upon 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 0.1 and 1.0 .mu.m, particularly 0.1 and 0.5 .mu.m, and 
have a pH in the range of 5.5 to 8.0. 
Compositions for inhalation or insufflation 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. Nebulized 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 5 mg per 
day, preferably about 10 mg per day and especially about 20 mg per day. A 
maximum dosage level for the NK-1 receptor antagonist is about 1500 mg per 
day, preferably about 1000 mg per day and especially about 500 mg 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 0.5 mg per day for the most 
potent compounds or about 20 mg per day for less potent compounds. A 
maximum dosage level for the antipsychotic agent is typically 30 mg per 
day for the most potent compounds or 200 mg 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 mania 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 mania 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), (V), (VI), (VII), (VIII), 
(IX), (X), (XI) and (XII) may be 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), (IV), (V), (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 (IC.sub.50) of 
less than 10 nM. 
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 mania 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 
mania. The compounds of this class advantageously exhibit a rapid onset of 
action and a reduced side-effect profile when compared against 
conventional treatments of mania. 
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 mania. 
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 mania, 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 hereinafter 
defined) for the manufacture of a medicament adapted for oral 
administration for the treatment or prevention of mania. 
The present invention also provides a method for the treatment or 
prevention of mania, 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 mania 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 mania is inadequately treated 
with lithium. Furthermore, some patients may be adversely affected by the 
side-effects of lithium. 
The present invention accordingly provides the use of 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 mania in a patient who is non-responsive to lithium or for 
whom lithium is contraindicated. 
The present invention also provides a method for the treatment or 
prevention of mania in a patient who is non-responsive to lithium or for 
whom lithium 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. 
There also exists a patient population in whom mania 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 mania 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 mania 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 and 96/05181, and International Patent 
Application No. PCT/GB97/01630. 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: 
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-1,2,4triazolo)m 
ethyl)-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-dimethylamin 
o)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-dimethylamin 
o)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-dimethylamino 
but-2-yn-yl)-3-(S)-(4-fluorophenyl)morpholine; 
(3S, 5R, 
6S)-3-2-cyclopropoxy-5-(trifluoromethoxy)phenyl-1-oxa-7-aza-spiro4.5!dec 
ane; 
(3R, 5R, 
6S)-3-2-cyclopropoxy-5-(trifluoromethoxy)phenyl-1-oxa-7-aza-spiro4.5! 
decane; 
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 Application No. PCT/GB97/01630 may be prepared 
according to the following methods: 
PREATION 1 
(2S)-1-tert-Butoxycarbonyl-2-phenylpiperidin-3-one 
Dimethyl sulfoxide (20.80 ml, 22.90 g, 29.3 mmol) in dichloromethane (75 
ml) was added dropwise to a cooled (-70.degree. C.) solution of oxalyl 
chloride (13.95 ml, 20.30 g, 160 mmol) in dichloromethane (350 ml). The 
mixture was stirred at -70.degree. 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; 
36.91 g, 133 mmol) in dichloromethane (150 ml) was added dropwise. The 
mixture was stirred at -70.degree. C. for 20 minutes, then allowed to warm 
to -30.degree. C. The mixture wag cooled to -50.degree. C. and 
triethylamine (55.95 ml, 40.45 g, 400 mmol) was added slowly. The mixture 
was allowed to warm to 0.degree. C. and diluted with ice-cooled 
dichloromethane (250 ml). The mixture was washed with ice cold aqueous 
citric acid solution (5%, 2.times.300 ml) and water (300 ml), dried 
(MgSO.sub.4), and the solvent was evaporated under reduced pressure to 
give the title compound as a yellow oil (42.3 g), which was used 
immediately without further purification. .sup.1 H NMR (250 MHz, 
CDCl.sub.3) .delta.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). 
PREATION 2 
(2S,3R)-1-tert-Butoxycarbonyl-3-hydroxy-3-(2-methylene-3-phenoxypropyl)-2-p 
henylpiperidine 
A solution of 3-(chloromagnesio)-2-(phenoxymethyl)-1-propene in THF (0.91M, 
3 ml) (Louw et. al., Tetrahedron, 48, 6087-6104, 1992, prepared from 2.74 
mmol 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 (3 ml). The mixture was stirred at room temperature 
for 1 hours, then saturated aqueous ammonium chloride (20 ml) was added 
and the mixture was extracted with ethyl acetate (20 ml). The organic 
phase was washed with brine, dried (MgSO.sub.4) and the solvent was 
evaporated under reduced pressure. The residue was purified by column 
chromatography on silica gel, eluting with hexane/ethyl acetate (100:0 
increasing to 80:20) to give the title compound. .sup.1 H NMR (360MHz, 
CDCl.sub.3) .delta.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.sup.+) 424 (M+1). 
PREATION 3 
(5R,6S)-3-Methylene-6-phenyl-1-oxa-7-(tert-butoxycarbonyl)aza-spiro4.5!dec 
ane 
To a cooled(-80.degree. C.) solution of 
(2S,3R)-1-tert-butoxycarbonyl-3-hydroxy-3-(2-methylene-3-phenoxypropyl)-2- 
phenylpiperidine (Preparation 2, 1.53 g, 3.62 mmol) in THF (20 ml) was 
added n-butyl lithium (2.5M in hexanes, 1.45 ml, 3.62 mmol) followed by a 
solution of zinc chloride (0.5M in THF, 7.24 ml, 3.62 mmol). The solution 
was allowed to warm to room temperature and 
tetrakis(triphenylphosphine)palladium (0) (0.23 g, 0.2 mmol) was added. 
The mixture was degassed with bubbling nitrogen and heated under reflux 
for 16 hours. The mixture was cooled and the solvent was evaporated under 
reduced pressure. The residue was partitioned between ethyl acetate and 2M 
sodium hydroxide. The organic phase was washed with saturated brine, dried 
(MgSO.sub.4) and purified by chromatography on a column containing silica 
gel (eluting with hexane containing increasing proportions of ethyl 
acetate between 0% to 5%). Evaporation of the fractions gave 
(6S,5R)-3-methylene-6-phenyl-1-oxa-7-(tert-butoxycarbonyl)aza-spiro4.5!de 
cane. .sup.1 H NMR (360 MHz, CDCl.sub.3) .delta.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 (1H,td J=12.5, 3.93 Hz), 2.5 (1H, ABd, J=15.4 Hz), 2.15 (2H, td, 
J=12., 0.4 Hz), 1.69 (2H, m), and 1.46 (9H,s). m/z (ES.sup.+) 329 
(M+2H-tBuOCO). 
PREATION 4 
(5R,6S)-3-Keto-6-phenyl-1-oxa-7-(tert-butoxycarbonyl)aza-spiro 4.5!decane 
Through a cooled (-80.degree. C.) solution of 
(5R,6S)-3-methylene-6-phenyl-1-oxa-7-(tert-butoxycarbonyl)aza-spiro4.5!de 
cane (Preparation 3; 0.665 g) in dichloromethane (5 ml) and methanol (5 ml) 
was bubbled a mixture of ozone and oxygen for 45 minutes. After the 
solution had been purged with nitrogen, dimethyl sulphide (0.5 ml) was 
added and then stirred under nitrogen at room temperature for 16 hours. 
The solvent was removed iib vacuo and the residue partitioned between 
ethyl acetate and water. The organic phase was dried (MgSO.sub.4), 
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. .sup.1 H NMR (250 MHz, CDCl.sub.3) 
.delta.7.58 (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=12.9, 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.sup.+) 332 (M+1). 
PREATION 5 
(5R,6S)-3-Trifluoromethylsulfonyloxy-6-phenyl-1-oxa-7-(tert-butoxycarbonvl) 
aza-spiro4.5!dec-3-ene 
To a cooled (-80.degree. C.) solution of 1M sodium hexamethyldisilazide 
(0.38 ml, 0.38 mmol) in THF was added a solution of 
(5R,6S)-3-keto-6-phenyl-1-oxa-7-(tert-butoxycarbonyl)aza-spiro4.5!decane 
(Preparation 4; 0.105 mg, 0.319 mmol) in THF (3 ml). The solution was 
stirred for 1 hours at -80.degree. C. then a solution of 
2-N,N-bis(trifluoromethylsulfonyl)amino!-5-chloropyridine (0.163 g, 0.415 
mmol) in THF (3 ml) was added. The solution was stirred at -80.degree. C. 
for 30 minutes then at room temperature for 30 minutes before being 
quenched by addition of saturated ammonium chloride solution and ethyl 
acetate. The dried (MgSO.sub.4) organic phase was purified by 
chromatography on a column containing silica gel (eluting with hexane 
containing increasing proportions of ethyl acetate between 0% to 5%). 
Evaporation of the fractions gave the title compound. .sup.1 H NMR (360 
MHz, CDCl.sub.3) .delta.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). 
PREATION 6 
(5R,6S)-3-Trimethylstannyl-6-phenyl-1-oxa-7-(tert-butoxycarbonyl)aza-spiro 
4.5!dec-3-ene 
To a degassed solution of 
(5R,6S)-3-trifluoromethylsulfonyloxy-6-phenyl-1-oxa-7-(tert-butoxycarbonyl 
)aza-spiro4.5!dec-3-ene (Preparation 5; 0.482 g, 1.04 mmol), lithium 
chloride (0.264 g, 6.25 mmol), lithium carbonate (0.076 g) and hexamethyl 
distannane(0.96 g, 2.9 mmol) in THF (10 ml) was added triphenylphosphine 
palladium (0) (0.06 g). The solution was degassed and then heated at 
60.degree. C. for 5 hours under nitrogen. Water (20 ml) and ethyl acetate 
(20 ml) 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. .sup.1 H NMR (360 MHz, CDCl.sub.3) .delta.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). 
PREATION 7 
(2S,3R)-1-tert-Butoxycarbonyl-3-(3-hydroxypropyn-1-yl)-2-phenylpiperidin-3- 
ol 
O-Trimethylsilylpropargyl alcohol (24.51 ml, 20.47 g, 160 ml) was added 
slowly to a cooled (-10.degree. C.) solution of ethylmagnesium bromide (1M 
in tetrahydrofuran, 160 ml, 160 mmol). The mixture was stirred at 
0.degree. C. for 20 minutes, then at room temperature for 2 hours. The 
mixture was cooled to -10.degree. C. and a solution of 
(2S)-1-tert-butoxycarbonyl-2-phenylpiperidin-3-one (Preparation 1; 42.3 g) 
in tetrahydrofuran (200 ml) was added dropwise over 30 minutes. (Internal 
temperature below -5.degree. C.). The mixture was stirred at room 
temperature for 14 hours, poured into water (300 ml) and saturated aqueous 
ammonium chloride (300 ml) and extracted with ethyl acetate (2.times.300 
ml). The combined organic fractions were washed with brine (300 ml), dried 
(MgSO.sub.4) and the solvent was evaporated under reduced pressure. The 
residue was dissolved in ethyl acetate (500 ml) and a solution of 
tetrabutylammonium fluoride (1M in THF, 160 ml, 160 mmol) was added 
dropwise. The mixture was stirred at room temperature for 30 minutes, 
water (300 ml) was added, and the layers were separated. The aqueous layer 
was extracted with ethyl acetate (2.times.300 ml) and the combined organic 
fractions were washed with water (300 ml) and brine (300 ml), dried 
(MgSO.sub.4) and the solvent was evaporated under reduced pressure to give 
the crude title compound as an orange oil (45 g). 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 (32.2 g). .sup.1 H NMR (CDCl.sub.3) 
.delta.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). 
PREATION 8 
2-Bromo-4-(trifluoromethoxy)phenol 
To a cooled (0.degree. C.) solution of 4-trifluoromethoxyphenol (35.6 g, 
0.2 mol) in chloroform (280 ml) was added dropwise a solution of bromine 
(32 g, 0.2 mol) in chloroform (50 ml). The solution was stirred at 
0.degree. C. for 1 hour and at room temperature for 2 hours. 
Dichloromethane (200 ml) and water (400 ml) ware added and the organic 
phase was washed further with water(400 ml), brine (200 ml) and dried 
(MgSO.sub.4). The solvent was removed and the residue was purified by 
distillation at reduced pressure to give the title compound. .sup.1 H NMR 
(250 MHz, CDCl.sub.3) .delta.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). 
PREATION 9 
2-Benzyloxy-5-(trifluoromethoxy)bromobenzene 
2-Bromo-4-(trifluoromethoxy)phenol (Preparation 8; 5 g, 20 mmol) was 
dissolved in N,N-dimethylformamide (60 ml), and potassium carbonate (5.4 
g, 40 mmol) was added, followed by benzyl bromide (3.5 ml, 30 mmol), and 
the reaction was stirred at ambient temperature for 15 hours. The reaction 
was diluted with water (150 ml) and extracted into ethyl acetate 
(3.times.60ml). The combined organic fractions were washed with water (100 
ml), brine (100 ml), dried (MgSO.sub.4) and evaporated in vacuo. 
Purification on silica, eluting with 2% and 5% ethyl acetate in hexane 
gave the title compound as a clear oil (6.7 g, 96%). .sup.1 H NMR (250 
MHz, CDCl.sub.3) .delta.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). 
PREATION 10 
Z-(2S,3R)-1-tert-Butoxycarbonyl-3-(3-hydroxyprop-1-en-1-yl)-2-phenylpiperid 
in-3-ol 
Palladium on calcium carbonate, poisoned with lead (Lindlar catalyst, 2 g) 
was added to a solution of 
(2S,3R)-1-tert-butoxycarbonyl-3-(3-hydroxypropyn-1yl)-2-phenylpiperidin-3- 
ol (Preparation 7; 32 g, 96.6 mmol) in ethyl acetate (300 ml) 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 (32 g, 100%). .sup.1 H NMR (360 MHz, 
CDCl.sub.3) .delta.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.sup.+) 334 (M+1). 
PREATION 11 
(5R,6S)-6-Phenyl-1-oxa-7-(tert-butoxycarbonyl)aza-spiro4.5!dec-3-ene 
Diethylazodicarboxylate (18.2 ml, 115 mmol) in THF (100 ml) was added 
dropwise to a solution of 
Z-(2S,3R)-1-tert-butoxycarbonyl-3-(3-hydroxyprop-1-en-1-yl)-2-phenylpiperi 
din-3-ol (Preparation 10; 32 g, 96 mmol) and triphenylphosphine (30.2 g, 
115 mmol) in THF (700 ml). The mixture was stirred at 0.degree. 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 (23.4 
g, 77%). .sup.1 H NMR (CDCl.sub.3) .delta.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, mn), 3.05 (1H, m), 2.05 (1H, m), 
1.75 (3H, m), and 1.37 (9H, s). m/z (ES.sup.+) 316 (M+1). 
PREATION 12 
2-Benzyloxy-5-(trifluoromethoxy)benzene 
Benzyl bromide (66.17 ml, 95.35 g, 0.56 mol) was added to a mixture of 
4-(trifluoromethoxy)phenol (90.26 g, 0.51 mol) and potassium carbonate 
(140.97 g, 1.2 mol) in dimethylformamide (160 ml) and the mixture was 
stirred at room temperature for 72 hours. The mixture was poured into 
water (1.5 l) and extracted with ethyl acetate (3.times.500 ml). The 
combined organic fractions were washed with aqueous sodium carbonate 
(saturated, 500 ml), dried (MgSO.sub.4) and the solvent was evaporated 
under reduced pressure to give the title compound as a colorless solid 
(133.5 g, 99%). .sup.1 H NMR (360 MHz, CDCl.sub.3) d 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). 
PREATION 13 
2-Benzyloxy-5-(trifluoromethoxy)iodobenzene 
Iodine (71.96 g, 0.28 mol) in chloroform was added dropwise to a mixture of 
2-benzyloxy-5-(trifluoromethoxy)benzene (Preparation 12, 73.06 g, 0.27 
mol) and silver trifluoroacetate (71.57 g, 0.32 mol) 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%, 
2.times.2 l), dried (MgSO.sub.4) 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 (108.03 g), containing 11% unreacted 
2-benzyloxy-5-(trifluoromethoxy)iodobenzene. .sup.1 H NMR (360 MHz, 
CDCl.sub.3) d 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). 
PREATION 14 
(5R, 
6S)-3-(2-Benzyloxy-5-(trifluoromethoxy)phenyl)-6-phenyl-1-oxa-7-(tert-buto 
xycarbonyl)aza-spiro4.5!dec-3-ene 
(5R,6S)-3-Trimethylstannyl-6-phenyl-1-oxa-7-(tert-butoxycarbonyl)aza-spiro 
4.5!dec-3-ene (Preparation 6; 6.43 mmol), lithium chloride (0.163 g), 
benzyloxy-5-(trifluoromethoxy)phenol (Preparation 9; 7.7 mmol) in toluene 
(25 ml) was degassed before addition of triphenylphosphine palladium (0) 
(0.37 g). The solution was degassed thoroughly before heating to 
110.degree. 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. .sup.1 H NMR (360 MHz, CDCl.sub.3) 6 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). 
PREATION 15 
(3S,5R,6S)-3-(2-Hydroxy-5-(trifluoromethoxy)phenyl)-6-phenyl-1-oxa-7-(tert- 
butoxycarbonvl)aza-spiro4.5!decane 
(5R,6S)-3-(2-Benzyloxy-5-(trifluoromethoxy)phenyl)-6-phenyl-1-oxa-7-(tert-b 
utoxycarbonyl)aza-spiro 4.5!dec-3-ene (Preparation 14) (3.88 g) was 
dissolved in ethyl acetate (15 ml) and methanol (15 ml). Palladium 
hydroxide on carbon (1.00 g) 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-oxa-7-(tert 
-butoxycarbonyl)aza-spiro4.5!decane (191 mg), .sup.1 H NMR (250 MHz, 
CDCl.sub.3) .delta.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-spiro4.5!decane (2.3 g), .sup.1 H NMR (360 MHz, 
CDCl.sub.3) .delta.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). 
PREATION 16 
(3R,5R,6S)-3-(2-Benzyloxy-5-(trifluoromethoxy)phenyl)-6-phenyl-1-oxa-7-(ter 
t-butoxycarbonyl)aza-spiro4.5!decane 
A mixture of 2-benzyloxy-5-(trifluoromethoxy)iodobenzene (Preparation 13, 
21.8 g, 55.2 mmol), 
(5R,6S)-6-phenyl-1-oxa-7-(tert-butoxycarbonyl)aza-spiro4.5!dec-3-ene 
(Preparation 11, 7.0 g, 22.1 mmol), tetra-n-butylammonium chloride (6.18 
g, 22.2 mmol), lithium chloride (9.35 g, 0.22 mol) and potassium formate 
(5.64 g, 67.0 mmol) in dimethylformamide (100 ml) was degassed with a 
firestone valve (5.times.). Palladium acetate (491 mg, 2.2 mmol) was added 
and the mixture was degassed with a firestone valve (5.times.). The 
mixture was stirred at 60.degree. C. for 15 hours, then further 
2-benzyloxy-5-(trifluoromethoxy)iodobenzene (Preparation 13, 4.32 g, 11.0 
mmol), potassium formate (2.78 g, 33.5 mmol) and palladium acetate (260 
mg, 1.1 mmol) were added. The mixture was stirred at 60.degree. C. for 22 
hours, cooled and filtered. The solvent was evaporated under reduced 
pressure, water (600 ml) was added and the mixture was extracted with 
ethyl acetate (2.times.300 ml). The combined organic fractions were washed 
with brine (300 ml), dried (MgSO.sub.4) 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 (9.42 g, 73%). .sup.1 H NMR (360 MHz, CDCl.sub.3) d 
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). 
PREATION 17 
(3R,5R,6S)-3-(2-Hydroxy-5-(trifluoromethoxy)phenyl)-6-phenyl-1-oxa-7-(tert- 
butoxycarbonyl)aza-spiro4.5!decane 
Palladium on carbon (10%, 0.59 g) was added to a solution of 
(3R,5R,6S)-3-(2-benzyloxy-5-(trifluoromethoxy)phenyl)-6-phenyl-1-oxa-7-(te 
rt-butoxycarbonyl)aza-spiro4.5!decane (Preparation 16, 6.10 g, 10.5 mmol) 
in methanol-water (99:1, 200 ml) 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. .sup.1 H NMR (360 MHz, CDCl.sub.3) d 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). 
PREATION 18 
(3S, 
5R,6S)-3-2-(1-Phenylthiocycloprop-1-yl)oxy-5-(trifluoromethoxy)phenyl!-6- 
phenyl-1-oxa-7-(tert-butoxycarbonyl)aza-spiro4.5!decane 
(3S,5R,6S)-3-(2-Hydroxy-5-(trifluoromethoxy)phenyl)-6-phenyl-1-oxa-7-(tert- 
butoxycarbonyl)aza-spiro4.5!decane (Preparation 15) (290 mg, 0.59 mmol) 
was dissolved in toluene (5 ml) and silver carbonate (179 mg 0.65 mmol) 
was added in one portion. (1-Iodocycloprop-1-yl)phenylsulfide (Cohen T. 
and Matz J. R., J. Am. Chem. Soc. 1980, 102, 6902) (180 mg, 0.65 mmol) was 
then added over one minute at room temperature. The mixture was stirred at 
55.degree. C. for 4 hours, then further portions of silver carbonate (179 
mg, 0.65 mmol) and (1-iodocycloprop-1-yl)phenylsulfide (180 mg, 0.65 mmol) 
were added. The mixture was stirred at 55.degree. 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 (120 mg, 32%). .sup.1 H NMR (250 MHz, 
CDCl.sub.3) .delta.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.sup.+) 
642 (M+1). 
PREATION 19 
(3R,5R,6S)-3-2-(1-Phenylthiocycloprop-1-yl)oxy-5-(trifluoromethoxy)phenyl! 
-6-phenyl-1-oxa-7-(tert-butoxycarbonyl)aza-spiro4.5!decane 
Prepared from 
(3R,5R,6S)-3-(2-hydroxy-5-(trifluoromethoxy)phenyl)-6-phenyl-1-oxa-7-(tert 
-butoxycarbonyl)aza-spiro4.5!decane (Preparation 17) according to the 
method of Preparation 18. .sup.1 H NMR (360 MHz, CDCl.sub.3) .delta.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=13 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.sup.+) 642 (M+1). 
PREATION 20 
(3S,5R 
6S)-3-2-Cyclopronoxy-5-(trifluoromethoxy)phenyl!-6-phenyl-1-oxa-7-(tert-b 
utoxycarbonyl)aza-spiro4.5!decane 
Naphthalene (120 mg, 0.936 mmol) was dissolved in THF (1.5 ml) under 
nitrogen and freshly cut lithium metal (7.0 mg, 0.94 mmol) 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.degree. C., then 
(3S,5R,6S)-3-2-(1-phenylthiocycloprop-1-yl)oxy-5-(trifluoromethoxy)phenyl 
!-6-phenyl-1-oxa-7-(tert-butoxycarbonyl)aza-spiro4.5!decane (Preparation 
18) (120 mg, 0.187 mmol) in THF (0.5 ml) was added over 1 minute. The 
reaction mixture was stirred for 30 minutes, then water (5 ml) and ether 
(10 ml) were added. The layers were separated and the aqueous layer was 
extracted with ether (10 ml). The combined organic fractions were dried 
(MgSO.sub.4) 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 (58.6 mg, 59%). .sup.1 H NMR (250 MHz, 
CDCl.sub.3) .delta.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.sup.+) 
534 (M+1). 
PREATION 21 
(3R,5R,6S)-3-2-Cyclopropoxy-5-(trifluoromethoxy)phenyl!-6-phenyl-1-oxa-7-( 
tert-butoxycarbonyl)aza-spiro 4.5!decane 
Naphthalene (120 mg, 0.936 mmol) was dissolved in THF (1.5 ml) under 
nitrogen and freshly cut lithium metal (7.0 mg, 0.94 mmol) 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-(trifluoromethoxy)phenyl 
!-6-phenyl-1-oxa-7-(tert-butoxycarbonyl)aza-spiro4.5!decane (Preparation 
19, 135 mg, 0.21 mmol) in THF (2 ml) under nitrogen was cooled to 
-78.degree. 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 (5 ml) was added and the mixture was warmed 
to room temperature. Ether (10 ml) was added and the layers were 
separated. The aqueous phase was extracted with a further portion of ether 
(10 ml) and the combined organic phases were dried (MgSO.sub.4) 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 (87 mg, 78%). 
.sup.1 H NMR (360 MHz, CDCl.sub.3) .delta.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.sup.+) 534 (M+1). 
COMPOUND A 
(3 
S,5R,6S)-3-2-Cyclopropoxy-5-(trifluoromethoxy)phenyl!-6-phenyl-1-oxa-7-az 
a-spiro4.5!decane Hydrochloride 
Trifluoroacetic acid (2.5 ml) was added dropwise to a stirred, cooled 
0.degree. C.) solution of 
(3S,5R,6S)-3-2-cyclopropoxy-5-(trifluoromethoxy)phenyl!-6-phenyl-1-oxa-7- 
(tert-butoxycarbonyl)aza-spiro 4.5! decane (Preparation 20; 492 mg, 0.92 
mmol) in dichloromethane (25 ml) and the mixture was stirred at room 
temperature for 3 hours. The mixture was poured into water (50 ml), the pH 
was adjusted to 10.0 with aqueous sodium hydroxide (4M) and the mixture 
was extracted with dichloromethane (3.times.50 ml). The combined organic 
fractions were dried (MgSO.sub.4) and the solvent was evaporated under 
reduced pressure. The residue was purified by flash column chromatography 
on silica gel, eluting with dichloromethane/methanol/ammonia (aq.) 
(96:4:0.4 increasing to 94:6:0.6). The residue was dissolved in ethanol 
(20 ml), cooled in ice and ethereal hydrogen chloride (1M, 1.8 ml, 1.8 
mmol) was added dropwise. The mixture was stirred at 0.degree. C. for 5 
minutes, then the solvent was evaporated under reduced pressure. The 
residue was crystallized from ether (20 ml)/ethanol (0.5 ml) and the solid 
was collected and dried in vacuo to give the title compound as a colorless 
solid (354 mg, 89%). m.p. 214-216.degree. C., .sup.1 H NMR (500 MHz, 
CD.sub.3 OD) .delta.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. C.sub.24 
H.sub.26 F.sub.3 NO.sub.3.HCl requires: C, 61.34; H, 5.79; N, 2.98%. 
COMPOUND B 
(3R,5R,6S)-3-2-Cyclopropoxy-5-(trifluoromethoxy)phenyl!-6-phenyl-1-oxa--7- 
aza-spiro4.5!decane 
Prepared from the compound of Preparation 21 according to the method used 
for Compound A. .sup.1 H NMR (360 MHz, CDCl.sub.3) .delta.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.sup.+) 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 (IC.sub.50) of less than 10 nM, 
favourably less than 2 nM and preferably less than 1 nM. 
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 3.times.10.sup.5 
receptors per cell. Cells are grown in monolayer culture, detached from 
the plate with enzyme-free dissociation solution (Speciality Media Inc.), 
and washed prior to use in the assay. .sup.125 I-Tyr.sup.8 -substance P 
(0.1 nM, 2000 Ci/mmol; New England Nuclear) is incubated in the presence 
or absence of test compounds (dissolved in 5 .mu.l dimethylsulphoxide, 
DMSO) with 5.times.10.sup.4 CHO cells. Ligand binding is performed in 0.25 
ml of 50 mM Tris-HCl, pH7.5, containing 5mM MnCl.sub.2, 150 mM NaCl, 0.02% 
bovine serum albumin (Sigma), 50 .mu.g/ml chymostatin (Peninsula), 0.1 nM 
phenylmethylsulphonyl fluoride, 2 .mu.g/ml pepstatin, 2.mu.g/ml leupeptin 
and 2.8 .mu.g/ml furoyl saccharine. The incubation proceeds at room 
temperature until equilibrium is achieved (&gt;40 minutes) and the 
receptor-ligand complex is harvested by filtration over GFIC filters 
pre-soaked in 0.1% polyethylenimine using a Tomtek 96-well harvester. 
Non-specific binding is determined using excess substance P (1 .mu.M) and 
represents &lt;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 (35-70 g) are anaesthetised by 
inhalation of an isoflurane/oxygen mixture to permit exposure of the 
jugular vein in order to permit administration of test compounds or 
vehicle in an injection volume of 5 ml/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 
AlaL-Pro.sup.9,Me-Leu.sup.10 !-substance P-(7-11)) is infused directly 
into the cerebral ventricles (e.g. 3 pmol in 5 .mu.l i.c.v., depending on 
test substance) by vertical insertion of a cuffed 27 gauge needle to a 
depth of 4.5 mm below bregma. The scalp incision is closed and the animal 
allowed to recover from anaesthesia in a clear perspex observation box (25 
cm.times.20 cm.times.20 cm). 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 10 g 
of tinned cat food. At 60 minutes following oral dosing, cisplatin (10 
mg/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 are screened to ensure that a vigorous vocalisation 
response is reproducibly elicited following maternal separation. The pups 
are placed individually in an observation cage (55 cm.times.39 cm.times.19 
cm) 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 60 
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 AlaL-Pro.sup.9,Me-Leu.sup.10 
!-substance P-(7-11)), under anaesthesia, directly into the central 
ventricles is inhibited when a CNS-penetrant NK-1 receptor antagonist is 
administered intravenously immediately prior to GR73632 challenge, wherein 
hind foot-tapping over a period of five minutes following recovery from 
the anaesthesia is inhibited with an ID.sub.50 .ltoreq.3 mg/kg, and 
preferably with an ID.sub.50 .ltoreq.1 mg/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 ID.sub.50 .ltoreq.30 mg/kg, and preferably with an ID.sub.50 
.ltoreq.10 mg/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 ID.sub.50 
.ltoreq.20 mg/kg, preferably with an ID.sub.50 .ltoreq.10 mg/kg, and 
especially with an ID.sub.50 .ltoreq.5 mg/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 ID.sub.50 .ltoreq.20 mg/kg, 
preferably with an ID.sub.50 .ltoreq.10 mg/kg, and especially with an 
ID.sub.50 .ltoreq.5 mg/kg. 
A suitable selection cascade for NK.sub.1 antagonists of use according to 
the present invention is as follows: 
(i) Determine affinity for human NK.sub.1 receptor in radioligand binding 
studies (Assay 1); select compounds with IC.sub.50 .ltoreq.10 nM, 
preferably IC.sub.50 .ltoreq.2 nM, especially IC.sub.50 .ltoreq.1 nM. 
(ii) Determine ability of compounds to penetrate CNS by their ability to 
inhibit foot tapping in gerbils induced by central injection of an 
NK.sub.1 agonist (Assay 2); select compounds that inhibit foot tapping 
with ID.sub.50 .ltoreq.3 mg/kg i.v., and preferably ID.sub.50 .ltoreq.1 
mg/kg i.v. when administered immediately prior to central NK.sub.1 agonist 
challenge, or ID.sub.50 .ltoreq.30 mg/kg p.o., and preferably ID.sub.50 
.ltoreq.10 mg/kg p.o. 1 hour prior to challenge. 
(iii) Determine central duration of action of compounds in gerbil foot 
tapping assay following intravenous administration 24 hours prior to 
central NK.sub.1 agonist challenge; select compounds showing 
.ltoreq.25-fold loss of potency compared with ID.sub.50 determined in step 
(ii) above with the proviso that ID.sub.50 .ltoreq.10 mg/kg i.v., and 
preferably .ltoreq.5 mg/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 ID.sub.90 .ltoreq.3 mg/kg p.o., 
and preferably ID.sub.90 .ltoreq.1 mg/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 10 guinea-pig 
pups (Assay 4)). Select compounds with ID.sub.50 .ltoreq.20 mg/kg, and 
preferably ID.sub.50 .ltoreq.10 mg/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 .ltoreq.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: IC.sub.50 =0.1 nM 
gerbil foot-tapping (5 mins.): ID.sub.50 =0.36 mg/kg i.v. 
gerbil foot-tapping (24 hrs.): ID.sub.50 =0.33 mg/kg i.v. 
ferret emesis: ID.sub.90 &lt;3 mg/kg p.o.

The following example illustrates pharmaceutical compositions according to 
the invention. 
______________________________________ 
EXAMPLE 1 Tablets containing 50-300 mg of NK-1 antagonist 
Amount mg 
______________________________________ 
NK-1 antagonist 50.0 100.0 300.0 
Microcrystalline cellulose 
80.0 80.0 80.0 
Modified food corn starch 
80.0 80.0 80.0 
Lactose 189.5 139.5 139.5 
Magnesium Stearate 
0.5 0.5 0.5 
______________________________________ 
The active ingredient, cellulose, lactose and a portion of the corn starch 
are mixed and granulated with 10% corn starch paste. The 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 50 mg, 100 mg and 300 mg of the NK-1 
receptor antagonist per tablet. 
______________________________________ 
EXAMPLE 2 Parenteral injection 
Amount 
______________________________________ 
Active Ingredient 10 to 300 mg 
Citric Acid Monohydrate 
0.75 mg 
Sodium Phosphate 4.5 mg 
Sodium Chloride 9 mg 
Water for injection to 10 ml 
______________________________________ 
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. 
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 antip)sychotic agent will depend upon the choice of 
active ingredients. 
______________________________________ 
EXAMPLE 3 Tablets containing 50-300 mg of NK-1 antagonist and 
5-10 mg 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 cellulose 
80.0 80.0 80.0 80.0 80.0 80.0 
Modified food corn starch 
80.0 80.0 80.0 80.0 80.0 80.0 
Lactose 184.5 179.5 134.5 
129.5 
134.5 
129.5 
Magnesium Stearate 
0.5 0.5 0.5 0.5 0.5 0.5 
______________________________________ 
______________________________________ 
EXAMPLE 4 Tablets containing 50-300 mg of NK-1 antagonist and 
25 mg of chlorpromazine hydrochloride 
Amount mg 
______________________________________ 
NK-1 antagonist 50.0 100.0 300.0 
chlorpromazine hydrochloride 
25.0 25.0 25.0 
Microcrystalline cellulose 
80.0 80.0 80.0 
Modified food corn starch 
80.0 80.0 80.0 
Lactose 164.5 114.5 114.5 
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 50 mg, 100 mg and 300 mg of the 
CNS-penetrant NK-1 receptor antagonist per tablet.