Substituted morpholine derivatives and their use as therapeutic agents

The present invention relates to compounds of formula (I), wherein R.sup.1 is hydrogen, halogen, C.sub.1-6 C 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 are 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 selected from the definitions of R.sup.1 ; R.sup.5 is selected from the definitions of R.sup.2 ; 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 an aminoalkyl group; R.sup.9a and R.sup.9b are hydrogen or C.sub.1-4 alkyl, or R.sup.9a and R.sup.9b are joined to form a C.sub.5-7 ring; X is C.sub.1-4 alkylene optionally substituted by oxo; and Y is a C.sub.1-4 alkyl group optionally substituted by hydroxyl; with the proviso that if Y is C.sub.1-4 alkyl, R.sup.6 is substituted at least by an aminoalkyl group; and pharmaceutically acceptable salts and prodrugs thereof. The compounds are of particular use in the treatment of pain, inflammation, migraine and emesis.

This application is a 371 of PCT/G894/02819 filed Dec. 23, 1994. 
This invention relates to a class of aromatic compounds which are useful as 
tachykinin antagonists. More particularly, the compounds of the invention 
contain an amine-substituted azo-heterocyclic moiety. 
The tachykinins are a group of naturally occurring peptides found widely 
distributed throughout mammalian tissues, both within the central nervous 
system and in peripheral nervous and circulatory systems. 
At present, there are three known mammalian tachykinins referred to as 
substance P, neurokinin A (NKA, substance K, neuromedin L) and neurokinin 
B (NKB, neuromedin K) (for review see J. E. Maggio, Peptides (1985) 
6(suppl. 3), 237-242). The current nomenclature designates the three 
tachykinin receptors mediating the biological actions of substance P, NKA 
and NKB as the NK.sub.1, NK.sub.2 and NK.sub.3 receptors, respectively. 
Evidence for the usefulness of tachykinin receptor antagonists in pain, 
headache, especially migraine, Alzheimer's disease, multiple sclerosis, 
attenuation of morphine withdrawal, cardiovascular changes, oedema, such 
as oedema caused by thermal injury, chronic inflammatory diseases such as 
rheumatoid arthritis, asthma/bronchial hyperreactivity and other 
respiratory diseases including allergic rhinitis, inflammatory diseases of 
the gut including ulcerative colitis and Crohn's disease, ocular injury 
and ocular inflammatory diseases, proliferative vitreoretinopathy, 
irritable bowel syndrome and disorders of bladder function including 
cystitis and bladder detruser hyper-reflexia is reviewed in "Tachykinin 
Receptors and Tachykinin Receptor Antagonists", C. A. Maggi, R. 
Patacchini, P. Rovero and A. Giachetti, J. Auton. Pharmacol. (1993) 13, 
23-93. 
For instance, substance P is believed inter alia to be involved in the 
neurotransmission of pain sensations [Otsuka et al, "Role of Substance P 
as a Sensory Transmitter in Spinal Cord and Sympathetic Ganglia" in 1982 
Substance P in the Nervous System, Ciba Foundation Symposium 91, 13-34 
(published by Pitman) and Otsuka and Yanagisawa, "Does Substance P Act as 
a Pain Transmitter?" TIPS (1987) 8, 506-510], specifically in the 
transmission of pain in migraine (B. E. B. Sandberg et al, J. Med Chem, 
(1982) 25, 1009) and in arthritis [Levine et al Science (1984) 226, 
547-549]. Tachykinins have also been implicated in gastrointestinal (GI) 
disorders and diseases of the GI tract such as inflammatory bowel disease 
[Mantyh et al Neuroscience (1988) 25(3), 817-37 and D. Regoli in "Trends 
in Cluster Headache" Ed. Sicuteri et al Elsevier Scientific Publishers, 
Amsterdam (1987) page 85)] and emesis [F. D. Tattersall et al, Eur. J. 
Pharmacol., (1993) 250, R5-R6]. It is also hypothesised that there is a 
neurogenic mechanism for arthritis in which substance P may play a role 
[Kidd et al "A Neurogenic Mechanism for Symmetrical Arthritis" in The 
Lancet, 11 Nov. 1989 and Gronblad et al, "Neuropeptides in Synovium of 
Patients with Rheumatoid Arthritis and Osteoarthritis" in J. Rheumatol. 
(1988) 15(12), 1807-10]. Therefore, substance P is believed to be involved 
in the inflammatory response in diseases such as rheumatoid arthritis and 
osteoarthritis, and fibrositis [O'Byrne et al, Arthritis and Rheumatism 
(1990) 33, 1023-8]. Other disease areas where tachykinin antagonists are 
believed to be useful are allergic conditions [Hamelet et al, Can. J. 
Pharmacol. Physiol. (1988) 66, 1361-7], immunoregulation [Lotz et al, 
Science (1988) 241, 1218-21 and Kimball et al, J. Immunol. (1988) 141(10), 
3564-9] vasodilation, bronchospasm, reflex or neuronal control of the 
viscera [Mantyh et al, PNAS (1988) 85, 3235-9] and, possibly by arresting 
or slowing .beta.-amyloid-mediated neurodegenerative changes [Yankner et 
al, Science (1990) 250, 279-82] in senile dementia of the Alzheimer type, 
Alzheimer's disease and Down's Syndrome. 
Tachykinin antagonists may also be useful in the treatment of small cell 
carcinomas, in particular small cell lung cancer (SCLC) [Langdon et al, 
Cancer Research (1992) 52, 4554-7]. 
Substance P may also play a role in demyelinating diseases such as multiple 
sclerosis and amyotrophic lateral sclerosis [J. Luber-Narod et al, poster 
C.I.N.P. XVIIIth Congress, 28th Jun.-2nd Jul. 1992], and in disorders of 
bladder function such as bladder detrusor hyper-reflexia (Lancet, 16th May 
1992, 1239). 
It has furthermore been suggested that tachykinins have utility in the 
following disorders: depression, dysthymic disorders, chronic obstructive 
airways disease, hypersensitivity disorders such as poison ivy, 
vasospastic diseases such as angina and Reynauld's disease, fibrosing and 
collagen diseases such as scleroderma and eosinophilic fascioliasis, 
reflex sympathetic dystrophy such as shoulder/hand syndrome, addiction 
disorders such as alcoholism, stress related somatic disorders, 
neuropathy, neuralgia, disorders related to immune enhancement or 
suppression such as systemic lupus erythmatosus (European patent 
specification no. 0 436 334), ophthalmic disease such as conjuctivitis, 
vernal conjunctivitis, and the like, and cutaneous diseases such as 
contact dermatitis, atopic dermatitis, urticaria, and other eczematoid 
dermatitis (European patent specification no. 0 394 989). 
European patent specification no. 0 577 394 (published 5th Jan. 1994) 
discloses morpholine and thiomorpholine tachykinin receptor antagonists of 
the general formula 
##STR2## 
wherein R.sup.1a is a large variety of substituents; 
R.sup.2a and R.sup.3a are inter aria hydrogen; 
R.sup.4a is inter alia 
##STR3## 
R.sup.5a is inter alia optionally substituted phenyl; R.sup.6a, R.sup.7a 
and R.sup.8a are a variety of substituents; 
X.sup.a is O, S, SO or SO.sub.2 ; 
Y.sup.a is inter alia O; and 
Z.sup.a is hydrogen or C.sub.1-4 alkyl. 
European patent specification no. 0 528 495 (published 24th Feb. 1993) 
discloses azacyclic derivatives useful as tachykinin antagonists, which 
compounds have the general formula: 
##STR4## 
wherein n is 1, 2 or 3; 
X.sup.b is O or S; 
R.sup.1b is optionally substituted phenyl; 
R.sup.2b is aryl, heteroaryl, benzhydryl or benzyl; 
R.sup.4b and R.sup.5b are independently H, halo, CH.sub.2 OR.sup.9b, 
C.sub.1-6 alkyl, oxo, CO.sub.2 R.sup.10b or CONR.sup.10b R.sup.11b. 
R.sup.8b is H, COR.sup.9b, CO.sub.2 R.sup.10b or optionally substituted 
C.sub.1-6 alkyl; 
R.sup.9b is H, C.sub.1-6 alkyl or phenyl; and 
R.sup.10b and R.sup.11b are independently H or C.sub.1-6 alkyl. 
We have now found a further class of non-peptides which are potent 
antagonists of tachykinins, especially of substance P. 
It is desirable that compounds may be administered orally and by injection. 
Compounds have now been discovered which act as potent non-peptide 
tachykinin antagonists and which, by virtue of their advantageous aqueous 
solubility, are particularly easily formulated for administration by both 
the oral and injection routes, for example in aqueous media. 
Furthermore, the compounds of the present invention possess a particularly 
advantageous profile of activity having potent antagonist activity at the 
NK.sub.1 receptor and a long duration of action. The compounds of the 
present invention, and in particular their pharmaceutically acceptable 
acid addition salts, are also particularly suited to a wide variety of 
pharmaceutical formulations by virtue of their stability. 
The present invention provides compounds of the formula (I): 
##STR5## 
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 C.sub.1-4 alkoxy, 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 one 
or two groups selected from hydroxy or C.sub.1-4 alkyl optionally 
substituted by a C.sub.1-4 alkoxy or hydroxyl 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 group of formula ZNR.sup.7 R.sup.8 as defined above; 
and pharmaceutically acceptable salts and prodrugs thereof. 
Certain particularly apt compounds of the present invention include those 
wherein R.sup.1 is hydrogen, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, halo or 
CF.sub.3. 
Most aptly R.sup.2 is hydrogen, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, halogen 
or CF.sub.3. 
Most aptly R.sup.3 is hydrogen, fluorine, chlorine or CF.sub.3. 
Favourably R.sup.1 is fluorine, chlorine or CF.sub.3. 
Favourably R.sup.2 is hydrogen, fluorine, chlorine or CF.sub.3. 
Favourably R.sup.3 is hydrogen, fluorine, chlorine or CF.sub.3. 
Preferably R.sup.1 and R.sup.2 are in the 3 and 5 positions of the phenyl 
ring. 
More preferably R.sup.1 is 3-fluoro or 3-CF.sub.3. 
More preferably R.sup.2 is 5-fluoro or 5-CF.sub.3. 
More preferably R.sup.3 is hydrogen. 
Most preferably R.sup.1 is 3-F or 3-CF.sub.3, R.sup.2 is 5-CF.sub.3 and 
R.sup.3 is hydrogen. 
Most aptly R.sup.4 is hydrogen. 
Most aptly R.sup.5 is hydrogen, fluorine, chlorine or CF.sub.3. 
Preferably R.sup.4 is hydrogen and R.sup.5 is hydrogen or 4-fluoro. 
Most aptly R.sup.9a and R.sup.9b are each independently hydrogen or methyl. 
Preferably R.sup.9a is hydrogen. Preferably R.sup.9b is hydrogen. Most 
preferably R.sup.9a and R.sup.9b are both hydrogen. 
From the foregoing it will be appreciated that a particularly apt sub-group 
of compounds of this invention are those of the formula (Ia) and 
pharmaceutically acceptable salts and prodrugs thereof: 
##STR6## 
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 (I). 
According to a second or further aspect of the present invention, a 
preferred class of compound of formula (I) or (Ia) is that wherein Y 
represents a C.sub.1-4 alkyl group substituted by a hydroxy group; or a 
pharmaceutically acceptable salt or prodrug thereof. 
According to a further or alternative aspect of the present invention, 
another preferred class of compound of formula (I) or (Ia) is that wherein 
Y represents a C.sub.1-4 alkyl group, with the proviso that R.sup.6 is 
substituted at least by a group of the formula ZNR.sup.7 R.sup.8 as 
defined above; or a pharmaceutically acceptable salt or prodrug thereof. 
According to another aspect of the present invention, a further preferred 
class of compound of formula (I) or (Ia) is that wherein 
Y represents a C.sub.1-4 alkyl group; and 
R.sup.6 represesents a 5-membered or 6-membered heterocyclic ring 
containing 2 or 3 nitrogen atoms optionally substituted by .dbd.O or 
.dbd.S and 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 C.sub.1-4 alkoxy, 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 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; 
or a pharmaceutically acceptable salt or prodrug thereof. 
According to yet another aspect of the present invention, a preferred class 
of compounds of formula (I) or (Ia) is that wherein 
Y represents a C.sub.1-4 alkyl group; and 
R.sup.6 is a 5-membered or 6-membered heterocyclic ring containing 2 or 3 
nitrogen atoms optionally substituted by .dbd.O or .dbd.S and 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 or C.sub.1-4 alkyl, or C.sub.2-4 alkyl substituted by 
C.sub.1-4 alkoxy or hydroxyl, R.sup.8 is hydrogen or C.sub.1-4 alkyl or 
C.sub.2-4 alkyl substituted by C.sub.1-4 alkoxy, hydroxyl or a 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, 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 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; 
or a pharmaceutically acceptable salt or prodrug thereof. 
According to a further aspect of the present invention, another preferred 
class of compound of formula (I) or (Ia) is that wherein 
Y represents a C.sub.1-4 alkyl group substituted by a hydroxyl group; and 
R.sup.6 is a 5-membered or 6-membered heterocyclic ring containing 2 or 3 
nitrogen atoms optionally substituted by .dbd.O or .dbd.S 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 or C.sub.1-4 alkyl, or C.sub.2-4 alkyl substituted by 
C.sub.1-4 alkoxy or hydroxyl, R.sup.8 is hydrogen or C.sub.1-4 alkyl or 
C.sub.2-4 alkyl substituted by C.sub.1-4 alkoxy or hydroxyl; 
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 which may optionally contain an 
oxygen ring atom 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 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; 
or a pharmaceutically acceptable salt or prodrug thereof. 
According to another aspect of the present invention, a further preferred 
class of compound of formula (I) or (Ia) is that wherein 
R.sup.6 is a 5-membered or 6-membered heterocyclic ring containing 2 or 3 
nitrogen atoms optionally substituted by .dbd.O or .dbd.S 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 cycloalkyl; 
R.sup.7 is hydrogen or C.sub.1-4 alkyl, or C.sub.2-4 alkyl substituted by 
C.sub.1-4 alkoxy or hydroxyl, R.sup.8 is hydrogen or C.sub.1-4 alkyl or 
C.sub.2-4 alkyl substituted by C.sub.1-4 alkoxy or hydroxyl; 
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 which may optionally contain an 
oxygen ring atom 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 Z, R.sup.7 and the nitrogen atom to which that are attached form a 
heteroaliphatic ring to 4 to 7 ring atoms which may optionally contain an 
oxygen ring atom; 
or a pharmaceutically acceptable salt or prodrug thereof. 
A preferred group Y for compounds of the formulae (I) or (Ia) is the 
CH.sub.2 OH group. 
Another preferred group Y for compounds of the formulae (I) or (Ia) is the 
CH.sub.3 group. 
Particularly apt values for X for compounds of the formulae (I) or (Ia) 
include CH.sub.2, CH(CH.sub.3) and CH.sub.2 CH.sub.2 of which the CH.sub.2 
group is preferred. 
Favourably R.sup.6 is a 5-membered ring. 
In particular, R.sup.6 may, bearing in mind the proviso in the definition 
of formula (I), represent a heterocyclic ring selected from: 
##STR7## 
Particularly preferred heterocyclic rings represented by R.sup.6 are 
selected from: 
##STR8## 
Most especially, R.sup.6 may represent a heterocyclic ring selected from: 
##STR9## 
A particularly preferred heterocyclic ring represented by R.sup.6 is: 
##STR10## 
One favoured group of compounds of this invention are of the formula (Ib) 
and pharmaceutically acceptable salts and prodrugs thereof: 
##STR11## 
wherein A.sup.1, A.sup.2 and A.sup.3 are defined in relation to formula 
(Ia) and wherein Z, R.sup.7 and R.sup.8 are as defined in relation to 
formula (I). 
A further favoured group of compounds of the present invention are of the 
formula (Ic) and pharmaceutically acceptable salts and prodrugs thereof: 
##STR12## 
wherein A.sup.1, A.sup.2 and A.sup.3 are as defined in relation to formula 
(Ia) and Q.sup.1 is CH or N or C-ZNR.sup.7 R.sup.8 wherein Z, R.sup.7 and 
R.sup.8 are as defined in relation to formula (I). 
Another favoured group of compounds of the present invention are of the 
formula (Id) and pharmaceutically acceptable salts and prodrugs thereof: 
##STR13## 
wherein A.sup.1, A.sup.2 and A.sup.3 are defined in relation to formula 
(Ia), Q.sup.2 is CH or N and Z, R.sup.7 and R.sup.8 are as defined in 
relation to formula (I). 
With respect to compounds of the formulae (I), (Ia), (Ib), (Ic) and (Id), Z 
may be a linear, branched or cyclic group. Favourably Z contains 1 to 4 
carbon atoms and most favourably 1 or 2 carbon atoms. A particularly 
favourable group Z is CH.sub.2. 
With respect to compounds of the formulae (I), (Ia), (Ib), (Ic) and (Id), 
R.sup.7 may aptly be a C.sub.1-4 alkyl group or a C.sub.2-4 aikyl group 
substituted by a hydroxyl or C.sub.1-2 alkoxy group, R.sup.8 may aptly be 
a C.sub.1-4 alkyl group or a C.sub.1-4 alkyl group substituted by a 
hydroxyl or C.sub.1-2 alkoxy group, or R.sup.7 and R.sup.8 may be linked 
so that, together with the nitrogen atom to which they are attached, they 
form an azetidinyl, pyrrolidinyl, piperidyl, morpholino, thiomorpholino, 
piperazino or piperazino group substituted on the nitrogen atom by a 
C.sub.1-4 alkyl group or a C.sub.2-4 alkyl group substituted by a hydroxy 
or C.sub.1-2 alkoxy group. 
Where the group NR.sup.7 R.sup.8 represents a heteroaliphatic ring of 4 to 
7 ring atoms and said ring contains a double bond, a particularly 
preferred group is 3-pyrroline. 
Where the group NR.sup.7 R.sup.8 represents a non-aromatic azabicyclic ring 
system, such a system may contain between 6 and 12, and preferably between 
7 and 10, ring atoms. Suitable rings include 5-azabicyclo[2.1.1]hexyl, 
5-azabicyclo[2.2.1 ]heptyl, 6-azabicyclo[3.2.1]octyl, 
2l-azabicyclo[2.2.2]octyl, 6-azabicyclo[3.2.2]nonyl, 
6-azabicycio[3.3.1]nonyl, 6-azabicyclo[3.2.2]decyl, 7-azabicyclo[4.3.1 
]decyl, 7-azabicyclo[4.4.1]undecyl and 8-azabicyclo[5.4.1]dodecyl, 
especially 5-azabicyclo[2.2.1]heptyl and 6-azabicycio[3.2.1]octyl. 
Where R.sup.8 represents a C.sub.2-4 alkyl group substituted by a 5 or 6 
membered heteroaliphatic ring containing one or two heteroatoms selected 
from N, O and S, suitable rings include pyrrolidino, piperidino, 
piperazino, morpholino, or thiomorpholino. Particularly preferred are 
nitrogen containing heteroaliphatic rings, especially pyrrolidino and 
morpholino rings. 
Particularly suitable moieties ZNR.sup.7 R.sup.8 include those wherein Z is 
CH.sub.2 or CH.sub.2 CH.sub.2 and NR.sup.7 R.sup.8 is amino, methylamino, 
dimethylamino, diethylamino, azetidinyl, pyrrolidino and morpholino. 
Further preferred moleties represented by ZNR.sup.7 R.sup.8 are those 
wherein Z is CH.sub.2 or CH.sub.2 CH.sub.2, R.sup.7 represents hydrogen, 
C.sub.1-4 alkyl or C.sub.3-6 cycloalkyl and R.sup.8 is C.sub.2-4 alkyl 
substituted by one or two substituents selected from hydroxy, C.sub.1-2 
alkoxy, azetidinyl, pyrrolidino, piperidino, morpholino or thiomorpholino. 
In particular, Z is preferably CH.sub.2 and NR.sup.7 R.sup.8 is preferably 
dimethylamino, azetidinyl or pyrrolidino, especially dimethylamino. 
With regard to compounds of the formulae (Ia), (Ib), (Ic) and (Id), A.sup.1 
is preferably fluorine or CF.sub.3 ; A.sup.2 is preferably CF.sub.3 ; and 
A.sup.3 is preferably fluorine. 
As used herein, the term "alkyl" or "alkoxy" as a group or part of a group 
means that the group is straight or branched. Examples of suitable alkyl 
groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl and 
t-butyl. Examples of suitable alkoxy groups include methoxy, ethoxy, 
n-propoxy, i-propoxy, n-butoxy, s-butoxy and t-butoxy. 
The cycloalkyl groups referred to herein may represent, for example, 
cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. A suitable 
cycloalkylalkyl group may be, for example, cyclopropylmethyl. 
As used herein, the terms "alkenyl" and "alkynyl" as a group or part of a 
group means that the group is straight or branched. Examples of suitable 
alkenyl groups include vinyl and allyl. A suitable alkynyl group is 
propargyl. 
When used herein the term halogen means fluorine, chlorine, bromine and 
iodine. The most apt halogens are fluorine and chlorine of which fluorine 
is preferred. 
Specific compounds within the scope of this invention include: 
2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl) 
ethoxy)-4-(2,3-dihydro-5-(N,N-dimethylamino)methyl-2-oxo-1,3-imidazol-4-yl 
)methyl-3-(S)-(4-fluorophenyl) morpholine; 
4-(2,3-dihydro-5-(N,N-dimethylamino)methyl-2-oxo-1,3-imidazol-4-yl)methyl-3 
-(S)-(4-fluorophenyl)-2-(R)-(1-(R)-(3-fluoro-5-(trifluoromethyl)phenyl) 
ethoxy)morpholine; 
3-(S)-(4-fluorophenyl)-2-(R)-(1-(R)-(3-fluoro-5-(trifluoromethyl)phenyl) 
ethoxy)-4-(2,3-dihydro-2-oxo-5-pyrrolidinomethyl-1,3-imidazol-4-yl)methylm 
orpholine; 
2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl) 
ethoxy)-3-(S)-(4-fluorophenyl)-4-(2,3-dihydro-2-oxo-5-pyrrolidinomethyl-1, 
3-imidazol-4-yl)methylmorpholine; 
2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl) 
ethoxy)-3-(S)-(4-fluorophenyl)-4-(2,3-dihydro-5-(4-hydroxypiperidino)methy 
l-2-oxo-1,3-imidazol-4-yl)methylmorpholine; 
3-(S)-(4-fluorophenyl)-2-(R)-(1-(R)-(3-fluoro-5-(trifluoromethyl)phenyl) 
ethoxy)-4-(2,3-dihydro-5-morpholinomethyl-2-oxo 
-1,3-imidazol-4-yl)methylmorpholine; 
2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl) 
ethoxy)-3-(S)-(4-fluorophenyl)-4-(2,3-dihydro-5-morpholinomethyl-2-oxo-1,3 
-imidazol -4-yl)methylmorpholine; 
4-(5-azetidinylmethyl-2,3-dihydro-2-oxo-1,3-imidazol-4-yl)methyl-2-(R)-(1-( 
R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(4-fluorophenyl) morpholine; 
2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl) 
ethoxy)-3-(S)-(4-fluorophenyl)-4-(2,3-dihydro-5-(N-methylpiperazinyl)methy 
l-2-oxo-1,3-imidazol-4-yl)methylmorpholine; 
2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl) 
ethoxy)-3-(S)-(4-fluorophenyl)-4-(2,3-dihydro-5-(N-(2-morpholinoethyl)amin 
omethyl)-2-oxo-1,3-imidazol-4-yl)methylmorpholine; 
2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl) 
ethoxy)-3-(S)-(4-fluorophenyl)-4-(2,3-dihydro-2-oxo-5-(N-(2-pyrrolidinoeth 
yl) aminomethyl)-1,3-imidazol-4-yl)methylmorpholine; 
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; 
2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl) 
ethoxy)-3-(S)-(4-fluorophenyl)-4-(N-(N'-methylaminoethyl)-1,2,4-triazol-3- 
yl) methylmorpholine; 
and pharmaceutically acceptable salts or prodrugs thereof. 
Further preferred compounds within the scope of the present invention 
include: 
2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl) 
ethoxy)-3-(S)-(4-fluorophenyl)-4-(5-(N-methylaminomethyl)-1,2,3-triazol-4- 
yl) methylmorpholine; 
4-(5-aminomethyl)-1,2,3-triazol-4-yl) methyl-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-(5-pyrrolidinomethyl)-1,2,3-triazol-4-yl) 
methylmorpholine; 
4-(5-(azetidinylmethyl)-1,2,3-triazol-4-yl)methyl-3-(S)-(4-fluorophenyl)-2- 
(R)-(1-(R)-(3-fluoro-5-(trifluoromethyl)phenyl)ethoxy) morpholine; 
3-(S)-(4-fluorophenyl)-2-(R)-(1-(R)-(3-fluoro-5-(trifluoromethyl)phenyl) 
ethoxy)-4-(5-(pyrrolidinomethyl)-1,2,3-triazol-4-yl)methylmorpholine; 
3-(S)-(4-fluorophenyl)-2-(R)-(1-(R)-(3-fluoro-5-(trifluoromethyl)phenyl) 
ethoxy)-4-(5-(morpholinomethyl)-1,2,3-triazol-4-yl)methylmorpholine; 
4-(5-(N,N-dimethylaminomethyl)-1,2,3-triazol-4-yl)methyl-3-(S)-(4-fluorophe 
nyl)-2-(R)-(1-(R)-(3-(trifluoromethyl)phenyl)ethoxy) morpholine; 
2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl) 
ethoxy)-3-(S)-(4-fluorophenyl)-4-(5-(N'-methylpiperazinomethyl)-1,2,3-tria 
zol-4-yl) methylmorpholine; 
2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl) 
ethoxy)-3-(S)-(4-(1-(2-pyrrolidinoethyl)-1,2,3-triazol-4-yl)methylmorpholi 
ne; 
2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl) 
ethoxy)-3-(S)-phenyl-4-(2-(2-pyrrolidinoethyl) 
-1,2,3-triazol-4-yl)methylmorpholine; 
2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl) 
ethoxy)-3-(S)-(4-fluorophenyl)-4-(5-(morpholinomethyl)-1,2,3-triazol-4-yl) 
methylmorpholine; 
4-(5-azetidinylmethyl)-1,2,3-triazol-4-yl) 
methyl-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-(5-(pyrrolinomethyl)-1,2,3-triazol-4-yl)m 
ethylmorpholine; 
2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl) 
ethoxy)-4-(5-(bis(methoxyethyl)aminomethyl)-1,2,3-triazol-4-yl)methyl-3-(S 
)-(4-fluorophenyl)morpholine; 
2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl) 
ethoxy)-4-(2-chloro-5-morpholinomethyl-1,3-imidazol-4-yl)methyl-3-(S)-(4-f 
luorophenyl) morpholine; 
2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl) 
ethoxy)-4-(5-(N,N-dimethylaminomethyl)-1,3-imidazol-4-yl)methyl-3-(S)-(4-f 
luorophenyl) morpholine; 
2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl) 
ethoxy)-4-(5-(N,N-dimethylaminomethyl)-1,2,4-triazol-3-yl)methyl-3-(S)-(4- 
fluorophenyl) morpholine; 
2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl) 
ethoxy)-4-(5-N-(2,2-dimethoxyethyl)-N 
-methylaminomethyl)-1,2,3-triazol-4-yl)methyl-3-(S) -phenylmorpholine; 
2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl) ethoxy)-4-(5-(2-methoxyethyl) 
aminomethyl-1,2,3-triazol-4-yl)methyl-3-(S) -phenylmorpholine; 
2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl) 
ethoxy)-4-(5-(N-(2-methoxyethyl)-N-methyl) 
aminomethyl-1,2,3-triazol-4-yl)methyl-3-(S) -phenylmorpholine; 
2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl) 
ethoxy)-4-(5-(N-isopropyl-N-(2-methoxyethyl) 
aminomethyl-1,2,3-triazol-4-yl)methyl-3-(S) -phenylmorpholine; 
2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl) 
ethoxy)-4-(5-(N-cyclopropyl-N-(2-methoxyethyl) 
aminomethyl-1,2,3-triazol-4-yl)methyl-3-(S) -phenylmorpholine; 
2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl) 
ethoxy)-4-(5-N,N-dibutylaminomethyl-1,2,3-triazol-4-yl)methyl-3-(S)-phenyl 
morpholine; 
2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl) 
ethoxy)-4-(5-N,N-diisopropylaminomethyl-1,2,3-triazol-4-yl)methyl-3-(S)-ph 
enylmorpholine; 
and pharmaceutically acceptable salts or prodrugs thereof. 
Yet further preferred compounds within the scope of the present invention 
include: 
2-(R)-(1-(S)-(3,5-bis(trifluoromethyl)phenyl)-2-hydroxyethoxy)-3-(S)-(4-flu 
orophenyl)-4-(2,3-dihydro-3-oxo-1,2,4-triazol-5-yl) methylmorpholine; 
2-(R)-(1-(S)-(3,5-bis(trifluoromethyl)phenyl)-2-hydroxyethoxy)-3-(S)-(4-flu 
orophenyl)-4-(1,2,4-triazol-3-yl)methylmorpholine; 
4-(2,3-dihydro-3-oxo-1,2,4-triazol-5-yl)methyl-3-(S)-(4-fluorophenyl)-2-(R) 
-(1-(S)-(3-fluoro-5-(trifluoromethyl)phenyl)-2-hydroxyethoxy)morpholine; 
4-(2,3-dihydro-2-oxo-1,3-imidazol-4-yl)methyl-2-(R)-(1-(S)-(3,5-bis(trifluo 
romethyl) phenyl)-2-hydroxyethoxy)-3-(S)-(4-fluorophenyl) morpholine; 
4-(2,3-dihydro-2-oxo-5-pyrrolidinomethyl 
-1,3-imidazol-4-yl)methyl-2-(R)-(1-(S)-(3,5-bis(trifluoromethyl)phenyl)-2- 
hydroxyethoxy)-3-(S) -(4-fluorophenyl)morpholine; 
4-(2,3-dihydro-3-oxo-1,2,4-triazol-5-yl)-3-(S)-phenyl-2-(R)-(1-(S)-(3-(trif 
luoromethyl)phenyl)-2-hydroxyethoxy)morpholine; 
4-(2,3-dihydro-3-oxo-1,2,4-triazol-5-yl)methyl-2-(R)-(1-(S)-(3-fluoro-5-(tr 
ifluoromethyl)phenyl)-2-hydroxyethoxy)-3-(S) -phenylmorpholine; 
2-(R)-(1-(S)-(3,5-bis(trifluoromethyl)phenyl)-2-hydroxyethoxy)-4-(2,3-dihyd 
ro-3-oxo-1,2,4-triazol-5-yl)-3-(S) -phenylmethylmorpholine; 
3-(S)-phenyl-4-(1,2,4-triazol-3-yl)-2-(R)-(1-(S)-3-(trifluoromethyl)phenyl) 
-2-hydroxyethoxy)morpholine; 
and pharmaceutically acceptable salts or prodrugs thereof. 
Further preferred compounds within the scope of the present invention are 
described in the Examples described herein. 
In a further aspect of the present invention, the compounds of formula (I) 
will preferably be prepared in the form of a pharmaceutically acceptable 
salt, especially an acid addition salt. 
For use in medicine, the salts of the compounds of formula (I) will be 
non-toxic pharmaceutically acceptable salts. Other salts may, however, be 
useful in the preparation of the compounds according to the invention or 
of their non-toxic pharmaceutically acceptable salts. Suitable 
pharmaceutically acceptable salts of the compounds of this invention 
include acid addition salts which may, for example, be formed by mixing a 
solution of the compound according to the invention with a solution of a 
pharmaceutically acceptable acid such as hydrochloric acid, fumaric acid, 
p-toluenesulphonic acid, maleic acid, succinic acid, acetic acid, citric 
acid, tartaric acid, carbonic acid, phosphoric acid or suiphuric acid. 
Salts of amine groups may also comprise quaternary ammonium salts in which 
the amino nitrogen atom carries a suitable organic group such as an alkyl, 
alkenyl, alkynyl or aralkyl moiety. Furthermore, where the compounds of 
the invention carry an acidic moiety, suitable pharmaceutically acceptable 
salts thereof may include metal salts such as alkali metal salts, e.g. 
sodium or potassium salts; and alkaline earth metal salts, e.g. calcium or 
magnesium salts. 
The present invention includes within its scope prodrugs of the compounds 
of formula (I) above. In general, such prodrugs will be functional 
derivatives of the compounds of formula (I) which are readily convertible 
in vivo into the required compound of formula (I). Conventional procedures 
for the selection and preparation of suitable prodrug derivatives are 
described, for example, in "Design of Prodrugs", ed. H. Bundgaard, 
Elsevier, 1985. 
A prodrug may be a pharmacologically inactive derivative of a biologically 
active substance (the "parent drug" or "parent molecule") that requires 
transformation within the body in order to release the active drug, and 
that has improved delivery properties over the parent drug molecule. The 
transformation in vivo may be, for example, as the result of some 
metabolic process, such as chemical or enzymatic hydrolysis of a 
carboxylic, phosphoric or sulphate ester, or reduction or oxidation of a 
susceptible functionality. 
Thus, for example, certain preferred prodrugs may not be antagonists of 
tachykinin, particularly substance P, activity to any significant extent 
(or not at all). Such compounds, however, are still advantageous in 
treating the various conditions described herein, especially where an 
injectable formulation is preferred. 
The advantages of a prodrug may lie in its physical properties, such as 
enhanced water solubility for parenteral administration compared with the 
parent drug, or it may enhance absorption from the digestive tract, or it 
may enhance drug stability for long-term storage. Ideally a prodrug will 
improve the overall efficacy of a parent drug, for example, through the 
reduction of toxicity and unwanted effects of drugs by controlling their 
absorption, blood levels, metabolism, distribution and cellular uptake. 
A particularly preferred class of prodrugs of the compounds of the present 
invention is that wherein the hydroxyl moiety of the group Y in formula 
(I) (when Y if C.sub.1-4 alkyl substituted by hydroxyl) is derivatized. 
It will be appreciated that a further class of prodrugs of the compounds of 
the present invention is that wherein the heterocyclic group represented 
by R.sup.6 in formula (I) is derivatized, or alternatively, wherein both 
the hydroxyl moiety of the group Y (when Y is C.sub.1-4 alkyl substituted 
by hydroxyl) and the heterocyclic group represented by R.sup.6 in formula 
(I) are derivatized. 
Suitable prodrug derivatives include: 
(a) --(CHR.sup.10).sub.n --PO(OH)O--.M.sup.+ ; 
(b) --(CHR.sup.10).sub.n --PO(O--).sub.2.2M.sup.+ ; 
(c) --(CHR.sup.10).sub.n --PO(O--).sub.2.D.sup.2+ ; 
(d) --(CHR.sup.10).sub.n --SO.sub.3 --.M.sup.+ ; 
(e) --COCH.sub.2 CH.sub.2 CO.sub.2 --.M.sup.+ ; 
(f) --COH; 
(g) --CO(CH.sub.2).sub.n N(R.sup.10).sub.2 ; and 
(h) --(CH(R.sup.10)O).sub.n --COR.sup.11, 
wherein 
n is zero or 1; 
M.sup.+ is a pharmaceutically acceptable monovalent counterion; 
D.sup.2+ is a pharmaceutically acceptable divalent counterion; 
R.sup.10 is hydrogen or C.sub.1-3 alkyl; and 
R.sup.11 is a group selected from --O(CH.sub.2).sub.2 
NH.sub.3.sup.+.M.sup.- ; 
--O(CH.sub.2).sub.2 NH.sub.2 (R.sup.12).sup.+.M.sup.- ; --OCH.sub.2 
CO.sub.2.sup.-.M.sup.+ ; 
--OCH(CO.sub.2.sup.-.M.sup.+)CH.sub.2 CO.sub.2.sup.-.M.sup.+ ; --OCH.sub.2 
CH(NH.sub.3.sup.30)CO.sub.2.sup.- ; 
--OC(CO.sub.2.sup.-.M.sup.+)(CH.sub.2 CO.sub.2.sup.-.M.sup.+).sub.2 ; and 
##STR14## 
in which M.sup.- is a pharmaceutically acceptable monovalent counterion, 
and R.sup.12 is hydrogen, C.sub.1-4 alkyl or C.sub.2-4 alkyl substituted 
by a hydroxyl or C.sub.1-4 alkoxy group. 
Particularly preferred prodrug derivatives are: 
(a) --(CHR.sup.10).sub.n --PO(OH)O.sup.-.M.sup.+ ; 
(b) --(CHR.sup.10).sub.n --PO(O--).sub.2.2M.sup.+ ; 
(c) --(CHR.sup.10).sub.n --PO(O--).sub.2.D.sup.2+ ; 
especially where n is zero. 
The term "parent molecule", "parent compound" or "parent drug" refers to 
the biologically active entity that is released via enzymatic action of a 
metabolic or catabolic process, or via a chemical process following 
administration of the prodrug. The parent compound may also be the 
starting material for the preparation of its corresponding prodrug. 
While all of the usual routes of administration are useful with the above 
prodrugs, the preferred routes of administration are oral and intravenous. 
After gastrointestinal absorption or intravenous administration, the 
prodrugs are hydrolyzed or otherwise cleaved in vivo to the corresponding 
parent compounds of formula (I), or a pharmaceutically acceptable salt 
thereof. Since the parent compounds may less than optimally soluble in 
aqueous solutions, the above prodrugs provide a distinct advantage by 
virtue of their relatively enhanced aqueous solubility. 
Examples of negative monovalent counterions defined herein as "M.sup.- " 
include acetate, adipate, benzoate, benzenesulfonate, bisulfate, butyrate, 
camphorate, camphOrsulfonate, citrate, ethanesulfonate, fumarate, 
hemisulfate, 2-hydroxyethylsulfonate, heptanoate, hexanoate, 
hydrochloride, hydrobromide, hydroiodide, lactate, malate, maleate, 
methanesulfonate, 2-naphthalenesulfonate, oxalate, pamoate, persulfate, 
picrate, pivalate, propionate, salicylate, stearate, succinate, sulfate, 
tartrate, tosylate (p-toluenesulfonate), and undecanoate. 
Base salts (which are pharmaceutically acceptable monovalent cations 
defined herein as "M.sup.+ " or pharmaceutically acceptable divalent 
cations defined herein as "D.sup.2+ ", if appropriate) include ammonium 
salts, alkali metal salts such as sodium, lithium and potassium salts, 
alkaline earth metal salts such as aluminium, calcium and magnesium salts, 
salts with organic bases such as dicyclohexylamine salts, 
N-methyl-D-glucamine, and salts with amino acids such as arginine, lysine, 
ornithine, and so forth. If M.sup.+ is a monovalent cation, it is 
recognised that if the definition 2M.sup.+ is present, each of M.sup.+ 
may be the same or different. In addition, it is similarly recognised that 
if the definition 2M.sup.+ is present, a divalent cation D.sup.2+ may 
instead be present. Also, the basic nitrogen-containing groups may be 
quaternized with such agents as: lower alkyl halides, such as methyl, 
ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates 
like dimethyl, diethyl and dibutyl; diamyl sulfates; long chain halides 
such as decyl, lauryl, myristyl and stearyl chlorides, bromides and 
iodides; aralkyl halides like benzyl bromide and others. The non-toxic 
physiologically acceptable salts are preferred, although other salts are 
also useful, such as in isolating or purifying the product. 
The salts may be formed by conventional means, such as by reacting the free 
base form of the product with one or more equivalents of the appropriate 
acid in a solvent or medium in which the salt is insoluble, or in a 
solvent such as water which is removed in vacuo or by freeze drying or by 
exchanging the anions of an existing salt for another anion on a suitable 
ion exchange resin. 
A particularly preferred sub-class of prodrugs of the compounds of the 
present invention is that defined by the formula (Ie) and pharmaceutically 
acceptable salts thereof: 
##STR15## 
wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.9a, 
R.sup.9b and X are as defined in relation to formula (I) and P in a circle 
is PO(OH)O--.M.sup.+, PO(O--).sub.2.2M.sup.+, or PO(O--).sub.2.D.sup.2+. 
Another preferred sub-class of prodrugs of the compounds of the present 
invention is that defined by the formula (If) and pharmaceutically 
acceptable salts thereof: 
##STR16## 
wherein A.sup.1, A.sup.2 and A.sup.3 are as defined in relation to formula 
(Ia), X and R.sup.6 are as defined in relation to formula (I), and P in a 
circle is PO(OH)O --.M.sup.+, PO(O--).sub.2.2M.sup.+, or 
PO(O--).sub.2.D.sup.2+. 
An especially preferred sub-group of prodrugs of the compounds of the 
present invention is that defined by formula (Ig) and pharmaceutically 
acceptable salts thereof: 
##STR17## 
wherein A.sup.1, A.sup.2 and A.sup.3 are as defined in relation to formula 
(Ia), Q.sup.1 is as defined in relation to formula (Ic) and P in a circle 
is PO(OH)O--.M .sup.+, PO(O--).sub.2.2M.sup.+, or PO(O--).sub.2.D.sup.2+. 
A yet further preferred sub-group of prodrugs of the compounds of the 
present invention is that defined by formula (Ih) and pharmaceutically 
acceptable salts thereof: 
##STR18## 
wherein A.sup.1, A.sup.2 and A.sup.3 are as defined in relation to formula 
(Ia), Q.sup.1 and Q.sup.2 are as defined in relation to formulae (Ic) and 
(Id), respectively, and P in a circle is PO(OH)O--.M.sup.+, 
PO(O--).sub.2.2M.sup.+, or PO(O--).sub.2.D.sup.2+. 
Specific prodrug derivatives within the scope of this invention include: 
2-(R)-(1-(S)-(3,5-bis(trifluoromethyl)phenyl)-2-phosphoryloxyethoxy)-3-(S)- 
(4-fluorophenyl)-4-(2,3-dihydro-3-oxo-1,2,4-triazol-5-yl) methylmorpholine; 
2-(R)-(1-(S)-(3,5-bis(trifluoromethyl)phenyl)-2-phosphoryloxyethoxy)-3-(S)- 
(4-fluorophenyl)-4-(1,2,4-triazol-3-yl)methylmorpholine; 
4-(2,3-dihydro-3-oxo-1,2,4-triazol-5-yl)methyl-2-(R)-(1-(S)-3-fluoro-5-(tri 
fluoromethyl)phenyl)-2-phosphoryloxyethoxy)-3-(S) -phenylmorpholine; 
2-(R)-(1-(S)-(3,5-bis(trifluoromethyl)phenyl)-2-phosphoryloxyethoxy)-4-(2,3 
-dihydro-3-oxo-1,2,4-triazol-5-yl)methyl-3-(S)-phenylmorpholine; 
and pharmaceutically acceptable salts thereof. 
With regard to compounds of the formulae (If), (Ig) and (Ih), A.sup.1 is 
preferably fluorine or CF.sub.3 ; A.sup.2 is preferably CF.sub.3 ; and 
A.sup.3 is preferably fluorine. 
The present invention includes within its scope solvates of the compounds 
of formula (I) and salts thereof, for example, hydrates. 
The compounds according to the invention have at least three asymmetric 
centres, and may accordingly exist both as enantiomers and as 
diastereoisomers. It is to be understood that all such isomers and 
mixtures thereof are encompassed within the scope of the present 
invention. 
The preferred compounds of the formula (I), (Ia), (Ib), (Ic), (Id), (Ie), 
(If), (Ig) and (Ih) will have the 2- and 3- substituent cis and the 
preferred stereochemistry at the 2-position is that possessed by the 
compound of Example 1 (i.e. 2-(R)-), the preferred stereochemistry of the 
3-position is that possessed by the compound of Example 1 (i.e. 3-(S)), 
and the preferred stereochemistry of the carbon to which the group Y is 
either (R) when Y is C.sub.1-4 alkyl (e.g. methyl) or (S) when Y is 
C.sub.1-4 alkyl substituted by hydroxy (e.g. CH.sub.2 OH). Thus for 
example as shown in formula (Ii) 
##STR19## 
The present invention further provides pharmaceutical compositions 
comprising one or more compounds of formula (I) in association with a 
pharmaceutically acceptable carrier. 
Preferably the compositions according to the invention are in unit dosage 
forms such as tablets, pills, capsules, powders, granules, solutions or 
suspensions, or suppositories, for oral, parenteral or rectal 
administration, or administration by inhalation or insufflation. 
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 or peanut 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, 
polyvinylpyrrolidone or gelatin. 
Preferred compositions for administration by injection include those 
comprising a compound of formula (I), 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 anionic agents such as sodium 
bis-(2-ethylhexyl)sulfosuccinate (docusate sodium), cationic agents, such 
as alkyltrimethylammonium bromides, (e.g. cetyltrimethylammonium bromide 
(cetrimide)), and 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 pre-mixed emulsion composition or alternatively it may be 
dissolved in an oil (e.g. soybean oil, safflower oil, cottonseed oil, 
sesame oil, corn oil or almond oil) and an emulsion formed 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 gylcerol 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 0.51 .mu.m, and 
have a pH in the range of 5.5 to 8.0. 
Particularly preferred emulsion compositions are those prepared by mixing a 
compound of formula (I) with Intralipid.TM. or the components thereof 
(soybean oil, egg phospholipids, glycerol and water). 
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. Nebulised solutions may be breathed directly from the 
nebulising device or the nebulising device may be attached to a face mask, 
tent or intermittent positive pressure breathing machine. Solution, 
suspension or powder compositions may be administered, preferably orally 
or nasally, from devices which deliver the formulation in an appropriate 
manner. 
The present invention futher provides a process for the preparation of a 
pharmaceutical composition comprising a compound of formula (I), which 
process comprises bringing a compound of formula (I) into association with 
a pharmaceutically acceptable carrier or excipient. 
The compounds of formula (I) are of value in the treatment of a wide 
variety of clinical conditions which are characterised by the presence of 
an excess of tachykinin, in particular substance P, activity. These may 
include disorders of the central nervous system such as anxiety, 
depression, psychosis and schizophrenia; epilepsy; neurodegenerative 
disorders such as dementia, including senile dementia of the Alzheimer 
type, Alzheimer's disease and Down's syndrome; demyelinating diseases such 
as MS and ALS and other neuropathological disorders such as peripheral 
neuropathy, for example diabetic and chemotherapy-induced neuropathy, and 
postherpetic and other neuralgias; small cell carcinomas such as small 
cell lung cancer; respiratory diseases, particularly those associated with 
excess mucus secretion such as chronic obstructive airways disease, 
bronchopneumonia, chronic bronchitis, cystic fibrosis and asthma, and 
bronchospasm; inflammatory diseases such as inflammatory bowel disease, 
psoriasis, fibrositis, osteoarthritis, rheumatoid arthritis, pruritis and 
sunburn; allergies such as eczema and rhinitis; hypersensitivity disorders 
such as poison ivy; ophthalmic diseases such as conjunctivitis, vernal 
conjunctivitis, and the like; ophthalmic conditions associated with cell 
proliferation such as proliferative vitreoretinopathy; cutaneous diseases 
such as contact clermatitis, atopic dermatitis, urticaria, and other 
eczematoid dermatitis; addiction disorders such as alcoholism; stress 
related somatic disorders; reflex sympathetic dystrophy such as 
shoulder/hand syndrome; dysthymic disorders; adverse immunological 
reactions such as rejection of transplanted tissues and disorders related 
to immune enhancement or suppression such as systemic lupus erythematosus; 
gastrointestinal (GI) disorders and diseases of the GI tract such as 
disorders associated with the neuronal control of viscera, ulcerative 
coliris, Crohn's disease, irritable bowel syndrome and emesis, including 
acute, delayed or anticipatory emesis such as emesis induced by 
chemotherapy, radiation, toxins, viral or bacterial infections, pregnancy, 
vestibular disorders, motion, surgery, migraine, and variations in 
intercranial pressure, in particular, for example, drug or radiation 
induced emesis or postoperative nausea and vomiting; disorders of blaclder 
function such as cystiris, bladder detrusor hyper-reflexia and 
incontinence; fibrosing and collagen diseases such as scleroderma ancl 
eosinophilic fascioliasis; disorders of blood flow caused by vasodilation 
and vasospastic diseases such as angina, migraine and Reynaud's disease; 
and pain or nociception, for example, that attributable to or associated 
with any of the foregoing conditions, especially the transmission of pain 
in migraine. 
The compounds of formula (I) are also of value in the treatment of a 
combination of the above conditions, in particular in the treatment of 
combined post-operative pain and post-operative nausea and vomiting. 
The compounds of formula (I) are particularly useful in the treatment of 
emesis, including acute, delayed or anticipatory emesis, such as emesis 
induced by chemotherapy, radiation, toxins, pregnancy, vestibular 
disorders, motion, surgery, migraine, and variations in intercranial 
pressure. Most especially, the compounds of formula (I) are of use in the 
treatment of emesis induced by antineoplastic (cytotoxic) agents including 
those routinely used in cancer chemotherapy. 
Examples of such chemotherapeutic agents include alkylating agents, for 
example, nitrogen mustards, ethyleneimine compounds, alkyl sulphonates and 
other compounds with an alkylating action such as nitrosoureas, cisplatin 
and dacarbazine; antimetabolites, for example, folic acid, purine or 
pyrimidine antagonists; mitotic inhibitors, for example, vinca alkaloids 
and derivatives of poclophyllotoxin; and cytotoxic antibiotics. 
Particular examples of chemotherapeutic agents are described, for instance, 
by D. J. Stewart in Nausea and Vomiting: Recent Research and Clinical 
Advances, Eds. J. Kucharczyk et al, CRC Press Inc., Boca Raton, Fla., USA 
(1991) pages 177-203, especially page 188. Commonly used chemotherapeutic 
agents include cisplatin, dacarbazine (DTIC), dactinomycin, 
mechlorethamine (nitrogen mustard), streptozocin, cyclophosphamide, 
carmustine (BCNU), Iomustine (CCNU), doxorubicin (adriamycin), 
daunorubicin, procarlaazine, mitomycin, cytarabine, etoposide, 
methotrexate, 5-fluorouracil, vinblastine, vincristine, bleomycin and 
chlorambucil [R. J. Gralla et al in Cancer Treatment Reports (1984) 68(1), 
163-172]. 
The compounds of formula (I) are also of use in the treatment of emesis 
induced by radiation including radiation therapy such as in the treatment 
of cancer, or radiation sickness; and in the treatment of post-operative 
nausea and vomiting. 
It will be appreciated that the compounds of formula (I) may be presented 
together with another therapeutic agent as a combined preparation for 
simultaneous, separate or sequential use for the relief of emesis. Such 
combined preparations may be, for example, in the form of a twin pack. 
A further aspect of the present invention comprises the compounds of 
formula (I) in combination with a 5-HT.sub.3 antagonist, such as 
ondansetron, granisetron or tropisetron, or other anti-emetic medicaments, 
for example, a dopamine antagonist such as metoclopramide. Additionally, a 
compound of formula (I) may be administered in combination with an 
anti-inflammatory corticosteroid, such as dexamethasone. Furthermore, a 
compound of formula (I) may be administered in combination with a 
chemotherapeutic agent such as an alkylating agent, antimetabolite, 
mitotic inhibitor or cytotoxic antibiotic, as described above. In general, 
the currently available dosage forms of the known therapeutic agents for 
use in such combinations will be suitable. 
When tested in the ferret model of cisplatin-induced emesis described by F. 
D. Tattersall et al, in Eur. J. Pharmacol., (1993) 250, R5-R6, the 
compounds of the present invention were found to attenuate the retching 
and vomiting induced by cisplatin. 
The compounds of formula (I) are also particularly useful in the treatment 
of pain or nociception and/or inflammation and disorders associated 
therewith such as, for example, neuropathy, such as diabetic and 
chemotherapy-induced neuropathy, postherpetic and other neuralgias, 
asthma, osteroarthritis, rheumatoid arthritis and especially migraine. 
The present invention further provides a compound of formula (I) for use in 
therapy. 
According to a further or alternative aspect, the present invention 
provides a compound of formula (I) for use in the manufacture of a 
medicament for the treatment of physiological disorders associated with an 
excess of tachykinins, especially substance P. 
The present invention also provides a method for the the treatment or 
prevention of physiological disorders associated with an excess of 
tachykinins, especially substance P, which method comprises administration 
to a patient in need thereof of a tachykinin reducing amount of a compound 
of formula (I) or a composition comprising a compound of formula (I). 
For the treatment of certain conditions it may be desirable to employ a 
compound according to the present invention in conjunction with another 
pharmacologically active agent. For example, for the treatment of 
respiratory diseases such as asthma, a compound of formula (I) may be used 
in conjunction with a bronchodilator, such as a .beta..sub.2 -adrenergic 
receptor antagonist or tachykinin antagonist which acts at NK-2 receptors. 
The compound of formula (I) and the bronchodilator may be administered to 
a patient simultaneously, sequentially or in combination. 
The present invention accordingly provides a method for the treatment of a 
respiratory disease, such as asthma, which method comprises administration 
to a patient in need thereof of an effective amount of a compound of 
formula (I) and an effective amount of a bronchodilator. 
The present invention also provides a composition comprising a compound of 
formula (I), a bronchodilator, and a pharmaceutically acceptable carrier. 
The excellent pharmacological profile of the compounds of the present 
invention offers the opportunity for their use in therapy at low doses 
thereby minimising the risk of unwanted side effects. 
In the treatment of the conditions associated with an excess of 
tachykinins, a suitable dosage level is about 0.001 to 50 mg/kg per day, 
in particular about 0.01 to about 25 mg/kg, such as from about 0.05 to 
about 10 mg/kg per day. 
For example, in the treatment of conditions involving the neurotransmission 
of pain sensations, a suitable dosage level is about 0.001 to 25 mg/kg per 
day, preferably about 0.005 to 10 mg/kg per day, and especially about 
0.005 to 5 mg/kg per day. The compounds may be administered on a regimen 
of 1 to 4 times per day, preferably once or twice per day. 
In the treatment of emesis using an injectable formulation, a suitable 
dosage level is about 0.001 to 10 mg/kg per day, preferably about 0.005 to 
5 mg/kg per day, and especially 0.01 to 2 mg/kg per day. The compounds may 
be administered on a regimen of 1 to 4 times per day, preferably once or 
twice per day. 
It will be appreciated that the amount of a compound of formula (I) 
required for use in any treatment will vary not only with the particular 
compounds or composition 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 
attendant physician. 
According to a general process (A), the compounds according to the 
invention may be prepared from compounds of formula (II) 
##STR20## 
wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5 and Y are as defined 
in relation to formula (I) by reaction with a compound of formula (III): 
EQU S.sup.1 --X--R.sup.61 (III) 
where X is as defined in relation to formula (I), R.sup.6a is a group of 
the formula R.sup.6 as defined in relation to formula (Ia) or a precursor 
therefor and X.sup.1 is a leaving group such as bromine or chlorine; and, 
if R.sup.6a is a precursor group, converting it to a group R.sup.6 (in 
which process any reactive group may be protected and thereafter 
deprotected if desired). 
This reaction may be performed in conventional manner, for example in an 
organic solvent such as dimethylformamide in the presence of an acid 
acceptor such as potassium carbonate. 
According to another process (B), compounds of formula (I) wherein R.sup.6 
represents 1,2,3-triazol-4-yl substituted by CH.sub.2 NR.sup.7 R.sup.8 and 
X is --CH.sub.2 --, may be prepared by reaction of a compound of formula 
(IV) 
##STR21## 
with an azide, for example, sodium azide in a suitable solvent such as 
dimethylsulphoxide at a temperature of between 40.degree. C. and 
100.degree. C., followed by reduction of the carbonyl group adjacent to 
--NR.sup.7 R.sup.8 using a suitable reducing agent such as lithium 
aluminium hydride at at a temperature between -10.degree. C. and room 
temperature, conveniently at room temperature. 
Alternatively, according to a process (C), compounds of formula (I) wherein 
R.sup.6 represents 1,2,3-triazol-4-yl substituted by CH.sub.2 NR.sup.7 
R.sup.8, and X is --CH.sub.2 --, may be prepared by reaction of a compound 
of formula (V) 
##STR22## 
with an amine of formula NHR.sup.7 R.sup.8, in a suitable solvent such as 
an ether, for example, dioxan, at elevated temperature, for example, 
between 50.degree. C. and 100.degree. C., in a sealed tube, or the like. 
This reaction is based upon that described in Chemische Berichte (1989) 
122, p. 1963. 
According to another process, (D), compounds of formula (I) wherein R.sup.6 
represents substituted or unsubstituted 1,3,5 -triazine may be prepared by 
reaction of intermediates of formula (VI): 
##STR23## 
with substituted or unsubstituted 1,3,5-triazine. 
The reaction is conveniently effected in a suitable organic solvent, such 
as acetonitrile, at elevated temperature, such as 80.degree.-90.degree. 
C., preferably about 82.degree. C. 
According to a further process, (E), compounds of formula (I) wherein 
R.sup.6 represents substituted or unsubstituted 1,2,4 -triazine may be 
prepared by reaction of an intermediate of formula (VII) with a dicarbonyl 
compound of formula (VIII): 
##STR24## 
wherein R.sup.35 represents H or a suitable substituent such as ZNR.sup.7 
R.sup.8. 
The reaction is conveniently effected in a suitable organic solvent, such 
as an ether, e.g. tetrahydrofuran, conveniently at ambient temperature. 
According to a further process (F), compounds of formula (I) wherein 
R.sup.6 represents a substituted 1,2,4-triazolyl group may be prepared by 
reaction of an intermediate of formula (II) with a compound of formula 
(IX) 
##STR25## 
wherein X is as defined in relation to formula (I), Hal is a halogen atom, 
for example, bromine, chlorine or iodine and R.sup.18 is H, CONH.sub.2 or 
OCH.sub.3 (which is converted to an oxo substituent under the reaction 
conditions), in the presence of a base, followed where necessary by 
conversion to a compound of formula (I), for example, by reduction of the 
CONH.sub.2 group to CH.sub.2 NH.sub.2. 
Suitable bases of use in the reaction include alkali metal carbonates such 
as, for example, potassium carbonate. The reaction is conveniently 
effected in an anhydrous organic solvent such as, for example, anhydrous 
dimethylformamide, preferably at elevated temperature, such as about 
140.degree. C. 
A suitable reducing agent for the group CONH.sub.2 is lithium aluminium 
hydride, used at between -10.degree. C. and room temperature. 
According to another process, (G), compounds of formula (I) wherein R.sup.6 
represents thioxotriazolyl may be prepared from intermediates of formula 
(X) 
##STR26## 
by reaction with a compound of formula HNCS, in the presence of a base. 
Suitable bases of use in the reaction include organic bases such as, for 
example, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). The reaction is 
conveniently effected in a suitable organic solvent, such as alcohol, e.g. 
butanol. 
Further details of suitable procedures will be found in the accompanying 
Examples. 
Compounds of formula (I) may also be prepared from other compounds of 
formula (I) using suitable interconversion procedures. For example, 
compounds of formula (I) wherein X represents C.sub.1-4 alkyl may be 
prepared from compounds of formula (I) wherein X represents C.sub.1-4 
alkyl substituted by oxo by reduction, for example, using borane or 
lithium aluminium hydride. Suitable interconversion procedures will be 
readily apparent to those skilled in the art. 
Intermediates of formula (IV) may be prepared from intermediates of formula 
(II) by reaction with an acetylene compound of formula 
HC.ident.C--CH.sub.2 -Hal in the presence of a base such as potassium 
carbonate in a suitable solvent such as dimethylformamide, conveniently at 
room temperature, followed by reaction of the resultant acetylene 
intermediate with an amide of formula Hal--CO--NR.sup.7 R.sup.8 in the 
presence of suitable catalysts including bis(triphenylphosphine) 
palladium(II) chloride, copper(I) iodide and triphenylphosphine in a 
suitable solvent such as triethylamine, preferably at reflux. 
Intermediates of formula (V) may be prepared from a compound of formula 
(XI) 
##STR27## 
wherein Hal is a halogen atom, for example, chlorine, bromine or iodine, 
especially chlorine, by reaction with an azide, for example, sodium azide 
in a suitable solvent such as dimethylsulphoxide at or below room 
temperature. 
Compounds of formula (XI) may be prepared by a dropwise addition of an 
intermediate of formula (II) to a dihaloacetytene of formula Hal--CH.sub.2 
--C.ident.C--CH.sub.2 --Hal where each Hal is independently chlorine, 
bromine or iodine, especially chlorine. The reaction is conveniently 
effected in a suitable solvent such as dimethylformamide in the presence 
of a base such as potassium carbonate. 
Intermediates of formula (VI) may be prepared from intermediates of formula 
(II) by reaction with a compound of formula Hal--X--C(NH)NH.sub.2, where 
Hal and X are as previously defined. 
Intermecliates of formula (VII) may be prepared from intermediates of 
formula (II) by reaction with a compound of formula 
Hal--X--C(NH)NHNH--Boc, wherein Hal and X are as previously defined and 
Boc stands for t-butoxycarbonyl, followed by deprotection under acidic 
conditions. 
Compounds of formula (VIII) are commercially available or may be prepared 
from commercially available compounds by known methods. 
Compounds of formula (IX) may be prepared as described in J. Med. Chem., 
(1984) 27, 849. 
Intermediates of formula (X) may be prepared from the corresponding ester 
by treatment with hydrazine. The reaction is conveniently effected in a 
suitable organic solvent, such as an alcohol, for example, ethanol, at 
elevated temerpature. 
For compounds wherein R.sup.6 is a heterocycle substituted by a ZNR.sup.7 
R.sup.8 group where Z is CH.sub.2, certain favoured compounds of formula 
(I) may be prepared from a corresponding compound with a hydrogen atom in 
place of the ZNR.sup.7 R.sup.8. Thus, for example a compound of the 
formula (I) wherein R.sup.6 is an imidazolinone group carrying a CH.sub.2 
NR.sup.7 R.sup.8 moiety may be prepared from a corresponding compound 
lacking the CH.sub.2 NR.sup.7 R.sup.8 moiety by reaction with formaldehyde 
and an amine NHR.sup.7 R.sup.8 under conventional Mannich reaction 
conditions, for example in methanol with heating. If desired a pre-formed 
reagent such as R.sup.7 R.sup.8 N.sup.+ .dbd.CH.sub.2.I.sup.- may be 
employed and a tertiary amine such as triethylamine used as acid acceptor. 
Alternatively a compound of formula (I) wherein R.sup.6 is an imidazolinone 
group lacking a CH.sub.2 NR.sup.7 R.sup.8 may be reacted with 
paraformaldehyde and an amine for example a secondary amine such as 
pyrrolidine to give a compound wherein the imidazolinone ring is 
substituted by CH.sub.2 NR.sup.7 R.sup.8 where 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 which may optionally contain an oxygen ring atom or a 
second nitrogen atom which will be part of a NH or NR.sup.c moiety, where 
R.sup.c is as previously defined. 
This reaction may be performed in a conventional manner, for instance, in a 
suitable solvent such as an alcohol, for example, methanol at an elevated 
temperature up to the boiling point of the solvent. 
A further alternative method for the preparation of certain compounds of 
formula (I) involves the reaction of an intermediate of formula (II) as 
defined above with one of the compounds of formula (XII): 
##STR28## 
wherein each LG, which may be the same or different, is a leaving group, 
such as an alkyl- or arylsulphonyloxy group (e.g. mesylate or tosylate) 
or, in particular, a halogen atom, (e.g. bromine, chlorine or iodine) and 
X and Z are as defined in formula (I), followed by reaction of the 
resultant compound with an amine NHR.sup.7 R.sup.8 to complete the 
ZNR.sup.7 R.sup.8 moiety. 
This reaction is conveniently effected in an organic solvent such as 
dimethylformamide in the presence of an acid acceptor such as potassium 
carbonate. 
It will be appreciated that, where necessary, reactive groups may be 
protected, thus for example, the NH groups of an imidazolinone of formula 
(XIIa) may be protected by any suitable amine protecting group such as an 
acetyl group. 
The preferred phosphate prodrugs of the compounds of the present invention 
may be prepared in a stepwise manner from a compound of formula (I) 
wherein Y is, for example, --CH.sub.2 OH--. 
Thus, the hydroxy compound is first treated with 
dibenzyloxydiethylaminophosphine in a suitable solvent such as 
tetrahydrofuran, preferably in the presence of an acid catalyst such as 
tetrazole. The resultant compound (Y.dbd.CH.sub.2 OP(OCH.sub.2 Ph).sub.2) 
is then oxidised using, for example, 4-methylmorpholine-N-oxide to give 
the dibenzyl-protected phosphate. Deprotection by catalytic hydrogenation 
or transfer hydrogenation (palladium catalyst on carbon and ammonium 
formate), in a suitable solvent such as methanol at reflux, yields the 
desired phosphate prodrug which may be converted to any desired salt form 
by conventional methodology. 
In an alternative two-step method, the hydroxy compound of formula (I) may 
be reacted with a suitable base such as sodium hydride in tetrahydrofuran, 
and tetrabenzylpyrophosphate added to yield the dibenzyl-protected 
phosphate which may be deprotected as described above. 
The compounds of the formula (II) may be prepared as shown in the following 
Scheme in which Ar.sup.1 represents the R.sup.1, R.sup.2, R.sup.3 
substituted phenyl group; Ar.sup.2 represents the R.sup.4, R.sup.5 
substituted phenyl group and Ph represents phenyl: 
##STR29## 
L-Selectride is lithium tri-sec-butylborohydride. 
The following references describe methods which may be applied by the 
skilled worker to the chemical synthesis set forth above once the skilled 
worker has read the disclosure herein: 
(i) D. A. Evans et al., J. Am. Chem. Soc., (1990) 112, 4011. 
(ii) I. Yanagisawa et al., J. Med. Chem., (1984) 27, 849. 
(iii) R. Duschinsky et al., J. Am. Chem. Soc., (1948) 70, 657. 
(iv) F. N. Tebbe et al., J. Am. Chem. Soc., (1978) 100, 3611. 
(v) N. A. Petasis et al., J. Am. Chem. Soc., (1990) 112, 6532. 
(vi) K. Takai et al., J. Org. Chem., (1987) 52, 4412. 
The Examples disclosed herein produce predominently the preferred isomers. 
The unfavoured isomers are also produced as minor components. If desired 
they may be isolated and employed to prepare the various stereoisomers in 
conventional manner, for example chromatography using an appropriate 
column. However, the skilled worker will appreciate that although the 
Examples have been optimized to the production of the preferred isomers, 
variation in solvent, reagents, chromatography etc can be readily employed 
to yield the other isomers. 
It will be appreciated that compounds of the formula (I) wherein R.sup.6 
contains an .dbd.O or .dbd.S substituent can exist in tautomeric forms. 
All such tautomeric forms and mixtures thereof are included within this 
invention. Most aptly the .dbd.O or .dbd.S substituent in R.sup.6 is the 
.dbd.O substituent. 
Where they are not commercially available, the intermediates of formula 
(III) above may be prepared by the procedures described in the 
accompanying Examples or by alternative procedures which will be readily 
apparent to one skilled in the art. 
During any of the above synthetic sequences it may be necessary and/or 
desirable to protect sensitive or reactive groups on any of the molecules 
concerned. This may be achieved by means of conventional protecting 
groups, such as those described in Protective Groups in Organic Chemistry, 
ed. J. F. W. McOmie, Plenum Press, 1973; and T. W. Greene and P. G. M. 
Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991. The 
protecting groups may be removed at a convenient subsequent stage using 
methods known from the art. 
The exemplified compounds of this invention were tested by the methods set 
out at pages 36 to 39 of International Patent Specification No. WO 
93/01165. The compounds or, in the case of prodrugs, the parent compounds, 
were found to be active with IC.sub.50 at the NK.sub.1 receptor of less 
than 10 nM on said test method.