USE OF NK-1 RECEPTOR ANTAGONISTS FOR TREATING EATING DISORDERS

UTILISATION DES ANTAGONISTES DU RECEPTEUR DE NK-1 DANS LE TRAITEMENT DES TROUBLES ALIMENTAIRES

English Abstract

The present invention provides the use of an NK-1 receptor antagonist,
optionally with an anorectic agent, for the manufacture of a medicament for
the treatment or prevention of eating disorders, methods of treatment using
the NK-1 receptor antagonist and pharmaceutical compositions and products
containing it.

French Abstract

La présente invention porte sur l'utilisation d'un antagoniste du récepteur de NK-1, éventuellement avec un agent anorexique, en vue de fabriquer un médicament destiné à être utilisé dans le traitement ou la prévention des troubles alimentaires. L'invention porte également sur des procédés de traitement utilisant l'antagoniste du récepteur de NK-1 et sur des compositions pharmaceutiques et les produits qu'elles contiennent.

Claims

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CLAIMS

1. Use of a NK-1 receptor antagonist for the manufacture of a
medicament for the treatment or prevention of eating disorders.

2. Use according to claim 1 which further comprises the
simultaneous, separate or sequential administration of an anorectic agent.

3. A pharmaceutical composition for the treatment or
prevention of eating disorders comprising a NK-1 receptor antagonist,
together with at least one pharmaceutically acceptable carrier or
excipient.

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

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

6. A method for the treatment or prevention of eating disorders,
which method comprises administration to a patient in need of such
treatment of an effective amount of a NK-1 receptor antagonist.

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

8. A use according to claim 1 or 2, a composition according to
claim 3 or 4, a product according to claim 5 or a method according to claim
6 or 7 wherein the NK-1 receptor antagonist is a compound of formula I:


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Image
wherein
R1 is selected from the group consisting of:
(1) C1-6alkyl, 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) C1-6 alkyl, unsubstituted or substituted with halo, -CF3,
-OCH3, or phenyl,
(ii) C1-6alkoxy,
(iii) oxo,



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(iv) thioxo,


(v) cyano,


(vi) -SCH3,


(vii) phenyl,


(viii) hydroxy,


(ix) trifluoromethyl,

(x) -(CH2)m-NR9R10, wherein m is 0, 1 or 2, and R9 and R10
areindependently selected from:
(I) hydrogen,
(II) C1-6alkyl,
(III) hydroxy C1-6alkyl, and
(IV) phenyl,
(xi) -NR9COR10, wherein R9 and R10 are as defined above,
and
(xii) -CONR9R10, wherein R9 and R10 are as defined above,
R2 and R3 are independently selected from the group consisting of:
(1) hydrogen;
(2) C1-6alkyl
(3) C2-6alkenyl, and
(5) phenyl;

X is -O-;

R4 is

Image,
R5 is phenyl, unsubstituted or substituted with halo;
R6, R7 and R8 are independently selected from the group consisting of:
(1) hydrogen,
(2) C1-6alkyl,
(3) halo, and



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(4) -CF3;
Y is -O-; and
Z is hydrogen or C1-4alkyl;
or a pharmaceutically acceptable salt thereof.
9. A use according to claim 1 or 2, a composition according to
claim 3 or 4, a product according to claim 5 or a method according to claim
6 or 7 wherein the NK-1 receptor antagonist is a compound of formula IIa:

Image

wherein:
A1 is fluorine or CF3;
A2 is fluorine or CF3;
A3 is fluorine or hydrogen;
R6 is a 5-membered or 6-membered heterocyclic ring containing 2 or
3 nitrogen atoms optionally substituted by =O, =S or a C1-4alkyl group,
and optionally substituted by a group of the formula ZNR7R8 where
Z is C1-6alkylene or C3-6cycloalkylene;
R7 is hydrogen, C1-4alkyl, C3-7cycloalkyl or C3-7cycloalkylC1-4alkyl, or
C2-4alkyl substituted by C1-4alkoxy or hydroxyl;
R8 is hydrogen, C1-4alkyl, C3-7cycloalkyl or C3-7cycloalkylC1-4alkyl, or
C2-4alkyl substituted by one or two substituents selected from C1-4alkoxy,
hydroxyl or a 4, 5 or 6 membered heteroaliphatic ring containing one or
two heteroatoms selected from N, O and S;




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or R7, R8 and the nitrogen atom to which they are attached form a
heteroaliphatic ring of 4 to 7 ring atoms, optionally substituted by a
hydroxy group, and optionally containing a double bond, which ring may
optionally contain an oxygen or sulphur ring atom, a group S(O) or S(O)2
or a second nitrogen atom which will be part of a NH or NR c moiety where
R c is C1-4alkyl optionally substituted by hydroxy or C1-4alkoxy;
or R7, R8 and the nitrogen atom to which they are attached form a
non-aromatic azabicyclic ring system of 6 to 12 ring atoms;
or Z, R7 and the nitrogen atom to which they are attached form a
heteroaliphatic ring of 4 to 7 ring atoms which may optionally contain an
oxygen ring atom;
or a pharmaceutically acceptable salt thereof.
10. A use according to claim 1 or 2, a composition according to
claim 3 or 4, a product according to claim 5 or a method according to claim
6 or 7 wherein the NK-1 receptor antagonist is a compound of formula III:
Image
wherein:
R2 and R3 are independently selected from the group consisting of:
(1) hydrogen,
(2) C1-6alkyl,
(3) C2-6alkenyl, and
(4) phenyl;




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R6, R7 and R8 are independently selected from the group consisting of:
(1) hydrogen,
(2) C1-6alkyl,
(3) fluoro,
(4) chloro,
(5) bromo,
(6) iodo, and
(7) -CF3;

R11, R12 and R13 are independently selected from the group consisting of:
(1) fluoro,
(2) chloro,
(3) bromo, and
(4) iodo;

A is unsubstituted 1-6alkyl;
B is selected from the group consisting of:
Image



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Image
p is 0 or 1;
X is selected from:
(a) -PO(OH)O- ~ M+, wherein M+ is a pharmaceutically
acceptable monovalent counterion,
(b) -PO(O-)2 ~ 2M+,
(c) -PO(O-)2 ~ D2+, wherein D2+ is a pharmaceutically acceptable
divalent counterion,
(d) -CH(R4)-PO(OH)O- ~ M+, wherein R4 is hydrogen or C1-3alkyl,
(e) -CH(R4)-PO(O-)2 ~ 2M+,
(f) -CH(R4)-PO(O-)2 ~ D2+,
(i) -CO-CH2CH2-CO2- ~ M+,
(j) -CH(CH3)-O-CO-R5, wherein R5 is selected from the group
consisting of:



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Image


Y is -O-;
Z is hydrogen or C1-6alkyl;
or a pharmaceutically acceptable salt thereof.
11. A use according to claim 1 or 2, a composition according to
claim 3 or 4, a product according to claim 5 or a method according to claim
6 or 7 wherein the NK-1 receptor antagonist is a compound of formula IVa:



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Image
wherein
A1 is fluorine or CF3;
A2 is fluorine or CF3;
A3 is fluorine or hydrogen;
X is a group of the formula NR6R7 or a C- or N-linked imidazolyl
ring;
Y is hydrogen or C1-4alkyl optionally substituted by a hydroxy
group;
R6 is hydrogen, C1-6alkyl, C3-7cycloalkyl, C3-7cycloalkylC1-4alkyl,
phenyl, or C2-4alkyl substituted by C1-4alkoxy or hydroxy;
R7 is hydrogen, C1-6alkyl, C3-7cycloalkyl, C3-7cycloalkylC1-4alkyl,
phenyl, or C2-4alkyl substituted by one or two substituents selected from
C1-4alkoxy, hydroxy or a 4, 5 or 6 membered heteroaliphatic ring
containing one or two heteroatoms selected from N, O and S;
or R6 and R7, together with the nitrogen atom to which they are
attached, form a saturated or partially saturated heterocyclic ring of 4 to 7
ring atoms, which ring may optionally contain in the ring one oxygen or
sulphur atom or a group selected from NR8, S(O) or S(O)2 and which ring
may be optionally substituted by one or two groups selected from
hydroxyC1-4alkyl, C1-4alkoxyC1-4alkyl, oxo, COR a or CO2R a where R a is
hydrogen or C1-4alkyl;



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or R6 and R7 together with the nitrogen atom to which they are
attached, form a non-aromatic azabicyclic ring system of 6 to 12 ring
atoms; and
R8 is hydrogen, C1-4alkyl, hydroxyC1-4alkyl or C1-4alkoxyC1-4alkyl;
or a pharmaceutically acceptable salt thereof.
12. A use according to claim 1 or 2, a composition according to
claim 3 or 4, a product according to claim 5 or a method according to claim
6 or 7 wherein the NK-1 receptor antagonist is a compound of formula V:
Image
wherein:
Y is (CH2)n wherein n is an integer from 1 to 4, and wherein any one
of the carbon-carbon single bonds in said (CH2)n may optionally be
replaced by a carbon-carbon double bond, and wherein any one of the
carbon atoms of said (CH2)n may optionally be substituted with R4, and
wherein any one of the carbon atoms of said (CH2)n may optionally be
substituted with R7;
Z is (CH2)m wherein m is an integer from 0 to 6, and wherein any
one of the carbon-carbon single bonds of (CH2)m may optionally be replaced
by a carbon-carbon double bond or a carbon-carbon triple bond, and any
one of the carbon atoms of said (CH2)m may optionally be substituted with
R8.
R1 is hydrogen or C1-8alkyl optionally substituted with hydroxy,
C1-4alkoxy or fluoro;



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R2 is a radical selected from hydrogen, C1-6 straight or branched
alkyl, C3-7cycloalkyl wherein one of the CH2 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-C2-6alkyl, benzhydryl and benzyl, wherein each of said
aryl and heteroaryl groups and the phenyl moieties of said benzyl,
phenyl-C2-6alkyl and benzhydryl may optionally be substituted with one or more
substituents independently selected from halo, nitro, C1-6 alkyl, C-6alkoxy,
trifluoromethyl, amino, C1-6alkylamino, C1-6alkyl-O-CO, C1-6alkyl-O-CO-
C1-6alkyl, C1-6alkyl-CO-O, C1-6alkyl-CO-C1-6alkyl-O-, C1-6alkyl-CO,
C1-6alkyl-CO-C1-6alkyl-, di-C1-6alkylamino, -CONH-C1-6alkyl,
C1-6alkyl-CO-NH-C1-6alkyl, -NHCOH and -NHCO-C1-6alkyl; and wherein
one of the phenyl moieties of said benzhydryl may optionally be replaced
by naphthyl, thienyl, furyl or pyridyl;
R5 is hydrogen, phenyl or C1-6alkyl;
or R2 and R5 together with the carbon to which they are attached,
form a saturated ring having from 3 to 7 carbon atoms wherein one of the
CH2 groups in said ring may optionally be replaced by oxygen, NH or
sulfur;
R3 is aryl selected from phenyl and naphthyl; heteroaryl selected
from indanyl, thienyl, furyl, pyridyl, thiazolyl, isothiazolyl, oxazolyl,
isoxazolyl, triazolyl, tetrazolyl and quinolyl; and cycloalkyl having 3 to 7
carbon atoms wherein one of the (CH2) 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 C3-7cycloalkyl may
optionally be substituted with one or two substituents, each of said
substituents being independently selected from halo, nitro, C1-6alkyl,
C1-6alkoxy, trifluoromethyl, amino, C1-6alkylamino, -CO-NH- C1-6alkyl,
C1-6alkyl-CO-NH-C1-6alkyl, -NHCOH and -NHCO-C1-6alkyl;


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R4 and R7 are each independently selected from hydroxy, halogen,
halo, amino, oxo, cyano, methylene, hydroxymethyl, halomethyl,
C1-6alkylamino, di-C1-6alkylamino, C1-6alkoxy, C1-6alkyl-O-CO,
C1-6alkyl-O-CO-C1-6alkyl, C1-6alkyl-CO-O, C1-6alkyl-CO-C1-6alkyl-O-,
C1-6alkyl-CO-, C1-6alkyl-CO-C1-6alkyl, and the radicals set forth in the
definition of R2;
R6 is -NHCOR9, -NHCH2R9, SO2R8 or one of the radicals set forth in
any of the definitions of R2, R4 and R7;
R8 is oximino (=NOH) or one of the radicals set forth in any of the
definitions of R2, R4 and R7;
R9 is C1-6alkyl, hydrogen, phenyl or phenylC1-6alkyl;
with the proviso that (a) when m is 0, R8 is absent, (b) when R4, R6, R7 or
R8 is as defined in R2, it cannot form together with the carbon to which it
is attached ,a ring with R5, and (c) when R4 and R7 are attached to the
same carbon atom, then either each of R4 and R7 is independently selected
from hydrogen, fluoro and C1-6alkyl, or R4 and R7, together with the carbon
to which they are attached, for a C3-6 saturated carbocyclic ring that forms
a spiro compound with the nitrogen-containing ring to which they are
attached;
or a pharmaceutically acceptable salt thereof.
13. A use according to claim 1 or 2, a composition according to
claim 3 or 4, a product according to claim 5 or a method according to claim
6 or 7 wherein the NK-1 receptor antagonist is a compound of formula VI:

Image

wherein:


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radicals R are phenyl radicals optionally 2- or 3-substituted by a
halogen atom or a methyl radical;
R1 is optionally substituted phenyl, cyclohexadienyl, naphthyl,
indenyl or optionally substituted heterocycle;
R2 is H, halogen, OH, alkyl, aminoalkyl, alkylaminoalkyl,
dialkylaminoalkyl, alkyloxy, alkylthio, acyloxy, carboxy, optionally
substituted alkyloxycarbonyl, benzyloxycarbonyl, amino or acylamino;
R3 is optionally 2-substituted phenyl;
R4 is OH or fluorine when R5 is H;
or R4 and R5 are OH;
or R4 and R5 together form a bond;
or a pharmaceutically acceptable salt thereof.
14. A use according to claim 1 or 2, a composition according to
claim 3 or 4, a product according to claim 5 or a method according to claim
6 or 7 wherein the NK-1 receptor antagonist is a compound of formula VII:
Image
wherein:
Ar represents an optionally substituted mono-, di- or tricyclic
aromatic or heteroaromatic group;
T represents a bond, a hydroxymethylene group, a
C1-4alkoxymethylene group or a C1-5alkylene group;
Ar' represents a phenyl group which is unsubstituted or substituted
by one or more substituents selected from halogen, preferably chlorine or
fluorine, trifluoromethyl, C1-4alkoxy, C1-4alkyl where the said substituents
may be the same or different; a thienyl group; a benzothienyl group; a
naphthyl group; or an indolyl group;


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R represents hydrogen, C1-4alkyl, .omega.-C-4alkoxyC1-4alkyl, or
.omega.-C2-4alkanoyloxyC2-4alkyl;
Q represents hydrogen;
or Q and R together form a 1,2-ethylene, 1,3-propylene or
1,4-butylene group;
Am+ represents the radical
Image
in which X1, X2 and X3, 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.
15. A use according to claim 1 or 2, a composition according to
claim 3 or 4, a product according to claim 5 or a method according to claim
6 or 7 wherein the NK-1 receptor antagonist is a compound of formula VIII
Image
wherein:
R1 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;
R2 represents cycloalkyl or an optionally substituted aryl or
heteroaryl group;
R3 represents hydrogen, alkyl, carbamoyl or an alkanoyl or alkenoyl
group optionally substituted by carboxy or esterified or amidated carboxy;


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R4 represents an optionally substituted aryl group or an optionally
partially saturated heteroaryl group;
X1 represents methylene, ethylene, a bond, an optionally ketalised
carbonyl group or an optionally etherified hydroxymethylene group;
X2 represents alkylene, carbonyl or a bond; and
X3 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;
or a pharmaceutically acceptable salt thereof.
16. A use according to claim 1 or 2, a composition according to
claim 3 or 4, a product according to claim 5 or a method according to claim
6 or 7 wherein the NK-1 receptor antagonist is a compound of formula IX:
Image
wherein:
R1 is aryl, or a group of the formula:
Image
X is CH or N; and
Z is O or N-R5, in which R5 is hydrogen or lower alkyl;
R2 is hydroxy or lower alkoxy;
R3 is hydrogen or optionally substituted lower alkyl;
R4 is optionally substituted ar(lower)alkyl;
A is carbonyl or sulfonyl; and



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Y is a bond or lower alkenylene;
or a pharmaceutically acceptable salt thereof.
17. A use according to claim 1 or 2, a composition according to
claim 3 or 4, a product according to claim 5 or a method according to claim
6 or 7 wherein the NK-1 receptor antagonist is a compound of formula X:
Image
wherein:
R1 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 C1-7cycloalkyl may optionally be substituted with
one or two substituents, said substituents being independently selected
from chloro, fluoro, bromo, iodo, nitro, C1-10alkyl optionally substituted
with from one to three fluoro groups, C1-10alkoxy optionally substituted
with from one to three fluoro groups, amino, C1-10alkyl-S-, C1-10alkyl-S(O)-,
C1-10alkyl-SO2-, phenyl, phenoxy, C1-10alkyl-SO2NH-,
C1-10alkyl-SO2NH-C1-10akyl-, C1-10alkylamino-diC1-10alkyl-, cyano, hydroxy,
cycloalkoxy having 3 to 7 carbon atoms, C1-6alkylamino, C1-6dialkylamino,
HC(O)NH- and C1-10alkyl-C(O)NH-; and
R2 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, C1-10alkyl
optionally substituted with from one to three fluoro groups and C1-10alkoxy
optionally substituted with from one to three fluoro groups;



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or a pharmaceutically acceptable salt thereof.
18. A use according to claim 1 or 2, a composition according to
claim 3 or 4, a product according to claim 5 or a method according to claim
6 or 7 wherein the NK-1 receptor antagonist is a compound of formula XI:
Image
wherein:
R1 is a C1-4alkoxy group;
R2 is
Image
R3 is a hydrogen or halogen atom;
R4 and R5 may each independently represent a hydrogen or halogen
atom, or a C1-4alkyl, C1-4alkoxy or trifluoromethyl group;
R6 is a hydrogen atom, a C1-4alkyl, (CH2)m cyclopropyl, -S(O)n C1-4alkyl,
phenyl, NR7R8, CH2C(O)CF3 or trifluoromethyl group;
R7 and R8 may each independently represent a hydrogen atom, or a
C1-4alkyl or acyl group;
x represents zero or 1;
n represents zero, 1 or 2; and
m represents zero or 1;



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or a pharmaceutically acceptable salt thereof.
19. A use according to claim 1 or 2, a composition according to
claim 3 or 4, a product according to claim 5 or a method according to claim
6 or 7 wherein the NK-1 receptor antagonist is a compound of formula XII:

Image

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, C1-3alkoxy,
trifluoromethyl, C1-4alkyl, phenyl-C1-3alkoxy, or C1-4alkanoyl groups;
R1 is trityl, phenyl, diphenylmethyl, phenoxy, phenylthio,
piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, indolinyl, indolyl,
benzothienyl, hexamethyleneiminyl, benzofuranyl, tetrahydropyridinyl,
quinolinyl, isoquinolinyl, reduced quinolinyl, reduced isoquinolinyl,
phenyl-(C1-4alkyl)-, phenyl-(C1-4alkoxy)-, quinolinyl-(C1-4alkyl)-,
isoquinolinyl-(C1-4alkyl)-, reduced quniolinyl-(C1-4alkyl)-, reduced
isoquinolinyl-(C1-4alkyl)-, benzoyl-(C1-3alkyl)-, C1-4alkyl, or -NH-CH2-R5;



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any one of which R1 groups may be substituted with halo, C1-4alkyl,
C1-4alkoxy, trifluoromethyl, amino, C1-4alkylamino, di(C1-4alkyl)amino, or
C2-4alkanoylamino;
or any one of which R1 groups may be substituted with phenyl,
piperazinyl, C3-8cycloalkyl, benzyl, C1-4alkyl, piperidinyl, pyridinyl,
pyrimidinyl, C2-6alkanoylamino, pyrrolidinyl, C2-6alkanoyl, or
C1-4alkoxycarbonyl;
any one of which groups may be substituted with halo, C1-4alkyl,
C1-4alkoxy, trifluoromethyl, amino, C1-4alkylamino, di(C1-4alkyl)amino, or
C2-4alkanoylamino;
or R1 is amino, a leaving group, hydrogen, C1-4alkylamino, or
di(C1-4alkyl)amino;
R5 is pyridyl, anilino-(C1-3alkyl)-, or anilinocarbonyl;
R2 is hydrogen, C1-4alkyl, C1-4alkylsulfonyl, carboxy-(C1-3alkyl)-,
C1-3alkoxycarbonyl-(C1-3alkyl)-, or -CO-R6;
R6 is hydrogen, C1-4alkyl, C1-3haloalkyl, phenyl, C1-3alkoxy,
C1-3hydroxyalkyl, amino, C1-4alkylamino, di(C1-4alkyl)amino, or -(CH2)q-R7;
q is zero to 3;
R7 is carboxy, C1-4alkoxycarbonyl, C1-4alkylcarbonyloxy, amino,
C1-4alkylamino, di(C1-4alkyl)amino, C1-6alkoxycarbonylamino, or phenoxy,
phenylthio, piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, indolinyl,
indolyl, benzothienyl, benzofuranyl, quinolinyl, phenyl-(C1-4alkyl)-,
quinolinyl-(C1-4alkyl)-, isoquinolinyl-(C1-4alkyl)-, reduced
quinolinyl-(C1-4alkyl)-, reduced isoquinolinyl-(C1-4alkyl)-, benzoyl-C1-
3alkyl;
any one of which aryl or heterocyclic R7 groups may be substituted
with halo, trifluoromethyl, C1-4alkoxy, C1-4alkyl, amino, C1-4alkylamino,
di(C1-4alkyl)amino, or C2-4alkanoylamino;
or any one of which R7 groups may be substituted with phenyl,
piperazinyl, C3-8cycloalkyl, benzyl, piperidinyl, pyridinyl, pyrimidinyl,
pyrrolidinyl, C2-6alkanoyl, or C1-4alkoxycarbonyl;



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any of which groups may be substituted with halo, trifluoromethyl,
amino, C1-4alkoxy, C1-4alkyl, C1-4alkylamino, di(C1-4alkyl)amino, or
C2-4alkanoylamino;
R6 is hydrogen or C1-6alkyl;
R3 is phenyl, phenyl-(C1-6alkyl)-, C3-8cycloalkyl, C5-8cycloalkenyl,
C1-8alkyl, naphthyl, C2-8alkenyl, or hydrogen;
any one or which groups except hydrogen may be substituted with
one or two halo, C1-3alkoxy, C1-3alkylthio, nitro, trifluoromethyl, or
C1-3alkyl groups; and
R4 is hydrogen or C1-3alkyl;
with the proviso that if R1 is hydrogen or halo, R3 is phenyl,
phenyl-(C1-6alkyl)-, C3-8cycloalkyl, C5-8cycloalkenyl, or naphthyl;
or a pharmaceutically acceptable salt thereof.
20. A use, composition, product or method according to any one of
the preceding claims wherein the NK-1 receptor antagonist is orally
active, long acting and CNS-penetrant.
21. A use according to claim 1 or 2, a composition according to
claim 3 or 4, a product according to claim 5 or a method according to claim
6 or 7 wherein the NK-1 receptor antagonist is selected from the classes of
compounds described in EP-A-0577394, WO-A-9508549, WO-A-9518124,
WO-A-9523798 and WO-A-9605181.
22. A use according to claim 1 or 2, a composition according to
claim 3 or 4, a product according to claim 5 or a method according to claim
6 or 7 wherein the NK-1 receptor antagonist is selected from
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;



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2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-4-(3-(5-oxo-1H,4H-1,2, 4-
triazolo)methyl)-3-(S)-phenyl-morpholine;
2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-
4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)morpholine;
2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(5-(N,N-
dimethylamino)methyl-1,2,3-triazol-4-yl)methyl-3-(S)-phenylmorpholine;
2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(5-(N,N-
dimethylamino)methyl-1,2,3-triazol-4-yl)methyl-3-(S)-(4-
fluorophenyl)morpholine;
2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-
4-(3-(4-monophosphoryl-5-oxo-1H-1,2,4-triazolo)methyl)morpholine;
2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-
4-(3-(1-monophosphoryl-5-oxo-1H-1,2,4-triazolo)methyl)morpholine;
2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-
4-(3-(2-monophosphoryl-5-oxo-1H-1,2,4-triazolo)methyl)morpholine;
2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-
4-(3-(5-oxyphosphoryl-1H-1,2,4-triazolo)methyl)morpholine;
2-(S)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-
4-(3-(1-monophosphoryl-5-oxo-4H-1,2,4-triazolo)methyl)morpholine;
2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(4-N,N-
dimethylaminobut-2-yn-yl)-3-(S)-(4-fluorophenyl)morpholine;
or a pharmaceutically acceptable salt thereof.
23. A use, composition, product or method according to any one of
the preceding claims wherein the anorectic agent is selected from
aminorex, amphechloral, amphetamine, benzphetamine,
chlorphentermine, clobenzorex, cloforex, clominorex, clortermine,
cyclexedrine, dexfenfluramine, dextroamphetamine, diethylpropion,
diphemethoxidine, N-ethylamphetamine, fenbutrazate, fenfluramine,
fenisorex, fenproporex, fludorex, fluminorex, furfurylmethylamphetamine,
levamfetamine, levophacetoperane, mazindol, mefenorex,



-98-
metamfepramone, methamphetamine, norpseudoephedrine, pentorex,
phendimetrazine, phenmetrazine, phentermine, phenylpropanolamine,
picilorex and sibutramine; or a pharmaceutically acceptable salt thereof.
24. A use, composition, product or method according to any one of
the preceding claims wherein the anorectic agent is a halogenated
amphetamine derivative.
25. A use, composition, product or method according to claim 24
wherein the amphetamine derivative is selected from chlorphentermine,
cloforex, clortermine, dexfenfluramine, fenfluramine, picilorex and
sibutramine; or a pharmaceutically acceptable salt thereof.
26. A use, composition, product or method according to any one of
claims 1 to 25 wherein the eating disorder is obesity.
27. A use, composition, product or method according to any one of
claims 1 to 25 wherein the eating disorder is bulimia nervosa.
28. A use, composition, product or method according to any one of
claims 1 to 25 wherein the eating disorder is a compulsive eating disorder.

Description

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WO 98/47513 PCT/GB98/01161
-1-
USE OF NK-1 RECEPTOR ANTAGONISTS FOR
TREATING EATING DISORDERS
This invention relates to the treatment or prevention of eating
disorders by the administration of a N:K-1 receptor antagonist, optionally
in combination with an anorectic agent.
Eating disorders commonly arise through an imbalance in a
subject's appetite, or desire to eat. It is recognised that appetite is
influenced by the interaction of central and peripheral systems, most
likely acting through the effects of neuropeptides on the so-called feeding
and safety centres in the hypothalamus region of the brain. For instance,
neuropeptides released by the gut in rEaponse to a meal may serve to
modulate the intake of further food.
Alterations of appetite may lead to eating disorders including
obesity, bulimia nervosa, and compulsive eating disorders.
Obesity is a chronic disease that is highly prevalent in modern
society and is associated not only with a social stigma, but also with
decreased life span and numerous medical problems, including adverse
psychological development, reproductive disorders such as polycystic
ovarian disease, dermatological disorders such as infections, varicose
veins, Acanthosis nigricans, and eczema, exercise intolerance, diabetes
mellitus, insulin resistance, hypertension, hypercholesterolemia,
cholelithiasis, osteoarthritis, orthopedic injury, thromboembolic disease,
cancer, and coronary heart disease. Rissanen et al, British Medical
Journal, 301:$35-837 (1990).
Bulimia nervosa is characterised by recurrent episodes of
overeating, or binges, followed by severe dieting often associated with self
induced vomiting, abuse of laxatives or diuretics, or excessive exercise to
avoid weight gain. Frequent vomiting or purging may result in electrolyte
disturbances and erosion of dental enamel.


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Complusive eating disorders may or may not be associated with
other neurological disorders. One well characterised compulsive eating
disorder is Prader-Willi syndrome, a congential disorder characterised by
infantile hypotonia, hypogonadism and facial dysmorphism, with
subsequent development of hyperplagia and abnormalities of behaviour
and intellect.
Treatment regimens for eating disorders typically include the use of
anorectic agents, such as amphetamine derivatives.
p-Chloroamphetamine and other halogenated amphetamines promote
serotonin (5-hydroxytryptamine; 5-HT) release from platelets and neurons.
A rapid release of serotonin is followed by a prolonged and selective
depletion of serotonin in the brain. The most widely used example of this
class of compound is fenfluramine and its (S'~-isomer, dexfenfluramine.
The precise mechanism of action of these compounds is uncertain,
however, fenfluramine and dexfenfluramine are both useful in the
treatment of bulimia nervosa and obesity, and fenfluramine has also
produced promising results in the management of Prader-Willi syndrome.
Neurokinin 1 (NK-l; 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 such conditions 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).
We have now found that NK-1 receptor antagonists are effective in
the treatment of eating disorders, as evidenced by their activity in vivo in
a model of diet-induced obesity.
Furthermore, a combination of an anorectic agent with a NK-1
receptor antagonist may provide an enhanced anorectic effect. They may
also provide for a rapid onset of action to combat eating disorders thereby
enabling prescription on an "as-needed" basis.


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A particularly preferred class of NK-1 receptor antagonists of use in
the present invention are those which a.re able to cross the blood-brain
barrier, otherwise known as CNS- or br ain-penetrant compounds.
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 eating disorders.
The present invention also provides a method for the treatment or
prevention of eating disorders, which method comprises administration to
a patient in need of such treatment 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 eating
disorders comprising a NK-1 receptor antagonist, together with at least
one pharmaceutically acceptable carrier or excipient.
In a further embodiment of the present invention there is provided
the use of a NK-1 receptor antagonist fcrr the manufacture of a
medicament for the treatment or prevention of obesity.
The present invention also provides a method for the treatment or
prevention of obesity, which method comprises administration to a patient
in need of such treatment an effective amount of a NK-1 receptor
antagonist.
In an alternative embodiment 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 bulimia nervosa.
The present invention also provides a method for the treatment or
prevention of bulimia nervosa, which method comprises administration to
a patient in need of such treatment an Effective amount of a NK-1 receptor
antagonist.
In a further embodiment of the present invention there is provided
the use of a NK-1 receptor antagonist for the manufacture of a


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medicament for the treatment or prevention of compulsive eating
disorders.
The present invention also provides a method for the treatment or
prevention of compulsive eating disorders, which method comprises
administration to a patient in need of such treatment an effective amount
of a NK-1 receptor antagonist.
In an alternative embodiment of the present invention there is
provided the use of a NK-1 receptor antagonist for the manufacture of a
medicament for reducing the total body fat mass in an obese mammal,
especially a human.
The present invention also provides a method for reducing the total
body fat mass in an obese mammal, especially a human, which method
comprises administration to a patient in need of such treatment an
effective amount of a NK-1 receptor antagonist.
The present invention further provides the use of a NK-1 receptor
antagonist and an anorectic agent for the manufacture of a medicament
for the treatment or prevention of eating disorders.
The present invention also provides a method for the treatment or
prevention of eating disorders, which method comprises administration to
a patient in need of such treatment an amount of a NK-1 receptor
antagonist and an amount of an anorectic 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
anorectic agent, together with at least one pharmaceutically acceptable
carrier or excipient.
It will be appreciated that the NK-1 receptor antagonist and
anorectic agent may be present as a combined preparation for
simultaneous, separate or sequential use for the treatment or prevention
of eating disorders. Such combined preparations may be, for example, in
the form of a twin pack.


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In a further or alternative aspect of the present invention, there is
therefore provided a product comprising a NK-1 receptor antagonist and
an anorectic agent as a combined preparation for simultaneous, separate
or sequential use in the treatment or prevention of eating disorders.
In a further embodiment of the present invention there is provided
the use of a NK-1 receptor antagonist and an anorectic agent for the
manufacture of a medicament for the treatment or prevention of obesity.
The present invention also provides a method for the treatment or
prevention of obesity, which method comprises administration to a patient
in need of such treatment an amount o:f a NK-1 receptor antagonist and an
amount of an anorectic agent, such that together they give effective relief.
It will be appreciated that the NK-1 receptor antagonist and
anorectic agent may be present as a combined preparation for
simultaneous, separate or sequential use for the treatment or prevention
of obesity. 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 anorectic agent as a combined preparation for simultaneous, separate
or sequential use in the treatment or prevention of obesity.
In an alternative embodiment of the present invention there is
provided the use of a NK-1 receptor antagonist and an anorectic agent for
the manufacture of a medicament for the treatment or prevention of
bulimia nervosa.
The present invention also provides a method for the treatment or
prevention of bulimia nervosa, which method comprises administration to
a patient in need of such treatment an amount of a NK-1 receptor
antagonist and an amount of an anorecaic agent, such that together they
give effective relief.
It will be appreciated that the NK-1 receptor antagonist and
anorectic agent may be present as a combined preparation for


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simultaneous, separate or sequential use for the treatment or prevention
of bulimia nervosa. 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 anorectic agent as a combined preparation for simultaneous, separate
or sequential use in the treatment or prevention of bulimia nervosa.
In a further embodiment of the present invention there is provided
the use of a NK-1 receptor antagonist and an anorectic agent for the
manufacture of a medicament for the treatment or prevention of
compulsive eating disorders.
The present invention also provides a method for the treatment or
prevention of compulsive eating disorders, which method comprises
administration to a patient in need of such treatment an amount of a NK-1
receptor antagonist and an amount of an anorectic agent, such that
together they give effective relief.
It will be appreciated that the NK-1 receptor antagonist and
anorectic agent may be present as a combined preparation for
simultaneous, separate or sequential use for the treatment or prevention
of compulsive eating disorders. Such combined preparations may be, for
example, in the form of a twin pack.
In a further or alternative aspect of the present invention, there is
therefore provided a product comprising a NK-1 receptor antagonist and
an anorectic agent as a combined preparation for simultaneous, separate
or sequential use in the treatment or prevention of compulsive eating
disorders.
In an alternative embodiment of the present invention there is
provided the use of a NK-1 receptor antagonist and an anorectic agent for
the manufacture of a medicament for reducing the total body fat mass in
an obese mammal, especially a human.


CA 02287487 1999-10-18
WO 98/47513 PCT/GB98/01161
_ 7 .
The present invention also provides a method for reducing the total
body fat mass in an obese mammal, especially a human, which method
comprises administration to a patient in need of such treatment an
amount of a NK-1 receptor antagonist and an amount of an anorectic
agent, such that together they give effective relief. _
It will be appreciated that the NK-1 receptor antagonist and
anorectic agent may be present as a combined preparation for
simultaneous, separate or sequential use for reducing the total body fat
mass in an obese mammal, especially a human. 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 anorectic agent as a combined preparation for simultaneous, separate
or sequential use in reducing the total body fat mass in an obese mammal,
especially a human.
It will be appreciated that when using a combination of the present
invention, both the NK-1 receptor antagonist and the anorectic agent will
be administered to a patient, within a reasonable period of time. The
compounds 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 anorectic
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.


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_g-
By "reasonable period of time" is meant a time period that is not in
excess of about 1 hour. That is, for example, if the anorectic agent is
provided as a tablet, then within one hour, the NK-1 receptor antagonist
should be administered, either in the same type of dosage form, or another
dosage form which provides effective delivery of the medicament.
The compositions of the present invention are useful for the
prevention or treatment of eating disorders. As used herein, the term
"eating disorders" includes obesity, bulimia nervosa and compulsive
eating disorders.
As used herein "obesity" refers to a condition whereby a mammal
has a Body Mass Index (BMI), which is calculated as weight per height
squared (kg/m2), of at least 25.9. Conventionally, those persons with
normal weight, have a BMI of 19.9 to less than 25.9.
The obesity herein may be due to any cause, whether genetic or
environmental. Examples of disorders that may result in obesity or be the
cause of obesity include overeating and bulimia, polycystic ovarian
disease, craniopharyngioma, the Prader-Willi Syndrome, Frohlich's
syndrome, Type II diabetes, GH-deficient subjects, normal variant short
stature, Turner's syndrome, and other pathological conditions showing
reduced metabolic activity or a decrease in resting energy expenditure as a
percentage of total fat-free mass, e.g, children with acute lymphoblastic
leukemia.
"Treatment" refers to reducing the BMI of the mammal to less than
about 25.9, and maintaining that weight for at least 6 months. The
treatment suitably results in a reduction in food or calorie intake by the
mammal.
"Prevention" refers to preventing obesity from occurring if the
treatment is administered prior to the onset of the obese condition.
Moreover, if treatment is commenced in already obese subjects, such
treatment is expected to prevent, or to prevent the progression of, the
medical sequelae of obesity, such as, e.g., arteriosclerosis, Type II
diabetes,


CA 02287487 1999-10-18
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_g_
polycycstic ovarian disease, cardiovascular diseases, osteoarthritis,
dermatological disorders, hypertension, insulin resistance,
hypercholesterolezriia, hypertriglyceridemia, and cholelithiasis.
Thus, in one aspect, this invention relates to the inhibition and/or
complete suppression of lipogenesis in obese mammals, i.e., the excessive
accumulation of lipids in fat cells, which is one of the major features of
human and animal obesity, as well as loss of total body weight. In another
aspect, the invention ameliorates the conditions that are a consequence of
the disease, such as preventing or arresting the progression of polycystic
ovarian disease so that the patient is no longer infertile, and increasing
the insulin sensitivity andlor decreasing or eliminating the need or usage
of insulin in a diabetic patient, e.g., one with adult-onset diabetes or Type
II diabetes.
"Mammals" include animals of economic importance such as bovine,
ovine, and porcine animals, especially those that produce meat, as well as
domestic animals, sports animals, zoo animals, and humans, the latter
being preferred.
The compositions of the present invention are especially useful for
the treatment of or prevention of eating disorders where the use of an
anorectic agent is generally prescribed. By the use of a combination of a
NK-1 receptor antagonist and an anorectic agent in accordance with the
present invention, it is now also possible to treat or prevent eating
disorders in patients for whom conventional anorectic therapy might not
be wholly successful or where dependance upon the anorectic therapy is
prevalent.
Suitable anoretic agents of use in the combinations of the present
invention include, but are not limited t;o, aminorex, amphechloral,
amphetamine, benzphetamine, chlorphentermine, clobenzorex, cloforex,
clominorex, clortermine, cyclexedrine, dexfenfluramine,
dextroamphetamine, diethylpropion, diphemethoxidine, N-
ethylamphetamine, fenbutrazate, fenfluramine, fenisorex, fenproporex,


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fludorex, fluminorex, furfurylmethylamphetamine, levamfetamine,
levophacetoperane, mazindol, mefenorex, metamfepramone,
methamphetamine, norpseudoephedrine, pentorex, phendimetrazine,
phenmetrazine, phentermine, phenylpropanolamine, picilorex and
sibutramine; and pharmaceutically acceptable salts thereof.
Particularly preferred anorectic agents include amphetamine and
derivatives thereof such as amphetamine, benzphetamine,
chlorphentermine, clobenzorex, cloforex, clotermine, dexfenfluramine,
dextroamphetamine, diethylpropion, N ethylamphetamine, fenfluramine,
fenproporex, furfurylmethylamphetamine, levamfetamine, mefenorex,
metamfepramone, methamphetamine, norpseudoephedrine, pentorex,
phendimetrazine, phenmetrazine, phentermine, phenylpropanolamine,
picilorex and sibutramine; and pharmaceutically acceptable salts thereof.
A particularly suitable class of anorectic agent are the halogenated
amphetamine derivatives, including chlorphentermine, cloforex,
clortermine, dexfenfluramine, fenfluramine, picilorex and sibutramine;
and pharmaceutically acceptble salts thereof;
Particularly preferred halogenated amphetamine derivatives of use
in the present invention include: fenfluramine and dexfenfluramine, and
pharmaceutically acceptable salts thereof.
Another particularly preferred anorectic agent is phentermine.
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,


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-lL-
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, 94/101'd0, 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, 95/1537_1, 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//0562, 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//7362, 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.
Particularly preferred NK-1 receptor antagonists are those
described in European Patent Specific<~tion No. 0 577 394, i.e. compounds
of formula (I):
3 X R9
(I)
R2 N R5
y
R
or a pharmaceutically acceptable salt thereof, wherein:
Rl is selected from the group consisting of:
(1) hydrogen;
(2) C1-salkyl, unsubstituted or substituted with one or more of the
substituents selected from:
(a) hydroxy,
(b) oxo,
(c) C1-ealkoxy,


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WO 98/47513 PCT/GB98/01161
-I2-
(d) phenyl-Ci.salkoxy,


(e) phenyl,


(f) -CN,


(g) halo,


(h) -NR~RI~, wherein R9 and Rl~ are independently
__


selected from:


(i) hydrogen,


(ii) C1-calkyl,


(iii) hydroxy-Ci_calkyl, and


(iv) phenyl,


(i) -NR~COR1~, wherein R~ and R1~ are as defined
above,


(j) -NR9COzRl~, wherein R9 and Rl~ are as defined
above,


(k) -CONR9R1~, wherein R9 and Rl~ are as defined
above,


(1) -COR9, wherein R9 is as defined above,


(m) -COzR9, wherein R~ 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,




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(O} pyrimidyl,


(P) pyrrolyl,


(fa) quinolyl,


(R) tetrazolyl,


(S) thiadiazolyl,


(T) thiazolyl,


(U) thienyl,


triazolyl,


(V~ azetidinyl,


(X) 1,4-dioxanyl,


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) Ci.salkyl, unsubstituted or substituted
with halo, -CFs,


-OCHs, or phenyl,


(ii) C1-salkoxy,


(iii) oxo,


(iv) hydroxy,


(v) thioxo,


(vi) -SRS, wherein R'' is as defined above,


(vii) halo,


(viii) cyano,


(ix) phenyl,


{x) trifluoromethyl,




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(xi) -(CHz)m-NR9Rlo, wherein m is 0, 1 or 2,
and Ro and Rlo


are as defined above,


(xii) -NRgCORlo, wherein R~ and Rlo are as defined
above,


(xiii) -CONR9Rlo, wherein R9 and Rlo are as defined
above,


(xiv) -COzR~, wherein R9 is as defined above,
and


(xv) -(CH2)m-OR9, wherein m and R9 are as defined
above;


(3) Cz-salkenyl,
unsubstituted or
substituted with
one or more of the


substituent(s) selected
from:


(a) hydroxy,


(b) oxo,


(c) Ci-salkoxy,


(d) phenyl-C1-salkoxy,


(e) phenyl,


{f) -CN,


(g) halo,


(h) -CONR9Rls, wherein Ro and Rlo are as defined
above,


(i) -COR9, wherein Ro is as defined above,


(j) -COzR~, wherein R9 is as defined above,


(k) heterocycle, wherein the heterocycle is
as defined


above;
(4) CZ-salkynyl;
(5) phenyl, unsubstitued or substituted with one or more of the
substituent(s) selected from:
(a) hydroxy,
(b) Ci-salkoxy,
(c) C i-salkyl,
(d) C2-salkenyl,
(e) halo,
-CN,
(g) -NOa,
(h) -CFs,


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(i) -(CH2)m-NR9R1~, wherein m, Rs and Rls are as defined
above,
(j) -NR~CORI~, wherein R~ and Rl~ are as defined
above,


(k) -NR9COZRls, wherein R~ and Rz~ are as defined
above,


(1) -CONRsRIa, wherein R9 and Rls are as defined
above,


(m) -COzNR~RIS, wherein R~ and Rls are as defined
above,


(n) -COR9, wherein R~ is as defined above,


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


R2 and R3 are independently selected from the group consisting of:
(1} hydrogen;
(2) Ci-salkyl, unsubstituted or substituted with one or more of the
substituents selected from:
(a) hydroxy,
(b) oxo,
(c) C1-salkoxy,
(d) phenyl-C1-salkoxy,
(e) phenyl,
(fj -CN,
(g} halo,
(h) -NR9Rls, wherein R"~ and Rls are independentlv
selected from:
(i) -NR~CORIS, wherein R9 and Rls are as defined above,
(j) -NR~COzRIS, wherein R9 and R1~ are as defined above,
(k) -CONR~Rls, wherein R~ and Rls are as defined above,
(1) -COR9, wherein R~ i.s as defined above, and
(m) -COzR9, wherein R~ is as defined above;
(3) Cz.salkenyl, unsubstituted or substituted with one or more of the
substituent(s) selected from:
(a) hydroxy,
(b) oxo,


CA 02287487 1999-10-18
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-16-
(c) Ci-salkoxy,


(d) phenyl-C1-salkoxy,


(e) phenyl,


(f) -CN,


(g) halo, .


(h) -CONR9R1~ wherein R9 and Rl~ are as defined
above,


(i) -COR9, wherein R~ is as defined above,


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


(4) C2-salkynyl;


(5) phenyl, unsubstituted or substituted with one or
more of the


substituent(s) selected
from:


(a) hydroxy,


(b) C i-salkoxy,


(c) Ci-salkyl,


(d) Cz-salkenyl,


(e) halo,


(f) -CN,


(g) -NOz


(h) -CFs,


(i) -(CHZ)m-NR9Rls, wherein m, Rs and Rls are
as defined


above,
(j) -NR9COR1~, wherein R9 and Rl~ are as defined
above,


(k) -NR9C02R1~, wherein R9 and Rl~ are as defined
above,


(1) -CONR~Rls, wherein Rs and Rls are as defined
above,


(m) -COaNR9Rl~, wherein R9 and Rl~ are as defined
above,


(n) -CORs, wherein R9 is as defined above,


(o) -COzR~, wherein Rs is as defined above;


and the groups R1 and RZ may be joined together to form a heterocyclic
ring selected from the group consisting of:
(a) pyrrolidinyl,


CA 02287487 1999-10-18
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-17-
(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 l.salkyl,


(ii) oxo,


(iii) Ci-salkoxy,


(iv) -NR~RIS, wherein 1~,~ and Rl~ are as defined
above,


(v) halo, and


(vi) trifluoromethyl;


and the groups RZ and R3 may be joined together to form a carbocyclic ring
selected from the group consisting of:
(a) cyclopentyl,
(b) cyclohexyl,
(c) phenyl,
and wherein the carbocyclic ring is unsubstituted or substituted with one
or more substituents selected from:
(i) C1-salkyl,
(ii) C1-salkoxy,
(iii) -NRsRl~, wherein Fps and Rls are as defined above,
(iv) halo, and
(v) trifluoromethyl;
and the groups R2 and R3 may be joined together to form a heterocyclic
ring selected from the group consisting of:
(a) pyrrolidinyl,


CA 02287487 1999-10-18
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-18-
(b) piperidinyl,


(c) pyrrolyl,


(d) pyridinyl,


(e) imidazolyl,


(f) furanyl,


(g) oxazolyl,


(h) thienyl, and


(i) thiazolyl,


and wherein
the heterocyclic
ring is unsubstituted
or substituted
with one


or more
substituent(s)
selected from:


(i) C1_~alkyl,


(11) OXO,


(iii) Ci.~alkoxy,


(iv) -NR~RI~, wherein R~ and Rl~ 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) -SOZ-;


R4 is selected from the group consisting o~
(1)
R~
i
R'
,Y w
Ra
(2) -Y-C1-salkyl, wherein alkyl is unsubstituted or substituted with
one or more of the substituents selected from:


CA 02287487 1999-10-18
WO 98/47513 PCT/GB98/01161
- 1~ _ _
(a) hydroxy,


(b) oxo,


(c) C1-salkoxy,


(d) phenyl-Ci.3alkoxy,


(e) phenyl,


(fj -CN,


(g) halo,


(h) -NR9R10, wherein 1~,9 and R10 are as defined
above,


(i) -NRsCORIS, wherein R~ and Rls are as defined
above,


(j) -NR9COzRls, wherein R~ and Ri~ are as defined
above,


(k) -CONRsRIS, wherein R9 and R1~ are as defined
above,


(1) -COR9, wherein R~ is as defined above,


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


(3) -Y-CZ.salkenyl,
wherein the a.lkenyl
is unsubstituted
or


substituted with
one or more of
the substituent(s)
selected from:


(a) hydroxy,


(b) oxo,


(c) Ci-salkoxy,


(d) phenyl-Ci-aalkoxy,


(e) phenyl,


(fj -CN,


(g) halo,


(h) -CONRsRIS, wherein R~ and Rls are as defined
above,


(i) -CORs, wherein R~ is as defined above,


(j) -COzR~, wherein Rs is as defined above,


(4) -O(CO)-phenyl,
wherein the phenyl
is unsubstituted
or


substituted with
one or more of
Rs, R7and R8;



Re is selected from the group consisting of:
(1) phenyl, unsubstituted or substituted with one or more of Rll, Riz
and Rls ;


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(2) C1-salkyl, unsubstituted
or substituted
with one or more
of the


substituent(s) selected
from:


(a) hydroxy,


(b) oxo,


(c) C1-salkoxy,


(d) phenyl-Ci-salkoxy,


(e) phenyl,


(fj -CN,


(g) halo,


(h) -NR~RI~, wherein R~ and Rls are as defined
above,


(i) -NR~COR1~, wherein R~ and Rls are as defined
above,


(j) -NR9COzRl~, wherein Rs and Rls are as defined
above,


(k) -CONR9R1~, wherein R9 and Rl~ are as defined
above,


(1) -COR9, wherein R~ is as defined above,


(m) -COaR9, wherein R~ is as defined above;


(3) Cz-salkenyl,
unsubstituted or
substituted with
one or more of
the


substituent(s) selected
from:


(a) hydroxy,


(b) oxo,


(c) C1-salkoxy,


(d) phenyl-C1-salkoxy,


(e) phenyl,


(fj -CN,


(g) halo,


(h) -CONR~RI~, wherein R9 and Rls are as defined
above,


(i) -CORs, wherein Rs is as defined above,


(j) -COaR9, wherein R~ is as defined above;


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



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


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(2) C1-salkyl, unsubstituted
or substituted
with one or more
of the


substituents selected
from:


(a) hydroxy,


(b) oxo,


(c) Ci-salkoxy, __


(d} phenyl-Ci-salkoxy,


(e) phenyl,


(fj -CN,


(g) halo,


(h) -NR9Rlo, wherein Rs and Rla are as defined
above,


(i) -NR9CORla, wherein Rs and Rl~ are as defined
above,


(j) -NR9C02R1~, wherein R9 and RI~ are as defined
above,


(k) -CONR9R1~, wherein R9 and Rl~ are as defined
above,


(1) -COR9, wherein R9 is as defined above, and


(m) -COaRs, wherein R'~ is as defined above;


(3} Ca-salkenyl,
unsubstituted or
substituted with
one or more of
the


substituent(s) selected
from:


(a) hydroxy,


(b) oxo,


(c) C1-salkoxy,


(d) phenyl-Cl.salkoxy,


(e) phenyl,


(fj -CN,


(g) halo,


(h) -CONR9Rlo wherein R9 and Rl~ are as defined
above,


(i) -COR9 wherein Rs is as defined above,


(j) -COZR9, wherein R~ is as defined above;


(4) CZ-salkynyl;


(5) phenyl, unsubstituted or substituted with one or
more of the


substituent(s)
selected from:


(a) hydroxy,




CA 02287487 1999-10-18
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-22-
(b) C 1-salkoxy,


(c) C l.salkyl,


(d) Cz-salkenyl,


(e) halo,


(fj -CN,


(g) -NOa,


(h) -CFs,


(i) -(CH2)m-NR9Rls, wherein m, Rs and Ri~ are
as defined


above,
(j) -NR9CORls, wherein R~ and Rls are as defined
above,


(k) -NRsCOzRI~, wherein R9 and Rla are as defined
above,


(1) -CONR~Rl~, wherein Rs and Ri~ are as defined
above,


(m} -COaNR9Rl~, wherein R9 and Rl~ are as defined
above,


(n) -COR9, wherein R9 is as defined above;


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


(6) halo,


(7) - CN,


(8) - CFs,


(9) - NOz,


(10) -SR14, wherein R14 is hydrogen or Ci-salkyl,


(11) -SOR14, wherein R14 is as defined above,


(12) -SOzRl4, wherein R14 is as defined above,


(13) NR~CORIS, wherein R9 and Rls are as defined above,


(14) CONR~CORl~, wherein R9 and Rl~ are as defined
above,


(15) NR9R1~, wherein R9 and Rl~ are as defined above,


(16) NR~COaRis, wherein R~ and Rl~ are as defined
above,


(17) hydroxy,


(18) Cl.salkoxy,


(19) COR9, wherein R9 is as defined above,


(20) COzRs, wherein R9 is as defined above,




CA 02287487 1999-10-18
WO 98/47513 PCT/GB98/01161
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Rii, Riz and R13 are independently selected from the definitions of R~, R7
and R8, or -OX;
Y is selected from the group consisting of:
(1) a single bond, __
(2) -O-,
(3) -S-,
(4) -CO-,
(5) -CHZ-,
(6) -CHRlb-, and
(7) -CRl5Rm-, wherein Rl~ and ltl~ are independently selected from
the group consisting of:
(a) Ci-salkyl, unsubstii;uted or substituted with one or
more of the substituents selected from:
(i) hydroxy,
(ii) oxo,
(iii) Ci-salkoxy,
(iv) phenyl-C1-salkoxy,
(v) phenyl,
(vi) -CN,
(vii) halo,
(viii) -NR9R1~, wherein R~ and Rl~ are as defined above,
(ix) -NR~COR1~, wherein R~ and Rl~ are as defined above,
(x) -NR~COzRI~, wherein R9 and Rl~ are as defined above,
(xi) -CONR9R1~, wherein R~ and Rl~ are as defined above,
(xii) -CORD, wherein R~ is as defined above, and
(xiii) -COzR~, wherein R'3 is as defined above;
(b) phenyl, unsubstituted or substituted with one or more
of the substituent(s) selected from:
(i) hydroxy,
(ii) C i-salkoxy,


CA 02287487 1999-10-18
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-24-
(iii) C i.salkyl,
(iv) Cz-salkenyl,
(v) halo,
(vi) -CN,
(vii) -N02,
(viii) -CFa,
(ix) -(CH2)m-NR9R1~, wherein m, Rs and Rl~ are as defined
above,
(x) -NR9COR1~, wherein Rs and Rl~ are as defined
above,


(xi) -NR9COZR1~, wherein R9 and Rl~ are as defined
above,


(xii) -CONR9R1~, wherein R9 and Rl~ are as defined
above,


(xiii) -COZNR9R1~, wherein R9 and Rl~ are as defined
above,


(xiv) -COR9, wherein Rs is as defined above,
and


(xv) -COzR~, wherein R9 is as defined above;


Z is selected from:
(1) hydrogen,
(2) Ci-4alkyl, and
(3) hydroxy, with the proviso that if Y is -O-, Z is other than
hydroxy, or if Y is -CHR15-, then Z and R15 may be joined together to form
a double bond.
Particularly preferred compounds of formula (I) are those wherein:
Rl is selected from the group consisting of:
(1) Ci-salkyl, substituted with one or more of the substituents
selected from:
(a) heterocycle, wherein the heterocycle is selected from
the group consisting o~
(A) benzimidazolyl,
(B) imidazolyl,
(C) isoxazolyl,
(D) isothiazolyl,


CA 02287487 1999-10-18
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-25-
(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) C1-salkyl, unsubstituted or substituted
with halo, -CFs,


-OCHa, or phenyl,


(ii) C i-salkoxy,


(iii) oxo,


(1V) th10X0,


(v) cyano,


(Vl) -SCH3,


(vii) phenyl,


(viii) hydroxy,


(ix) trifluoromethyl,


(x) -(CHa)m-NR9Rlo, wherein m is 0, 1 or 2,
and R9 and Rlo


areindependently
selected from:


(I) hydrogen,


(II} C1-salkyl,


(III} hydroxyCl-salkyl, and


(I~ phenyl,


(xi) -NRoCORIO, wherein R9 and Rlo are as defined
above,


and
(xii) -CONRsRlo, wherein R9 and Rlo are as defined above,
R2 and R3 are independently selected from the group consisting of:


CA 02287487 1999-10-18
WO 98/47513 PCT/GB98/01161
-26-
(1) hydrogen;
(2) Ci-salkyl
(3) C2-salkenyl, and
(5) phenyl;
X is -O-;
R4 is
Rs
i
R'
,Y ~ '
Rs
R~ is phenyl, unsubstituted or substituted with halo;
R~, R7 and R8 are independently selected from the group consisting of:
(1) hydrogen,


{2) C1-salkyl,


(3) halo,
and


(4) -CFs;


Y is -O-; and
Z is hydrogen or Cl.4alkyl;
and pharmaceutically acceptable salts thereof.
Particularly preferred compounds of formula (I) are:
4-(3-(1,2, 4-triazolo)methyl)-2(S)-(3, 5-bis(trifluoromethyl)benzyloxy)-3(S)-
phenyl-morpholine;
4-(3-(1,2,4-triazolo)methyl)-2(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3(R)-
phenyl-morpholine;
4-(3-(5-oxo-1H,4H-1, 2,4-triazolo)methyl)-2(S)-(3, 5-
bis(trifluoromethyl)benzyloxy)-3(S)-phenyl-morpholine; and
2-(R)-(1-(R)-(3,5-bis(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.


CA 02287487 1999-10-18
WO 98/47513 PCT/GB98/01161
-27-
Further preferred NK-1 receptor antagonists are those described in
International (PCT) Patent Specification No. WO 95/18124, i.e. compounds
of formula (II):
R'
RZ _
Rsa O O
R3 (II)
sb N i
R i -~~R4
,X
Rs Rs
or a pharmaceutically acceptable salt or prodrug thereof, wherein
R1 is hydrogen, halogen, C1-salkyl, C1-salkoxy, CFs, NOz, CN, SRa,
SORa, SOaRa, COzRa, CONRaRb, CZ.salkenyl, Cz-salkynyl or Ci-4alkyl
substituted by Cl.4alkoxy, where Ra and Rb each independently represent
hydrogen or C1-4alkyl;
R2 is hydrogen, halogen, Cl.salkyl, C1-salkoxy substituted by
C1-4alkoxy or CFs;
R3 is hydrogen, halogen or CF3;
R4 is hydrogen, halogen, Ci-salkyl, Cl.salkoxy, CFs, NOz, CN, SRe,
SORa, SOzRa, C02Ra, CONRaRb, Ca-salkenyl, C2.salkynyl or C1-alkyl
substituted by C1-4alkoxy, where R$ and Rb each independently represent
hydrogen or C1-4alkyl;
R5 is hydrogen, halogen, C1-salkyl, Ci-salkoxy substituted by
C1-4alkoxy or CFs;
Rs is a 5-membered or 6-membe:red heterocyclic ring containing 2 or
3 nitrogen atoms optionally substituted by =O, =S or a Cl.4alkyl group, and
optionally substituted by a group of the formula ZNR7R8 where
Z is C1-salkylene or Cs.scycloalkylene;
R7 is hydrogen, Cl.4alkyl, Cs-~cyc:loalkyl or Cs-7cycloalkylC~_.~alkyl, or
CZ-4alkyl substituted by Ci-4alkoxy or hydroxyl;


CA 02287487 1999-10-18
WO 98/47513 PCT/GB98/01161
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R$ is hydrogen, Ci-4alkyl, Cs_7cycloalkyl or Cs-7cyclo-alkylCi.4alkyl, or
C2-4alkyl substituted by one or two substituents selected from Ci-4alkoxy,
hydroxyl or a 4, 5 or 6 membered heteroaliphatic ring containing one or
two heteroatoms selected from N, O and S;
or R7, R8 and the nitrogen atom to which they are attached form a
heteroaliphatic ring of 4 to 7 ring atoms, optionally substituted by a
hydroxy group, and optionally containing a double bond, which ring may
optionally contain an oxygen or sulphur ring atom, a group S(O) or S(O)z
or a second nitrogen atom which will be part of a NH or NR~ moiety where
R~ is C1-4alkyl optionally substituted by hydroxy or C1-4alkoxy;
or R7, R8 and the nitrogen atom to which they are attached form a
non-aromatic azabicyclic ring system of 6 to 12 ring atoms;
or Z, R7 and the nitrogen atom to which they are attached form a
heteroaliphatic ring of 4 to 7 ring atoms which may optionally contain an
oxygen ring atom;
R~~ and R9b are each independently hydrogen or C1-4alkyl, or Rya and
Rib are joined so, together with the carbon atoms to which they are
attached, there is formed a Cs-7 ring;
X is an alkylene chain of 1 to 4 carbon atoms optionally substituted
by oxo; and
Y is a Ci-4alkyl group optionally substituted by a hydroxyl group;
with the proviso that if Y is Ci-4alkyl, R~ is susbstituted at least by a
group of formula ZNR7R$ as defined above.
Particularly preferred compounds of formula (II) are those of
formula (IIa) and pharmaceutically acceptable salts thereof:


CA 02287487 1999-10-18
WO 98/47513 PCT/GB98/01161
-29-
A'
Y
O O~ I ~ z
C A
N
i
RsiX w s
A
(IIa)
wherein:
A1 is fluorine or CFs;
AZ is fluorine or CFa;
A3 is fluorine or hydrogen;
and X, Y and R~ 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 Spec~cation No. WO 95/23798, i.e. compounds of
formula (III):
Rs
i
R3 X Y w , R'
Rz N . / Z R$ (III)
Rm
(O)a A ,
Ri3 Ria
or a pharmaceutically acceptable salt thereof, wherein:


CA 02287487 1999-10-18
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-30-
RZ and R3 are independently selected from the group consisting of
(1) hydrogen,
(2) Ci-salkyl, unsubstituted or substituted with one or more of the
substituents selected from:
(a) hydroxy,
(b) oxo,
(c) C1-salkoxy,
(d) phenyl-C1-salkoxy,
(e) phenyl,
(f) -CN,
(g) halo,
(h) -NR~Rls, wherein R9 and Rls are independently
selected from:
(i) hydrogen,


(ii) C1-salkyl,


(iii) hydroxy-C1-salkyl, and


(iv) phenyl,


(i) -NR~COR1~, wherein R~ and Rls are as defined
above,


(j) -NR~C02Rls, wherein R9 and R1~ are as defined
above,


(k) -CONR~RIS, wherein Rs and Rls are as defined
above,


(1) -COR9, wherein Rs is as defined above, and


(m) -COzRs, wherein R~ is as defined above;


(3) Cz-salkenyl,
unsubstituted or
substituted with
one or more of
the


substituent(s) selected
from:


(a) hydroxy,


(b) oxo,


(c) Ci-salkoxy,


(d) phenyl-C1-salkoxy,


(e) phenyl,


(f) -CN,


(g) halo,




CA 02287487 1999-10-18
WO 98!47513 PCT/GB98101161
-31-
(h) -CONR9R1~ wherein R9 and Rl~ are as defined
above,


(i) -CORs wherein R9 is as defined above,


(j) -C02R~, wherein R~ is as defined above;


(4) Cz-salkynyl;


(5) phenyl, unsubstituted or substituted with one or
more of the


substituent(s)
selected from:


(a) hydroxy,


(b) C1-salkoxy,


(c) Ci-salkyl,


(d) Cz-salkenyl,


(e) halo,


(f) -CN,


(g} -NO2,


(h) -CFa,


(i) -(CHz)m-NR9R1~, wherein m, Rs and Rl~ are
as defined


above,
(j) -NR9COR1~, wherein Rs and R1~ are as defined
above,


(k) -NR9COzRla, wherein R~ and Rl~ are as defined
above,


(1) -CONR9R1~, wherein R~ and Rl~ are as defined
above,


(m) -C02NRsRl~, wherein Rs and Rl~ are as defined
above,


(n) -COR9, wherein Rs is as defined above,


(o) -COzRs, wherein Rs is as defined above;


and the groups RZ and R3 may be joined together to form a carbocyclic ring
selected from the group consisting of:
(a) cyclopentyl,
(b) cyclohexyl,
- (c) phenyl,
and wherein the carbocyclic ring is unsubstituted or substituted with one
or more substituents selected from:
(i) C 1-salkyl,


CA 02287487 1999-10-18
WO 98147513 PCT/GB98/01161
-32-
(ii) Ci-salkoxy,
(iii) -NR~RIS, wherein R~ and Rls are as defined above,
(iv) halo, and
(v) trifluoromethyl;
and the groups
RZ and R3
may be joined
together to
form a heterocyclic


ring selected
from the group
consisting
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) Ci-salkyl,


(ii) oxo,


(iii) C1-salkoxy,


(iv) -NReRI~, wherein Rs and Rls are as defined
above,


(v) halo, and


(vi) trifluoromethyl;


Rs, R7 and R8 are independently selected from the group consisting of:
(1) hydrogen;
(2) Cl.salkyl, unsubstituted or substituted with one or more of the
substituents selected from:
(a) hydroxy,
(b) oxo,


CA 02287487 1999-10-18
WO 98/47513 PCT/GB98/01161
-33-
(c) C i-salkoxy,


(d) phenyl-C1-salkoxy,


(e) phenyl,


. (fj -CN,


(g) halo, _.


(h) -NR,sg,io, wherein R~ and Rls are as defined
above,


(i) -NR9COR1~, wherein Rs and Rl~ are as defined
above,


(j) -NR9C02R1o, wherein Rs and Rl~ are as defined
above,


(k) -CONR9Rlo, wherein R9 and Rla are as defined
above,


(1) -CORs, wherein Rs is as defined above, and


(m) -COaRs, wherein Rs is as defined above;


(3) Cz-salkenyl, unsubstituted
or substituted with one
or more of the


substituent(s) selected from:


(a) hydroxy,


(b) oxo,


(c) C l.salkoxy,


(d) phenyl-C1-salkoxy,


(e) phenyl,


(f) -CN,


(g) halo,


(h) -CONR9R1~ wherein Rs and Rls are as defined
above,


(i) -CORs wherein R9 is as defined above,


(j) -C02Rs, wherein R'~ is as defined above;


(4) Cz-salkynyl;


(5) phenyl, unsubstituted or substituted with one or
more of the


substituent(s) selected from:


(a) hydroxy,


(b) C1-salkoxy,


(c) Ci-salkyl,


(d) Ca.salkenyl,


(e) halo,




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WO 98/47513 PCTlGB98/01161
- 34 - -
(~ -CN,
(g) -NOz,
(h) -CFs,
(i) -(CHz)m-NR9Rls, wherein m, Rs and Rl~ are as defined
above,
(j) -NR9COR1~, wherein R9 and Rl~ are as defined
above,


(k) -NR~COaRi~, wherein R9 and Rls are as defined
above,


(1) -CONR9R1~, wherein R9 and R1~ are as defined
above,


(m) -COzNR9Rl~, wherein R9 and Rl~ are as defined
above,


(n) -COR9, wherein R~ is as defined above,


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


(6) halo,


(7) -CN,


(8) -CFs,


(9) -NOz,


(10) -SR14, wherein R14 is hydrogen or Cl.salkyl,


(I1) -SOR14, wherein R14 is as defined above,


(12) -SOzRl4, wherein R14 is as defined above,


(13) NR9COR1~, wherein Rs and Rl~ are as defined above,


(14) CONR9CORls, wherein R~ and Rls are as defined
above,


(15) NR9R1~, wherein R9 and Rl~ are as defined above


,


(16) NR9C02R1~, wherein R9 and Rl~ are as defined above,


(17) hydroxy,


(18) Ci-salkoxy,


{19) COR9, wherein R9 is as defined above,


(20) COzR9, wherein R~ is as defined above,


(21) 2-pyridyl,


(22) 3-pyridyl,


(23) 4-pyridyl,


(24) 5-tetrazolyl,


(25) 2-oxazolyl, and




CA 02287487 1999-10-18
WO 98/47513 PCT/GB98/01161
-35-
(26) 2-thiazolyl;
Rll, R12 and R13 are independently selected from the definitions of Rs, R7
and R8, or -OX;
_.


A is selected from the group consisting of:


(1) C1-salkyl, unsubstituted
or substituted
with one or more
of the


substituents selected
from:


(a) hydroxy,


to (b) oxo,


(c) C1-salkoxy,


(d) phenyl-C1-3alkoxy,


(e) phenyl,


(f) -CN,


(g) halo, wherein halo i.s fluoro, chloro, bromo
or iodo,


(h) -NR9R1~, wherein R~ and Rl~ are as defined
above,


(i) -NR9COR1~, wherein R~ and Rl~ are as defined
above,


(j) -NR~COzRI~, wherein R~ and Rl~ are as defined
above,


(k) -CONR9R1~, wherein R9 and Rl~ are as defined
above,


(1) -CORD, wherein Rs :is as defined above, and


(m) -COzR~, wherein R~ is as defined above;


(2) C2-salkenyl,
unsubstituted or
substituted with
one or more of
the


substituent(s) selected
from:


(a) hydroxy,


(b) oxo,


(c) Cl.salkoxy,


(d) phenyl-C1-salkoxy,


(e) phenyl,


(fj -CN,


(g) halo,




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WO 98/47513 PCT/GB98/01161
- 36 - -
(h) -CONR9R1~ wherein R~ and R1~ are as defined above,
(i) -CORD wherein R~ is as defined above, and
(j) -COzR~, wherein R~ is as defined above; and
(3) C2-salkynyl;
B is a heterocycle, wherein the heterocycle is selected from the group
consisting of:
N N 'X X~ g X~ H
N-N N-N N-N
N O ~N~O WN~O WN~S
X H
N_~ X
N-N N-N _ X
S ~ S / O,X N N
X ~N~S X
~1 N
N-N
N_NX ~_~ ~ N / ,N
N N ~N.
N i
X X X


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WO 98/47513 PCT/GB98/01161
-37-
X ~ X
N=N ' '
,N- / N~ ~C / N
N X ~~C N
X
rHr ~ / ' _.
.~~ / .X / X -
N S ~ ~ . ~ S- N
X N N X
-~N,X N ~~ N
X N X
1
N N~ N
i i i
X X X
and wherein the heterocycle may be substituted in addition to -X with one
or more substituent(s) selected from:
(i) C1-salkyl, unsubstituted or substituted with halo, -CFs,
-OCHs, or phenyl,


(ii) C i.calkoxy,


(iii) oxo,


(iv) hydroxy,


(v) thioxo,


(vi) -SRo, wherein R9 is as defined above,


(vii) halo,


(viii) cyano,


. (ix) phenyl,


(x) trifluoromethyl,


(xi) -(CHz)m-NR9Rlo, wherein m is 0, 1 or 2,
and R~ and Rlo


are as defined above,





CA 02287487 1999-10-18
WO 98/47513 PCT/GB98/01161
-3 - _
(xii) -NR9COR1~, wherein R9 and Rl~ are as defined above,
(xiii) -CONR9R1~, wherein R9 and Rl~ are as defined above,
(xiv) -COZR9, wherein R~ is as defined above, and
(xv) -(CH2)m-OR9, wherein m and R9 are as defined above;
pis0orl;
X is selected from:
(a) -PO(OH)O- ~ M+, wherein M+ is a pharmaceutically
acceptable monovalent counterion,
(b) -PO(O-)2 ~ 2M+,
(c) -PO(O-)2 ~ D2+, wherein DZ+ is a pharmaceutically acceptable
divalent counterion,
(d) -CH(R4)-PO(OH)O- ~ M+, wherein R4 is hydrogen or Ci-aalkyl,
(e) -CH(R,4)-PO(O-)2 ~ 2M+,
(fj -CH(R4)-PO(O-)a ~ DZ+~
(g) -SOs- ~ M+,
(h) -CH(R4)-SOs- ~ M+,
(i) -CO-CH2CHz-C02- ~ M+,
(j) -CH(CHs)-O-CO-R5, wherein R~ is selected from the group
consisting o~

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WO 98/47513 PCT/GB98/01161
-39-
( ) \ O ~~ NH3+ M
HZ+ M.
(u) \O~.N.Rs
\O~COZ M+
CO 2 M+
(iv) \ O CO . M+
2 '
\ ~~ COa
(v) O
NH3
C02 M+
(vi) - O ' CO2 M
COZ M+
COZ M+
(vii) ~ O ~ ( ; and
\
(k} hydrogen, with the proviso that if p is 0 and none of Rll, Riz
or R13 are -OX, then X is other than hydrogen;
Y is selected from the group consisting of:
(1) a single bond,
(2) -O-,
(3) -S-,
(4) -CO-,


CA 02287487 1999-10-18
WO 98/47513 PCT/GB98/01161
-40-
(5) -CHz-,


(6) -CHR15- , and


(7) -CRlSRIS_, wherein
Rls and Rls are independently
selected from


the group consisting
of


(a) C1-salkyl, unsubstituted
or substituted with
one or more of


the substituents selected
from:


(i) hydroxy,


(ii) oxo,


(iii) C1-salkoxy,


{iv) phenyl-C1-salkoxy,


(v) phenyl,


(vi) -CN,


(vii) halo,


(viii) -NR9R1~, wherein Rs and RIS are as defined
above


,


(ix) -NR~CORl~, wherein R9 and Rls are as defined
above,


(x) -NR9COzRls, wherein Rs and Rl~ are as defined
above,


(xi) -CONR9R1~, wherein Rs and R1~ are as defined
above,


(xii) -COR9, wherein R~ is as defined above, and


(xiii) -COzR~, wherein Rs is as defined above;


(b) phenyl, unsubstituted
or substituted with
one or more of the


substituent(s) selected
from:


(i) hydroxy,


(ii) C1-salkoxy,


(iii) C1-salkyl,


(iv) Cz-salkenyl,


(v) halo,


(vi) -CN,


(vii) -NOz,


(viii) -CFs,


(ix) -(CHz)m-NRgRIS, wherein m, R~ and Rls are as
defined


above,


CA 02287487 1999-10-18
WO 98/47513 PCT/GB98101161
-41-
(x) -NRsCORIa, wherein Rs and Rl~ are as defined above,
(xi) -NR9C02R1~, wherein Rs and Rls are as defined above,
(xii) -CONR9R1~, wherein Rs and Rl~ are as defined above,
(xiii) -C02NR9R1~, wherein R9 and Rl~ are as defined above,
(xiv) -CORD, wherein R~ :is as defined above, and _
(xv) -COzR9, wherein R~ is as defined above;
Z is selected from:
(1) hydrogen,
(2) Cl.salkyl, and
(3) hydroxy, with the proviso that if Y is -O-, Z is other than
hydroxy, or if Y is -CHRI~-, then Z and R15 may be joined together to form
a double bond.
Particularly preferred compounds of formula (III) are those wherein:
Rz and R3 are independently selected from the group consisting o~
(1) hydrogen,
(2) Cl.salkyl,
(3) Cz-salkenyl, and
(4) phenyl;
Rs, R7 and R$ are independently selected from the group consisting o~
(1) hydrogen,
(2) C1-salkyl,
(3) fluoro,
(4) chloro,
(5) bromo,
(6) iodo, and
(7) -CFa;
Rll, Rlz and R13 are independently selected from the group consisting of:
(1) fluoro,
(2) chloro,
(3) bromo, and


CA 02287487 1999-10-18
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-42-
(4) iodo;
A is unsubstituted i-salkyl;
B is selected from the group consisting o~
N- N X X, X
N N N-~ N-N . _
N O ~N~O WN~O WN~S
X H
N_~ X
N-N N-N _ X
N S ~ S ~ O,X N N X
X H N ~N S.
N-NX ~ , ~ N
N N
N X X
X N X
/ N ~~O / N
N
H X H S
H
/ N\ X / N X
N S ~~~0, ~~~S,
N N
X
pis0orl;
X is selected from:
(a) -PO(OH)O- ~ M+, wherein M+ is a pharmaceutically
acceptable monovalent counterion,
(b) -PO(O-)z ~ 2M+,
(c) -PO(O-)z ' D2+, wherein D2+ is a pharmaceutically acceptable
divalent counterion,
(d) -CH(R4)-PO(OH)O- ~ M+, wherein R~ is hydrogen or Ci-salkyl,

CA 02287487 1999-10-18
WO 98147513 PCT/GB98/01161
- 43 -
(e) -CH(R4)-PO(O-)z ~ 2M+,
(f) -CH(R4)-PO(O-)z ~ Dz+,
(i) -CO-CH2CHz-COz- ~ M+,
(j) -CH(CHs)-0-CO-R5, wherein R5 is selected from the group
consisting of: -
(i) ~ O ~. NH 3+ M- ,
HZ+ M-
\O~~N~OH
\O~CC)2 M+ ,
CGZ M+
(iv) ~ O CCI - M+
2
~O~.CO2
(V) ,
NFC3
C02 M+
(vi) -O C02-M+
COZ- M+
CC)2 M+
(vii) ~O ~ I ; and
Y is -0-;
Z is hydrogen or Ci-calkyl;
and pharmaceutically acceptable salts thereof.


CA 02287487 1999-10-18
WO 98/47513 PCT/GB98/01161
-44-
Particularly preferred compounds of formula (III) include:
(1) 2-(S)-(3,5-bis(tri.fluoromethyl)benzyloxy)-3-(S)-phenyl-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-
(ethoxycarbonyloxy-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(trifiuoromethyl)phenyl)ethoxy)-3-(S)-(4-
fluorophenyl)-4-(3-(1-monophosphoryl-5-oxo-4H-1, 2, 4-
triazolo)methyl)morpholine;
and pharmaceutically acceptable salts thereof.
Further preferred NK-1 receptor antagonists are those described in
European Patent Specification No. WO 96/05181, i.e. compounds of
formula (I~:


CA 02287487 1999-10-18
WO 98/47513 PCT/GB98101161
-45-
Rl
//
R2
Y
R9a O O Rs
R9b / ~~ __
N
-~ R4
s
R
X
wherein
X is a group of the formula NRsR7 or a C- or N-linked imidazolyl
ring;
Y is hydrogen or C1-4alkyl optionally substituted by a hydroxy
group;
Rl is hydrogen, halogen, C1-salkyl, Cl.salkoxy, CFs, NOa, CN, SRa,
SORa, SOaRa, C02Ra, CONRaRb, CZ-salkenyl, Cz-salkynyl or Ci-9alkyl
substituted by C1-4alkoxy, wherein Ra and Rb each independently represent
hydrogen or Ci-4alkyl;
RZ is hydrogen, halogen, C1-salkyl, Ci.salkoxy substituted by
C1-4alkoxy or CFs;
R3 is hydrogen, halogen or CFs;
R4 is hydrogen, halogen, Cl.salkyl, C1-salkoxy, hydroxy, CFs, N02,
CN, SRa, SORB, SOzRa, C02Ra, CONRaRb, Cz-salkenyl, Ca.salkynyl or
C1-4alkyl substituted by C1-4alkoxy, wherein R$ and Rb are as previously
defined;
R5 is hydrogen, halogen, Ci-salkyl, C1-salkoxy substituted by
Ci-4alkoxy or CFa;
Rs is hydrogen, C1-salkyl, Cs-7cycloalkyl, Cs-7cycloalkylCi-4alkyl,
phenyl, or Ca.4alkyl substituted by Ci-4alkoxy or hydroxy;
R7 is hydrogen, C1_salkyl, Cs-7cycloalkyl, Cs-~cycloalkylCl-nalkyl,
phenyl, or Ca.4alkyl substituted by one or two substituents selected from


CA 02287487 1999-10-18
WO 98147513 PCT/GB98/01161
-46-
C1-aalkoxy, hydroxy or a 4, 5 or 6 membered heteroaliphatic ring
containing one or two heteroatoms selected from N, O and S;
or R~ and R7, together with the nitrogen atom to which they are
attached, form a saturated or partially saturated heterocyclic ring of 4 to 7
ring atoms, which ring may optionally contain in the ring one oxygen-or
sulphur atom or a group selected from NRB, S(O) or S(O)a and which ring
may be optionally substituted by one or two groups selected from
hydroxyCl-4alkyl, C1-4alkoxyCl-4alkyl, oxo, CORa or COaRa where Ra is as
previously defined;
or R6 and R7 together with the nitrogen atom to which they are
attached, form a non-aromatic azabicyclic ring system of 6 to 12 ring
atoms;
R8 is hydrogen, C1-4alkyl, hydroxyCi-4alkyl or C1-4alkoxyCi-4alkyl;
and
R9a and R9b are each independently hydrogen or C1-4alkyl, or Rya and
R9b are joined so, together with the carbon atoms to which they are
attached, there is formed a Cs-7 ring;
and pharmaceutically acceptable salts thereof.
Particularly preferred compounds of formula (IV) are those of
formula (IVa) and pharmaceutically acceptable salts thereof:
A'
i
z
A
O O
IVa
N
w A3
X
wherein
A1 is fluorine or CFs;


CA 02287487 1999-10-18
WO 98/47513 PCT/GB98/01161
-47-
A2 is fluorine or CFs;
A3 is fluorine or hydrogen; ,
and X and Y are as defined in relation t,o formula (I).
Specific compounds of formula (I'~ of use in the present invention
include:
2-(R)-(1-(R)-(3, 5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-
4-(4-morpholinobut-2-yn-yl)morpholine;;
2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(4-N,N-
dimethylaminobut-2-yn-yl)-3-(S)-(4-fluorophenyl)morpholine;
4-(4-azetidinylbut-2-yn-yl)-2-(R)-(1-(R)-1;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)morphaline;
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(trifluoromethyl)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-fluarophenyl)-2-(R}-(1-(R)-(3-fluoro-5-(trifluoromethyl)phenyl)
ethoxy)-4-(4-morpholinobut-2-yn-yl)morpholine;
3-(S)-(4-fluorophenyl)-4-(4-morpholinob ut-2-yn-yl)-2-(R)-(1-(R)-(3-
(trifluoromethyl)phenyl)ethoxy)morpholine;
4-(4-azetidinylbut-2-yn-yl}-3-(S)-(4-fluorophenyl}-2-(R)-(1-(R)-(3-
(trifluoromethyl)phenyl)ethoxy)morpho:line;
2-(R)-{1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(4-(N-(2-
methoxyethyl)-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;


CA 02287487 1999-10-18
WO 98/47513 PCT/GB98/01161
-48-
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-
dimethylamino)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)morphoiine;
4-(4-(7-azabicyclo[2.2.1]heptano)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)-4-(4-
diisopropylaminobut-2-yn-yl)-3-(S)-(4-fluorophenyl)morpholine;
2-(R)-(1-(R)-(3-fluoro-5-(trifluoromethyl)phenyl)ethoxy)-4-(4-(2-(S)-
(methoxymethyl)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 (~:
R'
Ra Ri
W N R3
Y ~ (VI
R2
N
R5
Re- (~)
Is


CA 02287487 1999-10-18
WO 98/47513 PCT/GB98/01161
-49~-
or a pharmaceutically acceptable salt thereof, wherein
Y is (CH2)n wherein n is an integer from 1 to 4, and wherein any one
of the carbon-carbon single bonds in said (CHz)n may optionally be
replaced by a carbon-carbon double bond, and wherein any one of the
carbon atoms of said (CHa)n may optionally be substituted with R4, an~i
wherein any one of the carbon atoms of said (CHa)n may optionally be
substituted with R7;
Z is (CHz)m wherein m is an integer from 0 to 6, and wherein any
one of the carbon-carbon single bonds of (CHz)m may optionally be replaced
by a carbon-carbon double bond or a carbon-carbon triple bond, and any
one of the carbon atoms of said (CHz)m may optionally be substituted with
R8~
Rl is hydrogen or C1-aalkyl optionally substituted with hydroxy,
C1-4alkoxy or fluoro;
RZ is a radical selected from hydrogen, C1-s straight or branched
alkyl, Cs-7cycloalkyl wherein one of the CHz groups in said cycloalkyl may
optionally be replaced by NH, oxygen or sulphur; aryl selected from phenyl
and naphthyl; heteroaryl selected from i.ndanyl, thienyl, furyl, pyridyl,
thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl and
quinolyl; phenyl-Cz-salkyl, benzhydryl and benzyl, wherein each of said
aryl and heteroaryl groups and the phenyl moieties of said benzyl, phenyl -
Cz-salkyl and benzhydryl may optionally be substituted with one or more
substituents independently selected from halo, nitro, C1-s alkyl, Cl.salkoxy,
trifluoromethyl, amino, C1-salkylamino, Cl.salkyl-O-CO, C1-salkyl-O-CO-
C1-salkyl, C1-salkyl-CO-O, C1-salkyl-CO-Ci-salkyl-O-, Cl.salkyl-CO,
Ci_salkyl-CO-C1-salkyl-, di-C1-salkylamino, -CONH-Ci-salkyl,
C1-salkyl-CO-NH-C1-salkyl, -NHCOH and -NHCO-Cl.salkyl; and wherein
one of the phenyl moieties of said benzhydryl may optionally be replaced
by naphthyl, thienyl, furyl or pyridyl;
R5 is hydrogen, phenyl or Cl.salkyl;


CA 02287487 1999-10-18
WO 98/47513 PCT/GB98/01161
-50-
or Rz and Rs together with the carbon to which they are attached,
form a saturated ring having from 3 to 7 carbon atoms wherein one of the
CHZ groups in said ring may optionally be replaced by oxygen, NH or
sulfur;
R3 is aryl selected from phenyl and naphthyl; heteroaryl selected
from indanyl, thienyl, furyl, pyridyl, thiazolyl, isothiazolyl, oxazolyl,
isoxazolyl, triazolyl, tetrazolyl and quinolyl; and cycloalkyl having 3 to 7
carbon atoms wherein one of the (CHz) groups in said cycloalkyl may
optionally be replaced by NH, oxygen or sulphur;
wherein each of said aryl and heteroaryl groups may optionally be
substituted with one or more substituents, and said Cs-7cycloalkyl may
optionally be substituted with one or two substituents, each of said
substituents being independently selected from halo, nitro, Cl.salkyl,
Cl.salkoxy, trifluoromethyl, amino, C1-salkylamino, -CO-NH- C1-salkyl,
Ci-salkyl-CO-NH-C1-salkyl, -NHCOH and -NHCO-Ci-salkyl;
R4 and R7 are each independently selected from hydroxy, halogen,
halo, amino, oxo, cyano, methylene, hydroxymethyl, halomethyl,
C1_salkylamino, di-Ci-salkylamino, C1-salkoxy, C1-salkyl-O-CO,
Ci.salkyl-O-CO-C1-salkyl, Cl.salkyl-CO-O, Cl.salkyl-CO-Ci-salkyl-O-,
C1-salkyl-CO-, C1-salkyl-CO-Cl.salkyl, and the radicals set forth in the
definition of R2;
Rs is -NHCOR~, -NHCHzR9, SOzRB or one of the radicals set forth in
any of the definitions of R2, R4 and R7;
R8 is oximino (=NOH) or one of the radicals set forth in any of the
definitions of R2, R4 and R7;
R~ is C1-salkyl, hydrogen, phenyl or phenylCl-salkyl;
with the proviso that (a) when m is 0, R8 is absent, (b) when R4, Rs, R~ or
R8 is as defined in Rz, it cannot form together with the carbon to which it
is attached ,a ring with R5, and (c) when R4 and R~ are attached to the
same carbon atom, then either each of R4 and R7 is independently selected
from hydrogen, fluoro and C1-salkyl, or R~ and R~, together with the carbon


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to which they are attached, for a Cs.s sai;urated carbocyclic ring that forms
a spiro compound with the nitrogen-containing ring to which they are
attached.
A particularly preferred compound of formula (~ is (2S,3S)-cis-3-(2-
methoxybenzylamino)-2-phenylpiperidine; or a pharmaceutically
acceptable salt thereof.
Another class of NK-1 receptor antagonists of use in the present
invention is that described in International Patent Specification No. WO
93/21155, i.e. compounds of formula (VI):
R R
O
NCH-R1 (VI)
Rs Iz
R
R3 R'
or a pharmaceutically acceptable salt thereof, wherein
radicals R are phenyl radicals optionally 2- or 3-substituted by a
halogen atom or a methyl radical;
Rl is optionally substituted phenyl, cyclohexadienyl, naphthyl,
indenyl or optionally substituted heterocycle;
RZ is H, halogen, OH, alkyl, aminoalkyl, alkylaminoalkyl,
dialkylaminoalkyl, alkyloxy, alkylthio, acyloxy, carboxy, optionally
substituted alkyloxycarbonyl, benzyloxycarbonyl, amino or acylamino;
R3 is optionally 2-substituted phenyl;
R4 is OH or fluorine when R5 is H;
or R4 and R5 are OH ;
or R~ and R5 together form a bond.
A particularly preferred compound of formula (VI) is (3aS, 4S, 7aS)-
7,7-diphenyl-4-(2-methoxyphenyl)-2-[(2S)-(2-methoxyphenyl)propionyl]
perhydroisoindol-4-0l; or a pharmaceutically acceptable salt thereof.


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Another class of NK-1 receptor antagonists of use in the present
invention is that described in European Patent Specification No.
0 591 040, i.e. compounds of formula (VII):
R Q
Ar-T-CO-~-CH2-~-CHZ-CHZ-Am +, A - (VII)
__
Are
wherein
Ar represents an optionally substituted mono-, di- or tricyclic
aromatic or heteroaromatic group;
T represents a bond, a hydroxymethylene group, a
C1-4alkoxymethylene group or a Ci-salkylene group;
Ar' represents a phenyl group which is unsubstituted or substituted
by one or more substituents selected from halogen, preferably chlorine or
fluorine, trifluoromethyl, C1-4alkoxy, Ci-4alkyl where the said substituents
may be the same or different; a thienyl group; a benzothienyl group; a
naphthyl group; or an indolyl group;
R represents hydrogen, C1-4alkyl, w-C1-4alkoxyCl-4alkyl, or
cu-Cz-4alkanoyloxyC2-4alkyl;
Q represents hydrogen;
or (a and R together form a 1,2-ethylene, 1,3-propylene or 1,4-
butylene group;
Am+ represents the radical
~.z---N
3
in which Xi, X2 and Xs, together with the nitrogen atom to which they are
attached, form an azabicyclic or azatricyclic ring system optionally
substituted by a phenyl or benzyl group; and
A- represents a pharmaceutically acceptable anion.


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A particularly preferred compound of formula (VII) is (+) 1-[2-[3-
(3,4-dichlorophenyl)-1-[(3-isopropoxyphenyl)acetyl]-3-piperidinyl]ethyl]-4-
phenyl-1-azabicyclo[2,2,2]octane; or a pharmaceutically acceptable salt,
especially the chloride, thereof.
Another class of NK-1 receptor antagonists of use in the presenf
invention is that described in European Patent Specification No.
0 532 456, i.e. compounds of formula (VIII):
R3
Rl--N X -X -Ra (VIII)
a i
R Xi
or a pharmaceutically acceptable salt thereof, wherein
R1 represents an optionally substituted aralkyl, aryloxyalykl,
heteroaralkyl, aroyl, heteroaroyl, cycloalkylcarbonyl, aralkanoyl,
heteroarylalkanoyl, aralkoxycarbonyl or arylcarbamoyl group or the acyl
group of an a-amino acid optionally N-substituted by a lower alkanoyl or
carbamoyl-lower alkanoyl group;
RZ represents cycloalkyl or an optionally substituted aryl or
heteroaryl group;
R3 represents hydrogen, alkyl, carbamoyl or an alkanoyl or alkenoyl
group optionally substituted by carboxy or esterified or amidated carboxy;
R4 represents an optionally substituted aryl group or an optionally
partially saturated heteroaryl group;
Xl represents methylene, ethylene, a bond, an optionally ketalised
carbonyl group or an optionally etherified hydroxymethylene group;
X2 represents alkylene, carbonyl gar a bond; and
Xs represents carbonyl, oxo-lower alkyl, oxo(aza)-lower alkyl, or an
alkyl group optionally substituted by phenyl, hydroxymethyl, optionally
esterified or amidated carboxy, or (in other than the a-position) hydroxy.
A particularly preferred compound of formula (VIII) is (2R*, 4S*)-2-
benzyl-1-(3, 5-dimethylbenzoyl}-N-(4-qui.nolinylmethyl)-4-piperidineamine;
or a pharmaceutically acceptable salt thereof.


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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)
i \
a /
CHz
R3
R1-Y-A- N -1---CONHCHCON ~ (IX)
R"
or a pharmaceutically acceptable salt thereof, wherein
RI is aryl, or a group of the formula:
i
\ ,x
z
X is CH or N; and
Z is O or N-Rb, in which R5 is hydrogen or lower alkyl;
R2 is hydroxy or lower alkoxy;
R3 is hydrogen or optionally substituted lower alkyl;
R4 is optionally substituted ar(lower)alkyl;
A is carbonyl or sulfonyl; and
Y is a bond or lower alkenylene.
A particularly preferred compound of formula (IX) is the compound
of formula (IXa)
HO
O
N \ ~
_N
(IXa)
O CH3 \
O
N
H3C/


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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)
,~~~ ~~ g,' __
N J.,,. R
H
(X)
or a pharmaceutically acceptable salt thereof, wherein
Rl is aryl selected from indanyl, phenyl and naphthyl; heteroaryl
selected from thienyl, furyl, pyridyl and quinolyl; and cycloalkyl having 3
to 7 carbon atoms, wherein one of said carbon atoms may optionally be
replaced by nitrogen, oxygen or sulfur; wherein each of said aryl and
heteroaryl groups may optionally be substituted with one or more
substituents, and said Ca-7cycloalkyl may optionally be substituted with
one or two substituents, said substituents being independently selected
from chloro, fluoro, bromo, iodo, nitro, Ci.loalkyl optionally substituted
with from one to three fluoro groups, Cl..loalkoxy optionally substituted
with from one to three fluoro groups, amino, Ci-ioalkyl-S-, Ci-ioalkyl-S(O)-,
C1-loalkyl-SOa-, phenyl, phenoxy, Cl.ioalkyl-SOzNH-,
Ci-ioalkyl-SOzNH-C1-loakyl-, C1-loalkyla:mino-diCl-ioalkyl-, cyano, hydroxy,
cycloalkoxy having 3 to 7 carbon atoms, Ci.calkylamino, C1-sdialkylamino,
HC(O)NH- and Cl.loalkyl-C(O)NH-; and
Rz is thienyl, benzhydryl, naphth;yl or phenyl optionally substituted
with from one to three substituents independently selected from chloro,
bromo, fluoro, iodo, cycloalkoxy having 3 to ? carbon atoms, C1-ioalkyl
optionally substituted with from one to three fluoro groups and Ci-loalkoxy
optionally substituted with from one to three fluoro groups.
A particularly preferred compound of formula (X) is (2S,3S)-3-(2-
methoxy-5-trifluoromethoxybenzyl)-ami.no-2-phenylpiperidine; or a
pharmaceutically acceptable salt thereof.


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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)
R2
(CHa)X ._
N ~ i
R
R~
N
H
4
R
R5
(XI)
or a pharmaceutically acceptable salt thereof, wherein
R1 is a C1-4alkoxy group;
RZ 1S
6
N
N
N-N '
R3 is a hydrogen or halogen atom;
R4 and R~ may each independently represent a hydrogen or halogen
atom, or a Ci-4alkyl, C1-4alkoxy or trifluoromethyl group;
R~ is a hydrogen atom, a C1-4alkyl, (CHz)mcyclopropyl, -S(O)"C1_
aalkyl, phenyl, NR7R8, CHzC(O)CFs or trifluoromethyl group;
R7 and R$ may each independently represent a hydrogen atom, or a
Ci-4alkyl or acyl group;
x represents zero or 1;
n represents zero, 1 or 2; and
m represents zero or 1.
Particularly preferred compounds of formula (~I) are (2-methoxy-5-
tetrazol-1-yl-benzyl)-([2S,3S]-2-phenyl-piperidin-3-yl)-amine; and [2-
methoxy-5-(5-trifluoromethyl-tetrazol-1-yl)-benzyl]-([2S,3S]-2-phenyl-
piperidin-3-yl)-amine; or a pharmaceutically acceptable salt thereof.


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Another class of tachykinin antagonists of use in the present
invention is that described in International Patent Specification No. WO
95/14017, i.e. compounds of formula (XII)
R$ R4
R- (CHZ)n- C - CHZ - N- (CH2)o- R3 __
NH R
(CO)P
(CH2)m
Rl (XII)
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, C1-salkoxy,
trifluoromethyl, C1-4alkyl, phenyl-Ci-salkoxy, or C1-4alkanoyl groups;
Rl is trityl, phenyl, diphenylmethyl, phenoxy, phenylthio,
piperazinyl, piperidinyl, pyrrolidinyl, m.orpholinyl, indolinyl, indolyl,
benzothienyl, hexamethyleneiminyl, benzofuranyl, tetrahydropyridinyl,
quinolinyl, isoquinolinyl, reduced quinolinyl, reduced isoquinolinyl,
phenyl-(Ci-4alkyl)-, phenyl-(C1-4alkoxy)-, quinolinyl-(Ci-4alkyl)-,
isoquinolinyl-(C1-4alkyl)-, reduced quniolinyl-(Ci-4alkyl)-, reduced
isoquinolinyl-(C1-4alkyl)-, benzoyl-(Ci-salkyl)-, Ci.4alkyl, or -NH-CHa-R5;
any one of which Rl groups may be substituted with halo, C1-4alkyl,
C1-4alkoxy, trifluoromethyl, amino, Cl.4alkylamino, di(C1-4alkyl)amino, or
C2-4alkanoylamino;
or any one of which Rl groups may be substituted with phenyl,
piperazinyl, Cs.acycloalkyl, benzyl, Ci-4alkyl, piperidinyl, pyridinyl,


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pyrimidinyl, Cz-~alkanoylamino, pyrrolidinyl, Cz-calkanoyl, .or
C1-4alkoxycarbonyl;
any one of which groups may be substituted with halo, Ci-alkyl,
C1-4alkoxy, trifluoromethyl, amino, Ci-4alkylamino, di{Ci-4alkyl)amino, or
Cz-4alkanoylamino;
or Rl is amino, a leaving group, hydrogen, C1-4alkylamino, or
di(C1-4alkyl)amino;
R5 is pyridyl, anilino-(C1-salkyl)-, or anilinocarbonyl;
R2 is hydrogen, C1-4alkyl, Ci_4alkylsulfonyl, carboxy-(C1-salkyl)-,
C1-aalkoxycarbonyl-(C1-salkyl)-, or -CO-R6;
R~ is hydrogen, C1-4alkyl, Ci-shaloalkyl, phenyl, Ci-salkoxy,
Ci-shydroxyalkyl, amino, Ci-4alkylamino, di(Ci-aalkyl)amino, or -(CHa)Q-R~;
q is zero to 3;
R7 is carboxy, C1-4alkoxycarbonyl, C1-4alkylcarbonyloxy, amino,
Ci-4alkylamino, di(Ci-4alkyl)amino, Ci-calkoxycarbonylamino, or phenoxy,
phenylthio, piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, indolinyl,
indolyl, benzothienyl, benzofuranyl, quinolinyl, phenyl-(Ci-4alkyl)-,
quinolinyl-(Ci.4alkyl)-, isoquinolinyl-(Ci-4alkyl)-, reduced quinolinyl-
(Ci-4alkyl)-, reduced isoquinolinyl-(Cl.4alkyl)-, benzoyl-Ci.salkyl;
any one of which aryl or heterocyclic R7 groups may be substituted
with halo, trifluoromethyl, C1-4alkoxy, C1-4alkyl, amino, Ci-4alkylamino,
di(C1-4alkyl)amino, or Cz-4alkanoylamino;
or any one of which R7 groups may be substituted with phenyl,
piperazinyl, Cs-scycloalkyl, benzyl, piperidinyl, pyridinyl, pyrimidinyl,
pyrrolidinyl, Cz-ealkanoyl, or Ci-4alkoxycarbonyl;
any of which groups may be substituted with halo, trifluoromethyl,
amino, C1-4alkoxy, C1-4alkyl, C1-4alkylamino, di(C1-4alkyl)amino, or
C2-~alkanoylamino;
Rs is hydrogen or Ci-alkyl;
R3 is phenyl, phenyl-(C1-alkyl)-, Cs-scycloalkyl, C~-scycloalkenyl,
Ci-salkyl, naphthyl, C2-salkenyl, or hydrogen;


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any one or which groups except hydrogen may be substituted with
one or two halo, C1-salkoxy, C1-aalkylthio, nitro, trifluoromethyl, or
C1-salkyl groups; and
R4 is hydrogen or C1-aalkyl;
with the proviso that if Rl is hydrogen or halo, R3 is phenyl, . __
phenyl-(Ci-salkyl)-, Cs.scYcloalkyl, Cs.scYcloalkenyl, or naphthyl.
A particularly preferred compound of formula (XII) is [N-(2-
methoxybenzyl)acetylamino]-3-(1H-indoa-3-yl)-2-[N-(2-(4-piperidin-1-
yl)piperidin-1-yl)acetylamino]propane; o:r a pharmaceutically acceptable
salt thereof.
The preferred compounds of formulae (I), (II), (III} and (I~ will
have the 2- and 3-substituents on the morpholine ring in the cis
arrangement, the preferred stereochemistry being as shown in the
following general formula:
i
O ,~,0~ w
~.2 a
R
Where the benzyloxy moiety is a-substituted, the preferred
stereochemistry of the a-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.


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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-Cl.~alkyl, e.g. phenyl-Cl.salkyl, 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, malefic acid, succinic acid, acetic acid,
citric
acid, tartaric acid, carbonic acid, phosphoric acid or sulphuric acid. Salts
of amine groups may also comprise the quaternary ammonium salts in
which the amino nitrogen atom carries an alkyl, alkenyl, alkynyl or
aralkyl group. Where the compound carries an acidic group, for example a


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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 anorectic agent of
use in the combinations of the present invention include those salts . _.
described above in relation to the salts of NK-1 receptor antagonists.
The present invention accordingly provides the use of a NK-1
receptor antagonist selected from the compounds of formulae (I), (II), (III),
(IV), (~, (VI), (VII), (VIII), (IX), (X), (Xl:) and (XII), for the manufacture
of
a medicament for the treatment or prevention of eating disorders.
The present invention also provides a method for the treatment or
prevention of eating disorders, which method comprises administration to
a patient in need of such treatment 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 (XI:f).
In a further aspect of the present; invention, there is provided a
pharmaceutical composition for the treatment or prevention of eating
disorders 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.
It will be appreciated that the NK-1 receptor antagonist selected
from the compounds of formulae (I), (II), (III}, (IV), (V), (VI), (VII),
(VIII),
(IX), (X), (XI) and (XII) may be used in combination with an anorectic
agent, present as a combined preparation for simultaneous, separate or
sequential use for the treatment or prevention of eating disorders. Such
combined preparations may be, for example, in the form of a twin pack.
In a further or alternative aspect; of the present invention, there is
therefore provided a product comprising a NK-1 receptor antagonist
selected from the compounds of formulae (I), (II), (III), (IV), (V), (VI),
(VII),
(VIII), (IX), (X), (XI) and (XII) and an anorectic agent as a combined


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preparation for simultaneous, separate or sequential use in the treatment
or prevention of eating disorders.
In a preferred aspect, the present invention accordingly provides the
use of a NK-1 receptor antagonist selected from the compounds of formulae
(I), (II), (III), (IV), (~, (VI), (VII), {VIII), (IX), (X), (XI) and (XII) and
a __
halogenated amphetamine derivative for the manufacture of a
medicament for the treatment or prevention of eating disorders.
The present invention also provides a method for the treatment or
prevention of eating disorders, which method comprises administration to
a patient in need of such treatment an 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) and a halogenated amphetamine
derivative 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
selected from the compounds of formulae (I), {II), (III), (IV), (V), (VI),
(VII),
(VIII), (IX), (X), (XI) and (XII) and a halogenated amphetamine derivative
together with at least one pharmaceutically acceptable carrier or
excipient.
In a further or alternative aspect of the present invention, there is
provided a product 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) and a halogenated amphetamine derivative as a
combined preparation for simultaneous, separate or sequential use in the
treatment or prevention of eating disorders.
Particularly preferred halogenated amphetamine derivatives are
selected from the group consisting of fenfluramine and dexfenfluramine.
Thus in a further preferred aspect, 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) and a halogenated amphetamine derivative selected from


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the group consisting of fenfluramine and dexfenfluramine; for the
manufacture of a medicament for the treatment or prevention of eating
disorders.
The present invention also provides a method for the treatment or
prevention of eating disorders, which method comprises administration to
a patient in need of such treatment an amount of a NK-1 receptor
antagonist selected from the compounds of formulae (I), (iI), (III), (IV), (~,
(VI), (VII), (VIII), (IX), (X), (XI) and (XII) and an amount of a halogenated
amphetamine derivative selected from the group consisting of
fenfluramine and dexfenfluramine, 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
selected from the compounds of formulae (I), (II), (III), (IV), (V), (VI},
(VII),
(VIII), (IX), (X), (XI) and (XII) and a halogenated amphetamine derivative
selected from the group consisting of fenfluramine and dexfenfluramine,
together with at least one pharmaceutically acceptable carrier or
excipient.
In a further or alternative aspect of the present invention, there is
provided a product 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) and a halogenated amphetamine derivative selected
from the group consisting of fenfluramine and dexfenfluramine, as a
combined preparation for simultaneous, separate or sequential use in the
treatment or prevention of eating disorders.
As stated above, the NK-1 receptor antagonist and the anorectic
agent may be formulated in a single pharmaceutical composition or
alternatively in individual pharmaceutical compositions for simultaneous,
separate or sequential use in accordancE: with the present invention.
Preferably the compositions according to the present invention are
in unit dosage forms such as tablets, pills, capsules, powders, granules,


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solutions or suspensions, or suppositories, for oral, parenteral or rectal
administration, by inhalation or insufflation or administration by trans-
dermal patches or by buccal cavity absorption wafers. Oral dosage forms
are particularly preferred (e.g. tablets, capsules, pills or 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


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suspensions, and flavoured emulsions vvith edible oils such as cottonseed
oil, sesame oil, coconut oil, peanut oil or soybean oil, as well as elixirs
and
similar pharmaceutical vehicles. Suitable dispersing or suspending agents
for aqueous suspensions include synthetic and natural gums such as
tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose,
methylcellulose, polyvinyl-pyrrolidone or gelatin.
Preferred compositions for administration by injection include those
comprising a NK-1 receptor antagonist as the active ingredient, in
association with a surface-active agent (or wetting agent or surfactant) or
in the form of an emulsion (as a water-:in-oil or oil-in-water emulsion).
Suitable surface-active agents include, in particular, non-ionic
agents, such as polyoxyethylenesorbitans (e.g. TweenT"" 20, 40, 60, 80 or
85) and other sorbitans (e.g. SpanT"' 20, 40, 60, 80 or 85). Compositions
with a surface-active agent will conveniently comprise between 0.05 and
5% surface-active agent, and preferably between 0.1 and 2.5%. It will be
appreciated that other ingredients may be added, for example mannitol or
other pharmaceutically acceptable vehicles, if necessary.
Suitable emulsions may be prep;~red using commercially available
fat emulsions, such as IntralipidT"", LiposynT"", InfonutrolT"",
LipofundinT°"
and LipiphysanT"". The active ingredient may be either dissolved in a pre-
mixed emulsion composition or alternatively it may be dissolved in an oil
(e.g. soybean oil, safflower oil, cottonseed oil, sesame oil, corn oil or
almond
oil) and an emulsion formed 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~m, particularly 0.1 and 0.5~m, and have a pH in the range of 5.5
to 8Ø


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Particularly preferred emulsion compositions are those prepared by
mixing a NK-1 receptor antagonist selected from the compounds of
formulae (I), (II), (III), (IV), (~, (VI), (VII), (VIII), (IX), (X), (XI) and
(XII)
with IntralipidT"" 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.
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.
The present invention further provides a process for the preparation
of a pharmaceutical composition comprising a NK-1 receptor antagonist
and an anorectic agent, which process comprises bringing a NK-1 receptor
antagonist and an anorectic 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
anorectic agent, are presented in a ratio which is consistent with the
manifestation of the desired effect. In particular, the ratio by weight of


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the NK-1 receptor antagonist and the anorectic 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 suitable dosage level for the NK-1 receptor antagonist about 0.05
to I500mg per day, preferably about 0.25 to I500mg per day, and
especially about 0.25 to 500mg/kg per day. The compounds may be
administered on a regimen of up to 6 tines per day, preferably 1 to 4 times
per day, especially 1 or 2 times daily.
A suitable dosage level for the anorectic agent is about 0.5 to
1500mg per day, preferably about 2.5 to 1000mg per day, and especially
about 2.5 to 500mg per day. The compounds may be administered on a
regimen of up to 6 times per day, preferably 1 to 4 times per day,
especially 1 or 2 times daily.
It will be appreciated that the amount of the NK-1 receptor
antagonist and (where present) the anorectic agent required for use in the
treatment or prevention of eating disorders will vary not only with the
particular compounds or compositions selected but also with the route of
administration, the nature of the condition being treated, and the age and
condition of the patient, and will ultimately be at the discretion of the
patient's physician or pharmacist.
The compounds of formulae (I), (I:I), (III), (IV), (~, (VI), (VII), (VIII),
(IX), (X), (XI) and (XII) may be preparect 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/:?1155, EP-A-0 591 040,
EP-A-0 532 456, EP-A-0 443 132, WO 92/17449, WO 95/08549 and
WO 95//4017, 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-I receptor affinity (ICso) of less
than 100nM.


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Even more preferred NK-1 receptor antagonists of use in the
present invention are compounds which are potent NK-1 receptor
antagonists with an NK-1 receptor affinity (ICSo) of less than IOnM,
favourably less than 2nM and preferably less than lnM.
5 Especially preferred NK-1 receptor antagonists of use in the prQSent
invention are orally active, long acting, CNS-penetrant NK-1 receptor
antagonists, identified using a combination of the following assays:
ASSAY 1: NK-1 Receptor bindin~~
10 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. Typically, the receptor is expressed
at a level of 3x105 receptors per cell. Cells are grown in monolayer culture,
15 detached from the plate with enzyme-free dissociation solution (Speciality
Media Inc.), and washed prior to use in the assay. laSl-~,r8-substance P
(O.lnM, 2000Ci/mmol; New England Nuclear) is incubated in the presence
or absence of test compounds (dissolved in 5~1 dimethylsulphoxide, DMSO)
with 5x104 CHO cells. Ligand binding is performed in 0.25m1 of 50mM
20 Tris-HCI, pH7.5, containing 5mM MnClz, 150mM NaCl, 0.02% bovine
serum albumin (Sigma), 50p.g/ml chymostatin (Peninsula), O.lnM
phenylmethylsulphonyl fluoride, 2~g/ml pepstatin, 2~.g1m1 leupeptin and
2.8~g/ml furoyl saccharine. The incubation proceeds at room temperature
until equilibrium is achieved (>40 minutes) and the receptor-ligand
25 complex is harvested by filtration over GF/C filters pre-soaked in 0.1%
polyethylenimine using a Tomtek 96-well harvester. Non-specific binding
is determined using excess substance P (1~,M) and represents <10% of
total binding.


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ASSAY 2: Gerbil Foot-Tapping
CNS-penetrant NK-1 receptor antagonists for use in the present
invention can be identified by their ability to inhibit foot tapping in
gerbils
induced by anxiogenic agents (such as pentagastrin) or central infusion of
NK-1 receptor agonists such as GR736;32, or caused by aversive _.
stimulation such as foot shock or single housing, based on the method of
Rupniak & Williams, Eur. J. Pharmacvl., 1994, 265, 179.
Male or female Mongolian gerbils (35-70g) are anaesthetised by
inhalation of an isoflurane/oxygen mixi;ure to permit exposure of the
jugular vein in order to permit administration of test compounds or vehicle
in an injection volume of approximately 5mllkg i.v. Alternatively, test
compounds may be administered orally or by subcutaneous or
intraperitoneal routes. A skin incision is then made in the midline of the
scalp to expose the skull. An anxiogenic agent (e.g. pentagastrin) or a
selective NK-I receptor agonist (e.g. G1~,73632 (d Ala[L-Pro9,Me-Leulo]-
substance P-(7-1I)) is infused directly into the cerebral ventricles (e.g.
3pmo1 in 5~,1 i.c.v., depending on test substance) by vertical insertion of a
cuffed 27 gauge needle to a depth of 4.5mm below bregma. The scalp
incision is closed and the animal allowE~d to recover from anaesthesia in a
clear perspex observation box (approximately 25cm x 20cm x 20cm). The
duration and/or intensity of hind foot tapping is then recorded
continuously for approximately 5 minutes. Alternatively, the ability of
test compounds to inhibit foot tapping evoked by aversive stimulation,
such as foot shock or single housing, may be studied using a similar
method of quantification.
ASSAY 3: Ferret Emesis
Individually housed male ferrets (1.0 -2.5 kg) are dosed orally by
gavage with test compound. Ten minui;es later they are fed with
approximately 100g of tinned cat food. At 60 minutes following oral
dosing, cisplatin (lOmg/kg) is given i.v. uia a jugular vein catheter


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inserted under a brief period of halothane anaesthesia. The catheter is
then removed, the jugular vein ligated and the skin incision closed. The
ferrets recover rapidly from the anaesthetic and are mobile within 10-20
minutes. The animals are observed continuously during recovery from the
anaesthetic and for 4 hours following the cisplatin injection, after which
time the animals are killed humanely. The numbers of retches and vomits
occurring during the 4 hours after cisplatin administration are recorded by
trained observers.
ASSAY 4: Separation-Induced Vocalisation
Male and female guinea-pigs pups are housed in family groups with
their mothers and littermates throughout the study. Experiments are
commenced after weaning when the pups are at least 2 weeks old. Before
entering an experiment, the pups may be screened to ensure that a
vigorous vocalisation response is reproducibly elicited following maternal
separation. The pups are placed individually in an observation cage
(approximately 55cm x 39cm x l9cm) in a room physically isolated from
the home cage for approximately 15 minutes and the duration and/or
number of vocalisation during this baseline period is recorded. Those
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 at least 30 to 60 minutes
(or for up to 4 hours following an oral dose, dependent upon the oral
pharmacokinetics of the test compound) before social isolation for 15
minutes as described above. The duration and/or number of vocalisation
on drug treatment days may be expressed as a percentage of the pre-
treatment baseline value for each animal or compared with values
obtained in vehicle-treated animals. The same subjects may be retested
once weekly for up to 6 weeks. Between 6 and 8 animals receive each test


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compound at each dose tested.
A suitable selection cascade for NKl antagonists of use according to
the present invention is as follows:
(i) Determine affinity for human NKl receptor in radioligand . _.
binding studies (Assay 1); select compounds with ICso <_ lOnM, preferably
ICso <_ 2nM, especially ICso _< lnM.
(ii) Determine ability of compounds to penetrate CNS by their
ability to inhibit foot tapping in gerbils induced by central injection of an
NKi agonist (Assay 2); select compounds that inhibit foot tapping with
IDso _< 3mg/kg i.v., and preferably IDso ~ lmglkg i.v. when administered
immediately prior to central NKl agonist challenge, or IDso <_ 30mg/kg p.o.,
and preferably IDso <_ lOmglkg p.o. 1 hour prior to challenge.
(iii) Determine central duration of action of compounds in gerbil foot
tapping assay following intravenous administration 24 hours prior to
central NKl agonist challenge; select compounds showing <_ 25-fold loss of
potency compared with IDso determined in step (ii) above with the proviso
that IDso <_ l0mg/kg i.v., and preferably _< 5mglkg i.v. after 24 hour
pre-treatment.
(iv) Determine oral bioavailabilii;y of compounds by
pharmacokinetic analysis, activity in gerbil foot tapping assay following
oral administration and/or by ability to inhibit cisplatin-induced emesis in
ferrets (Assay 3); select compounds with IDso 5 3mg/kg p.o., and preferably
IDso _< 1mg/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 serotonergic drugs (inhibi.tion of pharmacologically evoked
foot tapping in gerbils and/or inhibition of distress vocalisations in guinea-


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pig pups (Assay 4)). Select compounds with IDso < 20mg/kg, and preferably .
IDso _< lOmg/kg.
Yet further preferred compounds of use in the present
invention may be selected from those compounds which satisfy the NK-1
receptor binding criteria of step (i) which, in addition, have < 5-fold shift
in
affinity when incubated in the presence of human serum albumin (HSA) to
show non-specific protein binding.
One example of a NK-1 receptor antagonist of use in the present
invention is the compound 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)-
ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)-
morpholine, the preparation of which is described in International Patent
Specification No. WO 95/16679. In the aforementioned assays, this
compound has the following activity:
human NK-1 receptor binding: ICso=O.lnM
gerbil foot-tapping (5 minx.): IDso=0.36mg/kg i.v.
gerbil foot-tapping (24 hrs.): IDso=0.33mg/kg i.v.
ferret emesis: IDoo<3mg/kg p.o.
guinea-pig vocalisation IDso=0.73mg/kg p.o.
(4hrs. pretreatment)
Another 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)-4-(5-(N, N-dimethylamino)methyl-1,2, 3-
triazol-4-yl)methyl-3-(S)-phenylmorpholine, the preparation of which is
described in International Patent Specification No. WO 95/18124. In the
aforementioned assays, this compound has the following activity:
human NK-1 receptor binding: ICso=0.25nM
gerbil foot-tapping (5 rains.): ID~o=0.12mg/kg i.v.
gerbil foot-tapping (24 hrs.): IDSO=0.17mg/kg i.v.


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guinea-pig vocalisation: IDso=0.5mg/kg s:c.
The following assay has been used to demonstrate the potentiation
of the anorectic effects of dexfenfluramine in diet-induced obese mice when
co-administered with a NK-1 receptor antagonist. __
Evaluation of the Interaction of NK-1 Antagonists and Anorectic Aeents
on Food Intake and Bod Wei,~ht in Diet-Induced Obese Mice.
Mice:
Male C57BL/J mice were obtained from Jackson Labs at 3 weeks of
age. Half the mice were maintained an a wet diet consisting of sweetened
condensed milk and standard ground rodent chow (70%:30%, voi:vol).
Fresh wet chow was provided daily. These mice will be referred to as diet-
induced obese (DIO). The other half was maintained on just ground rodent
chow. These will be referred to as Non-Obese Littermates (NOL). Both
food and water were supplied czd libiturrx. Mice were housed with a 12
hour light/dark cycle (4.OOam lights on) through out the course of the
described studies.
Mice were weighed bi-weekly until a paint that both DIO and NOL
mice were weight stable (approximately 20 weeks). At this time, DIO mice
weighed significantly more than NOL mice (p20.01). DIO mice also
exhibited elevated insulin and glucose levels, as well as polyuria.
Food Intake:
(All food intake studies were peri:ormed on weight stable DIO mice.
Both food and water were available before treatment.)
The effect that the anorectic agent, dexfenflur amine had on food
intake in DIO mice was determined previously (ED~o = 3 mg/kg, ip}. The
combined effect that [2-methoxy-5-(5-trifluoromethyl-tetrazol-1-y~1)-benzyl]-
([2S,3Sj-2-phenyl-piperidin-3-yl)amine (GR205171) and dexfenfluramine


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had on food consumption was examined by observing the resulting changes
in food intake observed after treatment with dexfenfluramine, GR205171,
or combinations of dexfenfluramine with decreasing doses of GR 205171.
Mice were randomly assigned to one of the following treatment
groups:
~ SalinelSaline
~ Saline/GR 205171@20 mg/kg
~ Dexfenfluramine @ 3 mg/kg/ GR 205171@20 mg/kg
Dexfenfluramine @ 3 mg/kg/ GR 205171@10 mg/kg
~ Dexfenfluramine @ 3 mg/kg/ GR 205171@ 5 mg/kg
Mice received two injections approximately 30 wins apart. All
injections were administered ip., in a volume of 0.2 ml between 3.OOpm
and 3.30pm. Fresh chow was provided at the time of injection. Food
intake was measured 16 hours post-injection for each mouse.
Results shown in Figure 1 are expressed as inhibition of food intake
relative to that of saline treated animals.
Body Wed
(All weight studies are performed on DIO mice)
The effect that the combination of anorectic agents and NK-1
antagonists have on weight are examined using a chronic dosing regimen.
Mice are treated with dexfenfluramine, GR 205171, or combinations of
dexfenfluramine with decreasing doses of GR 205171, similar to those used
in the evaluation of food intake. Mice are dosed once daily, for 7 days with
body weights being measured at the start and conclusion of the study.
Changes in body weight are compared with that of saline treated mice.
Concurrent daily food intake measurements may be taken at this
time.


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The following examples illustrate pharmaceutical compositions
according to the invention.
These formulations 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 anorectic agent will depend upon the choice of active ingredients.
EXAMPLE 1 Tablets containing 50-300mg of NK-1 antagonist and l5mg
of dexfenfluramine
Amount
mg


NK-1 antagonist 50.0 100.0 300.0


dexfenfluramine 15.0 15.0 15.0


Microcrystalline cellulose80.0 80.0 80.0


Modified food corn 80.0 80.0 80.0
starch


Lactose 174.5 124.5 124.5


Magnesium Stearate 0.5 0.5 0.5


EXAMPLE 2 Tablets containin~,50-300mg of NK-1 antagonist and 60mg
of fenfluramine
Amount
mg


NK-1 antagonist 50.0 100.0 300.0


fenfluramine 60.0 60.0 60.0


Microcrystalline cellulose$0.0 80.0 80.0


Modified food corn starch80.0 80.0 80.0


Lactose 129.5 179.5 129.5


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


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then compressed into tablets containing 50mg, 100mg and 300mg of the
NK-1 receptor antagonist per tablet.
EXAMPLE 3 Parenteral injection
Amount


Active Ingredients 10 to 300mg


Citric Acid Monohydrate 0.75mg


Sodium Phosphate 4.5mg


Sodium Chloride 9mg


Water for injection to lOml


The sodium phosphate, citric acid monohydrate and sodium chloride
are dissolved in a portion of the water. The active ingredients are
dissolved or suspended in the solution and made up to volume.

Representative Drawing