AU744261B2 - Use of NK-1 receptor antagonists for treating eating disorders - Google Patents
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Description
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 NK-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 saiety centres in the hypothalamus region of the brain. For instance, neuropeptides released by the gut in response 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, 301:835-837 (1990).
Bulimia nervosa is characterised by recurrent episodes of overeating, or binges, followed by severe dieting often associated with selfinduced 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.
WO 98/47513 PCT/GB98/01161 -2- 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-1; substance P) receptor antagonists are being developed for the treatment of a number of physiological disorders associated with an excess or imbalance of tachykinins, and in particular substance P. Examples of 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.
A particularly preferred class of NK- 1 receptor antagonists of use in the present invention are those which are able to cross the blood-brain barrier, otherwise known as CNS- or brain-penetrant compounds.
The present invention accordingly provides the use of an orally active, CNS penetrant 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- I receptor antagonist.
In a further aspect of the present invention there is provided a pharmaceutical composition when used for the treatment or prevention of eating disorders comprising a see. NK- 1 receptor antagonist, together with at least one pharmaceutically acceptable carrier or excipient.
In another embodiment of the present invention there is provided a NK- 1 receptor 15 antagonist when used in the treatment or prevention of eating disorders.
0.0.00In a further embodiment of the present invention there is provided the use of an orally active, CNS penetrant NK- 1 receptor antagonist for the manufacture of a medicament for the treatment or prevention of eating disorders which result in or cause obesity.
The present invention also provides a method for the treatment or prevention of eating disorders which result in or cause 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 an 6:060: orally active, CNS penetrant NK- 1 receptor antagonist for the manufacture of a 25 medicament for the treatment or prevention of bulimia nervosa.
The present invention also provides a method for the treatment or prevention of 0. .:bulimia nervosa, which method comprises 'administration to a patient in need of sujfh treatment an effective amount of a NK-1 receptor antagonist.
In a further embodiment of the present invention there is provided the use of an orally active, CNS penetrant NK- 1 receptor antagonist 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 ,A L of such treatment an effective amount of a NK-l receptor antagonist.
[R:\LIBH]0101 Also disclosed herein is 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.
Also disclosed herein is 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-I 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, fee such that together they give effective relief.
:In a further aspect of the present invention, there is provided a pharmaceutical Is 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 ooo• treatment or prevention of eating disorders. Such combined preparations may be, for example, in the form ofa 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 when used simultaneously, separately or sequentially in the treatment or prevention of eating disorders.
In another embodiment of the present invention there is provided a NK-1 receptor antagonist and an anorectic agent when used 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 eating disorders which result in or cause obesity.
The present invention also provides a method for the treatment or prevention of eating disorders which result in or cause obesity, which method comprises administration to a patient in need of such treatment an amount of a NK-1 receptor antagonist and an Samount of an anorectic agent, such that together they give effective relief.
[R\LIBH]00859.doc:ael 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 which result in or cause 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 when used simultaneously, separately, or sequentially in the treatment or prevention of eating disorders which result in or cause obesity.
In an alternative embodiment of the present invention there is provided the use of a NK-l 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 !I :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 anorectic agent, Is such that together they give effective relief.
It will be appreciated that the NK-1 receptor and anorectic agent may be present as a combined preparation for simultaneous, separate or sequential use for the treatment or Sprevention ofbulimia nervosa. Such combined preparations may be, for example, in the •o o form of a twin pack.
20 In a further or alternative aspect of the present invention, there is therefore provided :i a product comprising a NK-1 receptor antagonist and an anorectic agent as a combined o• **preparation when used simultaneously, separately, or sequentially in the treatment or :o:oprevention 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-l 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.
[R:\LIBH]00859.doc:ael 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 when used simultaneously, separately, or sequentially in the treatment or prevention of compulsive eating disorders.
In another aspect of the present invention there is provided a pharmaceutical composition for the treatment or prevention of eating disorders, said composition comprising a NK-1 receptor antagonist and an anorectic agent, together with at least one pharmaceutically acceptable carrier or excipient.
Also disclosed herein is 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.
Also disclosed herein is 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 15 agent, such that together they give effective relief.
0••o 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.
e: 20 Also disclosed herein is 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, S 25 within a reasonable period of time. The compounds may be in the same pharmaceutically S° 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.
The next page is page 8 Li [R:\LIBH]01015.doc:ljg **we IADA Y LB\LIB F1 28402.doc: acI WO 98/47513 PCT/GB98/01161 -8- 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/m 2 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, arteriosclerosis, Type II diabetes, WO 98/47513 PCT/GB98/01161 -9polycycstic ovarian disease, cardiovascular diseases, osteoarthritis, dermatological disorders, hypertension, insulin resistance, hypercholesterolemia, hypertriglyceridemia, and cholelithiasis.
I.
Thus, in one aspect, this invention relates to the inhibition and/or complete suppression of lipogenesis in obese mammals, 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 and/or decreasing or eliminating the need or usage of insulin in a diabetic patient, 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 to, aminorex, amphechloral, amphetamine, benzphetamine, chlorphentermine, clobenzorex, cloforex, clominorex, clortermine, cyclexedrine, dexfenfluramine, dextroamphetamine, diethylpropion, diphemethoxidine, Nethylamphetamine, fenbutrazate, fenfluramine, fenisorex, fenproporex, WO 98/47513 PCT/GB98/01161 fludorex, fluminorex, furfurylmethylamphetamine, levamfetamine, levophacetoperane, mazindol, mefenbrex, 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, WO 98/47513 PCT/GB98/01161 -11 93/01165, 93/01169, 93/01170, 93/06099, 93/09116, 93/10073, 93/14113, 93/18023, 93/19064, 93/21155, 9321181, 93/23380, 93/24465, 94/01402, 94/02461, 94/03429, 94/03445, 94/04494, 94/04496, 94/05625, 94/07843, 94/10165, 94/10167, 94/10168, 94/10170, 94/11368, 94/13639, 94/13663, 94/14767, 94/15903, 94/19320, 94/19323, 94/20500, 94/26735, 94/26740, 94/29309, 95/02595, 95/04040, 95/04042, 95/06645, 95/07886, 95/07908, 95/08549, 95/11880, 95/14017, 95/15311, 95/16679, 95/17382, 95/18124, 95/18129, 95/19344, 95/20575, 95/21819, 96/22525, 95/23798, 95/26338, 95/28418, 95/30674, 95/30687, 96/05193, 96/05203, 96/06094, 96/07649, 96/10562, 96/16939, 96/18643, 96/20197, 96/21661, 96/29304, 96/29317, 96/29326, 96/29328, 96/31214, 96/32385, 96/37489, 97/01553, 97/01554, 97/03066, 97/08144, 97/14671, 97/17362, 97/18206, 97/19084, 97/19942 and 97/21702; and in British Patent Specification Nos. 2 266 529, 2 268 931, 2 269 170, 2 269 590, 2 271 774, 2 292 144, 2 293 168, 2 293 169, and 2 302 689.
Particularly preferred NK-1 receptor antagonists are those described in European Patent Specification No. 0 577 394, i.e. compounds of formula X R
(I)
R2 N R
R
or a pharmaceutically acceptable salt thereof, wherein:
R
1 is selected from the group consisting of: hydrogen; Ci.calkyl, unsubstituted or substituted with one or more of the substituents selected from: hydroxy, oxo, ClI-alkoxy, WO 98/47513 PTG9/16 PCT/GB98/01161 12 phenyl-C 1-3alkoxy, phenyl,
-CN,
halo, -NR9RO, wherein R 9 and RIO are independently.
selected from: hydrogen, (ii) C1.Galkyl, (iii) hydroxy-Cimalkyl, and (iv) phenyl, -NR9CORIO, wherein R9 and RIO are as defined above, -NR9CO 2 R1O, wherein R9 and RIO are as defined above, -CONR9RO, wherein R9 and RiO are as defined above, -COR9, wherein R9 is as defined above, (in) -CO 2 R9, wherein R9 is as defined above, heterocycle, wherein the heterocycle is selected from the group consisting of: benzimidazolyl, benzofuranyl, benzthiophenyl, benzoxazolyl, furanyl, imidazolyl, indolyl, isoxazolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridyl, WO 98/47513 PCT/GB98/O1 161 -13 pyrimidyl, pyrrolyl, quinolyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, azetidinyl, 1,4-dioxanyl, hexahydroazepinyl, oxanyl, (AA) piperazinyl, (AB) piperidinyl, (AC) pyrrolidinyl, (AD) tetrahydrofuranyl, and (AE) tetrahydrothienyl, and wherein the heterocylcie is unsubstituted or substituted with one or more substituent(s) selected from: Ci.oalkyl, unsubstituted or substituted with halo, -CF 3
-OCH
3 or phenyl, (ii) Ci-6alkoxy, (iii) oxo, (iv) hydroxy, thioxo, (vi) -SR 9 wherein R9 is as defined above, (vii) halo, (viii) cyano, (ix) phenyl, trifluoromethyl, WO 98/47513 PCT/GB98/01161 14- (xi) -(CH 2 )m-NR9R, wherein m is 0, 1 or 2, and R 9 and RIO are as defined above, (xii) -NR9COR1 0 wherein R9 and Rio are as defined above, (xiii) -CONRSR'O, wherein R 9 and Rio are as defined above, (xiv) -CO 2
R
9 wherein R 9 is as defined above, and (xv) -(CH 2 )m-OR 9 wherein m and R 9 are as defined above; C2-6alkenyl, unsubstituted or substituted with one or more of the substituent(s) selected from: hydroxy, oxo, Cl-6alkoxy, phenyl-C1.ialkoxy, phenyl,
-CN,
halo, -CONR9R1o, wherein R 9 and Rio are as defined above,
-COR
9 wherein R 9 is as defined above,
-CO
2
R
9 wherein R 9 is as defined above, heterocycle, wherein the heterocycle is as defined above; C2.
6 alkynyl; phenyl, unsubstitued or substituted with one or more of the substituent(s) selected from: hydroxy, Ci-calkoxy, C1.ialkyl, halo,
-CN,
-NO
2
-CF
3 WO 98/47513 PCT/GB98/01161 -(CH2)m-NR9R 1 O, wherein m, R 9 and Rio are as defined above, -NRgCORio, wherein R 9 and Rio are as defined above, -NRgCO 2
R
1 o, wherein R 9 and Rio are as defined above, -CONR9R1i, wherein R9 and Rio are as defined above,
-CO
2
NR
9 R1O, wherein R9 and Rio are as defined above,
-COR
9 wherein R 9 is as defined above, -CO2R 9 wherein R 9 is as defined above;
R
2 and R 3 are independently selected from the group consisting of: hydrogen; Cl.Ialkyl, unsubstituted or substituted with one or more of the substituents selected from: hydroxy, oxo, Ci-.alkoxy, phenyl-C1.3alkoxy, phenyl,
-CN,
halo, -NR9R1o, wherein R 9 and Rio are independently selected from: -NR9COR 1 O, wherein R 9 and Rio are as defined above, -NR9CO 2 R'O, wherein R 9 and Rio are as defined above, -CONR9Rio, wherein R 9 and Rio are as defined above,
-COR
9 wherein R 9 is as defined above, and
-CO
2
R
9 wherein R 9 is as defined above; C2.-alkenyl, unsubstituted or substituted with one or more of the substituent(s) selected from: hydroxy, oxo, WO 98/47513 PCT/GB98/01161 -16- Ci-Galkoxy, phenyl-C1-3alkoxy, phenyl,
-CN,
halo, -CONR9R 1 I wherein R 9 and Ri 1 are as defined above,
-COR
9 wherein R 9 is as defined above, -C0 2
R
9 wherein R9 is as defined above; C2-6alkynyl; phenyl, unsubstituted or substituted with one or more of the substituent(s) selected from: hydroxy, C1.6alkoxy, Ci-Galkyl, halo,
-CN,
-NO
2
-CF
3
-(CH
2 )m-NR 9
R
1 0 wherein m, R 9 and R 1 i are as defined above, -NR9COR1O, wherein R 9 and Rio are as defined above, -NR9CO 2
R
1 wherein R 9 and Rio are as defined above, -CONR9Rli, wherein R 9 and Ri 1 are as defined above, -C0 2 NR9RiO, wherein R 9 and Ro 1 are as defined above,
-COR
9 wherein R 9 is as defined above, -C0 2
R
9 wherein R 9 is as defined above; and the groups R' and R 2 may be joined together to form a heterocyclic ring selected from the group consisting of: pyrrolidinyl,
I
WO 98/47513 PCT/GB98/01161 17piperidinyl, pyrrolyl, pyridinyl, imidazolyl, oxazolyl, and thiazolyl, and wherein the heterocyclic ring is unsubstituted or substituted with one or more substituent(s) selected from: Ci- 6 alkyl, (ii) oxo, (iii) Cl-.alkoxy, (iv) -NR9R 10 wherein R 9 and Rio are as defined above, halo, and (vi) trifluoromethyl; and the groups R 2 and R 3 may be joined together to form a carbocyclic ring selected from the group consisting of: cyclopentyl, cyclohexyl, phenyl, and wherein the carbocyclic ring is unsubstituted or substituted with one or more substituents selected from: Ci- 6 alkyl, (ii) CI-.alkoxy, (iii) -NR9Rio, wherein R 9 and RIO are as defined above, (iv) halo, and trifluoromethyl; and the groups R 2 and R 3 may be joined together to form a heterocyclic ring selected from the group consisting of: pyrrolidinyl, WO 98/47513 PCT/GB98/01161 -18piperidinyl, pyrrolyl, pyridinyl, imidazolyl, furanyl, oxazolyl, thienyl, and thiazolyl, and wherein the heterocyclic ring is unsubstituted or substituted with one or more substituent(s) selected from: C1.calkyl, (ii) oxo, (iii) Ci.calkoxy, (iv) -NR9R1O, wherein R9 and Rio are as defined above, halo, and (vi) trifluoromethyl; X is selected from the group consisting of: and -S02-;
R
4 is selected from the group consisting of: (1)
R'
z
R
-Y-C1.aalkyl, wherein alkyl is unsubstituted or substituted with one or more of the substituents selected from: WO 98/47513 PCT/GB98/01161 -19 hydroxy, oxo, Ci-Galkoxy, phenyl-Cl.aalkoxy, phenyl,
-CN,
halo,
-NR
9 R10, wherein R 9 and RO0 are as defined above, -NR9COR
I
o, wherein R 9 and Rio are as defined above, -NR9CO 2 Ri°, wherein R 9 and Rio are as defined above, -CONR9R i o, wherein R 9 and Rio are as defined above,
-COR
9 wherein R 9 is as defined above, -C0 2
R
9 wherein R9 is as defined above; -Y-C2-6alkenyl, wherein the alkenyl is unsubstituted or substituted with one or more of the substituent(s) selected from: hydroxy, oxo, Ci.-alkoxy, phenyl-Cl.aalkoxy, phenyl,
-CN,
halo, -CONR9Rio, wherein R9 and Rio are as defined above,
-COR
9 wherein R 9 is as defined above, -C0 2
R
9 wherein R 9 is as defined above, -O(CO)-phenyl, wherein the phenyl is unsubstituted or substituted with one or more of R 6
R
7 and R 8 R" is selected from the group consisting of: phenyl, unsubstituted or substituted with one or more of R 1 R12 and R 1 3 WO 98/47513 PCT/GB98/01161 20 Ci-8alkyl, unsubstituted or substituted with one or more of the substituent(s) selected from: hydroxy, oxo, Ci-Galkoxy, phenyl-Cl.3alkoxy, phenyl,
-CN,
halo, -NR9Rio, wherein R 9 and Ro 1 are as defined above, -NR9CORio, wherein R 9 and Rio are as defined above, -NR9CO 2 Ro, wherein R 9 and Rio are as defined above, -CONR9R10, wherein R 9 and Rio are as defined above,
-COR
9 wherein R 9 is as defined above,
-CO
2
R
9 wherein R 9 is as defined above; C2.-alkenyl, unsubstituted or substituted with one or more of the substituent(s) selected from: hydroxy, oxo, Ci-6alkoxy, phenyl-Cl.salkoxy, phenyl,
-CN,
halo, -CONR9R1o, wherein R 9 and Rio are as defined above,
-COR
9 wherein R 9 is as defined above,
-CO
2
R
9 wherein R 9 is as defined above; heterocycle, wherein the heterocycle is as defined above;
R
6
R
7 and R are independently selected from the group consisting of: hydrogen; WO 98/47513 PCT/GB98/01161 -21 Ci.ralkyl, unsubstituted or substituted with one or more of the substituents selected from: hydroxy, oxo, Ci-6alkoxy, phenyl-Ci.aalkoxy, phenyl,
-CN,
halo, -NRSRiO, wherein R 9 and Rio are as defined above,
-NR
9 COR1O, wherein R 9 and R Io are as defined above, -NR9CO 2
R
10 wherein R 9 and Rio are as defined above, -CONR9R10, wherein R 9 and Rio are as defined above,
-COR
9 wherein R 9 is as defined above, and
-CO
2
R
9 wherein R 9 is as defined above; C2-6alkenyl, unsubstituted or substituted with one or more of the substituent(s) selected from: hydroxy, oxo, Ci-Galkoxy, phenyl-Ci.
3 alkoxy, phenyl,
-CN,
halo, -CONR9Rio wherein R 9 and Rio are as defined above,
-COR
9 wherein R 9 is as defined above,
-CO
2
R
9 wherein R 9 is as defined above; C2-.alkynyl; phenyl, unsubstituted or substituted with one or more of the substituent(s) selected from: hydroxy, WO 98/47513 WO 9847513PCT/GB98/O1 161 22 C i.Galkoxy, C 1-Galkyl, halo,
-CN,
-NO
2
-CF
3 -(CH2)m-NR 9
R
1 0 wherein in, R9 and RIO are as defined above, (6) (7) (8) (9) (11) (12) (13) (14) (16) (17) (18) (19) -NR9COR1O, wherein R9 and RIO are as defined a -NR9CO 2 RO, wherein R9 and RIO are as defined (1 CONR9RO, wherein R9 and RIO are as defined a (in) -CO 2 NR9R'O, wherein R9 and Rio are as defined -COR9, wherein R9 is as defined above;
-CO
2 R9, wherein R9 is as defined above; halo,
-CN,
-CF
3
-NO
2 -SR1 4 wherein Ri 4 is hydrogen or Ci.
5 alkyl,
-SOR'
4 wherein R1 4 is as defined above, -S0 2
R
14 wherein R' 4 is as defined above, INR9CORI 0 wherein R9 and RiO are as defined above,
CONR
9
COR
1 0 wherein R 9 and RIO are as defined above, NR9RO, wherein R9 and RIO are as defined above, NR9CO 2 RO, wherein R9 and RIO are as defined above, hydroxy, Ci.ralkoxy,
COR
9 wherein R 9 is as defined above, C0 2
R
9 wherein R 9 is as defined above, bove, ibove, hove, 3bove, WO 98/47513 PCT/GB98/01161 -23-
R
11
R
12 and R 13 are independently selected from the definitions of R
G
R
7 and R 8 or -OX; Y is selected from the group consisting of: a single bond,
-CO-,
-CH
2 -CHR15-, and -CR15RG-, wherein R15 and R 1 G are independently selected from the group consisting of: C1.calkyl, unsubstituted or substituted with one or more of the substituents selected from: hydroxy, (ii) oxo, (iii) C1-6alkoxy, (iv) phenyl-Cl.aalkoxy, phenyl, (vi) -CN, (vii) halo, (viii) -NR 9
R
1 0 wherein R 9 and R 1 O are as defined above, (ix) -NR9COR1o, wherein R 9 and RiO are as defined above,
-NR
9
CO
2
R
1 0 wherein R 9 and RIO are as defined above, (xi) -CONR 9 R1o, wherein R 9 and RIO are as defined above, (xii) -COR 9 wherein R 9 is as defined above, and (xiii) -CO 2
R
9 wherein R 9 is as defined above; phenyl, unsubstituted or substituted with one or more of the substituent(s) selected from: hydroxy, (ii) Ci.calkoxy, WO 98/47513 PCT/GB98/01161 -24- (iii) C1.-alkyl, (iv) halo, (vi) -CN, (vii) -NO 2 (viii) -CF 3 (ix) -(CH2)m-NR 9 Ro, wherein m, R 9 and RiO are as defined above, -NR9CORlO, wherein R 9 and Rio are as defined above, (xi) -NR9CO 2
R
1 wherein R 9 and Rio are as defined above, (xii) -CONR9R1O, wherein R 9 and Rio are as defined above, (xiii) -CO 2 NR9R10, wherein R 9 and RIO are as defined above, (xiv) -COR 9 wherein R 9 is as defined above, and (xv) -C0 2
R
9 wherein R9 is as defined above; Z is selected from: hydrogen, C1.
4 alkyl, and hydroxy, with the proviso that if Y is Z is other than hydroxy, or if Y is -CHR 15 then Z and R 1 may be joined together to form a double bond.
Particularly preferred compounds of formula are those wherein: Ri is selected from the group consisting of: CI-6alkyl, substituted with one or more of the substituents selected from: heterocycle, wherein the heterocycle is selected from the group consisting of: benzimidazolyl, imidazolyl, isoxazolyl, isothiazolyl, WO 98/47513 WO 9847513PCT/GB98/01 161 25 oxadiazolyl, pyrazinyl, pyrazolyl, pyridyl, pyrrolyl, tetrazolyl, thiadiazolyl, (L triazolyl, and piperidinyl, and wherein the heterocycle is unsubstituted or substituted with one or more substituent(s) selected from: Ci- 6 alkyl, unsubstituted or substituted with halo, -CF 3
-OCH
3 or phenyl, (ii) Cl-Galkoxy, (ini) oxo, (iv) thioxo, cyano, (vi) -SCH 3 (vii) phenyl, (viii) hydroxy, (ix) trifluoromethyl, -(CH2)m-NR 9 RlO, wherein m is 0, 1 or 2, and R 9 and RIO areindependently selected from: hydrogen, (11) Ci- 6 alkyl, (III) hydroxyCi-Galkyl, and (IV) phenyl, (xi) -NR9CORO, wherein R9 and Rio are as defined above, and (xii) -CONR9RO, wherein R9 and RIO are as defined above,
R
2 and R3 are independently selected from the group consisting of: WO 98/47513 WO 9847513PCT/GB98/01161 26 hydrogen; Cl-6alkyl C2.6alkenyl, and phenyl; X is
R
4 is z
R
R
5 is phenyl, unsubstituted or substituted with halo;
R
6 W~and R8 are independently selected from the group consisting of: hydrogen, C1.6alkyl, halo, and
-CF
3 Y is-0-; and Z is hydrogen or C1.
4 alkyl; and pharmaceutically acceptable salts thereof.
Particularly preferred compounds of formula are: 4-triazolo)methyl)-2(S) 5-bis(trifluoromethyl)benzyloxy)-3(S)phenyl-morpholine; 4-triazolo)methyl)-2 5-bis(trifluoromethyl)benzyloxy)- 3(R) phenyl-morpholine; 4-(3-(5-oxo- 1H,4H- 1, 2,4-triazolo)methyl)-2(S)-(3, bis(trifluoromethyl)benzyloxy)- 3(S)-phenyl-morpholine; and 5-bis(trifluoromethyl)phenyl)ethoxy)-3- (S)-(4-fluorophenyl)- 4-(3-(5-oxo- 1H, 4H- 1, 2 4 -triazolo)methyl)morpholine; or a pharmace utically acceptable salt thereof.
WO 98/47513 WO 9847513PCT/GB98/01 161 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):
YR
R 9 b N4 -x R ~R or a pharmaceutically acceptable salt or prodrug thereof, wherein RI is hydrogen, halogen, C 1-alkyl, Ci.Galkoxy, CF3, NO 2 CN, SRa SORa, SO 2 Ra, CO 2 Ra, CONRaRb, C2.6alkenyl, C2-alkynyl or CI-4alkyl substituted by C1.4alkoxy, where Ra and Rb each independently represent hydrogen or Cl4alkyl; R2 is hydrogen, halogen, Cl.Galkyl, Ci.6alkoxy substituted by C14alkoxy or CE 3
R
3 is hydrogen, halogen or CE 3
R
4 is hydrogen, halogen, C1-6alkyl, C1v6alkoxy, CE 3
NO
2 CN, SRa, SORa, SO 2 Ra, CO 2 Ra, CONRaRb, C2.oalkenyl, C2Gralkynyl or CI-4alkyl substituted by Cl4alkoxy, where Ra and Rb each independently represent hydrogen or C1.4alkyl; is hydrogen, halogen, Ovo6alkyl, Cl.(alkoxy substituted by C1.4alkoxy or CF 3 R6 is a 5-membered or 6-membered heterocyclic ring containing 2 or 3 nitrogen atoms optionally substituted by =S or a CL.4alkyl group, and optionally substituted by a group of the formula ZNR 7 R8 where Z is C 1 .o;alkylene or C3.rcycloalkylene; R7 is hydrogen, C1.
4 alkyl, C3.7cycloalkyl or C3.7cycloalky1C].- 1 alkyl, or C2.4alkyl substituted by Ci.4alkoxy or hydroxyl; WO 98/47513 PCT/GB98/01161 -28-
R
8 is hydrogen, Ci.
4 alkyl, C-.7cycloalkyl or C3.7cycloalkylC.4alkyl, or
C
2 .4alkyl substituted by one or two substituents selected from C1-4alkoxy, hydroxyl or a 4, 5 or 6 membered heteroaliphatic ring containing one or two heteroatoms selected from N, O and S; or R 7
R
8 and the nitrogen atom to which they are attached form a heteroaliphatic ring of 4 to 7 ring atoms, optionally substituted by a hydroxy group, and optionally containing a double bond, which ring may optionally contain an oxygen or sulphur ring atom, a group S(0) or S(0)2 or a second nitrogen atom which will be part of a NH or NRc moiety where Rc is C1.4alkyl optionally substituted by hydroxy or C1.4alkoxy; or R 7 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, R 7 and the nitrogen atom to which they are attached form a heteroaliphatic ring of 4 to 7 ring atoms which may optionally contain an oxygen ring atom;
R
9 a and R 9 b are each independently hydrogen or C1.4alkyl, or R9a and R9b are joined so, together with the carbon atoms to which they are attached, there is formed a C 5 7 ring; X is an alkylene chain of 1 to 4 carbon atoms optionally substituted by oxo; and Y is a C1-4alkyl group optionally substituted by a hydroxyl group; with the proviso that ifY is C.-4alkyl, R6 is susbstituted at least by a group of formula ZNR 7 R8 as defined above.
Particularly preferred compounds of formula (II) are those of formula (IIa) and pharmaceutically acceptable salts thereof: x
A
3 (Ila) wherein: A' is fluorine or CF 3
A
2 is fluorine or CF 3
A
3 is fluorine or hydrogen; V: and X, Y and R 6 are as defined in relation to formula (11).
Particularly preferred compounds of formula (11) include: 3 ,5-bis(trifluoromethyl)phenyl)ethoxy-4-(5-(dimethylamino)methy112,3-triazol- 4 -yl)methyl-3-(S)-phenylmorpholine;
SAO
V. 1 3 5-bis(trifluoromethyl)phenyl)ethoxy-4(5(dimethylamino)methy1-1,2,3-triazoland pharmaceutically acceptable salts thereof.
Further preferred NK-1 receptor antagonists are those described in European Patent Specification No. WO 95/23798, i.e. compounds of formula (Ill): R __7
R
3 0 O R2 N B R Q 1 (111) or a pharmaceutically acceptable salt thereof, wherein: [R:\L1BH]02896.doc:aak WO 98/47513 PCT/GB98/01161
R
2 and R 3 are independently selected from the group consisting of: hydrogen, C1.ialkyl, unsubstituted or substituted with one or more of the substituents selected from: hydroxy, oxo, C1-6alkoxy, phenyl-Cl.salkoxy, phenyl,
-CN,
halo, -NR9Rio, wherein R 9 and Rio are independently selected from: hydrogen, (ii) Ci-salkyl, (iii) hydroxy-Ci.salkyl, and (iv) phenyl,
-NR
9 COR1i, wherein R 9 and Rio are as defined above,
-NR
9
CO
2
R
10 wherein R 9 and RIO are as defined above, -CONR9Rio, wherein R9 and Rio are as defined above,
-COR
9 wherein R 9 is as defined above, and -C0 2
R
9 wherein R 9 is as defined above; C2-6alkenyl, unsubstituted or substituted with one or more of the substituent(s) selected from: hydroxy, oxo, CI.calkoxy, phenyl-Ci-salkoxy, phenyl,
-CN,
halo, WO 98/47513 PCT/GB98/01161 31-
-CONR
9
R
1 wherein R 9 and Rio are as defined above,
-COR
9 wherein R 9 is as defined above, -C0 2
R
9 wherein R 9 is as defined above; C2.6alkynyl; phenyl, unsubstituted or substituted with one or more of the substituent(s) selected from: hydroxy, Ci-calkoxy, Ci.
6 alkyl, halo,
-CN,
-NO
2
-CF
3
-(CH
2 )m-NR9R 1 wherein m, R 9 and Rio are as defined above, -NR9COR1I, wherein R 9 and Rio are as defined above,
-NR
9
CO
2 RiO, wherein R 9 and Rio are as defined above, -CONR9Rio, wherein R 9 and Rio are as defined above, -C02NR9Ri 1 wherein R 9 and Rio are as defined above,
-COR
9 wherein R 9 is as defined above, -C0 2
R
9 wherein R 9 is as defined above; and the groups R 2 and R3 may be joined together to form a carbocyclic ring selected from the group consisting of: cyclopentyl, cyclohexyl, phenyl, and wherein the carbocyclic ring is unsubstituted or substituted with one or more substituents selected from: Ci-.alkyl, WO 98/47513 PCT/GB98/01161 -32- (ii) C1.calkoxy, (iii) -NR 9 R1 0 wherein R 9 and R 1 0 are as defined above, (iv) halo, and trifluoromethyl; and the groups R 2 and R 3 may be joined together to form a heterocyclic ring selected from the group consisting of: pyrrolidinyl, piperidinyl, pyrrolyl, pyridinyl, imidazolyl, furanyl, oxazolyl, thienyl, and thiazolyl, and wherein the heterocyclic ring is unsubstituted or substituted with one or more substituent(s) selected from: Cl.-alkyl, (ii) oxo, (iii) Cl-6alkoxy, (iv) -NR9R 1 0 wherein R 9 and R 1 0 are as defined above, halo, and (vi) trifluoromethyl;
R
G
R
7 and R8 are independently selected from the group consisting of: hydrogen; Ci-.alkyl, unsubstituted or substituted with one or more of the substituents selected from: hydroxy, oxo, WO 98/47513 PCT/GB98/01161 -33- Ci-6alkoxy, phenyl-C1-3alkoxy, phenyl,
-CN,
halo, -NR9R l wherein R 9 and RiO are as defined above, -NR9CORO, wherein R 9 and Rio are as defined above, -NR9CO 2 RIO, wherein R 9 and Rio are as defined above, -CONR9R1', wherein R 9 and Rio are as defined above, -COR9, wherein R 9 is as defined above, and
-CO
2
R
9 wherein R 9 is as defined above; C2-6alkenyl, unsubstituted or substituted with one or more of the substituent(s) selected from: hydroxy, oxo, Ci.calkoxy, phenyl-Ci.-alkoxy, phenyl,
-CN,
halo, -CONR9Rio wherein R 9 and Rio are as defined above,
-COR
9 wherein R 9 is as defined above, -C02R 9 wherein R 9 is as defined above; C2-6alkynyl; phenyl, unsubstituted or substituted with one or more of the substituent(s) selected from: hydroxy, Ci.calkoxy, Ci.salkyl, halo, WO 98/47513 WO 9847513PCT/GB98/01 161 34
-CN,
-NO
2 -(CH2)m-NR 9 Rl 0 wherein m, R 9 and RIO are as defined above, (6) (7) (8) (9) (11 (12; (13; (14; (16; (17 (18 (19 (21 (22 (23 (24 -NR9CORIO, wherein R 9 and RIO are as defined a -NR9CO 2 RO, wherein R 9 and RIO are as defined -CONR9RO, wherein R9 and RIO are as defined a (in) -CO 2
NR
9 RO, wherein R9 and RIO are as defined -COR9, wherein R 9 is as defined above, -C0 2
R
9 wherein R9 is as defined above; halo,
-CN,
-NO
2 -SRi4, wherein R1 4 is hydrogen or -SOR1 4 wherein R 14 is as defined above,
-SO
2
RI
4 wherein R1 4 is as defined above, NR9CORI 0 wherein R9 and RIO are as defined above, CONR9CORIO, wherein R 9 and RIO are as defined above,
NR
9 RO, wherein R9 and RIO are as defined above, NR9CO 2 RO, wherein R9 and RIO are as defined above, hydroxy, C1.
6 alkoxy,
)COR
9 wherein R 9 is as defined above, )C02R9, wherein R 9 is as defined above, )2-pyridyl, )3-pyridyl, )4-pyridyl, )2-oxazolyl, and bove, tbove, bove, tbove, WO 98/47513 PCT/GB98/01161 (26) 2-thiazolyl;
R
11
R
12 and R 13 are independently selected from the definitions of R
G
R7 and R8, or -OX; A is selected from the group consisting of: Ci.
6 alkyl, unsubstituted or substituted with one or more of the substituents selected from: hydroxy, oxo, Ci-6alkoxy, phenyl-CI-3alkoxy, phenyl,
-CN,
halo, wherein halo is fluoro, chloro, bromo or iodo, -NR9RIO, wherein R 9 and Rio are as defined above, -NR9CORIO, wherein R 9 and Rio are as defined above, -NR9CO 2
R
1 wherein R 9 and Ri 1 are as defined above,
-CONR
9 RIO, wherein R 9 and R 1 0 are as defined above,
-COR
9 wherein R 9 is as defined above, and -C0 2
R
9 wherein R 9 is as defined above; C2.-alkenyl, unsubstituted or substituted with one or more of the substituent(s) selected from: hydroxy, oxo, C1.6alkoxy, phenyl-Cl.salkoxy, phenyl,
-CN,
halo, WO 98/47513 WO 9847513PCT/GB98/O1 161 36
-CONR
9 R1O wherein R 9 and RiO are as defined above, -COR9 wherein R 9 is as defined above, and -C0 2 R9, wherein R 9 is as defined above; and C2-6alkynyl; B is a heterocycle, wherein the heterocycle is selected from the group consisting of: N-N IxX
,H
N-N N 4 N- N NN 0N 0N IX
H
S
N
Ix x
N-N
N
N-N
N N 5
H
H
N-N
N 0' x
N-N
N AS
N-N
N
x
N
x
N-N
/N
N
x WO 98/47513 WO 9847513PCT/GB98/01 161 37
N=N
x N N
S
x IF
N
H
H
N
N 0
H
NO
x
H
N
jS
N
x I
N
x Nj
N
x X
N
N
N x
N
I
x and wherein the heterocycle may be substituted in addition to -X with one or more substituent(s) selected from: CI-Galkyl, unsubstituted or substituted with halo, -CF 3
-OCH
3 or phenyl, (ii) Cl-6alkoxy, (iii) oxo, (iv) hydroxy, thioxo, 0 (vi) -SR 9 wherein R 9 is as defined above, (vii) halo, (viii) cyano, (ix) phenyl, trifluoromethyl, (xi) -(CH 2 )m-NR9RO, wherein mi is 0, 1 or 2, and R9 and RIO are as defined above, WO 98/47513 WO 9847513PCT/GB98/O1 161 38 (xii) -NR9CORIO, wherein R 9 and RIO are as defined above, (xiii) -CONR9RO, wherein R 9 and RIO are as defined above, (xiv) -C0 2
R
9 wherein R9 is as defined above, and (xv) -(CH2)m-0R 9 wherein m and R9 are as defined above; p isO0 or 1; X is selected from: -PO(OH)0- wherein M+ is a pharmaceutically acceptable monovalent counterion, -PO(0-) 2 -2M+, -PO(0%2 D 2 wherein D 2 is a pharmaceutically acceptable divalent counterion, -CH(R4)-PO(OH)0- wherein R 4 is hydrogen or CI-3alkyl, -CH(R4)-PO(0-) 2 -2M+, -CH(R4)-PO(O4)2
D
2 -S0 3 -CH(R4)-SO3&-
-CO-CH
2
CH
2 -C0 2 6) -CH(CH 3 )-O-CO-R5, wherein R5 is selected from the group consisting of: WO 98/47513 WO 9847513PCT/GB98/O1 161 39 (i) (hi) (iii) (iv) (v) (vi) 0 I 0 C0 2
-M+
o C0 2
J
NH
3 -0 C02 M 1110 (vii) and hydrogen, with the proviso that if p is 0 and none of R1~ 2 or R3are -OX, then X is other than hydrogen; Y is selected from the group consisting of: a single bond, -00-, WO 98/47513 WO 9847513PCT/GB98/O1 161 40
-CH
2 -CHR'5-, and -CRl 5 R16-, wherein R 1 5 and RIG are independently selected from the group consisting of: Ci.
6 alkyl, unsubstituted or substituted with one or more of the substituents selected from: hydroxy, (ii) oxo, (iii) CI-6alkoxy, (iv) phenyl-C1.3alkoxy, phenyl, (vi) -CN, (vii) halo, (viii) -NR 9 RO, wherein R 9 and RIO are as defined above, (ix) -NR9CORIO, wherein R9 and RiO are as defined above,
-NR
9
CO
2 Ri0, wherein R9 and RIO are as defined above, (xi) -CONR9R10, wherein R 9 and RIO are as defined above, (xii) -COR9, wherein R 9 is as defined above, and (xiii) -CO 2 R9, wherein R9 is as defined above; phenyl, unsubstituted. or substituted with one or more of the substituent(s) selected from: hydroxy, (ii) Ci-Balkoxy, (ill) CI.Galkyl, (iv) halo, (vi) -CN, (vii) -NO 2 (viii) -CF 3 (ix) -(CH 2 )m-NR9RlO, wherein mn, R 9 and RIO are as defined above, WO 98/47513 PCT/GB98/01161 -41 -NRSCOR1o, wherein R 9 and Rio are as defined above, (xi) -NR 9
CO
2 R1 0 wherein R 9 and Rio are as defined above, (xii) -CONR9RIO, wherein R 9 and Rio are as defined above, (xiii) -CO 2 NR9R10, wherein R 9 and RIO are as defined above, (xiv) -COR 9 wherein R 9 is as defined above, and (xv) -CO 2
R
9 wherein R 9 is as defined above; Z is selected from: hydrogen, CI-6alkyl, and hydroxy, with the proviso that ifY is Z is other than hydroxy, or ifY is -CHR'5-, then Z and R 5 may be joined together to form a double bond.
Particularly preferred compounds of formula (III) are those wherein:
R
2 and R3 are independently selected from the group consisting of: hydrogen, Ci-6alkyl, C2.zalkenyl, and phenyl;
R
G
R7 and R S are independently selected from the group consisting of: hydrogen, Ci-ealkyl, fluoro, chloro, bromo, iodo, and -CF3;
R
1
R
12 and R 1 3 are independently selected from the group consisting of: fluoro, chloro, bromo, and WO 98/47513 WO 9847513PCT/GB98/01 161 42iodo; A is unsubstituted i-calkyl; B is selected from the group consisting of: Hxx N-N NNI
%N
N NO0N 1X
H
XH
N-N
N
N-
Ix x
N-N
N A
H
H
N-N
N 0 x
N-N
N
S,
x
N-N
N
N-N
N
x
N
x x
H
N S Ix
N
x
H
N
x
N
N
S
H
H
N x p isO0 or 1; X is selected from: -PO(OH)0- wherein M+ is a pharmaceutically acceptable monovalent counterion, -PO(0-) 2 2M+,
-PO(O-)
2
-D
2 wherein D 2 is a pharmaceutically acceptable divalent counterion, -CH(R4)-PO(OH)O. wherein RI is hydrogen or C1.3alkyl, WO 98/47513 WO 9847513PCT/GB98/01161 43 -CH(R4)-PO(O-) 2 -2M+,
-CO-CH
2
CH
2 -C0 2
-CH(CH
3
)-O-CO-R
5 wherein R5 is selected from the group consisting of: H2+ M' INI 0 -11
OH
(iv)
(V)
(vi) (Vii) O C0 2
M+
0~
CO
2 M
NH
3 0* C0 2
.M
0 ;and Yis Z is hydrogen or Ci- 6 alkyl; and pharmaceutically acceptable salts thereof.
WO 98/47513 WO 9847513PCT/GB98/Ol 161 44- Particularly preferred compounds of formula (III) include: 5-bis(trifiuoromethyl)benzyloxy)-3(S)phenyl4(3.(5oxo.
1H, 4W 1,2, 4-triazolo)methyl)morpholine N-oxide; 5-bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-4-(3-.(4- (ethoxycarbonyloxy- 1-ethyl) -5 -oxo- 11-1, 2,4triazolo)methyl)morpholine; 5-bis(trifluoromethyl)phenyl)ethoxy)- fluorophenyl)-4-(3-(4-monophosphoryl--oxo- 1H- 1,2,4triazolo)methyl)morpholine; 5-bis(trifluoromethyl)phenyl)ethoxy) (4fluorophenyl)-4-(3-(l-monophosphoryl-5-oxo- 1H- 1,2,4triazolo)methyl)morpholine; 5-bis(trifluoromethyl)phenyl)ethoxy) (4fluorophenyl)-4-(3-(2-monophosphoryl-5-oxo- 1H- 1,2,4triazolo)methyl)morpholine; 2- 5-bis(trifluoromethyl)phenyl)ethoxy)- fluorophenyl)-4- (5-oxyphosphoryl- 1H- 1,2,4triazolo)methyl)morpholine; 5-bis(trifluoromethyl)phenyl)ethoxy)-3- (4fluorophenyl)-4-(3-(l-monophosphoryl-5-oxo-4H- 1,2,4triazolo)methyl)morpholine; and pharmaceutically acceptable salts thereof.
Further preferred NK-1 receptor antagonists are those described in European Patent Specification No. WO 96/05181, i.e. compounds of formula (IV): WO 98/47513 WO 9847513PCT/GB98/cu 161 yR R9a 0 0
R
3 R 9T(N -(IV) x wherein X is a group of the formula NR6R7 or a C- or N-linked imidazolyl ring; Y is hydrogen or O1.4alkyl optionally substituted by a hydroxy group; RI is hydrogen, halogen, C 1.6alkyl, Ci-Galkoxy, OF 3
NO
2 ON, SRa, SORa, SO 2 Ra, CO 2 Ra, OONRaRb, C26alkenyl, O26alkynyl or OI-4alkyl substituted by C1p4alkoxy, wherein Ra and Rb each independently represent hydrogen or COl4alkyl;
R
2 is hydrogen, halogen, O1.Galkyl, Ci.o;alkoxy substituted by CI.4alkoxy or CF3;
R
3 is hydrogen, halogen or CF 3
R
4 is hydrogen, halogen, Ol-Galkyl, Oi.6alkoxy, hydroxy, OF 3
NO
2 ON, SRa, SORa, SO 2 Ra, OO 2 Ra, OONRaRb, 02-ralkenyl, 02-6alkynyl or Oi.4alkyl substituted by Ol-4alkoxy, wherein Ra and Rb are as previously defined; is hydrogen, halogen, Ol.6alkyl, Ol-ralkoxy substituted by Ol.4alkoxy or OF 3 RG is hydrogen, 0 i.6alkyl, C37cycloalkyl, O37cycloalkylCl .4alkyl, phenyl, or 02.4alkyl substituted by Op.4alkoxy or hydroxy; R7 is hydrogen, C 1-6alkyl, C37cycloalkyl, O37cycloalkylCl -4alkyl, phenyl, or 024alky1 substituted by one or two substituents selected from WO 98/47513 PCT/GB98/01161 -46- C14alkoxy, hydroxy or a 4, 5 or 6 membered heteroaliphatic ring containing one or two heteroatoms selected from N, 0 and S; or R 6 and R 7 together with the nitrogen atom to which they are attached, form a saturated or partially saturated heterocyclic ring of 4 to 7 ring atoms, which ring may optionally contain in the ring one oxygen- or sulphur atom or a group selected from NR8, S(0) or S(0) 2 and which ring may be optionally substituted by one or two groups selected from hydroxyC1-4alkyl, C1.4alkoxyC1.4alkyl, oxo, CORa or C0 2 Ra where Ra is as previously defined; or R 6 and R 7 together with the nitrogen atom to which they are attached, form a non-aromatic azabicyclic ring system of 6 to 12 ring atoms;
R
8 is hydrogen, C1.
4 alkyl, hydroxyC1.
4 alkyl or C1-4alkoxyC1.
4 alkyl; and
R
9 a and R 9 b are each independently hydrogen or C1.4alkyl, or R9a and
R
9 b 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'
Y A N 0 (IVa)
SA
3 x wherein A' is fluorine or CF 3 WO 98/47513 WO 9847513PCT/GB98/O1 161 47
A
2 is fluorine or CF 3
A
3 is fluorine or hydrogen; and X and Y are as defined in relation to formula Specific compounds of formula (IV) of use in the present invention include: 5-bis(trifluoromethyl)phenyl)ethoxy)- 3-(S)-(4-fluorophenyl)- 4-(4-morpholinobut-2-yn-yl)morpholine; 5-bis(trifluoromethyl)phenyl)ethoxy)-4-(4-N, Ndimethylaminobut-2-yn-yl)- 3-(S)-(4-fluorophenyl)morpholine; 4-(4-azetidinylbut-2-yn-yl)- 2- ethoxy)-3-(S)-(4-fluorophenyl)morpholine; 5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)- 4-(4-imidazolylbut-2-yn-yl)morpholine; 5-bis(trifluoromethyl)phenyl)ethoxy)-3- (S)-(4-fluorophenyl)- 4- (N-methylpiperazinyl)but-2-yn-yl)morphoine; 4-(4-bis(2-methoxyethyl)aminobut-2-yn-yl)-2-(R)-( bis(trifluoromethyl)phenyl)ethoxy) (4-fluorophenyl)morpholine; 5-bis(trifluoromethyl)phenyl)ethoxy)-3- (4-fluorophenyl) 4-(4-pyrrolidinobut-2-yn-yl)morpholine; (4-fluorophenyl)-2-(R)-(1-(R) -(3-fluoro- ethoxy)-4-(4-morpholinobut-2-yn-yl)morpholine; 3- (S)-(4-fluorophenyl)-4-(4-morpholinobut- 2-yn-yl) (trifluoromethyl)phenyl)ethoxy)morpholine; 4-(4-azetidinylbut-2-yn-yl)-3-(S)-(4-fluorophenyl)-2-(R)-(l-(R)-(3- (trifluoromethyl)phenyl)ethoxy)morpholine; 5-bis (trifluoromethyl)phenyl)ethoxy)-4- (2methoxyethyl)-N-methyl) aminobut-2-yn-yl)-3-(S)-phenylmorpholine; 2- 5-bis(trifluoromethyl)phenyl)ethoxy)-4- (4-(N-cyclopropyl-N- (2-methoxyethyl) amino)but-2-yn-yl) (S)-phenylmorpholine; 5-bis(trifluoromethyl)phenyl)ethoxy)-4-(4-(N-isopropyl-N-(2methoxyethyl)amino)but- 2-yn-yl) (S)-.phenylmorpholine; WO 98/47513 WO 9847513PCT/GB98/01161 48 N-dimethylamino)but-2-yn-yl)- 3-(S)-(4-fluorophenyl)- fluoro- 5-(trifluoromethyl)phenyl- 2-hydroxyethoxy)morpholine; 4- (4-azetidinylbut-2yn-yl)-3-(S)-(4-fluorophenyl)-2-(R).(1 (trifluoromethyl)phenyl)-2-hydroxyethoxy)morpholine; 5-bis(trifluoromethyl)phenyl)-2-hydroxyethoxy)-4-(4-.(N,
N-
dimethylamino)but-2-yn-yl)- 3- (5)-(4-fluorophenyl)morpholine; hydroxyethoxy)-3-(S)-(4-fluorophenyl)morpholine; 4-(4-N-bis(2-methoxy)ethyl-N-methylamino)but-2-yn-yl)-2-(R)- bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)morphoine; 2- 5-bis(trifluoromethyl)phenyl)ethoxy)- 3- (5)-(4-fluorop henyl)- (2-(S)-(methoxymethyl)pyrrolidino)but-2-yn-yl)morpholine; 4-(4-(7-azabicyclol2.2. 1]heptano)but-2-yn-yl)-2-(R)-(1-(R)-(3, bis(trifluoromethyl)phenyl)ethoxy)-3- (S)-(4-fluorophenyl)morpholine; 2- 5-bis(trifluoromethyl)phenyl)ethoxy)-4- (4diisopropylaminobut-2-yn-yl)-3- (S)-(4-fluorophenyl)morpholine; 2- -(3-fluoro-5-(trifluoromethyl)phenyl)ethoxy)-4- (methoxymethyl)pyrrolidino)but- 2-yn-yl)-3- (S)-phenylmorpholine; 2- 5-bis(trifluoromethyl)phenyl)ethoxy) (4-fluorophenyl) 4- -(hydroxymethyl)pyrrolidino)but-2-yn-yl)morpholine; and pharmaceutically acceptable salts thereof.
Another class of NX- 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 MV: R2
(V)
WO 98/47513 PCT/GB98/01161 -49or a pharmaceutically acceptable salt thereof, wherein Y is (CH 2 wherein n is an integer from 1 to 4, and wherein any one of the carbon-carbon single bonds in said (CH 2 )n may optionally be replaced by a carbon-carbon double bond, and wherein any one of the carbon atoms of said (CH 2 )n may optionally be substituted with R 4 and wherein any one of the carbon atoms of said (CH 2 )n may optionally be substituted with R 7 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 (CH 2 )m may optionally be substituted with R8;
R
1 is hydrogen or C1.salkyl optionally substituted with hydroxy, C1.4alkoxy or fluoro;
R
2 is a radical selected from hydrogen, C1.
6 straight or branched alkyl, C3-7cycloalkyl wherein one of the CH 2 groups in said cycloalkyl may optionally be replaced by NH, oxygen or sulphur; aryl selected from phenyl and naphthyl; heteroaryl selected from indanyl, thienyl, furyl, pyridyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl and quinolyl; phenyl-C2.Galkyl, 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, C1.calkoxy, trifluoromethyl, amino, C1-Galkylamino, CI.ealkyl-O-CO, C 1 alkyl-O-CO- C1-6alkyl, C1.6alkyl-CO-O, C1-6alkyl-CO-Cl.ialkyl-O-, Ciocalkyl-CO, Cl-6alkyl-CO-C 1 i.alkyl-, di-Ci-6alkylamino, -CONH-Cl.calkyl, Ci-6alkyl-CO-NH-C1.6alkyl, -NHCOH and -NHCO-Ci.calkyl; 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; WO 98/47513 PCT/GB98/01161 or R 2 and R 5 together with the carbon to which they are attached, form a saturated ring having from 3 to 7 carbon atoms wherein one of the
CH
2 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 (CH 2 groups in said cycloalkyl may optionally be replaced by NH, oxygen or sulphur; wherein each of said aryl and heteroaryl groups may optionally be substituted with one or more substituents, and said Ca-.cycloalkyl may optionally be substituted with one or two substituents, each of said substituents being independently selected from halo, nitro, C1.calkyl, Ci-.alkoxy, trifluoromethyl, amino, CI-6alkylamino, -CO-NH- Ci.
1 alkyl, CI-6alkyl-CO-NH-C1.
6 alkyl, -NHCOH and -NHCO-C1.6alkyl;
R
4 and R 7 are each independently selected from hydroxy, halogen, halo, amino, oxo, cyano, methylene, hydroxymethyl, halomethyl, Cl-calkylamino, di-Ci-calkylamino, C1.-alkoxy, C1.calkyl-O-CO, Cil.alkyl-O-CO-C1-6alkyl, C.i-alkyl-CO-O, C1.6alkyl-CO-Ci.salkyl-O-, Ci.Galkyl-CO-, C1.6alkyl-CO-C1-6alkyl, and the radicals set forth in the definition of R2;
R
6 is -NHCOR 9
-NHCH
2
R
9 S0 2 R8 or one of the radicals set forth in any of the definitions of R 2
R
4 and R7;
R
8 is oximino (=NOH) or one of the radicals set forth in any of the definitions of R 2
R
4 and R 7
R
9 is Ci.calkyl, hydrogen, phenyl or phenylCi1.alkyl; with the proviso that when m is 0, R 8 is absent, when R 4 RG, R 7 or
R
8 is as defined in R 2 it cannot form together with the carbon to which it is attached ,a ring with R 5 and when R 4 and R 7 are attached to the same carbon atom, then either each of R 4 and R 7 is independently selected from hydrogen, fluoro and CI-6alkyl, or R 4 and R 7 together with the carbon WO 98/47513 PCT/GB98/01161 -51to which they are attached, for a C 3 6 saturated carbocyclic ring that forms a spiro compound with the nitrogen-containing ring to which they are attached.
A particularly preferred compound of formula is 2
S,
3 S)-cis-3-(2methoxybenzylamino)-2-phenylpiperidine; or a pharmaceutically acceptable salt thereof.
Another class of NK-1 receptor antagonists of use in the present invention is that described in International Patent Specification No. WO 93/21155, i.e. compounds of formula (VI): R R 0 N LCH-R (VI) R 1 2
R
R
3
R
4 or a pharmaceutically acceptable salt thereof, wherein radicals R are phenyl radicals optionally 2- or 3-substituted by a halogen atom or a methyl radical;
R
1 is optionally substituted phenyl, cyclohexadienyl, naphthyl, indenyl or optionally substituted heterocycle;
R
2 is H, halogen, OH, alkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkyloxy, alkylthio, acyloxy, carboxy, optionally substituted alkyloxycarbonyl, benzyloxycarbonyl, amino or acylamino;
R
3 is optionally 2-substituted phenyl;
R
4 is OH or fluorine when R5 is H; or R 4 and R 5 are OH; or R 4 and R 5 together form a bond.
A particularly preferred compound of formula (VI) is (3aS, 4S, 7aS)- 7,7-diphenyl-4-(2-methoxyphenyl)-2-[(2S)-( 2 -methoxyphenyl)propionyl] perhydroisoindol-4-ol; or a pharmaceutically acceptable salt thereof.
WO 98/47513 PCT/GB98/01161 52- 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--CH--CH 2 -CH-Am A- (VII) Ar' 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.salkylene group; Ar' represents a phenyl group which is unsubstituted or substituted by one or more substituents selected from halogen, preferably chlorine or fluorine, trifluoromethyl, C1.4alkoxy, C1-4alkyl where the said substituents may be the same or different; a thienyl group; a benzothienyl group; a naphthyl group; or an indolyl group; R represents hydrogen, C1.4alkyl, co-C1-4alkoxyC1-4alkyl, or o0-C2.
4 alkanoyloxyC2.4alkyl; Q represents hydrogen; or Q and R together form a 1,2-ethylene, 1,3-propylene or 1,4butylene group; Am represents the radical 1.
in which Xi, X 2 and Xa, 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.
WO 98/47513 PCT/GB98/01161 -53- A particularly preferred compound of formula (VII) is (3,4-dichlorophenyl)- 1-[(3-isopropoxyphenyl)acetyl]-3-piperidinyl]ethyl]-4phenyl-l-azabicyclo[2,2,2]octane; or a pharmaceutically acceptable salt, especially the chloride, thereof.
Another class of NK-1 receptor antagonists of use in the present invention is that described in European Patent Specification No.
0 532 456, i.e. compounds of formula (VIII):
R
3 R'-N .XX--R 4
(VIII)
R
2
-X
I
or a pharmaceutically acceptable salt thereof, wherein
R
1 represents an optionally substituted aralkyl, aryloxyalykl, heteroaralkyl, aroyl, heteroaroyl, cycloalkylcarbonyl, aralkanoyl, heteroarylalkanoyl, aralkoxycarbonyl or arylcarbamoyl group or the acyl group of an ct-amino acid optionally N-substituted by a lower alkanoyl or carbamoyl-lower alkanoyl group;
R
2 represents cycloalkyl or an optionally substituted aryl or heteroaryl group;
R
3 represents hydrogen, alkyl, carbamoyl or an alkanoyl or alkenoyl group optionally substituted by carboxy or esterified or amidated carboxy;
R
4 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;
X
2 represents alkylene, carbonyl or a bond; and Xa 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 4S*)-2- 4 -quinolinylmethyl)-4-piperidineamine; or a pharmaceutically acceptable salt thereof.
WO 98/47513 PCT/GB98/01161 -54- 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) 2
CH
2
R
R-Y-A-N CONHCHCON (IX)
R
or a pharmaceutically acceptable salt thereof, wherein
R
I is aryl, or a group of the formula: z X is CH or N; and Z is 0 or N-R 5 in which R 5 is hydrogen or lower alkyl;
R
2 is hydroxy or lower alkoxy;
R
3 is hydrogen or optionally substituted lower alkyl;
R
4 is optionally substituted ar(lower)alkyl; A is carbonyl or sulfonyl; and Y is a bond or lower alkenylene.
A particularly preferred compound of formula (IX) is the compound of formula (IXa)
HO
0 o CH3 3? C (Ixa)
H
3
C
WO 98/47513 PCT/GB98/01161 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) H R N R N R 2
H
(X)
or a pharmaceutically acceptable salt thereof, wherein
R
1 is aryl selected from indanyl, phenyl and naphthyl; heteroaryl selected from thienyl, furyl, pyridyl and quinolyl; and cycloalkyl having 3 to 7 carbon atoms, wherein one of said carbon atoms may optionally be replaced by nitrogen, oxygen or sulfur; wherein each of said aryl and heteroaryl groups may optionally be substituted with one or more substituents, and said C3.7cycloalkyl 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.ioalkoxy optionally substituted with from one to three fluoro groups, amino, Ci-ioalkyl-S-, Ci.ioalkyl-S(O)-, Ci-loalkyl-SO2-, phenyl, phenoxy, Ci.loalkyl-SO 2
NH-,
Cl.loalkyl-SO 2 NH-Ci-ioakyl-, Cl-ioalkylamino-diCi-loalkyl-, cyano, hydroxy, cycloalkoxy having 3 to 7 carbon atoms, C.i-alkylamino, C1.-dialkylamino, HC(O)NH- and Cl.loalkyl-C(O)NH-; and
R
2 is thienyl, benzhydryl, naphthyl or phenyl optionally substituted with from one to three substituents independently selected from chloro, bromo, fluoro, iodo, cycloalkoxy having 3 to 7 carbon atoms, Ci-loalkyl 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 is (2S,3S)-3-(2methoxy-5-trifluoromethoxybenzyl)-amino-2-phenylpiperidine; or a pharmaceutically acceptable salt thereof.
WO 98/47513 PCT/GB98/01161 -56- 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)
R
2
(CH
2 N R3
NN
H HR4
R
(XI)
or a pharmaceutically acceptable salt thereof, wherein
R
1 is a C1.4alkoxy group; R2 is 6
N
NN
N-N
R
3 is a hydrogen or halogen atom;
R
4 and R 5 may each independently represent a hydrogen or halogen atom, or a C1.4alkyl, C1-4alkoxy or trifluoromethyl group;
R
G is a hydrogen atom, a C1.4alkyl, (CH2)mcyclopropyl, -S(O)nC 1 4alkyl, phenyl, NR 7 R8, CH 2
C(O)CF
3 or trifluoromethyl group;
R
7 and R 8 may each independently represent a hydrogen atom, or a C1.
4 alkyl or acyl group; x represents zero or 1; n represents zero, 1 or 2; and m represents zero or 1.
Particularly preferred compounds of formula (XI) are tetrazol-1-yl-benzyl)-([2S,3S]-2-phenyl-piperidin-3-yl)-amine; and [2- 1 -yl)-benzyl]- 3S]-2-phenylpiperidin-3-yl)-amine; or a pharmaceutically acceptable salt thereof.
WO 98/47513 WO 9847513PCT/GB98/01 161 57 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) N- R 4
I
(CO)p
(CH
2 )m II (XII) or a pharmaceutically acceptable salt thereof, wherein in 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, Ci-3alkoxy, trifluoromethyl, C1.
4 alkyl, phenyl-CI-3alkoxy, Or C 1.4alkanoyl groups; R' is trityl, phenyl, diphenylinethyl, phenoxy, phenylthio, piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, indolinyl, indolyl, benzothienyl, hexamethyleneiminyl, benzofuranyl, tetrahydropyridinyl, quinolinyl, isoquinolinyl, reduced quinolinyl, reduced isoquinolinyl, phenyl- (C I. alkyl) phenyl-(Ci .4alkoxy)-, quinolinyl-(Ci 4alkyl)-, isoquinolinyl-(CI- 4 alkyl)-, reduced quniolinyl-(CI -alkyl) reduced isoquinolinyl-(CI-4alkyl)-, benzoyl-(Clv3alkyl)-, C 1.4alkyl, or -NH-CH 2 any one of which R1 groups may be substituted with halo, CI-4alkyI, Cl4alkoxy, trifluoromethyl, amino, C 1 .4alkylamino, di(C 1.4alkyl)amino, or C2.
4 alkanoylamino; or any one of which R' groups may be substituted with phenyl, piperazinyl, C3.8cycloalkyl, benzyl, Cl.4alkyl, piperidinyl, pyridinyl, WO 98/47513 WO 9847513PCTIGB98/O1 161 58 pyrimidinyl, C 2 6alkanoylamino, pyrrolidinyl, C2.6alkanoyl, .or C i-4alkoxycarbonyl; any one of which groups may be substituted with halo, C1.
4 alkyl, C 1 4 alkoxy, trifluoromethyl, amino, C l.4alkylamino, di(C 14alkyl)amino, or
C
2 4 alkanoylamino; or R 1 is amino, a leaving group, hydrogen, C1.4alkylamino, or di(C I 4 alkyl)amino;
R
5 is pyridyl, aniino-(Cl.3alkyl)-, or anilinocarbonyl;
R
2 is hydrogen, C1-4alkyl, Cl.
4 alkylsulfonyl, carboxy-(CI-3alkyl)-, C 3 alkoxycarbonyl- (C .3alkyl)-, or -CO-R 6 RG is hydrogen, Ci- 4 alkyl, C1l3haloalkyl, phenyl, C1.3alkoxy, Cl 1 3 hydroxyalkyl, amino, C 1 .4alkylamino, di(C I 4alkyl) amino, or (CH2)q-R 7 q is zero to 3;
R
7 is carboxy, Cl-4alkoxycarbonyl, C1.4alkylcarbonyloxy, amino, CI-4alkylamino, di(C l.4alkyl)amino, C 1 -6alkoxycarbonylamino, or phenoxy, phenylthio, piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, indolinyl, indolyl, benzothienyl, benzofuranyl, quinolinyl, phenyl- (C 1.4alkyl)-, quinolinyl- (Cli 4 alkyl)-, isoquinolinyl- (Cv-4aIkyl) reduced quinolinyl- (Cl.
4 alkyl)-, reduced isoquinolinyl- (C l.4alkyl)-, benzoyl-C l3alkyl; any one of which aryl or heterocyclic R 7 groups may be substituted with halo, trifluoromethyl, CL.4alkoxy, Cj- 4 alkyl, amino, CI-4alkylamino, di(C 1.4alkyl)amino, or C2-4alkanoylamino; or any one of which R 7 groups may be substituted with phenyl, piperazinyl, C 3 .8cycloalkyl, benzyl, piperidinyl, pyridinyl, pyrimidinyl, pyrrolidinyl, C 2 6 alkanoyl, or C 1 4 alkoxycarbonyl; any of which groups may be substituted with halo, trifluoromethyl, amino, CI- 4 alkoxy, C l-4alkyl, C 1-4alkylamino, di(C 14alkyl)amino, or C2.4alkanoylamino; R8 is hydrogen or Ci-Galkyl;
R
3 is phenyl, phenyl-(Cl-6alkyl)-, C 3 -8cycloalkyl, C58cycloalkenyl, C i.salky1, naphthyl, C2.8alkenyl, or hydrogen; WO 98/47513 PCT/GB98/01161 -59any one or which groups except hydrogen may be substituted with one or two halo, Cls.alkoxy, C1.3alkylthio, nitro, trifluoromethyl, or C.-3alkyl groups; and
R
4 is hydrogen or C1.3alkyl; with the proviso that if R 1 is hydrogen or halo, R 3 is phenyl, phenyl-(Cl.6alkyl)-, Cs.scycloalkyl, C5.8cycloalkenyl, or naphthyl.
A particularly preferred compound of formula (XII) is methoxybenzyl)acetylamino]-3-(1H-indol-3-yl)-2-[N-(2-(4-piperidin-1yl)piperidin-l-yl)acetylamino]propane; or a pharmaceutically acceptable salt thereof.
The preferred compounds of formulae (III) and (IV) will have the 2- and 3-substituents on the morpholine ring in the cis arrangement, the preferred stereochemistry being as shown in the following general formula:
O)
R
Where the benzyloxy moiety is a-substituted, the preferred stereochemistry of the a-carbon is either when the substituent is an alkyl methyl) group or when the substituent is a hydroxyalkyl 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 straightchained or branched propyl and butyl groups. Particular alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl and tert-butyl.
WO 98/47513 PCT/GB98/01161 Unless otherwise defined herein, suitable alkenyl groups include straight-chained and branched alkenyl groups containing from 2 to 6 carbon atoms. Typical examples include vinyl and allyl groups.
Unless otherwise defined herein, suitable alkynyl groups include straight-chained and branched alkynyl groups containing from 2 to 6.carbon atoms. Typical examples include ethynyl and propargyl groups.
Unless otherwise defined herein, suitable cycloalkyl groups include groups containing from 3 to 7 carbon atoms. Particular cycloalkyl groups are cyclopropyl and cyclohexyl.
Unless otherwise defined herein, suitable aryl groups include phenyl and naphthyl groups.
A particular aryl-C 1 .,alkyl, e.g. phenyl-Ci.calkyl, group is benzyl.
Unless otherwise defined herein, suitable heteroaryl groups include pyridyl, quinolyl, isoquinolyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyranyl, furyl, benzofuryl, thienyl, benzthienyl, imidazolyl, oxadiazolyl and thiadiazolyl groups.
The term "halogen" as used herein includes fluorine, chlorine, bromine and iodine.
The compounds of use in this invention may have one or more asymmetric centres and can therefore exist as enantiomers and possibly as diastereoisomers. It is to be understood that the present invention relates to the use of all such isomers and mixtures thereof.
Suitable pharmaceutically acceptable salts of the NK-1 receptor antagonists of use in the present invention include acid addition salts which may, for example, be formed by mixing a solution of the compound with a solution of a pharmaceutically acceptable non-toxic acid such as hydrochloric acid, fumaric acid, maleic acid, succinic acid, acetic acid, citric acid, tartaric acid, carbonic acid, phosphoric acid or sulphuric acid. Salts of amine groups may also comprise the quaternary ammonium salts in which the amino nitrogen atom carries an alkyl, alkenyl, alkynyl or aralkyl group. Where the compound carries an acidic group, for example a WO 98/47513 PCT/GB98/01161 -61carboxylic 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
(III),
(VII), (VIII), (XI) 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 (III), (VII), (VIII), (XI) and (XII).
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 (III), (VII), (VIII), (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 (III), (VII), (VIII), (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 (III),
(VII),
(VIII), (XI) and (XII) and an anorectic agent as a combined WO 98/47513 PCT/GB98/01161 -62preparation 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 (III), (VII), (VIII), (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 (III), (VII), (VIII), (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 (III), (VII), (VIII), (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 (III), (VII), (VIII), (IX), (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 (III), (VII), (VIII), (XI) and (XII) and a halogenated amphetamine derivative selected from WO 98/47513 PCT/GB98/01161 -63the 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 (III), (VII), (VIII), (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 (III),
(VII),
(VIII), (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 (III), (VII), (VIII), (IX), (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, WO 98/47513 PCT/GB98/01161 -64solutions or suspensions, or suppositories, for oral, parenteral or rectal administration, by inhalation or insufflation or administration by transdermal patches or by buccal cavity absorption wafers. Oral dosage forms are particularly preferred 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 WO 98/47513 PCT/GB98/01161 suspensions, and flavoured emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil, peanut oil or soybean oil, as well as elixirs and similar pharmaceutical vehicles. Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinyl-pyrrolidone or gelatin.
Preferred compositions for administration by injection include those comprising a NK-1 receptor antagonist as the active ingredient, in association with a surface-active agent (or wetting agent or surfactant) or in the form of an emulsion (as a water-in-oil or oil-in-water emulsion).
Suitable surface-active agents include, in particular, non-ionic agents, such as polyoxyethylenesorbitans TweenTM 20, 40, 60, 80 or and other sorbitans SpanTM 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 It will be appreciated that other ingredients may be added, for example mannitol or other pharmaceutically acceptable vehicles, if necessary.
Suitable emulsions may be prepared using commercially available fat emulsions, such as IntralipidTM, LiposynT, InfonutrolTM, LipofundinTM and LipiphysanTM. The active ingredient may be either dissolved in a premixed emulsion composition or alternatively it may be dissolved in an oil soybean oil, safflower oil, cottonseed oil, sesame oil, corn oil or almond oil) and an emulsion formed upon mixing with a phospholipid 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 The fat emulsion will preferably comprise fat droplets between 0.1 and 1.0m, particularly 0.1 and 0.5pm, and have a pH in the range of to WO 98/47513 PCT/GB98/01161 -66- Particularly preferred emulsion compositions are those prepared by mixing a NK-1 receptor antagonist selected from the compounds of formulae (III), (VII), (VIII), (XI) and (XII) with IntralipidTM 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 WO 98/47513 PCT/GB98/01161 -67the 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 1500mg per day, preferably about 0.25 to 1500mg per day, and especially about 0.25 to 500mg/kg 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.
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 (III), (VII), (VIII), (XI) and (XII) may be prepared by the methods described in EP-A-0 577 394 (or WO 95/16679), WO 95/18124, WO 95/23798, WO 96/05181, EP-A-0 436 334, WO 93/21155, EP-A-0 591 040, EP-A-0 532 456, EP-A-0 443 132, WO 92/17449, WO 95/08549 and WO 95/14017, respectively.
Particularly preferred NK-1 receptor antagonists of the formulae (III), (VII), (VIII), (XI) and (XII) for use in the present invention are compounds which are potent NK-1 receptor antagonists, i.e. compounds with an NK-1 receptor affinity (IC 50 of less than 100nM.
WO 98/47513 PCT/GB98/01161 -68- 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 (ICoo) of less than favourably less than 2nM and preferably less than InM.
Especially preferred NK-1 receptor antagonists of use in the present 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 binding NK-1 receptor binding assays are performed in intact Chinese hamster ovary (CHO) cells expressing the human NK-1 receptor using a modification of the assay conditions described by Cascieri et al, J.
Pharmacol. Exp. Ther., 1992, 42, 458. Typically, the receptor is expressed at a level of 3x10 5 receptors per cell. Cells are grown in monolayer culture, detached from the plate with enzyme-free dissociation solution (Speciality Media Inc.), and washed prior to use in the assay. 125 I-Tyrs-substance P (0.lnM, 2000Ci/mmol; New England Nuclear) is incubated in the presence or absence of test compounds (dissolved in 51 dimethylsulphoxide, DMSO) with 5x10 4 CHO cells. Ligand binding is performed in 0.25ml of Tris-HC1, pH7.5, containing 5mM MnCl 2 150mM NaC1, 0.02% bovine serum albumin (Sigma), 50pg/ml chymostatin (Peninsula), 0.lnM phenylmethylsulphonyl fluoride, 2ug/ml pepstatin, 2[tg/ml leupeptin and 2.8pg/ml furoyl saccharine. The incubation proceeds at room temperature until equilibrium is achieved (>40 minutes) and the receptor-ligand complex is harvested by filtration over GF/C filters pre-soaked in 0.1% polyethylenimine using a Tomtek 96-well harvester. Non-specific binding is determined using excess substance P (gIM) and represents <10% of total binding.
WO 98/47513 PCT/GB98/01161 -69- 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 GR73632, or caused by aversive stimulation such as foot shock or single housing, based on the method of Rupniak Williams, Eur. J. Pharmacol., 1994, 265, 179.
Male or female Mongolian gerbils (35-70g) are anaesthetised by inhalation of an isoflurane/oxygen mixture to permit exposure of the jugular vein in order to permit administration of test compounds or vehicle in an injection volume of approximately 5ml/kg i.v. Alternatively, test compounds may be administered orally or by subcutaneous or intraperitoneal routes. A skin incision is then made in the midline of the scalp to expose the skull. An anxiogenic agent pentagastrin) or a selective NK-1 receptor agonist GR73632 (d Ala[L-Pro 9 ,Me-Leu'O]substance is infused directly into the cerebral ventricles (e.g.
3pmol in 5gl depending on test substance) by vertical insertion of a cuffed 27 gauge needle to a depth of 4.5mm below bregma. The scalp incision is closed and the animal allowed to recover from anaesthesia in a clear perspex observation box (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 minutes later they are fed with approximately 100g of tinned cat food. At 60 minutes following oral dosing, cisplatin (10mg/kg) is given i.v. via a jugular vein catheter WO 98/47513 PCT/GB98/01161 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 19cm) 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 minutes as described above. The duration and/or number of vocalisation on drug treatment days may be expressed as a percentage of the pretreatment 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 WO 98/47513 PCT/GB98/01161 -71compound at each dose tested.
A suitable selection cascade for NKi antagonists of use according to the present invention is as follows: Determine affinity for human NKI receptor in radioligand binding studies (Assay select compounds with IC 50 10nM, preferably 2nM, especially ICo 50 InM.
(ii) Determine ability of compounds to penetrate CNS by their ability to inhibit foot tapping in gerbils induced by central injection of an
NK
1 agonist (Assay select compounds that inhibit foot tapping with
ID
50 3mg/kg and preferably ID 50 1mg/kg i.v. when administered immediately prior to central NK 1 agonist challenge, or ID 5 o 30mg/kg p.o., and preferably ID 5 o 10mg/kg p.o. 1 hour prior to challenge.
(iii) Determine central duration of action of compounds in gerbil foot tapping assay following intravenous administration 24 hours prior to central NK 1 agonist challenge; select compounds showing 25-fold loss of potency compared with IDso determined in step (ii) above with the proviso that ID 50 10mg/kg and preferably 5mg/kg i.v. after 24 hour pre-treatment.
(iv) Determine oral bioavailability of compounds by pharmacokinetic analysis, activity in gerbil foot tapping assay following oral administration and/or by ability to inhibit cisplatin-induced emesis in ferrets (Assay select compounds with IDgo 5 3mg/kg and preferably
ID
9 0 1mg/kg p.o.
Particularly preferred compounds of use in the present invention are identified using steps to (iv) followed by step Determine activity of compounds in assays sensitive to conventional serotonergic drugs (inhibition of pharmacologically evoked foot tapping in gerbils and/or inhibition of distress vocalisations in guinea- WO 98/47513 PCT/GB98/01161 72pig pups (Assay Select compounds with ID 5 o 20mg/kg, and preferably IDo 0 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 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: IC 5 o=0.lnM gerbil foot-tapping (5 mins.): ID50=0.36mg/kg i.v.
gerbil foot-tapping (24 hrs.): ID5o=0.33mg/kg i.v.
ferret emesis: ID9o<3mg/kg p.o.
guinea-pig vocalisation ID 50 =0.73mg/kg p.o.
(4hrs. pretreatment) Another example of a NK-1 receptor antagonist of use in the present invention is the compound bis(trifluoromethyl)phenyl)ethoxy)-4-(5-(N,N-dimethylamino)methyl-1,2,3triazol-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: IC5o=0.25nM gerbil foot-tapping (5 mins.): ID5o=0.12mg/kg i.v.
gerbil foot-tapping (24 hrs.): IDo=0.17mg/kg i.v.
WO 98/47513 PCT/GB98/01161 -73guinea-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 Agents on Food Intake and Body Weight 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 on a wet diet consisting of sweetened condensed milk and standard ground rodent chow vol:vol).
Fresh wet chow was provided daily. These mice will be referred to as dietinduced 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 ad libitum. Mice were housed with a 12 hour light/dark cycle (4.00am lights on) through out the course of the described studies.
Mice were weighed bi-weekly until a point that both DIO and NOL mice were weight stable (approximately 20 weeks). At this time, DIO mice weighed significantly more than NOL mice (p 2 0.01). DIO mice also exhibited elevated insulin and glucose levels, as well as polyuria.
Food Intake: (All food intake studies were performed on weight stable DIO mice.
Both food and water were available before treatment.) The effect that the anorectic agent, dexfenfluramine had on food intake in DIO mice was determined previously (ED 5 o 3 mg/kg, ip). The combined effect that 2 -methoxy-5-(5-trifluoromethyl-tetrazol-1-yl)-benzyl]- ([2S,3S]-2-phenyl-piperidin-3-yl)amine (GR205171) and dexfenfluramine WO. 98/47513 PCT/GB98/01161 -74had 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: Saline/Saline 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 mins apart. All injections were administered ip., in a volume of 0.2 ml between 3.00pm 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 Weight: (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.
WO 98/47513 PCT/GB98/01161 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 of dexfenfluramine NK-1 antagonist dexfenfluramine Microcrystalline cellulose Modified food corn starch Lactose Magnesium Stearate 50.
15.
80.
80.
174.
0.
Amount mg .0 100.0 .0 15.0 .0 80.0 0 80.0 .5 124.5 5 0.5 300.0 15.0 80.0 80.0 124.5 EXAMPLE 2 Tablets containing 50-300mg of NK-1 antagonist and of fenfluramine NK-1 antagonist fenfluramine Microcrystalline cellulose Modified food corn starch Lactose Magnesium Stearate Amount mg 50.0 100.0 300.0 60.0 60.0 60.0 80.0 80.0 80.0 80.0 80.0 80.0 129.5 179.5 129.5 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 WO. 98/47513 PCT/GB98/01161 -76then compressed into tablets containing 50mg, 100mg and 3 00mg of the NK-1 receptor antagonist per tablet.
EXAMPLE 3 Parenteral injection Active Ingredients Citric Acid Monohydrate Sodium Phosphate Sodium Chloride Water for injection Amount 10 to 300mg 0.75mg 9mg to 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.
Claims (131)
1. Use of an orally active, CNS-penetrant NK-1 receptor antagonist for the manufacture of a medicament for the treatment or prevention of eating disorders.
2. The use according to claim 1 which further comprises the simultaneous, separate or sequential administration of an anorectic agent.
3. The use according to claim 1 or 2, wherein the NK-1 receptor antagonist is a compound of formula I R X R 4 R N (I) wherein R 1 is selected from the group consisting of: C1-6alkyl, substituted with one or more of 10 the substituents selected from: heterocycle, wherein the heterocycle is selected from the group consisting of: benzimidazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, (F) pyrazinyl, pyrazolyl, pyridyl, pyrrolyl, tetrazolyl, thiadiazolyl, triazolyl, and (M) piperidinyl, and wherein the heterocycle is unsubstituted or substituted with one or more substituent(s) selected from: C1-6alkyl, unsubstituted or substituted with halo, -CF3, -OCH 3 or 5i phenyl, (ii) Cl6alkoxy, (iii) oxo, (iv) thioxo, cyano, (vi) -SCH 3 (vii) phenyl, (viii) hydroxy, (ix) trifluoromethyl, (CH2)mNR9Rio, wherein m is 0, 1 or 2, and R 9 and Ro 1 are independently selected from: hydrogen, (11) Cl-6alkyl, (III) hydroxyCl-6alkyl, and (IV) phenyl, (xi) -NR9COR10 wherein R 9 and R 1 i are as defined above, and (xii) -CONR9RIO, wherein R9 and R10 are as defined above, R 2 and R3 are independently selected from the group consisting of: hydrogen; (2) R 6 Y 8 R Cl6alkyl, C2-6alkenyl, and phenyl; X is R 4 is z R5 is phenyl, unsubstituted or substituted with halo; R 6 R 7 and R8 are independently selected from the group consisting of: hydrogen, Cl-6alkyl, halo, and -CF 3 Y is and Z is hydrogen or C1.4alkyl; or a pharmaceutically acceptable salt thereof.
4. The use according to claim 1 or 2, wherein the NK-1 receptor antagonist is a compound of formula Ila: [i:\DayLib\LII3H]00830doc:lj, 78 A' 0 O A 2 R 6 A 3 (lla) wherein A 1 is fluorine or CF 3 A 2 is fluorine or CF 3 A 3 is fluorine or hydrogen; X is an alkylene chain of 1 to 4 carbon atoms optionally substituted by oxo; Y is a C-4alkyl group optionally substituted by a hydroxyl group; R 6 is a 5-membered or 6-membered heterocyclic ring containing 2 or 3 nitrogen s atoms optionally substituted by =S or a Ci-4alkyl group, and optionally substituted by a group of the formula ZNR7R8 where Z is C1-6alkylene or C3-6cycloalkylene; R 7 is hydrogen, C1.4alkyl, C3-7cycloalkyl or C3.7cycloalkylCl4alkyl, or C2-4alkyl substituted by C-4alkoxy or hydroxyl; R 8 is hydrogen, C1-4alkyl, C3.-cycloalkyl or C3-7cycloalkylCl.4alkyl, or C24alkyl substituted by one or two substituents selected from C14alkoxy, hydroxyl or a 4, 5 or 6 membered heteroaliphatic ring o 10 containing one or two heteroatoms selected from N, O and S; or R 7 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(0) or S(0) 2 or a second nitrogen atom which will be part of a NH or NRc moiety where R c is C1.4alkyl optionally substituted by hydroxy or Cl4alkoxy; or R 7 R 8 5 and the nitrogen atom to which they are attached form a non-aromatic azabicyclic ring system of 6 to 12 ring atoms; or Z, R 7 and the nitrogen atom to which they are attached form a heteroaliphatic ring of 4 to 7 ring atoms which may optionally contain an oxygen ring atom; or a pharmaceutically acceptable salt thereof. The use according to claim 1 or 2, wherein the NK-1 receptor antagonist is a compound of formula III: R 6 R 7 N (O)p R R1 3 R 12 wherein: R2 and R 3 are independently selected from the group consisting of: hydrogen; (2) C1l6alkyl, C2-6alkenyl, and phenyl; R 6 R7 and R8 are independently selected from the group L consisting of: hydrogen, Ci.alkyl, fluoro, chloro, bromo, iodo, and -CF 3 z 25 R 12 and R 13 are independently selected from the group consisting of: fluoro, chloro, (3) [I:\DayLib\LIBH00830.doc:jg 79 bromo, and aodo; A is unsubstituted Ci- 6 alkyl;- B is selected from the group consisting of: NA N- N x "X N N)KO N-ilN N I, NI I N s X H N I NS X H x N-N l'N 0. x N-N I.I 7 N-N- N-X N-- ~N N x NAN N 0 x N N 0 H 1 x N N S N S II S VAor p is 0or1 -X is selected from: wherein M+ is a pharmaceutically monovalent counterion, (b) -PO(O-) 2 -PO(O-) 2 .D 2 wherein D 2 +is a pharmaceutically acceptable divalent counterion, -CH(R 4 wherein R 4 is hydrogen or C1-3alkyl, -CH(R 4 2 .2M, (f) CH(R 4 2 D2+, -CO-CH 2 CH 2 -CO 2 0) -CH (CH 3 )-O-CO-R5, wherein R 5 is selected from H 2 +M the group consisting of: (ii)~NH OHN C0 2 -M N 0 CO 2 -M (v) (iii) 0 C0jM+ (iv) NH 3 C0jM C 2-M+ i) I(vii) and Y is Z is hydrogen or C 16 alkyl; or a pharmaceutically acceptable salt thereof.
6. The use according to claim 1 or 2, wherein the NK-1 receptor antagonist is a compound of formula lVa: (IVa) [I;\DayI-ib\LII3H]00830.doc:Ijg wherein A 1 is fluorine or CF 3 A 2 is fluorine or CF 3 A 3 is fluorine or hydrogen; X is a group of the formula NR 6 R 7 or a C- or N-linked imidazolyl ring; Y is hydrogen or Cl.alkyl optionally substituted by a hydroxy group; R 6 is hydrogen, Cl-6alkyl, C3-7cycloalkyl, C3.7cycloalkylClAalkyl, phenyl, or C2-4alkyl substituted by Clialkoxy or hydroxy; R 7 is hydrogen, Ci.6alkyl, C3-7cycloalkyl, C3-7cycloalkylClalkyl, phenyl, or C2Aalkyl substituted by one or two substituents selected from Cl-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 R 7 together with the nitrogen atom to which they are attached, form a saturated or partially saturated heterocyclic ring of 4 to 7 ring atoms, which ring may optionally contain in the ring one oxygen or sulphur atom or a group selected from NR 8 S(0) or o1 S(0) 2 and which ring may be optionally substituted by one or two groups selected from hydroxy- C14alkyl, C-4alkoxyCl-4alkyl, oxo, CORa or CO 2 Ra where R a is hydrogen or Cl4alkyl; or R6 and R 7 together with the nitrogen atom to which they are attached, form a non-aromatic azabicyclic ring system of 6 to 12 ring atoms; and R 8 is hydrogen, C-4alkyl, hydroxy C1.4alkyl or C14alkyl Cl4alkyl; or a pharmaceutically acceptable salt thereof.
7. The use according to claim 1 or 2, wherein the NK-1 receptor antagonist is a compound of formula V: R R S R 2 R R R (v) wherein: Y is (CH 2 )n wherein n is an integer from 1 to 4, and wherein any one of the carbon-carbon single bonds in said (CH 2 )n may optionally be replaced by a carbon-carbon double bond, and wherein any one of the carbon atoms of said (CH 2 )n may optionally be substituted with R4, and wherein any one of the carbon atoms of said (CH 2 )m 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 R1 is hydrogen or C8.salkyl optionally substituted with hydroxy, Ci-4alkoxy or fluoro; R 2 is a radical selected from hydrogen, Ci.6 straight or branched alkyl, C3.7cycloalkyl wherein one of the CH 2 groups in said cycloalkyl may optionally be replaced by NH, oxygen or sulphur; aryl selected from phenyl and naphthyl; heteroaryl selected from indanyl, thienyl, furyl, pyridyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl and quinolyl; phenyl-C2-6alkyl, benzhydryl and benzyl, Swherein each of said aryl and heteroaryl groups and the phenyl moieties of said benzyl, phenyl- [I:\DayLib\LIBH ]00830docIjg 81 C2-alkyl and benzhydryl may optionally be substituted with one or more substituents indepeendently selected from halo, nitro, C.lealkyl, C1-6alkoxy, trifluoromethyl, amino, Cl6alkylamino, Cl.-alkyl-O- CO, Ci-6alkyl-O-CO-Cl.-alkyl, Cl.6alkyl-O-CO, Cl-salkyl-CO-Cl.-alkyl-O-, C1-.alkyl-CO, Cl.-alkyl-CO- NHCi.ealkyl-, di-C-ialkylamino, -CONH-Ci-lalkyl, Cl-6alkyl-CO-NH-C1-6alkyl, -NHCOH and -NHCO- Ci-alkyl; and wherein one of the phenyl moieties of said benzhydryl may optionally be replaced by naphthyl, thienyl, furyl or pyridyl; R 5 is hydrogen, phenyl or Cl.-alkyl; 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 CH 2 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 (CH 2 groups in said cycloalkyl may optionally be replaced by NH, oxygen or sulphur; wherein each of said aryl and heteroaryl groups may optionally be substituted with one or more substituents, and said C3-7cycloalkyl may optionally be substituted with one or two substituents, each of said substituents being independently selected from halo, nitro, Cl.-alkyl, is C1-6alkoxy, trifluoromethyl, amino, Cl-6alkylamino, -CO-NH-C 16 alkyl, C1-6alkyl-CO-NH-C Ci.salkyl, -NHCOH and -NHCO- Cl.ealkyl; R 4 and R 7 are each independently selected from hydroxy, halogen, halo, amino, oxo, cyano, methylene, hydroxymethyl, halomethyl, C1.-alkylamino, di-Ci.-alkylamino, C1-6alkoxy, C1-alkyl-O-CO, Cl.6alkyl-O-CO-C 1 alkyl, Cl-alkyl-CO-O, C-Calkyl-CO-C 1 .ealkyl-O-, Cl-alkyl-CO-, Cl-6alkyl-CO-C1.ealkyl, and the radicals set forth in the definition of R2; R6 is 20 -NHCOR9, -NHCH 2 R9, S0 2 R 9 or one of the radicals set forth in any of the definitions of R 2 R 4 and R 7 R8 is oximino (=NOH) or one of the radicals set forth in any of the definitions of R2, R 4 and R7; o9. R 9 is Ci-6alkyl, hydrogen, phenyl or phenylCi-6alkyl; with the proviso that when m is 0, R8 is absent, 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 when R4 and R 7 are attached to the same carbon atom, then either each of R4 and R 7 is independently selected from hydrogen, fluoro and C1.-alkyl, or R4 and R 7 together with the carbon to which they are attached, for a C3.-saturated carbocyclic ring that forms a spiro compound with the nitrogen-containing ring to which they are attached; or a pharmaceutically acceptable salt thereof.
8. The use according to claim 1 or 2, wherein the NK-1 receptor antagonist is a compound of formula VI: S R N--/7 R RR 3 N R(V R3 R R (VI) [I:\DayLib\LIBH]0083O.doc:ljg IIV~-~Cr~ 82 wherein: radicals R are phenyl radicals optionally 2- or 3-substituted by a halogen atom or a methyl radical; Ri 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; R 3 is optionally 2-substituted phenyl; R 4 is OH or fluorine when R5 is H; or R 4 and R 5 are OH; or R 4 and R 5 together form a bond; or a pharmaceutically acceptable salt thereof.
9. The use according to claim 1 or 2, wherein the NK-1 receptor antagonist is a compound of formula VII: R Q I I Ar-T-CO-N-CH 2 C-H-C H2-Am+,A' I Ar' (VII) 0 wherein: Ar represents an optionally substituted mono-, di- or tricyclic aromatic or heteroaromatic group; T represents a bond, a hydroxymethylene group, a Ci4alkoxymethylene group or a C1-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, C14alkoxy, C1-4alkyl where the said substituents may be the same or different; a thienyl group; a benzothienyl group: a naphthyl group: or an indolyl group; R represents hydrogen, C14alkyl, co-C1.4alkoxy- Ci-4alkyl or o-C2-4alkanoyloxyC2-4alkyl; Q represents hydrogen; or Q and R together form a x1 Xg N I® 1,2-ethylene, 1,3-propylene or 1,4-butylene group; Am represents the radical X 3 'x 2 in which X1, X 2 and X 3 together with the nitrogen atom to which they are attached, form an azabicyclic or azatricyclic ring system optionally substituted by a phenyl or benzyl group; and A- represents a 20 pharmaceutically acceptable anion. The use according to claim 1 or 2, wherein the NK-1 receptor antagonist is a compound of formula VIII R 3 /-4 R-N X 2 -N-X 3 -R 4 R( X,V (VIII) wherein: Ri represents an optionally substituted aralkyl, aryloxyalykl, heteroaralkyl, aroyl, heteroaroyl, cycloalkylcarbonyl, aralkanoyl, heteroarylalkanoyl, aralkoxycarbonyl or arylcarbamoyl group or the acyl group of an ou-amino acid optionally N-substituted by a lower alkanoyl or carbamoyl-lower alkanoyl group; R 2 represents cycloalkyl or an optionally substituted aryl or heteroaryl group; R3 represents hydrogen, alkyl, carbamoyl or an alkanoyl or alkenoyl group L optionally substituted by carboxy or esterified or amidated carboxy; R 4 represents an optionally S 30 substituted aryl group or an optionally partially saturated heteroaryl group; X1 represents methylene, [I:\DayLib\BH]00830.doc:jg [I:\DayLib\LIBH0083.doc:Ijg 83 ethylene, a bond, an optionally ketalised carbonyl group or an optionally etherified hydroxymethylene group; X 2 represents alkylene, carbonyl or a bond; and X 3 represents carbonyl, oxo-lower alkyl, oxo(aza)-lower alkyl, or an alkyl group optionally substituted by phenyl, hydroxymethyl, optionally esterified or amidated carboxy, or (in other than the c-position) hydroxy; or a pharmaceutically acceptable salt thereof.
11. The use according to claim 1 or 2, wherein the NK- 1 receptor antagonist is a compound of formula IX: R H N-R 3 0 R 4 (IX) wherein: R 1 is aryl, or a group of the formula: X is CH or N; and Z is O or N-R 5 in which R 5 is hydrogen or lower alkyl; R 2 is hydroxy or lower alkoxy; R3 is hydrogen or optionally substituted lower alkyl; R 4 is optionally substituted ar(lower)alkyl; A is carbonyl or sulfonyl; and Y is a bond or lower alkenylene; or a pharmaceutically acceptable salt thereof.
12. The use according to claim 1 or 2, wherein the NK-1 receptor antagonist is a compound of formula X: H i (R S wherein: R 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 C3-7cycloalkyl may optionally be substituted with one or two substituents, said substituents being independently selected from chloro, fluoro, bromo, iodo, nitro, Ci-joalkyl optionally substituted with from one to three fluoro groups, CI-loalkoxy optionally substituted with from one to three fluoro groups, amino, Cl-ioalkyl-S-, Cv-ioalkyl-S(O)-, Ci-ioalkyl-SO 2 phenyl, phenoxy, Ci-o0alkyl-SO 2 NH-, C1-ioalkyl-SO 2 NH- Ci-ioalkyl-, Cl-ioalkylamino-diCi1loalkyl-, cyano, hydroxy, cycloalkoxy having 3 to 7 carbon atoms, Cl.ioalkylamino, Cl-6dialkylamino, HC(O)NH- and C-jioalkyl-C(O)NH-; and R 2 is thienyl, benzhydryl, naphthyl or phenyl optionally substituted with from one to three substituents independently selected from chloro, bromo, fluoro, iodo, cycloalkoxy having 3 to 7 carbon atoms, [l:\DayLib\LIBH]00830.doc:ljg 84 C1.1oalkoxy optionally substituted with from one to three fluoro groups and Ci-oalkyl optionally substituted with from one to three fluoro groups; or a pharmaceutically acceptable salt thereof.
13. The use according to claim 1 or 2, wherein the NK- 1 receptor antagonist is a compound of formula Xl: R2 1 (CH 2 )x OR3 R R4 N H R5 (XI) 66 R NN wherein: R 1 is a C14alkoxy group; R2 is NN R 3 is a hydrogen or halogen atom; R 4 and R 5 may each independently represent a hydrogen or halogen atom, or a Ci4alkyl, C14alkoxy or trifluoromethyl group; R 6 is a hydrogen atom, a C14alkyl, (CH2)mcyclopropyl, -S(O)nCl.4alkyl, phenyl, NR7R8, CH 2 C(O)CF 3 or trifluoromethyl group; R 7 and R 8 may each independently represent o a hydrogen atom, or a Ci4alkyl or acyl group; x represents zero or 1; n represents zero, 1 or 2; and m represents zero or 1; or a pharmaceutically acceptable salt thereof. ~14. The use according to claim 1 or 2, wherein the NK-1 receptor antagonist is a compound of formula XII: R 8 R-(CH 2 )--CH 2 -N-(CH 2 )-R 3 NH R (0O) (OH 2 )m (XII) is 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-Cl.3alkoxy, or C14alkanoyl groups; R 1 is trityl, phenyl, diphenylmethyl, phenoxy, phenylthio, piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, indolinyl, indolyl, benzothienyl, hexamethyleneiminyl, benzofuranyl, tetrahydropyridinyl, quinolinyl, isoquinolinyl, reduced quinolinyl, reduced isoquinolinyl, phenyl-(Cl4alkyl)-, phenyl-(Ci4alkoxy)-, quinolinyl-(C4alkyl)-, isoquinolinyl-(C 1 4 alkyl)-, reduced [IADayLib\LIBH]100830.docjg quniolinyl-(Ci-4alkyl)-, reduced isoquinolinyl-(Cl-4alkyl)-, benzoyl-(Cl-3alkyl)-, C1.4alkyl, or -NH-CH 2 any one of which R1 groups may be substituted with halo, C1-4alkyl, C1-4alkoxy, trifluoromethyl, amino, C14alkylamino, d i(C 1 -alkyI) amino, or Cl-4alkanoylamino; or any one of which R 1 groups may be substituted with phenyl, piperazinyl, C3-8cycloalkyl, benzyl, C1-4alkyl, piperizlinyl, pyridinyl, pyrimidinyl, C2-6alkanoylamino, pyrrolidinyl, C2-6alkanoyl, or Cl-4alkoxycarbonyl; any one of which groups may be substituted with halo, C14alkyl, C1-4alkoxy, trifluoromethyl, amino, Ct1ialkylamino, di(Cl-4alkyl)amino, or C2-4alkanoylamino;- or R 1 is amino, a ieaving group, hydrogen, Cv~alkylamino, or di(Cl.4alkyl)amino; R5 is pyridyl, anilino(Clv3alkyl)-, or anilinocarbonyl; R 2 is hydrogen, C14alkyl, C,4alkylsulfonyl, carboxy-(Cl- 3 alkyl)-, Cl-3alkoxycarbonyl-(Ci 3 alkyl)-, or -CO-l?6; R6 is hydrogen, Cl4alkyl, Clv3haloalkyl, phenyl, C1v3alkoxy, Cl-3hydroxyalkyl, amino, Cl4alkylamino, di(Cl~alkyl) amino, or (CH2)q-R 7 q is zero to 3; R7 is carboxy, C14alkoxycarbonyl, Cl-4alkylcarbonyloxy, amino, Cl~alkylamino, di(Cl-4alkyl) amino, Cl-6alkoxycarbonylamino, or phenoxy, phenylthio, piperazinyi, :piperidinyl, pyrrolidinyl, morpholinyl, indolinyl, indolyl, benzothienyl, benzofuranyl, quinolinyl, phenyl-(Cl-4alkyl)-, quinolinyl-(Cl 4alkyl)-, isoquinolinyl-(Cl-4alkyl)-, reduced quinolinyl-(Cl. 4 alkyl)-, reduced isoquinolinyl-(Cl~alkyl)-, benzoyl-Cl-3alkyl; any one of which aryl or heterocyclic R 7 groups may be substituted with halo, trifluoromethyl, C14alkoxy, C14alkyl, amino, Cl-4alkylamino, di(Cl-4alkyl)amino, or C2-4alkanoylamlno; or any one of which R7 groups may be substituted with *phenyl piperazinyl, C3-8CYCloalkyl, benzyl, piperidinyl, pyridlinyl, pyrimidinyl pyrrolidinyl, C2-6alkanoyl, or Cl-4alkoxycarbonyl; any of which groups may be substituted with halo, trifluoromethyl, amino, C14alkoxy, C14alkyl, Ci..alkylamino, di(Ci~alkyl)amino, or C24alkanoylamino; R 8 is hydrogen or Cl-6alkyl; R 3 is phenyl, phenyl-(Cli6alkyl)-, C3.8cycloalkyl, C5-8cycloalkenyl, Ci 8alkyI, naphthyi, 9 *C2-8alkenyl, or hydrogen; any one or which groups except hydrogen may be substituted with one or two halo, C.3alkoxy, Cl.3alkylthio, nitro, trifluoromethyl, or Cl-3alkyl groups; an' 4 i yrgno Cl-3alkyI; with the proviso that if R 1 is hydrogen or halo, R3 is phenyi, phenyl-(Cl-6akyl)-, C3-8cycloalkyl, C5-8cycloalkenyl or naphthyl; or a pharmaceutically acceptable salt thereof. The use according to claim 1 or 2, 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.
16. The use according to claim 1 or 2, wherein the NK-1 receptor antagonist is selected from 5-bis(trifluoromethyl)benzyloxy-3(S)-(4 -fluorophenyl)-4-(3-(5-oxo-1 H, 4H- 1,2,4- triazolo)methyl)morpholine; (trifluoromethyl)phenyl)ethoxy)4(3(5oxo1 H ,4H- 1,24tizl ehl--()pey-opoie 2-(S)-(3,5-bis (trifl uorometh yl) ben zyloxy)4.(3-(5 oxo-1 H ,4H-1,24tizl ehl--()pey-opoie 1 phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4(3(5oxo1 H ,4H-1 ,2,4-triazolo)methyl)morpholine; 1- UJLAA (R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-((N ,N dimethylamilno)methyl- 1,2,3-triazol-4-yl)methyl- [I:\DayLib\LIBH]00830.doc:Ijg 7-rEN 86 3-(S)-phenylmorpholine; dimethylamino)methyl-i 2 3 -triazol-4-yl)methyl-3-(S)-(4-fluorophenyl)morpholine; bis(trifluoromethyl)phenyl)ethoxy3(S)(4luorophenyl-4(3-(4-monophosphoryl-5-ox-1 H-i 2,4- triazolo)methyl)morpholine; (trifluoromethyl)phenyl)ethoxy)-3-(S)-(4. fluorophenyl)-4-(3-(1 -monophosphoryl-5-oxo- 1 H-i ,2,4-triazolo)methyl)morpholine; 1 5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(44fluoro phenyl)-4-(3-(2-monophosphoryl-5-oxo-1 H- 1, 2 4 -triazolo)methyl)morpholine; (R)-(3,5-bis (trifl uorom ethyl) phen yl)ethoxy)-3- (4- fluorophenyl)-4-(3-(5-oxyphosphoryl-.1 H-i ,2,4-triazolo)methyl) morphoiine; 1 bis(trifluoromethyl)phenyl)ethoxy3(S)(4fluorophenyl-4-(3-(1 -monophosphoryl-5-oxo-4H- 1, 2,4- triazolo)methyl)morpholine; -(R)-(3,5-bis(trifluoromethyl) phenyl)ethoxy)-4-(4-N, N dimethylaminobut-2-yn-yl)-3(S)-(4-fluorophenyl)morpholine; or a pharmaceutically acceptabie salt :.:thereof. .17. The use according to any one of claims 11to16, wherein the NK-i receptor antagonist is orally active, long acting and CNS-penetrant.
18. The use according to any one of claims 2 to 17, wherein the anorectic agent is selected from aminorex, amphechloral, amphetamine, benzphetamine, chlorphentermine, clobenzorex, cloforex, clominorex, clortermine, cyclexedrine, dexfenfluramine, dextroamphetamine, diethyipropion, diphemethoxidine, N-ethylamphetamine, fenbutrazate, fenfluramine, fenisorex, ****:fenproporex, fludorex, fluminorex, furfurylmethylamphetamine, levamnfetamine, levophacetoperane, 20 mazindol, mefenorex, metamfepramone, methamphetamine, norpseudoephedrine, pentorex, phendimetrazine, phenmetrazine, phentermine, phenyipropanolamine picilorex and sibutramine; or 0 a pharmaceutically acceptable salt thereof,
19. The use according to any one of claims 2 to 18, wherein the anorectic agent is a halogenated amphetamine derivative.
20. The use according to claim 19 wherein the amphetamine derivative is selected from ch lorphen term ine cloforex, clortermine, dexfenfluramine, fenfluramine, picilorex and sibutramine;I or a pharmaceutically acceptable salt thereof.
21. The use according to any one of claims 1 to 20, wherein the eating disorder results in or causes obesity.
22. The use according to any one of claims 1 to 20, wherein the eating disorder is bulimia nervosa.
23. The use according to any one of claims 1 to 20, wherein the eating disorder is a compulsive eating disorder. 1:\Day Li\LI B H 1008 30.doc:aj g
24. A pharmaceutical composition when used for the treatment or prevention of eating disorders, said composition comprising a NK-1 receptor antagonist, together with at least one pharmaceutically acceptable carrier or excipient. The composition when used according to claim 24 which further comprises an anorectic agent.
26. The composition when used according to claim 24 or 25, wherein the NK-1 receptor antagonist is a compound of formula I R 3 2RNXR R (I) wherein R 1 is selected from the group consisting of: Ci-alkyl, substituted with one or more of 0o the substituents selected from: heterocycle, wherein the heterocycle is selected from the group Sconsisting of: benzimidazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, (F) S: pyrazinyl, pyrazolyl, pyridyl, pyrrolyl, tetrazolyl, thiadiazolyl, triazolyl, and (M) o0S* piperidinyl, and wherein the heterocycle is unsubstituted or substituted with one or more substituent(s) selected from: Ci-6alkyl, unsubstituted or substituted with halo, -CF 3 -OCH3, or 15 phenyl, (ii) Ci-6alkoxy, (iii) oxo, (iv) thioxo, cyano, (vi) -SCH 3 (vii) phenyl, (viii) hydroxy, (ix) trifluoromethyl, (CH 2 )mNR 9 R 1 0 wherein m is 0, 1 or 2, and R 9 and R 1 0 are independently selected from: hydrogen, (II) Ci-alkyl, (III) hydroxyCl-alkyl, and (IV) phenyl, (xi) -NR 9 COR 1 0 wherein R 9 and R 1 0 are as defined above, and (xii) -CONR 9 Ro 1 wherein R 9 and R 10 are as defined above, R 2 and R 3 are independently selected from the group consisting of: hydrogen; (2) •R 6 ••R7 Y R 1• S* 20 Ci-6alkyl, C2-6alkenyl, and phenyl; X is R 4 is z R 5 is phenyl, unsubstituted or substituted with halo; R 6 R 7 and R 8 are independently selected from the group consisting of: hydrogen, Ci-6alkyl, halo, and -CF 3 Y is and Z is hydrogen or Cl4alkyl; or a pharmaceutically acceptable salt thereof.
27. The composition when used according to claim 24 or 25, wherein the NK-1 receptor antagonist is a compound of formula Ila: [R:\LIBH]01012.doc:ljg 88 A 1 o Y N0 A2 R 6 A 3 (lla) wherein A 1 is fluorine or CF3; A 2 is fluorine or CF3; A 3 is fluorine or hydrogen; X is an alkylene chain of 1 to 4 carbon atoms optionally substituted by oxo; Y is a C14alkyl group optionally substituted by a hydroxyl group; R 6 is a 5-membered or 6-membered heterocyclic ring containing 2 or 3 nitrogen atoms optionally substituted by =S or a C14alkyl group, and optionally substituted by a group of the formula ZNRTR 8 where Z is C1ialkylene or C3scycloalkylene; R 7 is hydrogen, C14alkyl, C3-7cycloalkyl or C37cycloalkylC14alkyl, or C24alkyl substituted by C14alkoxy or hydroxyl; R 8 is hydrogen, C4alkyl, C37cycloalkyl or C3.7cycloalkylC14alkyl, or C2alkyl substituted by one or two substituents selected from C-4alkoxy, hydroxyl or a 4, 5 or 6 membered heteroaliphatic ring S o containing one or two heteroatoms selected from N, 0 and S; or R 7 R 8 and the nitrogen atom to which they are attached form a heteroaliphatic ring of 4 to 7 ring atoms, optionally substituted by a hydroxy group, and optionally containing a double bond, which ring may optionally contain an oxygen or sulphur ring atom, a group S(0) or S(0)2 or a second nitrogen atom which will be part of a NH or NR C moiety where Rc is C14alkyl optionally substituted by hydroxy or C14alkoxy; or R 7 R 8 and the nitrogen atom to which they are attached form a non-aromatic azabicyclic ring system of 6 to 12 ring atoms; or Z, R 7 and the nitrogen atom to which they are attached form a heteroaliphatic ring of 4 to 7 ring atoms which may optionally contain an oxygen ring atom; or a pharmaceutically acceptable salt thereof.
28. The composition when used according to claim 24 or 25, wherein the NK-1 receptor antagonist is a compound of formula III: S R 6 O(O)p R- R N 3(11 B R' 3 R (III) wherein: R 2 and R 3 are independently selected from the group consisting of: hydrogen; (2) Ciealkyl, C26alkenyl, and phenyl; R 6 R 7 and R 8 are independently selected from the group -A consisting of: hydrogen, Ci-alkyl, fluoro, chloro, bromo, iodo, and -CF3; [R:\LIBH]01012.doc:ljg 89 R 1 1 R 12 and R 1 3 are independently selected from the group consisting of: fluoro, chloro, (3) bromo, and iodo; A is unsubstituted Ci-6alkyI; B is selected from the group consisting of: x 11x NAI N- X X\ N-M N NJ 0 NA N- S x N 0 N S X H N-N x N- N-N N) x N I x x N 0 H 0@ 6 0*e S 0S o S S @06 0 S. 0 S S *SeS S *0*0 00 *50 S *SS@@O 6 *50@ S @55* *0 5 *5 6 S S 6 0056 0O 0 *5 N N-A IN' S 01 r X H $Nx or X ;pis 0or1; X is selected from: wherein M+ is a pharmaceutically monovalent counterion, (b) -PO(O-) 2 -PO(O-) 2 wherein D 2 is a pharmaceutically acceptable divalent counterion, -CH(R 4 wherein R 4 is hydrogen or Cl-3alkyl, -CH(R 4 )-PO(Oj) 2 .2M, CH(R 4 2 -CO-CH 2 CH 2 -CO 2 -CH(CH 3 )-O-CO-R5, wherein R 5 is selected from the group consisting of: 0" N, O C0 2 -M+ CjM C0 2 M ,+iv 02M and Y 00 NH+ N 3 (vi) -0 C02jM+ C0-+ I(Vii) s Z is hydrogen or CI-6alkyl; or a pharmaceutically acceptable salt thereof.
29. The composition when used according to claim 24 or 25, wherein the NK-1 receptor antagonist is a compound of formula IVa: [R:\LIBH]0 10 12.doc: Ijg A 1 S O A2 A 3 x (IVa) wherein A 1 is fluorine or CF 3 A 2 is fluorine or CF 3 A 3 is fluorine or hydrogen; X is a group of the formula NR 6 R 7 or a C- or N-linked imidazolyl ring; Y is hydrogen or C14alkyl optionally substituted by a hydroxy group; R 6 is hydrogen, Ci-alkyl, C3a-cycloalkyl, C3.7cycloalkylC-4alkyl, phenyl, or 5 o 5 C24alkyl substituted by C14alkoxy or hydroxy; R 7 is hydrogen, Ci-alkyl, C3-7cycloalkyl, C3-7cycloalkylC14alkyl, phenyl, or C2-4alkyl substituted by one or two substituents selected from S: Cl4alkoxy, hydroxy or a 4, 5 or 6 membered heteroaliphatic ring containing one or two heteroatoms selected from N, O and S; or R 6 and R 7 together with the nitrogen atom to which they are attached, form a saturated or partially saturated heterocyclic ring of 4 to 7 ring atoms, which ring may 1o optionally contain in the ring one oxygen or sulphur atom or a group selected from NR 8 S(O) or S(O) 2 and which ring may be optionally substituted by one or two groups selected from hydroxy- C14alkyl, C14alkoxyC14alkyl, oxo, CORa or CO 2 Ra where Ra is hydrogen or C14alkyl; or R 6 and R 7 together with the nitrogen atom to which they are attached, form a non-aromatic azabicyclic ring system of 6 to 12 ring atoms; and R 8 is hydrogen, Cl4alkyl, hydroxy Ci4alkyl or C14alkyl C-4alkyl; 15 or a pharmaceutically acceptable salt thereof.
30. The composition when used according to claim 24 or 25, wherein the NK-1 receptor o antagonist is a compound of formula V: 0. 0 R 4R N R SR Re-(Z) 6 (V) 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 (CH 2 )n may optionally be substituted with R 4 and wherein any one of the carbon atoms of said (CH2)m may optionally be substituted with R 7 Z is [R:\LIBH]01012.doc:ljg (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 R 1 is hydrogen or Clialkyl optionally substituted with hydroxy, C14alkoxy or fluoro; R2 is a radical s selected from hydrogen, C1_ straight or branched alkyl, C.3-7cycloalkyl wherein one of the CH 2 groups in said cycloalkyl may optionally be replaced by NH, oxygen or sulphur; aryl selected from phenyl and naphthyl; heteroaryl selected from indanyl, thienyl, furyl, pyridyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl and quinolyl; phenyl-C2-6alkyl, benzhydryl and benzyl, wherein each of said aryl and heteroaryl groups and the phenyl moieties of said benzyl, phenyl- C26alkyl and benzhydryl may optionally be substituted with one or more substituents independently selected from halo, nitro, Cialkyl, C1_alkoxy, trifluoromethyl, amino, C1ialkylamino, Ci6alkyl-O- CO, C1ialkyl-O-CO-Ciealkyl, Ci-alkyl-O-CO, Clsalkyl-CO-Ci-alkyl--, C1ialkyl-CO, Ci-alkyl-CO- NHC1ialkyl-, di-Ci-alkylamino, -CONH-Ci-alkyl, Ciealkyl-CO-NH-C1ialkyl, -NHCOH and -NHCO- 0: Cvalkyl; and wherein one of the phenyl moieties of said benzhydryl may optionally be replaced by Is naphthyl, thienyl, furyl or pyridyl; R 5 is hydrogen, phenyl or Ci-alkyl; or R 2 and R 5 together with the *owe carbon to which they are attached, form a saturated ring having from 3 to 7 carbon atoms wherein one of the CH 2 groups in said ring may optionally be replaced by oxygen, NH or sulfur; R 3 is aryl selected from phenyl and naphthyl; heteroaryl selected from indanyl, thienyl, furyl, pyridyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl and quinolyl; and cycloalkyl having 3 to 7 carbon atoms wherein one of the (CH 2 groups in said cycloalkyl may optionally be replaced by NH, S S 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, Ci6alkyl, C1.alkoxy, trifluoromethyl, amino, Ciaalkylamino, -CO-NH-Ci-alkyl, Ci-alkyl-CO-NH-C Cisalkyl, -NHCOH and -NHCO- C1ialkyl; R 4 and R 7 are each independently selected from hydroxy, halogen, halo, amino, oxo, cyano, methylene, hydroxymethyl, halomethyl, Ciealkylamino, di-Clealkylamino, C1_alkoxy, Ci-alkyl-O-CO, Ciaalkyl-O-CO-Ci-alkyl, C1-6alkyl-CO-, C1ialkyl-CO-C1-6alkyl--, Ci-alkyl-CO-, Ci-alkyl-CO-Ciealkyl, and the radicals set forth in the definition of R 2 R 6 is -NHCOR9, -NHCH 2 R9, SO 2 R9 Or one of the radicals set forth in any of the definitions of R 2 R 4 and R 7 R8 is oximino (=NOH) or one of the radicals set forth in any of the definitions of R 2 R 4 and R 7 R 9 is C1-6alkyl, hydrogen, phenyl or phenylCi.ealkyl; with the proviso that when m is 0, R8 is absent, when R 4 R 6 R 7 or R 8 is as defined in R 2 it cannot form together with the carbon to which it is attached ,a ring with R 5 and when R4 and R7 are attached to the same carbon atom, A then either each of R 4 and R 7 is independently selected from hydrogen, fluoro and Ci-Balkyl, or R 4 S 35 .nd R 7 together with the carbon to which they are attached, for a C3-6ssaturated carbocyclic ring LU LJ (R:\LIBH]O 101 2.doc:ljg that forms a spiro compound with the nitrogen-containing ring to which they are attached; or a pharmaceutically acceptable salt thereof.
31. The composition when used according to claim 24 or 25, wherein the NK-1 receptor antagonist is a compound of formula VI: N R R3 R 4 R 2 (VI) wherein: radicals R are phenyl radicals optionally 2- or 3-substituted by a halogen atom or a methyl radical; R 1 is optionally substituted phenyl, cyclohexadienyl, naphthyl, indenyl or optionally substituted heterocycle; R 2 is H, halogen, OH, alkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkyloxy, alkylthio, acyloxy, carboxy, optionally substituted alkyloxycarbonyl, benzyloxycarbonyl, S 1o amino or acylamino; R 3 is optionally 2-substituted phenyl; R 4 is OH or fluorine when R 5 is H; or R 4 and R 5 are OH; or R 4 and R 5 together form a bond; or a pharmaceutically acceptable salt thereof.
32. The composition when used according to claim 24 or 25, wherein the NK-1 receptor antagonist is a compound of formula VII: R Q I I Ar-T-CO-N-CH 2 C 2 CH2-CH 2 -Am+,A' Ar' (VII) is wherein: Ar represents an optionally substituted mono-, di- or tricyclic aromatic or heteroaromatic group; T represents a bond, a hydroxymethylene group, a C14alkoxymethylene group or a group; Ar' represents a phenyl group which is unsubstituted or substituted by one or •g more substituents selected from halogen, preferably chlorine or fluorine, trifluoromethyl, C14alkoxy, C14alkyl where the said substituents may be the same or different; a thienyl group; a benzothienyl 20 group: a naphthyl group: or an indolyl group; R represents hydrogen, C1-4alkyl, co-Ci4alkoxy- C14alkyl or o-C24alkanoyloxyC24alkyl; Q represents hydrogen; or Q and R together form a xl 1,2-ethylene, 1,3-propylene or 1,4-butylene group; Am' represents the radical x 3 x 2 in which Xi, X 2 and X 3 together with the nitrogen atom to which they are attached, form an azabicyclic or azatricyclic ring system optionally substituted by a phenyl or benzyl group; and A- represents a pharmaceutically acceptable anion.
33. The composition when used according to claim 24 or 25, wherein the NK-1 receptor antagonist is a compound of formula VIII [R:\LIBH] 1012.doc:ljg 93 R 3 R-N X2-N-Xa-R 4 R2-X RX 1 (VIII) wherein: R 1 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; R 2 represents cycloalkyl or an optionally substituted aryl or heteroaryl group; R 3 represents hydrogen, alkyl, carbamoyl or an alkanoyl or alkenoyl group optionally substituted by carboxy or esterified or amidated carboxy; R 4 represents an optionally substituted aryl group or an optionally partially saturated heteroaryl group; Xi represents methylene, ethylene, a bond, an optionally ketalised carbonyl group or an optionally etherified 10o hydroxymethylene group; X 2 represents alkylene, carbonyl or a bond; and X 3 represents carbonyl, oxo-lower alkyl, oxo(aza)-lower alkyl, or an alkyl group optionally substituted by phenyl, hydroxymethyl, optionally esterified or amidated carboxy, or (in other than the a-position) hydroxy; or a pharmaceutically acceptable salt thereof.
34. The composition when used according to claim 24 or 25, wherein the NK- 1 receptor S 15 antagonist is a compound of formula IX: NN R A H N-R 3 Y O R 4 0 R (IX) x wherein: R 1 is aryl, or a group of the formula: X is CH or N; and Z isO or N-R, in which R5 is hydrogen or lower alkyl; R 2 is hydroxy or lower alkoxy; R 3 is hydrogen or optionally substituted lower alkyl; R 4 is optionally substituted ar(lower)alkyl; A is carbonyl or sulfonyl; and Y is a bond or lower alkenylene; or a pharmaceutically acceptable salt thereof.
35. The composition when used according to claim 24 or 25, wherein the NK-1 receptor antagonist is a compound of formula X: H I I 2 I H (X) wherein: R 1 is aryl selected from indanyl, phenyl and naphthyl; heteroaryl selected from ,5T77 thienyl, furyl, pyridyl and quinolyl; and cycloalkyl having 3 to 7 carbon atoms, wherein one of said [R:\LIBH]01012.docljg 94 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 C3.7cycloalkyl may optionally be substituted with one or two substituents, said substituents being independently selected from chloro, fluoro, bromo, iodo, nitro, Cl.ioalkyl optionally substituted with from one to three fluoro groups, Ci-loalkoxy optionally substituted with from one to three fluoro groups, amino, Ci-ioalkyl-S-, C.-loalkyl-S(O)-, Cl-ioalkyl-S02-, phenyl, phenoxy, Cl-ioalkyl-SO2NH-, Ci-.oalkyl-SO2NH- Ci-ioalkyl-, C-iioalkylamino-diC.-ioalkyl-, cyano, hydroxy, cycloalkoxy having 3 to 7 carbon atoms, Ci-ioalkylamino, Ci6dialkylamino, HC(O)NH- and C-1ioalkyl-C(O)NH-; and R 2 is thienyl, benzhydryl, naphthyl or phenyl optionally substituted with from one to three substituents independently selected from chloro, bromo, fluoro, iodo, cycloalkoxy having 3 to 7 carbon atoms, Ci-ioalkoxy optionally substituted with from one to three fluoro groups and C.-o1alkyl optionally substituted with from one to three fluoro groups; or a pharmaceutically acceptable salt thereof.
36. The composition when used according to claim 24 or 25, wherein the NK- 1 receptor antagonist is a compound of formula XI: R2 I S* (CH 2 )x H R' R 15 R 5 (XI) SR 6 N I wherein: R 1 is a C-4alkoxy group; R 2 is N-N ;R 3 is a hydrogen or halogen atom; R 4 and R 5 may each independently represent a hydrogen or halogen atom, or a Ci4alkyl, Ci4alkoxy or trifluoromethyl group; R 6 is a hydrogen atom, a C14alkyl, (CH2)mcyclopropyl, -S(O)nC1-alkyl, phenyl, NR 7 R8, CH2C(O)CF 3 or trifluoromethyl group; R 7 and R 8 may each independently represent a hydrogen atom, or a Ci4alkyl or acyl group; x represents zero or 1; n represents zero, 1 or 2; and m represents zero or 1; or a pharmaceutically acceptable salt thereof.
37. The composition when used according to claim 24 or 25, wherein the NK-1 receptor antagonist is a compound of formula XII: [R:\LIBH]0101 2.doc:jg R-(CH 2 )-C;-CH1 2 -N-(Lt2 1 12 NH R R 1 (XII) wherein: mnis 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, Cl-3alkoxy, trifluoromethyl, Ci1ialkyl, phenyl-Cl- 3 alkoxy, or C14alkanoyl groups; R 1 is trityl, phenyl, diphenylmethyl, phenoxy, phenylthio, piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, indolinyl, indolyl, benzothienyl, hexamethyleneiminyl, benzofuranyl, tetrahydropyridinyl, quinolinyl, isoquinolinyl, reduced quinolinyl, reduced isoquinolinyl, phenyl-(Cl~alky)-, phenyl-(Cl~alkoxy)-, quinolinyl-(Clgalkyl)-, isoquinolinyl-(Cl~alkyI)-, reduced quniolinyl-(Cl-4alkyl)-, reduced isoquinolinyl-(Cl~alkyl)-, benzoyl-(C13alky)-, C14alkyl, or -NH-CH 2 R 5 any one of which R 1 groups may be substituted with halo, Citalkyl, Cl.~alkoxy, trifluoromethyl, ****amino, C14alkylamino, d i(C 1 Aalkyl) amino, or C14alkanoylamino; or any one of which R 1 groups may be substituted with phenyl, piperazinyl, C3-8cycloalkyi, benzyl, C1-4alkyl, piperizlinyl, pyridinyl, pyrimidinyl, C2-6alkanoylamino, pyrrolidinyl, C2-6alkanoy, or Ci4alkoxycarbonyl; any one of which groups may be substituted with halo, Ci-4alkyl, C1-4alkoxy, trifluoromethyl, amino, Ct1talkylamino, di(Cl~alkyl)amino, or C2A4alkanoylamino; or RI is amino, a leaving group, hydrogen, Ci.4alkylamino, or di(Ci-4alkyI)amino; R 5 is pyridyI, anilino(Ci-3alkyI)-, or anilinocarbonyl; R 2 is hydrogen, Cl.~alkyl, C,4alkylsulfonyI, carboxy -3alkyl)- C-3alkoxycarbonyl-( 3 ly),o C- 6 6 i yrgn CiAalkyl, C1.3haloalkyl, phenyl, Cl-3alkoxy, Cl-3hydroxyalkyl, amino, C14alkylamino, di(Ci4alkyl) amino, or (CH2)q-R 7 q is zero to 3; R 7 is carboxy, Ci4alkoxycarbonyl, C14~alkylcarbonyloxy, amino, C14alkylamino, di(Cl~alkyI) amino, Ci-6alkoxycarbonylamino, or phenoxy, phenylthio, piperazinyl, 0::::piperidinyl, pyrrolidinyl, morpholinyl, indolinyl, indolyl, benzothienyl, benzofuranyl, quinolinyl, phenyI-(Cl~alkyl)-, quinolinyl-(Ci 4alkyI)., isoquinolinyl-(Cl~alkyl)., reduced quinolinyl-(Cl-4alkyl)-, reduced isoquinolinyl-(Cl~alkyl)-, benzoyl-Cl-3alkyl; any one of which aryl or heterocyclic R 7 groups may be substituted with halo, trifluoromethyl, C14alkoxy, C1-4alkyl, amino, Ci-4alkylamino, d i(Cl 4alkyI) amino, or C2-4alkanoylamlno; or any one of which R 7 groups may be substituted with phenyl piperazinyl, C3-8cycloalkyl, benzyl, piperidinyl, pyridinyl, pyrimidinyl pyrrolidinyl, C2e6alkanoyl, or Cttalkoxycarbonyl; any of which groups may be substituted with halo, trifluoromethyl, amino, Cl~alkoxy, CAalkyI, ClAalkylamino, di(Cl~alkyl)amino, or C24alkanoylamino; R 8 is hydrogen or C1-6alkyI; R 3 is phenyl, phenyl-(Cl-6alkyl)-, C3.8CYCloalkyl, C5-8cycloalkenyl, Cl-8alkyl, naphthyl, orhdoe;ay'nArwihgousecptyrge/a esbttue ihoeo V 30 C2-8alkenyl,orhdoe;ayoeowhcgrusecphyrgnmybsusitdwthner [R:\LIBtt]010 12.doc: ljg 1 a 96 two halo, C1.3alkoxy, Cl.3alkylthio, nitro, trifluoromethyl, or C1.3alkyI groups; and R 4 is hydrogen or Ci-3alkyl; with the proviso that if R 1 is hydrogen or halo, R 3 is phenyl, phenyl-(Ci-6alkyl)-, C3-8CYCloalkyl, C5-8cycloalkenyl or naphthyl; or a pharmaceutically acceptable salt thereof.
38. The composition when used according to claim 24 or 25, 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.
39. The composition when used according to claim 24 or 25, wherein the NK-1 receptor antagonist is selected from 5-bis(trifluoromethyl)benzyloxy-3(S)-(4 -fluorophenyl)-4-(3-(5- oxo- 1, 4H- 1,2,4-triazolo)methyl)morpholine; (trifluoromethyl)phenyl)ethoxy)- 4-(3-(5-oxo-1 H ,4H-1 ,2,4-triazolo)methyl)-3-(S)-phenyl-morpholine; bis(trifluoromethyl)benzyloxy)-4-(3-(5-oxo- H ,4H-1 ,2,4-triazolo)methyl)-3-(S)-phenyl-morpholine; 2- *00 (R)-(l1-(R)-(3,5-bis(trifluoromethyl)-phenyl)ethoxy)3(S)( 4 fluorophenyl)4(3(5oxo1 H ,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; 1 15(trifluoromethyl)phenyl)-ethoxy)-4-(5-(N ,N-dimethylamino)methyl-1 ,2,3-triazol-4-yl)methyl-3-(S)-(4- fluorophenyl)morpholine; -(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl). 4-(3-(4-monophosphoryl-5-oxo-1 H-i ,2,4-triazolo)methyl)morpholine; (trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)4-(3-( 1 -monophosphoryl-5-oxo-1 H-i ,2,4- triazolo)methyl)morpholine; 1 5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluoro phenyl)-4-(3-(2-monophosphoryl-5-oxo-1 H-i ,2,4-triazolo)methyl)morpholine; (trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl).4..(3-(s.oxyphosphory11 H-I ,2,4- triazolo)methyl) morpholine; -(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4- .i fluorophenyl)-4-(3-( 1 -monophosphoryl-5-oxo-4H-1 ,2,4-tnazolo)methyl)morpholine; 1 5:5.(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. Se.. *40. The composition when used according to any one of claims 24 to 39, wherein the NK- a 1 receptor antagonist is orally active, long acting and CNS-penetrant.
41. The composition when used according to any one of claims 25 to 40, 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, fludlorex, fluminorex, furfurylmethylamphetamine, levamfetamine, levophacetoperane, mazindol, mefenorex, metamfepramone, methamphetamine, \Anorpseudoephedrine, pentorex, phendimetrazine, phenmetrazine, phentermine, Sphenylpropanolamine picilorex and sibutramine; or a pharmaceutically acceptable salt thereof. [RALIBH]01012.doc:Ijg 96a
42. The composition when used according to any one of claims 25 to 41, wherein the anorectic agent is a halogenated amphetamine derivative.
43. The composition when used according to claim 42, wherein the amphetamine derivative is selected from chlorphentermine cloforex, clortermine, dexfenfluramine, fenfluramine, picilorex and sibutramine; or a pharmaceutically acceptable salt thereof.
44. The composition when used according to any one of claims eating disorder results in or causes obesity. The composition when used according to any one of claims eating disorder is bulimia nervosa. 0o 46. The composition when used according to any one of claims eating disorder is a compulsive eating disorder.
47. A product comprising a NK-1 receptor antagonist and an 24 to 43, wherein the 24 to 43, wherein the 24 to 43, wherein the anorectic agent as a 0* S. @OS I ,iS S. S.. S.r S.. combined preparation when used simultaneously, separately or sequentially in the treatment or prevention of eating disorders.
48. The product according to claim 47, wherein the NK-1 receptor antagonist is a compound of formula I S r 5015 4 S. 0 9005 0* S [R:\LIBH]01012.doc:ljg 97 R 3 X R 4 R NX R I( R (I) wherein R 1 is selected from the group consisting of: C1.6alkyl, substituted with one or more of the substituents selected from: heterocycle, wherein the heterocycle is selected from the group consisting of: benzimidazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, (F) pyrazinyl, pyrazolyl, pyridyl, pyrrolyl, tetrazolyl, thiadiazolyl, triazolyl, and (M) piperidinyl, and wherein the heterocycle is unsubstituted or substituted with one or more substituent(s) selected from: Ci-6alkyl, unsubstituted or substituted with halo, -CF 3 -OCH 3 or phenyl, (ii) C1-6alkoxy, (iii) oxo, (iv) thioxo, cyano, (vi) -SCH 3 (vii) phenyl, (viii) hydroxy, (ix) trifluoromethyl, (CH2)mNR9Rio, wherein m is 0, 1 or 2, and R 9 and Rio are independently S. o10 selected from: hydrogen, (II) Cl6ealkyl, (III) hydroxyC- 1 6 alkyl, and (IV) phenyl, (xi) -NR9COR1o, wherein R 9 and R 1 0 are as defined above, and (xii) -CONRgRO, wherein R 9 and R 1 0 are as defined above, R 2 and R3 are independently selected from the group consisting of: hydrogen; 6 **R :R C26alkyl, C2-6,alkenyl, and phenyl; X is R 4 is z Rs is phenyl, unsubstituted or substituted with halo; R 6 R7 and R8 are independently selected from the group 15i consisting of: hydrogen, C1i.alkyl, halo, and -CF 3 Y is and Z is hydrogen or C14alkyl; or a pharmaceutically acceptable salt thereof.
49. The product according to claim 47, wherein the NK-1 receptor antagonist is a compound of formula Ila: A 1 Y o R 6 A3 (lla) wherein A 1 is fluorine or CF 3 A 2 is fluorine or CF 3 A 3 is fluorine or hydrogen; X is an alkylene chain of 1 to 4 carbon atoms optionally substituted by oxo; Y is a C1-4alkyl group optionally substituted by a hydroxyl group; R6 is a 5-membered or 6-membered heterocyclic ring containing 2 or 3 nitrogen atoms optionally substituted by =S or a C.4alkyl group, and optionally substituted by a group of PA the formula ZNRTR8 where Z is C1-6alkylene or C3-6cycloalkylene; R 7 is hydrogen, C-4alkyl, S 25 C3-7cycloalkyl or C3-7cycloalkylC-4alkyl, or C2-4alkyl substituted by C1-4alkoxy or hydroxyl; R 8 is [I:\DayLib\LIBH10083O.doc:ljg 98 hydrogen, C14alkyl, C3s7cycloalkyl or C3-7cycloalkylC14alkyl, or C24alkyl substituted by one or two substituents selected from C14alkoxy, hydroxyl or a 4, 5 or 6 membered heteroaliphatic ring containing one or two heteroatoms selected from N, O and S; or R 7 R 8 and the nitrogen atom to which they are attached form a heteroaliphatic ring of 4 to 7 ring atoms, optionally substituted by a hydroxy group, and optionally containing a double bond, which ring may optionally contain an oxygen or sulphur ring atom, a group S(0) or S(O) 2 or a second nitrogen atom which will be part of a NH or NRc moiety where R c is C14alkyl optionally substituted by hydroxy or C1-4alkoxy; or R 7 R 8 and the nitrogen atom to which they are attached form a non-aromatic azabicyclic ring system of 6 to 12 ring atoms; or Z, R 7 and the nitrogen atom to which they are attached form a heteroaliphatic o1 ring of 4 to 7 ring atoms which may optionally contain an oxygen ring atom; or a pharmaceutically acceptable salt thereof.
50. The product according to claim 47, wherein the NK-1 receptor antagonist is a compound of formula III: 6 R R SR 8 R* 1 1 R B R 13 R 12 5 wherein: R2 and R3 are independently selected from the group consisting of: hydrogen; (2) C-6alkyl, C2-6alkenyl, and phenyl; R 6 R 7 and R 8 are independently selected from the group consisting of: hydrogen, C1.6alkyl, fluoro, chloro, bromo, iodo, and -CF 3 R 1 1 R 1 2 and R 1 3 are independently selected from the group consisting of: fluoro, chloro, (3) bromo, and iodo; A is unsubstituted C1-alkyl; B is selected from the group consisting of: N-U X N--i X O N -N XNU XN- NA S N-NX N 0J NA -S I N N 0 e -N S I N S X H N O N S H X X X N-N N- x N-N N-N N-N' NN N e x NN N N 0- XS N I I "N 0O NX X H o ssx N 0N S N I X xRA, X ,or X p is 0 or 1; X is selected from: wherein M+ is a pharmaceutically monovalent counterion, (b) [I:\DayLib\LIBH100830.doc:lie 99 -PO(O-) 2 -PO(O-) 2 wherein D 2 is a pharmaceutically acceptabie divalent counterion, -CH(R 4 wherein R 4 is hydrogen or Cl.3alkyl, -CH(R 4 2 .2M, CH(R 4 2 -CO-CH 2 CH 2 -CO 2 M, 0) -CH(CH 3 )-O-CO-R5, wherein R5 is selected +2M 0 ~NH 3 +M from the group consisting of: (ii) O C0 2 M Co 0 M C02- C0jM+ (iii) C0jM~ (iv) N 0 C02fM M (v i) (vC 0 2 (vii) C0 2 -M and Y is Z is hydrogen or C1v6alkyl; or a pharmaceutically acceptable salt thereof. .51. The product according to claim 47, wherein the NK-1 receptor antagonist is a compound of formula lVa:1 Al *Y A2 (0 0 10 X A (lVa) wherein A' is fluorine or CF 3 A 2 is fluorine or CF 3 A 3 is fluorine or hydrogen; X is a group of the formula NR 6 R7 or a C- or N-inked imidazolyl ring; Y is hydrogen or Cl~alkyl optionally substituted by a hydroxy group; R 6 is hydrogen, CI-6alkyl, C3-7CYCloalkyl, C3.7cycloalkylCl-4alkyl, phenyl, or C2Aalkyl substituted by ClAalkoxy or hydroxy; R 7 is hydrogen, Cl.6alkyl, C3-7cycloalkyl, C3.7cycloalkylCl.~alkyl, phenyl, or C2Aalkyl substituted by one or two substituents selected from ClAalkoxy, hydroxy or a 4, 5 or 6 membered heteroaliphatic ring containing one or two heteroatoms selected from N, 0 and S; or R 6 and R 7 together with the nitrogen atom to which they are attached, form a saturated or partially saturated heterocyclic ring of 4 to 7 ring atoms, which ring may optionally contain in the ring one oxygen or sulphur atom or a group selected from NR 8 S(0) or r 741 S (0) 2 and which ring may be optionally substituted by one or two groups selected from hydroxy- C lalkyl, CAalkoxyClAalkyl, oxo, CORa Or CO2Ra where Ra is hydrogen Or C1~ly;o R n [1:\Dayl-ib\LIF3H 100830.doc:i,_, 100 together with the nitrogen atom to which they are attached, form a non-aromatic azabicyclic ring system of 6 to 12 ring atoms; and R 8 is hydrogen, C.4alkyl, hydroxy C14alkyl or C14alkyl C 4alkyl; or a pharmaceutically acceptable salt thereof.
52. The product according to claim 47, wherein the NK-1 receptor antagonist is a compound of formula V: R 7 R R 1 3 R N R Rs-(Z) R6 R 6 (V) wherein: Y is (CH 2 )n wherein n is an integer from 1 to 4, and wherein any one of the carbon-carbon single bonds in said (CH 2 )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 R 4 and wherein any one of the carbon atoms of said (CH 2 )m may optionally be substituted with R 7 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 S* bond, and any one of the carbon atoms of said (CH 2 )m may optionally be substituted with R 1 is hydrogen or Ci.ealkyl optionally substituted with hydroxy, C14alkoxy or fluoro; R 2 is a radical 15 selected from hydrogen, C 1 -6 straight or branched alkyl, Ca.7cycloalkyl wherein one of the CH 2 groups in said cycloalkyl may optionally be replaced by NH, oxygen or sulphur; aryl selected from *o* phenyl and naphthyl; heteroaryl selected from indanyl, thienyl, furyl, pyridyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl and quinolyl; phenyl-C2- 6 alkyl, 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, Ci-6alkyl, C1.6alkoxy, trifluoromethyl, amino, Cl.alkylamino, C.-6alkyl-O- CO, CI-6alkyl-O-CO-Cl 6 alkyl, C-.6alkyl-O-CO, Ci-6alkyl-CO-Clealkyl-O-, Clsalkyl-CO, Ci.-alkyl-CO- NHC1-6alkyl-, di-Cl.6alkylamino, -CONH-Ci-6alkyl, C1-6alkyl-CO-NH-Cl 6 alkyl, -NHCOH and -NHCO- Ci-6alkyl; and wherein one of the phenyl moieties of said benzhydryl may optionally be replaced by naphthyl, thienyl, furyl or pyridyl; R 5 is hydrogen, phenyl or Cli6alkyl; or R 2 and R 5 together with the carbon to which they are attached, form a saturated ring having from 3 to 7 carbon atoms wherein one of the CH 2 groups in said ring may optionally be replaced by oxygen, NH or sulfur; R 3 is aryl selected from phenyl and naphthyl; heteroaryl selected from indanyl, thienyl, furyl, pyridyl, thiazolyl, Sisothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl and quinolyl; and cycloalkyl having 3 to 7 ,o carbon atoms wherein one of the (CH 2 groups in said cycloalkyl may optionally be replaced by NH, -O:\DayLib\LIBH100830.doc:lig 101 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, Ci.6alkoxy, trifluoromethyl, amino, Ci.6alkylamino, -CO-NH-Ci 6 alkyl, Ci-alkyl-CO-NH-C CC-6alkyl, -NHCOH and -NHCO- C1.6alkyl; R 4 and R 7 are each independently selected from hydroxy, halogen, halo, amino, oxo, cyano, methylene, hydroxymethyl, halomethyl, Ci-6alkylamino, di-Cil6alkylamino, Cil-alkoxy, Ci-alkyl-O-CO, C1-6alkyl-O-CO-Ci-6alkyl, Ci-alkyl-CO-O, Cl-alkyl-CO-Ci.-alkyl-O-, Cl.6alkyl-CO-, Cl-6alkyl-CO-CI- 6 alkyl, and the radicals set forth in the definition of R 2 R 6 is -NHCOR9, -NHCH 2 R 9 S0 2 R 9 or one of the radicals set forth in any of the definitions of R 2 R 4 and 0o R 7 R 8 is oximino (=NOH) or one of the radicals set forth in any of the definitions of R2, R 4 and R 7 R 9 is Ci.6alkyl, hydrogen, phenyl or phenylCl 6alkyl; with the proviso that when m is 0, R 8 is absent, when R 4 R 6 R 7 or R 8 is as defined in R 2 it cannot form together with the carbon to which it is attached ,a ring with R5, and when R 4 and R 7 are attached to the same carbon atom, then either each of R 4 and R 7 is independently selected from hydrogen, fluoro and C1.-alkyl, or R 4 5 and R 7 together with the carbon to which they are attached, for a C3-esaturated carbocyclic ring that forms a spiro compound with the nitrogen-containing ring to which they are attached; or a pharmaceutically acceptable salt thereof.
53. The product according to claim 47, wherein the NK-1 receptor antagonist is a compound of formula VI: R 0 R R 3 R 4 R 2 20 (VI) wherein: radicals R are phenyl radicals optionally 2- or 3-substituted by a halogen atom or a methyl radical; R 1 is optionally substituted phenyl, cyclohexadienyl, naphthyl, indenyl or optionally substituted heterocycle; R 2 is H, halogen, OH, alkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkyloxy, alkylthio, acyloxy, carboxy, optionally substituted alkyloxycarbonyl, benzyloxycarbonyl, amino or acylamino; R 3 is optionally 2-substituted phenyl; R 4 is OH or fluorine when R 5 is H; or R 4 and R5 are OH; or R4 and R5 together form a bond; or a pharmaceutically acceptable salt thereof.
54. The product according to claim 47, wherein the NK-1 receptor antagonist is a compound of formula VII: R Q I I Ar-T-CO-N-CH 2 -C-CH 2 -CH2-Am+,A- I Ar' (VII) [1:\DayLib\LIB H0083.doc:Ijg wherein: Ar represents an optionally substituted mono-, di- or tricyclic aromatic or heteroaromatic group; T represents a bond, a hydroxymethylene group, a Cl4alkoxymethylene group or a C1.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, C14alkoxy, C-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, o-Cl14alkoxy- C14alkyl or co-C2-4alkanoyloxyC24alkyl; Q represents hydrogen; or Q and R together form a X, N® 1,2-ethylene, 1,3-propylene or 1,4-butylene group; Am' represents the radical X 3 X 2 in which Xi, X 2 and X 3 together with the nitrogen atom to which they are attached, form an azabicyclic or to azatricyclic ring system optionally substituted by a phenyl or benzyl group; and A- represents a pharmaceutically acceptable anion.
55. The product according to claim 47, wherein the NK-1 receptor antagonist is a compound of formula VIII R3 R-N X 2 -N-X 3 -R R2 Xj,( (VIII) l wherein: Ri represents an optionally substituted aralkyl, aryloxyalykl, heteroaralkyl, aroyl, heteroaroyl, cycloalkylcarbonyl, aralkanoyl, heteroarylalkanoyl, aralkoxycarbonyl or arylcarbamoyl g roup or the acyl group of an a-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; R 3 represents hydrogen, alkyl, carbamoyl or an alkanoyl or alkenoyl group optionally substituted by carboxy or esterified or amidated carboxy; R4 represents an optionally substituted aryl group or an optionally partially saturated heteroaryl group; Xi represents methylene, ethylene, a bond, an optionally ketalised carbonyl group or an optionally etherified hydroxymethylene group; X 2 represents alkylene, carbonyl or a bond; and X 3 represents carbonyl, oxo-lower alkyl, oxo(aza)-lower alkyl, or an alkyl group optionally substituted by phenyl, hydroxymethyl, optionally esterified or amidated carboxy, or (in other than the a-position) hydroxy; or a pharmaceutically acceptable salt thereof.
56. The product according to claim 47, wherein the NK- 1 receptor antagonist is a compound of formula IX: [I ADayLib\LIBH0083O.doc:Ijg 103 NN R 1 ,A H N-R 3 Y 0 4 Ox R 4 (IX) wherein: R 1 is aryl, or a group of the formula: z X is CH or N; and Z is O or N-R 5 in which R 5 is hydrogen or lower alkyl; R 2 is hydroxy or lower alkoxy; R 3 is hydrogen or optionally substituted lower alkyl; R 4 is optionally substituted ar(lower)alkyl; A is carbonyl or sulfonyl; and Y is a bond or lower alkenylene; or a pharmaceutically acceptable salt thereof.
57. The product according to claim 47, wherein the NK-1 receptor antagonist is a compound of formula X: H H R N R H (X) wherein: Ri 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 C3.7cycloalkyl may optionally be substituted with one or two substituents, said substituents being independently selected from chloro, fluoro, bromo, iodo, nitro, Cl-loalkyl optionally substituted with 15 from one to three fluoro groups, Cl.ioalkoxy optionally substituted with from one to three fluoro groups, amino, Cl-loalkyl-S-, Cl.loalkyl-S(O)-, Cl-loalkyl-S0 2 phenyl, phenoxy, Ci.loalkyl-SO 2 NH-, C1-ioalkyl-SO 2 NH- Cl.loalkyl-, Ci.ioalkylamino-diCi- 1 oalkyl-, cyano, hydroxy, cycloalkoxy having 3 to 7 carbon atoms, C.lloalkylamino, Cv-dialkylamino, HC(O)NH- and Ci.1oalkyl-C(O)NH-; and R 2 is thienyl, benzhydryl, naphthyl or phenyl optionally substituted with from one to three substituents independently selected from chloro, bromo, fluoro, iodo, cycloalkoxy having 3 to 7 carbon atoms, Ci-ioalkoxy optionally substituted with from one to three fluoro groups and Ci-loalkyl optionally substituted with from one to three fluoro groups; or a pharmaceutically acceptable salt thereof.
58. The product according to claim 47, wherein the NK- 1 receptor antagonist is a compound of formula XI: [I\DayLib\L1BHj00830.doc:1jg 104 R HQ R (XI) N N wherein: R 1 is a C1alkoxy group; R 2 is N-N P 3 is a hydrogen or halogen atom; R 4 and R 5 may each independently represent a hydrogen or halogen atom, or a C14alkyI, Ci.4alkoxy or trifluoromethyl group; R 6 is a hydrogen atom, a Ci4alkyl, (CH2)mcyclopropyl, -S(O)nCi~alkyl, 5 phenyl, NR 7 R8, CH2C(O)CF 3 or trifluoromethyl group; W 7 and R 8 may each independently represent a hydrogen atom, or a Ci4alkyl or acyl group; x represents zero or 1; n represents zero, 1 or 2; and m represents zero or 1; or a pharmaceutically acceptable salt thereof.
59. The product according to claim 47, wherein the NK-1 receptor antagonist is a compound of formula XII: R-(C H 2 -UH 2 H 2 )-R NH R (OH 2 )m R1(XII) wherein: m is zero, 1, 2 or 3; n is zero or 1; o is zero, 1 or 2; p is zero or 1; R is phenyl, 2- or 3-indolyl, 2- or 3-indolinyl, benzothienyl, benzofuranyl, or naphthyl; which R groups may be substituted with one or two halo, C 13alkoxy, trifluoromethyl, Ci1ialkyl, phenyl-Cl-3akoxy, or Ci1ialkanoyl groups; R' is trityl, phenyl, diphenylmethyl, phenoxy, phenylthio, piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, indolinyl, indolyl, benzothienyl, hexamethyleneiminyl, benzofuranyl, tetrahydropyridinyl, quinolinyl, isoquinolinyl, reduced quinolinyl, reduced isoquinolinyl, phenyl-(Cl~alkyl)-, phenyl-(Cl~alkoxy)-, quinolinyl-(Cl-4alkyl)-, isoquinolinyl-(C,4alkyl)-, reduced quniolinyl-(C 1 4 alkyl)-, reduced isoquinolinyl-(ClAalkyl)-, benzoyl-(Ci- 3 alkyl)-, Cl4alkyl, or -NH-CH 2 R 5 any one of which R 1 groups may be substituted with halo, Cinalkyl, C14alkoxy, trifluoromethyl, amino, C14alkylamino, di(Cl-4alkyl)amino, or Cl4alkanoylamino; or any one of which R 1 groups may R4 be substituted with phenyl, piperazinyl, C3-Bcycloalkyl, benzyl, Ci.-ialkyl, piperizlinyl, pyridinyl, 2 1T0~[ADa yLi b\ LJIFBH 100830doc: I ig 105 pyrimidinyl, C2-6alkanoylamino, pyrrolidinyl, C2-6alkanoyl, or Cl-4alkoxycarbonyl; any one of which groups may be substituted with halo, C1-4alkyI, CI- 4 alkoxy, trifluoromethyl, amino, Cl-4alkylamino, di(C,4alkyl)amino, or C24alkanoylamino; or R 1 is amino, a leaving group, hydrogen, C14alkylamino, or di(Cl~alkyl)amino; R 5 is pyridyl, anilino(Cl-3alkyl)-, or anilinocarbonyl; R 2 is hydrogen, C,4alkyl, Ci1salkylsulfonyl, carboxy-(Cl-3alkyl)-, Cl-3alkoxycarbonyl-(Ci 3 alkyl)-, or -CO-R 6 R 6 is hydrogen, Ci4alkyl, Cl-3haloalkyl, phenyl, C1l3alkoxy, Cl-3hydroxyalkyl, amino, Ci4alkylamino, di(Cl4alkyl) amino, or (CH2)q-R 7 q is zero to 3; R 7 is carboxy, Ci4alkoxycarbonyl, Ci-4alkylcarbonyloxy, amino, Ci-4alkylamino, di(Ci-4alkyl) amino, Cl-6alkoxycarbonylamino, or phenoxy, phenylthio, piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, indolinyl, indolyl, benzothienyl, benzofuranyl, quinolinyl, o0 phenyl-(Clv4alkyl)-, quinolinyl-(Cl 4alkyl)-, isoquinolinyl-(Ci-4alkyl)-, reduced quinolinyl-(Cl~alkyl)-, reduced isoquinolinyl-(Cl-4alkyl)-, benzoyl-Cl-3alkyl; any one of which aryl or heterocyclic R 7 groups :..may be substituted with halo, trifluoromethyl, C14alkoxy, C14alkyl, amino, Cl-4alkylamino, 0*~*di(Cl-4alkyl)amino, or C24alkanoylamlno; or any one of which R7 groups may be substituted with :phenyl piperazinyl, C3-8Cycloalkyl, benzyl, piperidinyl, pyridinyl, pyrimidinyl pyrrolidinyl, C2-6alkanoyl, 15i or C,4alkoxycarbonyl; any of which groups may be substituted with halo, trifluoromethyl, amino, Ci4alkoxy, C14alkyl, Ci~alkylamino, di(Cl~alkyl)amino, or C24alkanoylamino; R 8 is hydrogen or Cl-6alkyl; R 3 is phenyl, phenyl-(Cv-6alkyl)-, C3-8cycloalkyl, C5-8cycloalkenyl, Cl-8alkyl, naphthyl, C2.8alkenyl, or hydrogen; any one or which groups except hydrogen may be substituted with one or two halo, Cl-3alkoxy, Cl.3alkylthio, nitro, trifluoromethyl, or Cl-3alkyl groups; and R 4 is hydrogen or C1l3alkyl; with the proviso that if R 1 is hydrogen or halo, R 3 is phenyl, phenyl-(Cl-6alkyl)-, C3-8cycloalkyl, C5-8cycloalkenyl or naphthyl; or a pharmaceutically acceptable salt thereof. The product according to claim 47, wherein the NK-1 receptor antagonist is selected from the classes of compounds described in EP-A-0577394, WO-A-9508549, WO-A-9518 124, WO-A-9523798 and WO-A-9605181.
61. The product according to claim 47, wherein the NK-1 receptor antagonist is selected from 5-bis(trifluoromethyl)benzyloxy-3(S)-(4 -fluorophenyl)-4-(3-(5-oxo-l1H, 4 H- 1,2,4- triazolo)methyl)morpholine; (trifluoromethyl)phenyl)ethoxy)-4-(3-(5-oxo-l1H ,4H- 1 2 4 -triazolo)methyl)-3-(S)-phenyl-morpholine; 2 (3,5-bis (trifl uorometh yl) ben zyloxy)-4-(3-(5- oxo- 1 H ,4H-1 2 ,4-triazolo)methyl)-3-(S)-phenyl-morpholine; 1 phenyl)ethoxy)-3-(S)-(4-fluorophenyl)4(3(5oxo1 H ,4H-1 ,2,4-triazolo)methyl)morpholine; 1- (R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)4(5(N ,N dimethylamino)methyl-1 ,2,3-triazol-4-yl)methyl- 3-(S)-phenylmorpholine; 1 (trifluoromethyl)phenyl)ethoxy)-4-(5-(N N- dimethylamino)methyl-1,23tizl4y ehl3()-4furpey~opoie -~triazolo)methyl)morpholine; 1 (trifluoromethyl)phenyl)ethoxy)-3-(S)-(4- 1:\DayLib\L B H]00830.doc: Ij g 106 fluorophenyl)-4-(3-(1 -monophosphoryl-5-oxo-1H- 1, 2 ,4-triazolo)methyl)morpholine; 5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluoro phenyl)-4-(3-(2-monophosphoryl-5oxo-1 H- 1, 2 ,4-triazolo)methyl)morpholine; (R)-(3,5-bis (trifluoromethyl)phenyl)ethoxy)-3-(S)-(4- fluorophenyl)-4-(3-(5-oxyphosphoryl-1 H-1 ,2,4-triazolo)methyl) morpholine; 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.
62. The product according to any one of claims 47 to 61, wherein the NK-1 receptor 1o antagonist is orally active, long acting and CNS-penetrant.
63. The product according to any one of claims 47 *to 62, wherein the anorectic agent is selected from aminorex, amphechloral, amphetamine, benzphetamine, chlorphentermine, clobenzorex, cloforex, clominorex, clortermine, cyclexedrine, dexfenfluramine, dextroamphetamine, diethylpropion, diphemethoxidine, N-ethylamphetamine, is fenbutrazate, fenfluramine, fenisorex, fenproporex, fludorex, fluminorex furfurylmethylamphetamine, levamfetamine, levophacetoperane, mazindol, mefenorex, metamfepramone, methamphetamine, norpseudoephedrine, pentorex, phendimetrazine, phenmetrazine, phentermine, phenylpropanolamine picilorex and sibutramine; or a pharmaceutically acceptable salt thereof. 20 64. The product according to any one of claims 47 to 63, wherein the anorectic agent is a halogenated amphetamine derivative. *65. The product according to claim 64 wherein the amphetamine derivative is selected from chlorphentermine cloforex, clortermine, dexfenfluramine, fenfluramine, picilorex and sibutramine; or a pharmaceutically acceptable salt thereof.
66. The product according to any one of claims 47 to 65, wherein the eating disorder results in or causes obesity.
67. The product according to any one of claims 47 to 65, wherein the eating disorder is bulimia nervosa.
68. The product according to any one of claims 47 to 65, wherein the eating disorder is a compulsive eating disorder.
69. A method for the treatment or prevention of eating disorders, which method comprises administration to patient in need of such treatment an effective amount of a NK-1 receptor antagonist. [I:\DayLib\LBH 100SO .doc: Ig V 107 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.
71. The method according to claim 69 or 70, wherein the NK-1 receptor antagonist is a compound of formula I R 3 X R 4 R N R (I) wherein R 1 is selected from the group consisting of: C1-6alkyl, substituted with one or more of the substituents selected from: heterocycle, wherein the heterocycle is selected from the group consisting of: benzimidazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, (F) pyrazinyl, pyrazolyl, pyridyl, pyrrolyl, tetrazolyl, thiadiazolyl, triazolyl, and (M) piperidinyl, and wherein the heterocycle is unsubstituted or substituted with one or more substituent(s) selected from: C-6alkyl, unsubstituted or substituted with halo, -CF3, -OCH 3 or phenyl, (ii) Cilealkoxy, (iii) oxo, (iv) thioxo, cyano, (vi) -SCH 3 (vii) phenyl, (viii) hydroxy, (ix) trifluoromethyl, (CH 2 )mNR 9 R'O, wherein m is 0, 1 or 2, and R 9 and R10 are independently 5i selected from: hydrogen, (II) Ci.-alkyl, (IIl) hydroxyCl-6alkyl, and (IV) phenyl, (xi) -NR 9 COR1o, wherein R 9 and RIo are as defined above, and (xii) -CONR 9 RO, wherein R 9 and RI0 are as defined above, R 2 and R 3 are independently selected from the group consisting of: hydrogen; (2) R 6 YR C1.6alkyl, C2-6alkenyl, and phenyl; X is R 4 is z R 5 is phenyl, unsubstituted or substituted with halo; R 6 R 7 and R 8 are independently selected from the group consisting of: hydrogen, Cliealkyl, halo, and -CF3; Y is and Z is hydrogen or Ci4alkyl; or a pharmaceutically acceptable salt thereof.
72. The method according to claim 69 or 70, wherein the NK-1 receptor antagonist is a compound of formula Ila: o Y N/v A2 [I:\DayLib\LIBH0083.doc:jg 108 wherein A 1 is fluorine or CF3; A 2 is fluorine or CF3; A 3 is fluorine or hydrogen; X is an alkylene chain of 1 to 4 carbon atoms optionally substituted by oxo; Y is a C.4alkyl group optionally substituted by a hydroxyl group; R 6 is a 5-membered or 6-membered heterocyclic ring containing 2 or 3 nitrogen atoms optionally substituted by =S or a C1.4alkyl group, and optionally substituted by a group of the formula ZNR 7 R8 where Z is C1.6alkylene or C3.6cycloalkylene; R 7 is hydrogen, Ci4alkyl, C3.7cycloalkyl or C3.7cycloalkylC14alkyl, or C2-4alkyl substituted by C1.4alkoxy or hydroxyl; R8 is hydrogen, C1-4alkyl, C3-7cycloalkyl or C3.icycloalkylC14alkyl, or C24alkyl 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, 0 and S; or R 7 R 8 and the nitrogen atom to o0 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(0) 2 or a second nitrogen atom which will be part of a NH or NR C moiety where Rc is C1-4alkyl optionally substituted by hydroxy or Ci-4alkoxy; or R 7 R 8 and the nitrogen atom to which they are attached form a non-aromatic azabicyclic ring system of 6 to 12 ring atoms; or Z, R 7 and the nitrogen atom to which they are attached form a heteroaliphatic ring of 4 to 7 ring atoms which may optionally contain an oxygen ring atom; or a pharmaceutically acceptable salt thereof. i 73. The method according to claim 69 or 70, wherein the NK-1 receptor antagonist is a S compound of formula IIl: 6 .0 R3 Y R Z z R 8 R 2 N (O)P A R 13 R 1 2 wherein: R 2 and R 3 are independently selected from the group consisting of: hydrogen; (2) Cilealkyl, C2-6alkenyl, and phenyl; R 6 R 7 and R 8 are independently selected from the group consisting of: hydrogen, Ciealkyl, fluoro, chloro, bromo, iodo, and -CF 3 R, R 12 and R 13 are independently selected from the group consisting of: fluoro, chloro, (3) bromo, and iodo; A is unsubstituted Cl-6alkyl; B is selected from the group consisting of: N- lX N-Il NA N N A N-O N N X H N N S X H [I:\DayLib\LIBH]00830.doc:ijg 109 x N-N IX N 0 1 x N-N NI N- N N-N N x N x N- N 0K x N 0 H 0-x x ~or A ;pis 0orl;1X is selected from: wherein M+ is a pharmaceutically monovalen conein kb -PO(0-) 2 .2M, -P0(0-) 2 .D 2 wherein D 2 +is a pharmaceutically acceptable divalent counterion, -CH(R 4 wherein R4 is hydrogen or Cl.3alkyl, -CH(R 4 P0(0-) 2 .2M, (f) CH(R 4 2 -C0-CH 2 CH 2 -CO 2 ()-CH(CH+)O-CO-R5, wherein R 5 is selected from +2M the group consisting of: M(i 0* 0 00 0 U@ 0 00 00 0 0 0 *00* *0S3 0 0*~S 0S 0 0a0 0 0 S .00* 0 a 0 *0 S 0 0 0* B 90*S C0-+ 0 C0 2 M M (iii)C~jM (iv) NH 3 CO-+ -0 0 2 -M t,(vi) I(Vii) and Y is Z is hydrogen or Cv-6alkyl; or a pharmaceutically acceptable salt 10 thereof.
74. The method according to claim 69 or 70, wherein the NK-1 receptor antagonist is a compound of formula lVa: (lVa) wherein A' is fluorine or CF 3 A 2 is fluorine or OF 3 A s fluorine or hydrogen; X is a group of the formula NR 6 R 7 or a C- or N-inked imidazolyl ring; Y is hydrogen or Citalkyl optionally substituted by a hydroxy group; R 6 is hydrogen, Ci-6alkyl, C3l7CYCloalkyl, C3.7cycloalkylCi~alkyl, phenyl, or Calkyl substituted by C1_4alkoxy or hydroxy; R 7 is hydrogen, C1.6alkyl, C3.lCYCloalkyl, [I:\DayLib\LIBH]00830.doc:Ijg 110 C3-7cycloalkylC14alkyl, phenyl, or C24alkyl substituted by one or two substituents selected from C14alkoxy, hydroxy or a 4, 5 or 6 membered heteroaliphatic ring containing one or two heteroatoms selected from N, O and S; or R 6 and R 7 together with the nitrogen atom to which they are attached, form a saturated or partially saturated heterocyclic ring of 4 to 7 ring atoms, which ring may optionally contain in the ring one oxygen or sulphur atom or a group selected from NR8, S(0) or S(0) 2 and which ring may be optionally substituted by one or two groups selected from hydroxy- C14alkyl, C14alkoxyC14alkyl, oxo, CORa or CO 2 Ra where Ra is hydrogen or Cl-4alkyl; or R 6 and R 7 together with the nitrogen atom to which they are attached, form a non-aromatic azabicyclic ring system of 6 to 12 ring atoms; and R 8 is hydrogen, C14alkyl, hydroxy C1-4alkyl or C14alkyl C.4alkyl; or a pharmaceutically acceptable salt thereof. The method according to claim 69 or 70, wherein the NK-1 receptor antagonist is a compound of formula V: 4 R R R 1 3 R2 y Y N R 3 N R 6 (V) wherein: Y is (CH 2 )n wherein n is an integer from 1 to 4, and wherein any one of the carbon-carbon S 15i single bonds in said (CH 2 )n may optionally be replaced by a carbon-carbon double bond, and wherein any one of the carbon atoms of said (CH 2 )n may optionally be substituted with R 4 and wherein any one of the carbon atoms of said (CH 2 )m may optionally be substituted with R 7 Z is (CH 2 )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 R 1 is hydrogen or Ciealkyl optionally substituted with hydroxy, C-4alkoxy or fluoro; R 2 is a radical selected from hydrogen, C16 straight or branched alkyl, C37cycloalkyl wherein one of the CH 2 groups in said cycloalkyl may optionally be replaced by NH, oxygen or sulphur; aryl selected from phenyl and naphthyl; heteroaryl selected from indanyl, thienyl, furyl, pyridyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl and quinolyl; phenyl-C26alkyl, 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, C16alkyl, Ci-6alkoxy, trifluoromethyl, amino, Ci.6alkylamino, Ci-6alkyl-O- CO, C1-6alkyl-O-CO-Cl6alkyl, Cl-6alkyl-O-CO, C16alkyl-CO-C 1 ealkyl-O-, Ci-alkyl-CO, Cl-6alkyl-CO- NHCiealkyl-, di-Ci.alkylamino, -CONH-Cli.alkyl, C1ialkyl-CO-NH-Cl. 6 alkyl, -NHCOH and -NHCO- [I:\DayLib\LIBH0083.doc:jg 111 C1-6alkyl; and wherein one of the phenyl moieties of said benzhydryl may optionally be replaced by naphthyl, thienyl, furyl or pyridyl; R s 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 CH 2 groups in said ring may optionally be replaced by oxygen, NH or sulfur; R 3 is aryl selected from phenyl and naphthyl; heteroaryl selected from indanyl, thienyl, furyl, pyridyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl and quinolyl; and cycloalkyl having 3 to 7 carbon atoms wherein one of the (CH 2 groups in said cycloalkyl may optionally be replaced by NH, oxygen or sulphur; wherein each of said aryl and heteroaryl groups may optionally be substituted with one or more substituents, and said C3-7cycloalkyl may optionally be substituted with one or two 0o substituents, each of said substituents being independently selected from halo, nitro, Cl6ealkyl, Cl.6alkoxy, trifluoromethyl, amino, Cl-alkylamino, -CO-NH-Cialkyl, Ci6ealkyl-CO-NH-C Ci6alkyl, -NHCOH and -NHCO- C1-6alkyl; R 4 and R 7 are each independently selected from hydroxy, halogen, halo, amino, oxo, cyano, methylene, hydroxymethyl, halomethyl, Ci6ealkylamino, di-Ci6ealkylamino, C1.6alkoxy, Ci.6alkyl-O-CO, C1-6alkyl-O-CO-Cl. 6 alkyl, C1.6alkyl-CO-O, C1.6alkyl-CO-C 1 -6alkyl-O-, 15 Cl6ealkyl-CO-, Cl6ealkyl-CO-Cl.alkyl, and the radicals set forth in the definition of R 2 R6 is -NHCOR 9 -NHCH 2 R 9 S0 2 R 9 or one of the radicals set forth in any of the definitions of R 2 R 4 and R 7 R 8 is oximino (=NOH) or one of the radicals set forth in any of the definitions of R 2 R 4 and R 7 R 9 is C1.6alkyl, hydrogen, phenyl or phenylCl.salkyl; with the proviso that when m is 0, R8 is absent, when R 4 R 6 R 7 or R 8 is as defined in R 2 it cannot form together with the carbon to 20 which it is attached ,a ring with RS, and when R4 and R 7 are attached to the same carbon atom, then either each of R 4 and R 7 is independently selected from hydrogen, fluoro and C1.6alkyl, or R 4 S• and R 7 together with the carbon to which they are attached, for a C3-6saturated carbocyclic ring that forms a spiro compound with the nitrogen-containing ring to which they are attached; or a pharmaceutically acceptable salt thereof.
76. The method according to claim 69 or 70, wherein the NK-1 receptor antagonist is a compound of formula VI: R R N R R 3 R 4 wherein: radicals R are phenyl radicals optionally 2- or 3-substituted by a halogen atom or a methyl radical; R 1 is optionally substituted phenyl, cyclohexadienyl, naphthyl, indenyl or optionally substituted heterocycle; R 2 is H, halogen, OH, alkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkyloxy, alkylthio, acyloxy, carboxy, optionally substituted alkyloxycarbonyl, benzyloxycarbonyl, [I:\DayLib\L1BH0083.doc:jg 112 amino or acylamino; R3 is optionally 2-substituted phenyl; R 4 is OH or fluorine when R 5 is H; or R 4 and R 5 are OH; or R 4 and R 5 together form a bond; or a pharmaceutically acceptable salt thereof.
77. The method according to claim 69 or 70, wherein the NK-1 receptor antagonist is a compound of formula VII: R Q Ar-T-CO-N-CH 2 -C-CH 2 -CH 2-Am,A I Ar' (VII) wherein: Ar represents an optionally substituted mono-, di- or tricyclic aromatic or heteroaromatic group; T represents a bond, a hydroxymethylene group, a C-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, C14alkoxy, C-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, C-4alkyl, o-C.4alkoxy- CCi4alkyl or o-C24alkanoyloxyC 2 4alkyl; Q represents hydrogen; or Q and R together form a X, 1,2-ethylene, 1,3-propylene or 1,4-butylene group; Am+ represents the radical x 3 x 2 in which X 1 X 2 and X 3 together with the nitrogen atom to which they are attached, form an azabicyclic or azatricyclic ring system optionally substituted by a phenyl or benzyl group; and A- represents a pharmaceutically acceptable anion.
78. The method according to claim 69 or 70, wherein the NK-1 receptor antagonist is a *oco compound of formula VIII R3 R N X2-N-X3-R4 R2 -X (VIII) wherein: R 1 represents an optionally substituted aralkyl, aryloxyalykl, heteroaralkyl, aroyl, heteroaroyl, cycloalkylcarbonyl, aralkanoyl, heteroarylalkanoyl, aralkoxycarbonyl or arylcarbamoyl group or the acyl group of an co-amino acid optionally N-substituted by a lower alkanoyl or carbamoyl-lower alkanoyl group; R 2 represents cycloalkyl or an optionally substituted aryl or heteroaryl group; R 3 represents hydrogen, alkyl, carbamoyl or an alkanoyl or alkenoyl group optionally substituted by carboxy or esterified or amidated carboxy; R 4 represents an optionally substituted aryl group or an optionally partially saturated heteroaryl group; X 1 represents methylene, ethylene, a bond, an optionally ketalised carbonyl group or an optionally etherified hydroxymethylene group; X 2 represents alkylene, carbonyl or a bond; and X 3 represents carbonyl, oxo-lower alkyl, oxo(aza)-lower alkyl, or an alkyl group optionally substituted by phenyl, [I:\DayLib\LIBH]00830.doc:jg 113 hydroxymethyl, optionally esterified or amidated carboxy, or (in other than the a-position) hydroxy; or a pharmaceutically acceptable salt thereof.
79. The use according to claim 1 or 2, wherein the NK- 1 receptor antagonist is a compound of formula IX: 0 N N R, A H N-R 3 Y 3 0 R (IX) wherein: R 1 is aryl, or a group of the formula: X is CH or N; and Z is O or N-R 5 in which R 5 is hydrogen or lower alkyl; R 2 is hydroxy or lower alkoxy; R 3 is hydrogen or optionally substituted lower alkyl; R 4 is optionally substituted ar(lower)alkyl; A is carbonyl or sulfonyl; and Y is a bond or lower alkenylene; or a pharmaceutically acceptable salt thereof. 1 0
80. The method according to claim 69 or 70, wherein the NK-1 receptor antagonist is a compound of formula X: R ^R 2 H (X) wherein: R 1 is aryl selected from indanyl, phenyl and naphthyl; heteroaryl selected from thienyl, furyl, pyridyl and quinolyl; and cycloalkyl having 3 to 7 carbon atoms, wherein one of said 15 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 C3-7cycloalkyl may optionally be substituted with one or two substituents, said substituents being independently selected from chloro, fluoro, bromo, iodo, nitro, C.o10alkyl optionally substituted with from one to three fluoro groups, C1i-oalkoxy optionally substituted with from one to three fluoro groups, amino, C1.1oalkyl-S-, Ci-ioalkyl-S(O)-, C1-ioalkyl-S0 2 phenyl, phenoxy, C.1-oalkyl-SO 2 NH-, Ci-ioalkyl-SO 2 NH- Ci-ioalkyl-, Cl-ioalkylamino-diC- 1 loalkyl-, cyano, hydroxy, cycloalkoxy having 3 to 7 carbon atoms, Ci-ioalkylamino, Ci-6dialkylamino, HC(O)NH- and C1-1oalkyl-C(O)NH-; and R 2 is thienyl, benzhydryl, naphthyl or phenyl optionally substituted with from one to three substituents independently selected from chloro, bromo, fluoro, iodo, cycloalkoxy having 3 to 7 carbon atoms, Cli-ialkoxy optionally substituted with from one to three fluoro groups and Cl.ioalkyl optionally substituted with from one to three fluoro groups; or a pharmaceutically acceptable salt thereof.
81. The method according to claim 69 or 70, wherein the NK- 1 receptor antagonist is a compound of formula XI: [1\DayLib\LBH00830.doc:Ijg 114 H C 2 R HQ (Xl1) NN wherein: R 1 is a Ci4alkoxy group; R 2 is N-N ;R 3 is a hydrogen or halogen atom; R 4 and R 5 may each independently represent a hydrogen or halogen atom, or a Ci4alkyl, C14alkoxy or trifluoromethyl group; R 6 is a hydrogen atom, a C14alkyl, (CH2)mcyclopropyl, -S(O)nlialkyl, 5 phenyl, NR 7 R8, CH2C(O)CF 3 or trifluoromethyl group; R 7 and R 8 may each independently represent a hydrogen atom, or a C,4alkyl or acyl group; x represents zero or 1; n represents zero, 1 or 2; and m represents zero or 1; or a pharmaceutically acceptable salt thereof. *82. The method according to claim 69 or 70, wherein the NK-1 receptor antagonist is a compound of formula XII: 1 1 3 R-(CH 2 )-U-UH 2 -N-(CHl 2 )-R NH 12 NH R 2 )M (XII) 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, C1l3alkoxy, trifluoromethyl, C14alkyl, phenyl-Cl-3alkoxy, or C14alkanoyl groups; R 1 is trityl, phenyl, diphenylmethyl, phenoxy, phenylthio, piperazinyl, piperidinyl,. pyrrolidinyl, morpholinyl, indolinyl, indolyl, benzothienyl, hexamethyleneiminyl, benzofuranyl, tetrahydropyridinyl, quinolinyl, isoquinolinyl, reduced quinolinyl, reduced isoquinolinyl, phenyl-(Ci-4alky)-, phenyl-(Clv4alkoxy)-, quinolinyl.(Ci Aalkyl)-, isoquinolinyl-(Cl-4alkyl)-, reduced quniolinyl-(Cl Aalkyl)-, reduced isoquinolinyl-(Clalkyl)-, benzoyl-(Cl-3alkyl)-, C14alkyl, or -NH-CH 2 R3 5 any one of which R 1 groups may be substituted with halo, Ci1ialkyl, Ci.4alkoxy, trifluoromethyl, amino, Ci4alkylamino, di(Cl~alkyl)amino, or Cl~alkanoylamino; or any one of which R 1 groups may be sbtttd wtgpey, pprznl C3-8cycloalkyl, benzyl, C14alkyl, piperizlinyl, pyridinyl, [I :\DayLib\LIBH 1]00830.doc: Ijg 115 pyrimidinyl, C2-6alkanoylamino, pyrrolidinyl, C2-6alkanoyl, or C14alkoxycarbonyl; any one of which groups may be substituted with halo, Ci-4alkyI, Cl~alkoxy, trifluoromethyl, amino, Cv.~alkylamino, di(ClAalkyl)amino, or C2Aalkanoylamino; or R 1 is amino, a leaving group, hydrogen, Ci.4alkylamino, or di(CiAalkyl)amino; R5 is pyridyl, anilino(CI- 3 alkyl)-, or anilinocarbonyl; R 2 is hydrogen, CiAalkyl, CiAalkylsulfonyl, carboxy-(Cl-3alkyl)-, Ci.3alkoxycarbonyl-(Cl- 3 alkyl)y, or -CO-R 6 R6 is hydrogen, Ci..alkyl, Cl-3haloalkyl, phenyi, C1v3alkoxy, C1.3hydroxyalkyl, amino, Cl~alkylamino, di(Cl~alkyl) amino, or (CH2)q-R 7 q is zero to 3; R 7 is carboxy, Cl~alkoxycarbonyl, CiAalkylcarbonyloxy, amino, Clv4alkylamino, di(Cl~alkyl) amino, Clv6alkoxycarbonylamino, or phenoxy, phenylthio, piperazinyl, piperidlinyl, pyrrolidinyl, morpholinyl, indolinyl, indolyl, benzothienyl, benzofuranyl, quinolinyl, o0 phenyl-(Cl.4alkyl)-, quinolinyl-(Cl 4alkyl)-, isoquinolinyl-(Cl~alkyl)-, reduced quinolinyI-(Ci~alkyl)-, reduced isoquinolinyl-(CiAalkyl)-, benzoyl-Cl-3alkyl; any one of which aryl or heterocyclic R 7 groups may be substituted with halo, trifluoromethyl, CjAalkoxy, C1.4alkyl, amino, CiAalkylamino, di(Cl~alkyI)amino, or C2Aalkanoylamlno;- or any one of which R7 groups may be substituted with phenyl piperazinyl, C3.8Cycloalkyl, benzyl, piperidinyl, pyridinyl, pyrimidinyl pyrrolidinyl, C2.6alkanoyl, 15i or CAalkoxycarbonyl; any of which groups may be substituted with halo, trifluoromethyl, amino, Cl~alkoxy, CiAalkyl, CiAalkylamino, d i(C1 Aalkyl) amino, Or C2A1alkanoylamino; R 8 is hydrogen or C16alkyl; R 3 is phenyl, phenyl.(Cl.6alkyl)-, C3.8Cycloalkyl, C5-8cycloalkenyl, Ci-8alkyl, naphthy, C2-8alkenyl, or hydrogen; any one or which groups except hydrogen may be substituted with one or two halo, Cl-3alkoxy, C1.3alkylthio, nitro, trifluoromethyl, or C1l3alkyl groups; and R 4 is hydrogen or 20 C1v3alkyl; with the proviso that if RI is hydrogen or halo, R 3 is phenyl, phenyl-(Cl6alkyl)-, C3-8cycloalkyl, C5-8cycloalkenyl or naphthyl; or a pharmaceutically acceptable salt thereof. *83. The method according to claim 69 or 70, wherein the NK-1 receptor antagonist is selected from the classes of compounds described in EP-A-0577394, WO-A-9508549, 18124, WO-A-9523798 and WO-A-96051 81.
84. The method according to claim 69 or 70, wherein the NK-1 receptor antagonist is selected from 5 -bis(trifluoromethyl)benzyloxy3(S)-(4 -fluorophenyl)-4-(3-(5-oxo-1 H, 4- 1 2 4 -triazolo)methyl)morpholine, (trifluoromethyl)phenyl)ethoxy)4(3-(5oxo- 1 H,4H- 1,24tizl ehl--()pey-opoie 2 (3,5-bis (trifl uo rometh yl) ben zyloxy)-4 (3-(5-oxo-1 H,4H-1 2 4 -triazolo)methyl)-3-(S)-phenyl-morpholine; 1 methyl)phenyl)ethoxy)3(S)-(4.fluorophenyl)4(3-(5-oxo1 H ,4H- 1,2,4-triazolo)methyl)morpholine; 3 5 -bis(trifluoromethyl)phenyl)ethoxy)-4(5(N ,N d imethylamino)methyl-1 ,2,3-triazol-4- ylmty--S-hnlopoie (trifluoromethyl)phenyl)ethoxy)-4-(5-(N ,N- dimethylamino)methyl-1 i 2 3 -triazol- 4 -yl)methyl-3-(S)-(4-fluorophenyl)morpholine; bis(trifluoromethyl)phenyl)ethoxy)3(S)(4fluorophenyl)4(3-(4-monphosphory 15 -o x 1 H-i 2,4- RA41 triazolo)methyl)morpholine; (trifluoromethyl)phenyl)ehoxy)3(S)(4- 1\Da yLib\LIB H]1008 30.doc: Ij g fluorophenyl)-4-(3-(1 -monophosphoryl-5-oxo-1 H-1 ,2,4-triazolo)methyl)morpholine; 5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluoro phenyl)-4-(3-(2-monophosphoryl-5-oxo-1 H- 1,2,4-triazolo)methyl)morpholine; (R)-(3,5-bis (trifluoromethyl)phenyl)ethoxy)-3-(S)-(4- fluorophenyl)-4-(3-(5-oxyphosphoryl-1 H-1 ,2,4-triazolo)methyl) morpholine; 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. The method according to any one of claims 69 to 84, wherein the NK-1 receptor io antagonist is orally active, long acting and CNS-penetrant.
86. The method according to any one of claims 70 to 85, 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, is fenproporex, fludorex, fluminorex, furfurylmethylamphetamine, levamfetamine, levophacetoperane, mazindol, mefenorex, metamfepramone, methamphetamine, norpseudoephedrine, pentorex, phendimetrazine, phenmetrazine, phentermine, phenylpropanolamine picilorex and sibutramine; or a pharmaceutically acceptable salt thereof. 9..
87. The method according to any one of claims 70 to 86, wherein the anorectic agent is a halogenated amphetamine derivative.
88. The method according to claim 87, wherein the amphetamine derivative is selected from chlorphentermine cloforex, clortermine, dexfenfluramine, fenfluramine, picilorex and sibutramine; or a pharmaceutically acceptable salt thereof.
89. The method according to any one of claims 69 to 88, wherein the eating disorder results in or causes obesity. The method according to any one of claims 69 to 88, wherein the eating disorder is bulimia nervosa.
91. The method according to any one of claims 69 to 88, wherein the eating disorder is a compulsive eating disorder.
92. A NK-1 receptor antagonist when used in the treatment or prevention of eating disorders.
93. The NK-1 receptor antagonist when used according to claim 92, wherein the NK-1 receptor antagonist is a compound of formula I [I:\DayLib\LIB Ii]00830.doc:Ijg 117 R 3 X R 4 R N R R (I) wherein R 1 is selected from the group consisting of: C1-6alkyl, substituted with one or more of the substituents selected from: heterocycle, wherein the heterocycle is selected from the group consisting of: benzimidazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, (F) pyrazinyl, pyrazolyl, pyridyl, pyrrolyl, tetrazolyl, thiadiazolyl, triazolyl, and (M) piperidinyl, and wherein the heterocycle is unsubstituted or substituted with one or more substituent(s) selected from: C1-6alkyl, unsubstituted or substituted with halo, -CF 3 -OCH 3 or phenyl, (ii) Ci-ealkoxy, (iii) oxo, (iv) thioxo, cyano, (vi) -SCH 3 (vii) phenyl, (viii) hydroxy, (ix) trifluoromethyl, (CH 2 )mNR9R1i, wherein m is 0, 1 or 2, and R 9 and R 1 0 are independently selected from: hydrogen, (II) Cl6alkyl, (111) hydroxyC1. 6 alkyl, and (IV) phenyl, (xi) -NR 9 COR0o, wherein R9 and Rlo are as defined above, and (xii) -CONR 9 R 1 o, wherein R 9 and R 1 0 are as defined above, R 2 and R 3 are independently selected from the group consisting of: hydrogen; (2) R 6 Y C1.6alkyl, C2-6alkenyl, and phenyl; X is R 4 is z R 5 is phenyl, unsubstituted or substituted with halo; R 6 R 7 and R 8 are independently selected from the group consisting of: hydrogen, C1-6alkyl, halo, and -CF 3 Y is and Z is hydrogen or Cl.alkyl; or a pharmaceutically acceptable salt thereof.
94. The NK-1 receptor antagonist when used according to claim 92, wherein the NK-1 receptor antagonist is a compound of formula Ila: to to 0 0 9 9 9 oY 6 A2 wherein A' is fluorine or CF 3 A 2 is fluorine or CF 3 A 3 is fluorine or hydrogen; X is an alkylene chain of 1 to 4 carbon atoms optionally substituted by oxo; Y is a C1.4alkyl group optionally substituted by a hydroxyl group; R 6 is a 5-membered or 6-membered heterocyclic ring containing 2 or 3 nitrogen atoms optionally substituted by =S or a C-4alkyl group, and optionally substituted by a group of the formula ZNR 7 R 8 where Z is Ci-6alkylene or C3-6cycloalkylene; R 7 is hydrogen, C14alkyl, S, C3-7cycloalkyl or C3.7cycloalkylCl-4alkyl, or C24alkyl substituted by C1.alkoxy or hydroxyl; R 8 is [I:\DayLib\LIBH]00830.doc:Ijg 118 hydrogen, C14alkyl, C3-7cycloalkyl or C3-7cycloalkylC14alkyl, or C24alkyl substituted by one or two substituents selected from C14alkoxy, hydroxyl or a 4, 5 or 6 membered heteroaliphatic ring containing one or two heteroatoms selected from N, 0 and S; or R 7 R 8 and the nitrogen atom to which they are attached form a heteroaliphatic ring of 4 to 7 ring atoms, optionally substituted by a hydroxy group, and optionally containing a double bond, which ring may optionally contain an oxygen or sulphur ring atom, a group S(O) or S(0) 2 or a second nitrogen atom which will be part of a NH or NRc moiety where R c is C14alkyl optionally substituted by hydroxy or C14alkoxy; or R 7 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, R 7 and the nitrogen atom to which they are attached form a heteroaliphatic ring of 4 to 7 ring atoms which may optionally contain an oxygen ring atom; or a pharmaceutically acceptable salt thereof. The NK-1 receptor antagonist when used according to claim 92, wherein the NK-1 receptor antagonist is a compound of formula IlI: R 6 R RR R D2/ R (O)p A B S R1 3 R 12 (I 5 wherein: R2 and R 3 are independently selected from the group consisting of: hydrogen; (2) Cl-alkyl, C2-6alkenyl, and phenyl; R 6 R 7 and R 8 are independently selected from the group consisting of: hydrogen, C1salkyl, fluoro, chloro, bromo, iodo, and -CF 3 R 11 R 1 2 and R 13 are independently selected from the group consisting of: fluoro, chloro, (3) bromo, and iodo; A is unsubstituted C16alkyl; B is selected from the group consisting of: N- N- I x 0 N N O N S S N x 8 0. N N-N N-N N-NN- X X 0 0 or pis 0 or 1; X is selected from: -PO(OH)O-*M wherein M is a pharmaceutically monovalent counterion, (b) [I:\DayLib\LIBH0083.doc:Ijg 119 -PO(O-) 2 2M, -PO(O-) 2 D 2 wherein D 2 is a pharmaceutically acceptable divalent counterion, -CH(R 4 wherein R 4 is hydrogen or Cl-3alkyI, -CH(R 4 2 .2M+, CH(R 4 2 -CO-CH2CH 2 -CO 2 ~)-CH(CH 3 )-O-CO-R5, wherein R 5 is selected +2M from the group consisting of:- (i C 0 2 M v (iii) 1 0 C02jM+,(v C0 2 0+ NH 3 (vi) -o C0jM I(vii) 02M ;and Y is Z is hydrogen or C1_6alkyl; or a pharmaceutically acceptable salt 0 0. P22 A2 thereof.
96. The NK-1 receptor antagonist when used according to claim 92, wherein the NK-1 receptor antagonist is a compound of formula lVa: (IVa) wherein A' is fluorine or OF 3 A 2 is fluorine or CF 3 A 3 is fluorine or hydrogen; X is a group of the formula NR 6 R 7 or a C- or N-inked imidazolyl ring; Y is hydrogen or Ci-4alkyl optionally substituted by a hydroxy group; R 6 is hydrogen, Ci-6alkyl, C3-7cycloalkyl, C3.7cyCloalkylC14alkyl, phenyl, or C24alkyl substituted by C14alkoxy or hydroxy; R 7 is hydrogen, C1-6alkyl C3-7cycloalkyl, C3-7CYCloalkylCi4alkyl, phenyl, or C2 4 salkyl substituted by one or two substituents selected from C14alkoxy, hydroxy or a 4, 5 or 6 membered heteroaliphatic ring containing one or two heteroatoms selected from N, 0 and S; or R 6 and R 7 together with the nitrogen atom to which they are attached, form a saturated or partially saturated heterocyclic ring of 4 to 7 ring atoms, which ring may optionally contain in the ring one oxygen or sulphur atom or a group selected from NR 8 S(0) or S(O) 2 and which ring may be optionally substituted by one or two groups selected from hydroxy- Cl-4alkyl, C,4alkoxyCl-4alkyl, oxo, CORa or CO2Ra where Ra is hydrogen or C14alkyl; or R 6 and R 7 C [1:\DayLib\LII3H]00830.doc:Ijg 120 together with the nitrogen atom to which they are attached, form a non-aromatic azabicyclic ring system of 6 to 12 ring atoms; and R 8 is hydrogen, CA4alkyl, hydroxy C14alkyl or C-4alkyl C1-4alkyl; or a pharmaceutically acceptable salt thereof.
97. The NK-1 receptor antagonist when used according to claim 92, wherein the NK-1 receptor antagonist is a compound of formula V: R 4 7 R R 1 3 N R R (Z) R6 R (V) 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 (CH 2 )n may optionally be replaced by a carbon-carbon double bond, and wherein any one of the carbon atoms of said (CH2n ay optionally be substituted with R4 and 0 wherein any one of the carbon atoms of said (CH 2 )m may optionally be substituted with R 4 andZ is 9: 10 wherein any one of the carbon atoms of said (CH2)m may optionally be substituted with R 7 Z is o (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 (CH 2 )m may optionally be substituted with R 1 is hydrogen or Cl-alkyl optionally substituted with hydroxy, C14alkoxy or fluoro; R 2 is a radical is selected from hydrogen, C-6 straight or branched alkyl, C3-7cycloalkyl wherein one of the CH 2 groups in said cycloalkyl may optionally be replaced by NH, oxygen or sulphur; aryl selected from *phenyl and naphthyl; heteroaryl selected from indanyl, thienyl, furyl, pyridyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl and quinolyl; phenyl-C26alkyl, 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, Cl.6alkyl, Ci-alkoxy, trifluoromethyl, amino, Cl_6alkylamino, C1.6alkyl-O- CO, Ci-ealkyl-O-CO-Ci-ealkyl, Ci-alkyl-O-CO, C1-alkyl-CO-ClCalkyl-O-, Cl6alkyl-CO, Cli-alkyl-CO- NHC1ialkyl-, di-Ci6alkylamino, -CONH-C-6alkyl, C1-alkyl-CO-NH-Cl6alkyl, -NHCOH and -NHCO- Ci6alkyl; and wherein one of the phenyl moieties of said benzhydryl may optionally be replaced by naphthyl, thienyl, furyl or pyridyl; R 5 is hydrogen, phenyl or C-6alkyl; or R 2 and R 5 together with the carbon to which they are attached, form a saturated ring having from 3 to 7 carbon atoms wherein one of the CH 2 groups in said ring may optionally be replaced by oxygen, NH or sulfur; R 3 is aryl selected from phenyl and naphthyl; heteroaryl selected from indanyl, thienyl, furyl, pyridyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl and quinolyl; and cycloalkyl having 3 to 7 carbon atoms wherein one of the (CH 2 groups in said cycloalkyl may optionally be replaced by NH, [I:\DayLib\LIBH]00830.doc:Ijg 121 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-alkyl, Cl.ealkoxy, trifluoromethyl, amino, Cl-.alkylamino, -CO-NH-C-ealkyl, Cl-ealkyl-CO-NH-C C1.ealkyl, -NHCOH and -NHCO- C1ialkyl; R 4 and R 7 are each independently selected from hydroxy, halogen, halo, amino, oxo, cyano, methylene, hydroxymethyl, halomethyl, C16alkylamino, di-C16alkylamino, Ci.alkoxy, C1-alkyl-O-CO, C1-6alkyl-O-CO-Clealkyl, Ci-.alkyl-CO-O, C1ealkyl-CO-Ci-ealkyl-O-, Cl.ealkyl-CO-, Cl-alkyl-CO-Clealkyl, and the radicals set forth in the definition of R 2 R 6 is -NHCOR 9 -NHCH 2 R 9 SO 2 R 9 or one of the radicals set forth in any of the definitions of R2, R 4 and 0t R 7 R 8 is oximino (=NOH) or one of the radicals set forth in any of the definitions of R2, R 4 and R 7 R 9 is Cl-ealkyl, hydrogen, phenyl or phenylCl6alkyl; with the proviso that when m is 0, R 8 is absent, when R 4 R 6 R 7 or R 8 is as defined in R 2 it cannot form together with the carbon to which it is attached ,a ring with R5, and when a n d n nd R 7 are attached to the same carbon atom, then either each of R 4 and R 7 is independently selected from hydrogen, fluoro and C1.6alkyl, or R 4 15 and R 7 together with the carbon to which they are attached, for a C36saturated carbocyclic ring that forms a spiro compound with the nitrogen-containing ring to which they are attached; or a pharmaceutically acceptable salt thereof.
98. The NK-1 receptor antagonist when used according to claim 92, wherein the NK-1 S receptor antagonist is a compound of formula VI: R o R R R 20R 3 R2 (VI) wherein: radicals R are phenyl radicals optionally 2- or 3-substituted by a halogen atom or a methyl radical; R 1 is optionally substituted phenyl, cyclohexadienyl, naphthyl, indenyl or optionally substituted heterocycle; R 2 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; R 4 is OH or fluorine when R 5 is H; or R 4 and R 5 are OH; or R 4 and R5 together form a bond; or a pharmaceutically acceptable salt thereof.
99. The NK-1 receptor antagonist when used according to claim 92, wherein the NK-1 receptor antagonist is a compound of formula VII: R Q I I Ar-T-CO-N-CH 2 -C-CH 2 -CH 2 -Am+,A I Ae' (VII) [I:\DayLib\LIBH]00830.doc:ljg 4 0 *8 0*4 C 00 S .r 0 bcO 9 C C 6 00 a a 122 wherein: Ar represents an optionally substituted mono-, di- or tricyclic aromatic or heteroaromatic group; T represents a bond, a hydroxymethylene group, a C.4alkoxymethylene group or a C1-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, C14alkoxy, C1alkyl 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, c-C-4alkoxy- C-4alkyl or o-C24alkanoyloxyC24alkyl; Q represents hydrogen; or Q and R together form a X, N 0 1,2-ethylene, 1,3-propylene or 1,4-butylene group; Am* represents the radical x 3 X 2 in which X 1 X 2 and X 3 together with the nitrogen atom to which they are attached, form an azabicyclic or azatricyclic ring system optionally substituted by a phenyl or benzyl group; and A- represents a pharmaceutically acceptable anion.
100. The NK-1 receptor antagonist when used according to claim 92, wherein the NK-1 receptor antagonist is a compound of formula VIII R 3 R N X 2 -N-X 3 -R 4 R2 X R-X (VIII) 5i wherein: RI 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; R 2 represents cycloalkyl or an optionally substituted aryl or heteroaryl group; R 3 represents hydrogen, alkyl, carbamoyl or an alkanoyl or alkenoyl group 20 optionally substituted by carboxy or esterified or amidated carboxy; R 4 represents an optionally substituted aryl group or an optionally partially saturated heteroaryl group; Xi represents methylene, ethylene, a bond, an optionally ketalised carbonyl group or an optionally etherified hydroxymethylene group; X 2 represents alkylene, carbonyl or a bond; and X 3 represents carbonyl, oxo-lower alkyl, oxo(aza)-lower alkyl, or an alkyl group optionally substituted by phenyl, hydroxymethyl, optionally esterified or amidated carboxy, or (in other than the a-position) hydroxy; or a pharmaceutically acceptable salt thereof.
101. The NK-1 receptor antagonist when used according to claim 92, wherein the NK-1 receptor antagonist is a compound of formula IX: [I:\DayLib\LIBH0083.doc:Ijg 123 NN X N R 1 ,A H N-R 3 Y 0 R 4 (IX) (IX) wherein: R 1 is aryl, or a group of the formula: z X is CH or N; and Z is 0 or N-R 5 in which R 5 is hydrogen or lower alkyl; R 2 is hydroxy or lower alkoxy; R 3 is hydrogen or optionally substituted lower alkyl; R 4 is optionally substituted ar(lower)alkyl; A is carbonyl or s sulfonyl; and Y is a bond or lower alkenylene; or a pharmaceutically acceptable salt thereof.
102. The NK-1 receptor antagonist when used according to claim 92, wherein the NK-1 receptor antagonist is a compound of formula X: H N R H N R2 .I H (X) wherein: R 1 is aryl selected from indanyl, phenyl and naphthyl; heteroaryl selected from 1 0 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 C3.7cycloalkyl may optionally be substituted with one or two substituents, said substituents being independently selected from chloro, fluoro, bromo, iodo, nitro, Ci.ioalkyl optionally substituted with 15 from one to three fluoro groups, Ci.ioalkoxy optionally substituted with from one to three fluoro groups, amino, Cl.loalkyl-S-, Cl.ioalkyl-S(O)-, Cl.ioalkyl-SO2-, phenyl, phenoxy, Cl-loalkyl-SO2NH-, C1.10alkyl-SO2NH- Ci-1oalkyl-, C1-ioalkylamino-diCi.oalkyl-, cyano, hydroxy, cycloalkoxy having 3 to 7 carbon atoms, Ci.ioalkylamino, Cl-6dialkylamino, HC(O)NH- and Cl-.oalkyl-C(O)NH-; and R 2 is thienyl, benzhydryl, naphthyl or phenyl optionally substituted with from one to three substituents independently selected from chloro, bromo, fluoro, iodo, cycloalkoxy having 3 to 7 carbon atoms, Ci-ioalkoxy optionally substituted with from one to three fluoro groups and Ci-ioalkyl optionally substituted with from one to three fluoro groups; or a pharmaceutically acceptable salt thereof.
103. The NK-1 receptor antagonist when used according to claim 92, wherein the NK-1 receptor antagonist is a compound of formula XI: [1:\DayLib\LIBH]00830.doc:ljg 124 R N HQ (Xl1) N N wherein: R 1 is a Ci4alkoxy group;, R 2 is N-N ;Ri yrgno aoe tm R 4 and R 5 may each independently represent a hydrogen or halogen atom, or a C14alkyl, C14~alkoxy or trifluoromethyl group; R 6 is a hydrogen atom, a Ci4alkyl, (CH2)mcyclopropyl, -S(O),lialkyl, 0.0. 5 phenyl, NR 7 R 8 CH 2 C(O)CF 3 or trifluoromethyl group; R 7 and R 8 may each independently represent 00 000000a hydrogen atom, or a C,4alkyl or acyl group; x represents zero or 1; n represents zero, 1 or 2; and m represents zero or 1; or a pharmaceutically acceptable salt thereof.
104. The NK-1 receptor antagonist when used according to claim 92, wherein the NK-1 receptor antagonist is a compound of formula XII: R a4 R-(CtH 2 )-C-CH 2 -N-(CH 2 0 R3 1 12 NH R 0 (00 0 0 (CH 2 )m R (XII1) wherein: m is zero, 1, 2 or 3; n is zero orn; o is zero, 1 or 2; p is zero orn; 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, tnifluoromethyl, C14alkyl, phenyl-Cl-3alkoxy, or Ci4alkanoyl groups; R' is trityl, phenyl, diphenylmethyl, phenoxy, phenylthio, piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, indolinyl, indolyl, benzothienyl, hexamethyleneiminyl, benzofuranyl, tetrahydropyridinyl, quinolinyl, isoquinolinyl, reduced quinolinyl, reduced isoquinolinyl, phenyl-(Cl~alkyl)-, phenyl-(Ci-4alkoxy)-, quinolinyl-(Ci-4alkyl)-, isoquinolinyl-(Cl~alkyl)-, reduced quniolinyl-(C,4alkyl)-, reduced isoquinolinyl-(Cl~alkyl)-, benzoyl-(Ci-3alkyl)-, Ci-4alkyl, or -NH-OH 2 R 5 any 'one of which R 1 groups may be substituted with halo, C,4alkyl, C14alkoxy, trifluoromethylh amino, C14~alkylamino, di(Cl-4alkyl)amino, or Ci~sal kanoyl amino; or any one of which R 1 groups may be substituted with phenyl, piperazinyl, C3-8cycloalkyl, benzyl, C14alkyl, piperizlinyl, pyridinyl, [I:\DayLib\LIBH]00830.docIjg 125 pyrimidinyl, C2-6alkanoylamino, pyrrolidinyl, C2-6alkanoyl, or Ci4alkoxycarbonyl; any one of which groups may be substituted with halo, C14alkyl, Ci-4alkoxy, trifluoromethyl, amino, Ci4alkylamino, di(Ci-4alkyf)amino, or C2-4alkanoylamino; or R 1 is amino, a leaving group, hydrogen, C14alkylamino, or di(C,4alkyl)amino; R 5 is pyridyl, anilino(Cl-3alkyl)-, or anilinocarbonyl; R 2 is hydrogen, C14alkyl, Ci4alkylsulfonyl, carboxy-(Cl. 3 alkyl)-, C1.3alkoxycarbonyl-(Cl- 3 alkyl)., or -CO-R 6 R 6 is hydrogen, C1-4alkyl, Cl-3haloalkyl, phenyl, C1l3alkoxy, Cl.3hydroxyalkyl, amino, Cl~alkylamino, di(Ci-4alkyl) amino, or (CH2)q-R 7 q is zero to 3; R 7 is carboxy, C14alkoxycarbonyl, Cl4alkylcarbonyloxy, amino, Ci-4alkylamino, di(C,4alkyl) amino, Cl-6alkoxycarbonylamino, or phenoxy, phenylthio, piperazinyl, piperidinyl, pyrrolidlinyl, morpholinyl, indolinyl, indolyl, benzothienyl, benzofuranyl, quinolinyl, 0 phenyl-(Cl~alkyl)-, quinolinyl-(Cl 4alkyl)-, isoquinolinyl-(Clakyl)-, reduced quinolinyl-(Cl-4alky)-, reduced isoquinolinyl-(Ci-4alkyl)-, benzoyl-Cl-3alkyl;, any one of which aryl or heterocyclic R 7 groups may be substituted with halo, trifluoromethyl, Ci~alkoxy, Cl4alkyl, amino, Clv4alkylamino, di(C i -alkyl) amino, or C2-4alkanoylamlno; or any one of which R 7 groups may be substituted with phenyl piperazinyl, C3.8CYCloalkyl, benzyl, piperidinyl, pyridinyl, pyrimidinyl pyrrolidinyl, C2-6alkanoyl, or Ci-4alkoxycarbonyl; any of which groups may be substituted with halo, trifluoromethyl, amino, C14alkoxy, C14alkyl, Ci4alkylamino, di(Cl~alkyl)amino, or C24alkanoylamino; R 8 is hydrogen or Cl-6alkyl; R 3 is phenyl, phenyl-(Cl-6alkyl)-, C3.8cycloalkyl, C5-8CYCloalkenyl, Cl-8alkyl, naphthyl, ::::C2-8alkenyl, or hydrogen; any one or which groups except hydrogen may be substituted with one or halo, C1l3alkoxy, C1.3alkylthio, nitro, trifluoromethyl, or Cl-3alkyl groups; and R 4 is hydrogen or Cl3alkyl; with the proviso that if R 1 is hydrogen or halo, R 3 is phenyl, phenyl-(Cl. 6 alky)-, C3-8cycloalkyl, C5-8cycloalkenyl or naphthyl; or a pharmaceutically acceptable salt thereof.
105. The NK-1 receptor antagonist when used according to claim 92, wherein the NK-1 receptor antagonist is selected from the classes of compounds described in EP-A-0577394, WO-A- 9508549, WO-A-95181 24, WO-A-9523798 and WO-A-9605181.
106. The NK-1 receptor antagonist when used according to claim 92, wherein the NK-1 receptor antagonist is selected from 5-bis(trifluoromethyl)benzyloxy-3(S)-(4 -fluorophenyl)- 4-(3-(5-oxo- 1 H, 4H- 1,2,4-triazolo)methyl)morpholine; 1 phenyl)ethoxy)-4-(3-(5-oxo-1 H ,4H-1 2 4 -triazolo)methyl)-3-(S)-pheny..morpholin; bis(trifl uo rom ethyl) ben zyloxy)-4(3(5oxo-1 H, ,4H-1, 2 4 -triazolo) meth yl) -3-(s)phen ylmo rphol ine; 2- 3 ,5-bis(trifluoromethyl)phenyl)ethoxy)3(S)-(4fluorophenyl)4(3(5oxo-1 HAH-1,2,4- triazolo)methyl)morpholine; -(R)-(3,S-bis(trifluoromethyl)phenyl)ethoxy)4-((N ,N dimethylamino)methyl-1 2 3 -triazol-4-yl)methyl-3-(S)-phenylrnorpholine; ,N-dimethylamino)methyl-1,2,3-triazol-4-yl)methyl-3-(S)-(4- fluorophenyl)morpholine; 3 ,5-bis(trifluoromethyl)phenyl)ethoxy)3(S)-(4fluorophenyl)- L 5 -(3-(4-monophosphoryl-5-oxo-1 H 1,2,4-triazolo) methyl) morph oline; 1 I:\Day Li b\L I BH]I00830A oc: Ij g 126 (trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(1 -monophosphoryl-5-oxo-1 H-1,2,4- triazolo)methyl)morpholine; 5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluoro phenyl)-4-(3-(2-monophosphoryl-5-oxo-1 H-1,2,4-triazolo)methyl)morpholine; (trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3(5oxyphosphoryl-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; phenyl)ethoxy)-4-(4-NN-dimethylaminobut-2-yn-yl)-3-(S)-(4-fluorophenyl) morpholine; or a pharmaceutically acceptable salt thereof.
107. The NK-1 receptor antagonist when used according to any one of claims 92 to 106, 1o wherein the NK-1 receptor antagonist is orally active, long acting and CNS-penetrant.
108. The NK-1 receptor antagonist when used according to any one of claims 92 to 107, wherein the eating disorder results in or causes obesity.
109. The NK-1 receptor antagonist when used according to any one of claims 92 to 107 wherein the eating disorder is bulimia nervosa.
110. The NK-1 receptor antagonist when used according to any one of claims 92 to 107 wherein the eating disorder is a compulsive eating disorder.
111. A NK-1 receptor antagonist and an anorectic agent when used in the treatment or prevention of eating disorders.
112. The NK-1 receptor antagonist and an anorectic agent when used according to claim 111, wherein the NK-1 receptor antagonist is a compound of formula I R 3 X 4 N R R (I) wherein R' is selected from the group consisting of: Cl.6alkyl, substituted with one or more of the substituents selected from: heterocycle, wherein the heterocycle is selected from the group consisting of: benzimidazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, (F) pyrazinyl, pyrazolyl, pyridyl, pyrrolyl, tetrazolyl, thiadiazolyl, triazolyl, and (M) piperidinyl, and wherein the heterocycle is unsubstituted or substituted with one or more substituent(s) selected from: C16alkyl, unsubstituted or substituted with halo, -CF 3 -OCH 3 or phenyl, (ii) ClI6alkoxy, (iii) oxo, (iv) thioxo, cyano, (vi) -SCH 3 (vii) phenyl, (viii) hydroxy, (ix) trifluoromethyl, (CH 2 )mNR9RiO, wherein m is 0, 1 or 2, and R 9 and R'Io are independently selected from: hydrogen, (II) Ci-alkyl, (111) hydroxyCi-alkyl, and (IV) phenyl, (xi) -NR 9 wherein R 9 and RIo are as defined above, and (xii) -CONRSR1O, wherein R 9 and RIo are as defined above, R 2 and R 3 are independently selected from the group consisting of: hydrogen; (2) [I:\DayLib\LIBH]0083.doc:jg 127 v R7 SYA8 Cil.alkyl, C2-6alkenyl, and phenyl; X is R 4 is z R5 is phenyl, unsubstituted or substituted with halo; R 6 R 7 and R8 are independently selected from the group consisting of: hydrogen, C1i6alkyl, halo, and -CF 3 Y is and Z is hydrogen or Ci1alkyl; or a pharmaceutically acceptable salt thereof.
113. The NK-1 receptor antagonist and an anorectic agent when used according to claim 111, wherein the NK-1 receptor antagonist is a compound of formula Ila: A 1 A 2 x o~ 2 R6 A 3 (lla) wherein A 1 is fluorine or CF 3 A 2 is fluorine or CF3; A 3 is fluorine or hydrogen; X is an alkylene chain of 1 to 4 carbon atoms optionally substituted by oxo; Y is a C1-4alkyl group optionally substituted by S 1 0 o a hydroxyl group; R 6 is a 5-membered or 6-membered heterocyclic ring containing 2 or 3 nitrogen atoms optionally substituted by =S or a C-4alkyl group, and optionally substituted by a group of the formula ZNR 7 R8 where Z is Cl-6alkylene or C3-cycloalkylene; R 7 is hydrogen, C1.4alkyl, C3-7cycloalkyl or C3-7cycloalkylClAalkyl, or C2-4alkyl substituted by Ci-4alkoxy or hydroxyl; R 8 is hydrogen, Ci-alkyl, C3-7cycloalkyl or C3-7cycloalkylCl.alkyl, or C2-4alkyl substituted by one or two 15 substituents selected from C1ialkoxy, hydroxyl or a 4, 5 or 6 membered heteroaliphatic ring containing one or two heteroatoms selected from N, 0 and S; or R 7 R 8 and the nitrogen atom to which they are attached form a heteroaliphatic ring of 4 to 7 ring atoms, optionally substituted by a hydroxy group, and optionally containing a double bond, which ring may optionally contain an oxygen or sulphur ring atom, a group S(0) or S(0) 2 or a second nitrogen atom which will be part of a NH or NRc moiety where R c is C-4alkyl optionally substituted by hydroxy or C-4alkoxy; or R 7 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, R 7 and the nitrogen atom to which they are attached form a heteroaliphatic ring of 4 to 7 ring atoms which may optionally contain an oxygen ring atom; or a pharmaceutically acceptable salt thereof.
114. The NK-1 receptor antagonist and an anorectic agent when used according to claim 111, wherein the NK-1 receptor antagonist is a compound of formula II1: [1:\DayLib\LB H]00830.doc: hg R 13 (Ill) wherein: R 2 and R3 are independently selected from the group consisting of: -hydrogen; (2) Cli 6 alkyl, C2-6alkenyl, and phenyl; R6, R7 and R8 are independently selected from the group consisting of: hydrogen, C1_6alkyl, fluoro, chloro, bromo, iodo, and -CF 3 P1 R 12 and R 13 are independently selected from the group consisting of: fluoro, chloro, (3) bromo, and iodo; A is unsubstituted Cl-6alkyl; B is selected from the group consisting of: N-0Il- x ,X H N-N/ N N-A N-N NS IN 0 4_N I S X H N ON X H 0% .0 :*0e .0* .00. 0:0.* x N- N N N 0 x N- N 'N" x N-N N x N-- N x N-I NzI x N H I N I I V or A pis 0or1;-X is selected from: wherein M+ is a pharmaceutically monovalent counterion, (b) -PO(O-) 2 -PO(O-) 2 .D 2 wherein D 2 is a pharmaceutically acceptable divalent counterion, -CH(R 4 wherein R 4 is hydrogen or C 13 alkyl, -CH(R 4 2 .2M+, CH(R 4 2 -CO-CH2CH 2 -CO 2 -eM, 0) -CH(CH34-O-CO-R5, wherein R 5 is selected NH 3 M O from the group consisting of: O 0 C0jM+ (vM (ii) 0 02-M+ (i v) N 3 (vi) -O C02jM+ C0_+ (vii) ;and Y is Z is hydrogen or C1_6alkyl; or a pharmaceutically acceptable salt thereof. [I:\DayLib\L1BH100830.doc:Ijg 129
115. The NK-1 receptor antagonist and an anorectic agent when used according to claim 111, wherein the NK-1 receptor antagonist is a compound of formula IVa: A 1 vA OA2 (0 0 OO N XA 3 x (IVa) wherein A 1 is fluorine or CF 3 A 2 is fluorine or CF 3 A 3 is fluorine or hydrogen; X is a group of the 5 formula NR 6 R 7 or a C- or N-linked imidazolyl ring; Y is hydrogen or C14alkyl optionally substituted by a hydroxy group; R 6 is hydrogen, C1-6alkyl, C3-7cycloalkyl, C3-7cycloalkylC1-4alkyl, phenyl, or C2-4alkyl substituted by C14alkoxy or hydroxy; R 7 is hydrogen, Ci.ealkyl, C3-7cycloalkyl, C3-7cycloalkylC14alkyl, phenyl, or C2-4alkyl substituted by one or two substituents selected from C-4alkoxy, hydroxy or a 4, 5 or 6 membered heteroaliphatic ring containing one or two heteroatoms 10 selected from N, O and S; or R 6 and R 7 together with the nitrogen atom to which they are attached, form a saturated or partially saturated heterocyclic ring of 4 to 7 ring atoms, which ring may optionally contain in the ring one oxygen or sulphur atom or a group selected from NR 8 S(0) or SS(O) 2 and which ring may be optionally substituted by one or two groups selected from hydroxy- Ci4alkyl, C14alkoxyC-4alkyl, oxo, CORa or CO2Ra where Ra is hydrogen or C1.4alkyl; or R 6 and R 7 15 together with the nitrogen atom to which they are attached, form a non-aromatic azabicyclic ring system of 6 to 12 ring atoms; and R 8 is hydrogen, Ci-4alkyl, hydroxy C1.4alkyl or C-4alkyl C.4alkyl; or a pharmaceutically acceptable salt thereof.
116. The NK-1 receptor antagonist and an anorectic agent when used according to claim 111, wherein the NK-1 receptor antagonist is a compound of formula V: 4 R7 R RN R 1 3 Y N R R R 8 R R(V) wherein: Y is (CH2)n wherein n is an integer from 1 to 4, and wherein any one of the carbon-carbon SRAL, single bonds in said (CH 2 )n may optionally be replaced by a carbon-carbon double bond, and [I ADayLi\LIBH00830.doc:Ijg 130 wherein any one of the carbon atoms of said (CH 2 )n may optionally be substituted with R 4 and wherein any one of the carbon atoms of said (CH 2 )m 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 R' is hydrogen or Ci.alkyl optionally substituted with hydroxy, C1-4alkoxy or fluoro; R 2 is a radical selected from hydrogen, C1.6 straight or branched alkyl, C3-7cycloalkyl wherein one of the CH 2 groups in said cycloalkyl may optionally be replaced by NH, oxygen or sulphur; aryl selected from phenyl and naphthyl; heteroaryl selected from indanyl, thienyl, furyl, pyridyl, thiazolyl, isothiazolyl, 0t 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, Ci.alkyl, C1-6alkoxy, trifluoromethyl, amino, Cl6ealkylamino, Ci.ealkyl-O- CO, Ci-ealkyl-O-CO-Ci.ealkyl, Cl6ealkyl-O-CO, C1-6alkyl-CO-Cl-ealkyl-0-, Cl-ealkyl-CO, Cl.6alkyl-CO- S is5 NHC.ealkyl-, di-C1-ealkylamino, -CONH-Cl.ealkyl, C-ealkyl-CO-NH-Cl.ealkyl, -NHCOH and -NHCO- Ci-ealkyl; and wherein one of the phenyl moieties of said benzhydryl may optionally be replaced by naphthyl, thienyl, furyl or pyridyl; R 5 is hydrogen, phenyl or Ci-ealkyl; 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 CH 2 groups in said ring may optionally be replaced by oxygen, NH or sulfur; R 3 is aryl S 20 selected from phenyl and naphthyl; heteroaryl selected from indanyl, thienyl, furyl, pyridyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl and quinolyl; and cycloalkyl having 3 to 7 carbon atoms wherein one of the (CH 2 groups in said cycloalkyl may optionally be replaced by NH, oxygen or sulphur; wherein each of said aryl and heteroaryl groups may optionally be substituted with one or more substituents, and said C3-7cycloalkyl may optionally be substituted with one or two substituents, each of said substituents being independently selected from halo, nitro, Ci.ealkyl, C1.ealkoxy, trifluoromethyl, amino, Cl-ealkylamino, -CO-NH-Ci-ealkyl, Cl.ealkyl-CO-NH-C CI.ealkyl, -NHCOH and -NHCO- Ci-alkyl; R 4 and R 7 are each independently selected from hydroxy, halogen, halo, amino, oxo, cyano, methylene, hydroxymethyl, halomethyl, C1-alkylamino, di-C1.ealkylamino, C1ealkoxy, Cl-alkyl-0-CO, Cl.-alkyl-O-CO-C 1 -6alkyl, Ciealkyl-CO-O, Cl.ealkyl-CO-Cliealkyl-O-, C-6alkyl-CO-, Cl-alkyl-CO-C1ialkyl, and the radicals set forth in the definition of R2; R 6 is -NHCOR 9 -NHCH 2 R 9 SO 2 R 9 or one of the radicals set forth in any of the definitions of R 2 R 4 and R 7 R 8 is oximino (=NOH) or one of the radicals set forth in any of the definitions of R2, R 4 and R 7 R 9 is Ciealkyl, hydrogen, phenyl or phenylCl-6alkyl; with the proviso that when m is 0, R 8 is absent, when R 4 R6, R 7 or R 8 is as defined in R2, it cannot form together with the carbon to 3A which it is attached ,a ring with R 5 and when R 4 and R 7 are attached to the same carbon atom, [l:\DayLib\LIBH]00830.doc:ljg 131 then either each of R 4 and R 7 is independently selected from hydrogen, fluoro and C1-6alkyl, or R 4 and R 7 together with the carbon to which they are attached, for a C3-6saturated carbocyclic ring that forms a spiro compound with the nitrogen-containing ring to which they are attached; or a pharmaceutically acceptable salt thereof.
117. The NK-1 receptor antagonist and an anorectic agent when used according to claim 111, wherein the NK-1 receptor antagonist is a compound of formula VI: R 0 Rs 5N R R 3 R 4 (VR2I) (VI) wherein: radicals R are phenyl radicals optionally 2- or3-substituted by a halogen atom or a methyl radical; R 1 is optionally substituted phenyl, cyclohexadienyl, naphthyl, indenyl or optionally o substituted heterocycle; R 2 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; R 4 is OH or fluorine when R5 is H; or R 4 i and R 5 are OH; or R 4 and R5 together form a bond; or a pharmaceutically acceptable salt thereof.
118. The NK-1 receptor antagonist and an anorectic agent when used according to claim 111, wherein the NK-1 receptor antagonist is a compound of formula VII: R Q Ar-T-CO-N-CH 2 -C-CH 2 -CH2-Am+ A I Ar' (VII) wherein: Ar represents an optionally substituted mono-, di- or tricyclic aromatic or heteroaromatic group; T represents a bond, a hydroxymethylene group, a C14alkoxymethylene group or a group; Ar' represents a phenyl group which is unsubstituted or substituted by one or more substituents selected from halogen, preferably chlorine or fluorine, trifluoromethyl, C14alkoxy, C14alkyl 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, C14alkyl, o-C-4alkoxy- Ci4alkyl or o-C24alkanoyloxyC 2 4alkyl; Q represents hydrogen; or Q and R together form a X1 N® 1,2-ethylene, 1,3-propylene or 1,4-butylene group; Am+ represents the radical x 3 X 2 in which X 1 X 2 and X 3 together with the nitrogen atom to which they are attached, form an azabicyclic or azatricyclic ring system optionally substituted by a phenyl or benzyl group; and A- represents a pharmaceutically acceptable anion.
119. The NK-1 receptor antagonist and an anorectic agent when used according to claim 111, wherein the NK-1 receptor antagonist is a compound of formula VIII [I:\DayLib\LIBH]00830.doc: jg 132 R -N X 2 -N-X 3 -R 4 R 2 X R-X 1 (VIII) wherein: R 1 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; R2 represents cycloalkyl or an optionally substituted aryl or heteroaryl group; R 3 represents hydrogen, alkyl, carbamoyl or an alkanoyl or alkenoyl group optionally substituted by carboxy or esterified or amidated carboxy; R 4 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 10 hydroxymethylene group; X 2 represents alkylene, carbonyl or a bond; and X 3 represents carbonyl, Soxo-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; or a pharmaceutically acceptable salt thereof.
120. The NK-1 receptor antagonist and an anorectic agent when used according to claim s 111, wherein the NK- 1 receptor antagonist is a compound of formula IX: R2 O O R4 N ND R ,A H N-R Y 1 k4 S(IX) wherein: R 1 is aryl, or a group of the formula: X is CH or N; and Z is O or in which R 5 is hydrogen or lower alkyl; R 2 is hydroxy or lower alkoxy; R3 is hydrogen or optionally substituted lower alkyl; R 4 is optionally substituted ar(lower)alkyl; A is carbonyl or sulfonyl; and Y is a bond or lower alkenylene; or a pharmaceutically acceptable salt thereof.
121. The NK-1 receptor antagonist and an anorectic agent when used according to claim 111, wherein the NK-1 receptor antagonist is a compound of formula X: H S 1 1 N R N 'R 2 I H (X) wherein: R 1 is aryl selected from indanyl, phenyl and naphthyl; heteroaryl selected from thienyl, furyl, pyridyl and quinolyl; and cycloalkyl having 3 to 7 carbon atoms, wherein one of said [I:\DayLib\LIBH0083.doc:Ijg 133 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 C3.7cycloalkyl 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-1oalkoxy optionally substituted with from one to three fluoro groups, amino, Ci.ioalkyl-S-, Ci-ioalkyl-S(O)-, Ci-ioalkyl-S0 2 phenyl, phenoxy, C-1ioalkyl-SO 2 NH-, Cl-ioalkyl-SO 2 NH- Cl-oalkyl-, Cl-ioalkylamino-diC 1 -ioalkyl-, cyano, hydroxy, cycloalkoxy having 3 to 7 carbon atoms, Cl-ioalkylamino, Cil-dialkylamino, HC(O)NH- and Cl-ioalkyl-C(O)NH-; and R2 is thienyl, benzhydryl, naphthyl or phenyl optionally substituted with from one to three substituents to independently selected from chloro, bromo, fluoro, iodo, cycloalkoxy having 3 to 7 carbon atoms, C.-ioalkoxy optionally substituted with from one to three fluoro groups and Ci-ioalkyl optionally substituted with from one to three fluoro groups; or a pharmaceutically acceptable salt thereof.
122. The NK-1 receptor antagonist and an anorectic agent when used according to claim 111, wherein the NK- 1 receptor antagonist is a compound of formula XI: (CH 2 x I H R N .H R4 5 Rs (XI) N R N wherein: R 1 is a Cl-4alkoxy group; R 2 is N- R3 is a hydrogen or halogen atom; R 4 and R 5 may each independently represent a hydrogen or halogen atom, or a Ci-4alkyl, C14alkoxy or trifluoromethyl group; R 6 is a hydrogen atom, a C-4alkyl, (CH2)mcyclopropyl, -S(O)nC1-4alkyl, phenyl, NR 7 R 8 CH 2 C(O)CF 3 or trifluoromethyl group; R 7 and R 8 may each independently represent a hydrogen atom, or a CiAalkyl or acyl group; x represents zero or 1; n represents zero, 1 or 2; and m represents zero or 1; or a pharmaceutically acceptable salt thereof.
123. The NK-1 receptor antagonist and an anorectic agent when used according to claim 111, wherein the NK-1 receptor antagonist is a compound of formula XII: [I:\DayLib\LIBH00830.doc:Ijg 134 R 8 R R-(UH 2 H 2 -N-(CH 2 R 3 1 12 NH R R (XII) wherein: m is zero, 1, 2 or 3; n is zero or 1; o is zero, 1 cr 2; p is zero or 1; Ris phenyl, 2- or 3-indolyl, 2- or 3-indolinyl, benzothienyl, benzofuranyl, or naphthyl; which R groups may be substituted with one or two halo, Cl-3alkoxy, trifluoromethyl, ClAalkyl, phenyl-Cl-3alkoxy, or Clalkanoyl groups;, R' is trityl, pheny, diphenylmethyl, phenoxy, phenylthio, piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, indolinyl, indolyl, benzothienyl, hexamethyleneiminyl, V benzofuranyl, tetrahydropyridinyl, quinolinyl, isoquinolinyl, reduced quinolinyl, reduced isoquinolinyl, *0* phenyl-(CAalkyl)-, phenyl-(CiAalkoxy)-, quinolinyl-(ClAalkyl)-, isoquinoliny!-(Ci-4alkyl)-, reduced .quniolinyI-(Cl~alkyl)-, reduced isoquinoliny-(CiAalky)-, ben zoyl-(C1. 3alkyl)-, ClAalkyl, or -NH-CH 2 0 R 5 any one of which R 1 groups may be substituted with halo, ClAalkyl, Cl~alkoxy, trifluoromethyl, amino, Cl~talkylamino, di(Ci-4alkyl)amino, or CiAalkanoylamino; or any one of which R1 groups may be substituted with phenyl, piperazinyl, C3-8cycloalkyl, benzyl, Cilialkyl, piperizlinyl, pyridinyl, *pyrimidinyl, C2.6alkanoylamino, pyrrolidinyl, C2-6alkanoyl, or Ci-4alkoxycarbonyl; any one of which groups may be substituted with halo, CiAalkyl, Ci-4alkoxy, trifluoromethyl, amino, Cl~alkylamino, di(Cl~alkyl)amino, or C2Aalkanoylamino; or R 1 is amino, a leaving group, hydrogen, Cl~alkylamino, or di(CiAalkyl)amino; R 5 is pyridyl, anilino(Cl.3alkyl)-, or anilinocarbonyl; R 2 is hydrogen, Cilialkyl, 0 *Cl~alkylsulfonyI, carboxy-(Ci- 3 alkyl)-, C 1 3alkoxycarbonyl-(Ci- 3 alkyl)-, or -CO-R6; R 6 is hydrogen, ClAalkyI, Ci.3haloalkyl, phenyl, C1.3alkoxy, Cl-3hydroxyalkyl, amino, Ci~alkylamino, di(Cl~alkyl) amino, or (CH2)q-R 7 q is zero to 3; R 7 is carboxy, CAalkoxycarbonyl, Cv.~alkylcarbonyloxy, amino, ClAalkyiamino, di(Ci~alkyI) amino, C1.6alkoxycarbonylamino, or phenoxy, phenylthio, piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, indolinyl, indolyl, benzothienyl, benzofuranyl, quinolinyl, phenyl-(ClAalkyi)-, quinolinyl-(Cl 4alkyI)-, isoquinolinyl-(Cl~alkyl)-, reduced quinolinyl-(CiAalky)-, reduced isoquinolinyI-(Cl~alkyI)-, benzoyl-Cl-3alkyl; any one of which aryl or heterocyclic R7 groups may be substituted with halo, trifluoromethyl, ClAalkoxy, Cl~alkyI, amino, ClAalkylamino, di(ClAalkyl)amino, or C2Aalkanoylamlno; or any one of which R 7 groups may be substituted with phenyl piperazinyl, C3-8cycloalkyI, benzyl, piperidlinyl, pyridinyl, pyrimidinyl pyrrolidinyl, C2-6alkanoyI, or Ci.-salkoxycarbonyl; any of which groups may be substituted with halo, trifluoromethyl, amino, Cl.~alkoxy, CAalkyI, C14alkylamino, di(CiAalkyi)amino, or C2Aalkanoylamino; R 8 is hydrogen or C1_6alkyI; R 3 is phenyl, phenyI-(Ci-6alky)-, C3-8cycloalkyl, C5-8cycloalkenyl, C1iaalkyl, naphthyl, C2-alkenyI, or hydrogen; any one or which groups except hydrogen may be substituted with one or (I 1\DayLi b\LIB H]00830.doc: Ij g two halo, C1l3alkoxy, Cl-3alkylthio, nitro, trifluoromethyl, or Cl-3alky groups; and RI is hydrogen or C1. 3 alkyl; with the proviso that if R1 is hydrogen or halo, R 3 is phenyl, phenyl-(Cl 1 6 alky)-, C3-8cycloalkyl, C5-8CYCloalkenyI or naphthyl; or a pharmaceutically acceptable salt thereof.
124. The NK-1 receptor antagonist and an anorectic agent when used according to claim 111, wherein the NK-1 receptor antagonist is selected from the classes of compounds described in E P-A-0577394, WO-A-9508549, WO-A-95 18124, WO-A-9523798 and WO-A-9605 181.
125. The NK-1 receptor antagonist and an anorectic agent when used according to claim 111, wherein the NK-1 receptor antagonist is selected from benzyloxy-3(S)-(4 -fluorophenyl)-4-(3-(5.oxo- 1H, 4H-1 ,2,4-triazolo)methyl)morpholine; 1 0 (3,5-bis (trifluoromethyl)phenyl)ethoxy)4(3.(5oxo-1 H ,4H-1 ,2,4-triazolo)methyl)-3-(S)-phenyl. V.:morpholine; 2 -(S)-(3,5-bis(trifluoromethyl)benzyloxy)4.(3(5oxo-1 H ,4H-1,2,4-triazolo)methyl)-3- o (S)-phenyl-morpholine; 3 ,5-bis(trifluoromethyl)-phenyl)ethoxy-3.(S)(4-fluorophenyl)y H,4H-1 ,2,4-triazolo)methyl)morpholine; a ae ethoxy)-4-(5(N,N-dimethylamino)methyl-1,23tizl4y ehl--S-hnlopoie 3 ,5-bis(trifluoromethyl)phenyl)ethoxy)4((NNdimethylamino)methyl-1,2,3-triazol-4- yl)methyl-3-(S)-(4-fluorophenyl)morpholine; 1 -(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3 (S)-(4-fluorophenyl).4-(3-(4monophosphoryls5oxo1 H-i ,2,4-triazolo)methyl)morpholine; 1- bog* (R)-(3,5-bis (trifl uorometh yl) phen yl) ethoxy)3(s)(4-fluoroph enyl)4(3-(l -mono phospho *see 1H-i 2 ,4-triazolo)methyl)morpholine; 5-bis(trifluoromethyl)phenyl)ethoxy)3(S).(4- 20: fluoro phenyl)-4-(3-(2-monophosphorylsoxol1 H-i 2 ,4-triazolo)methyl)morpholine; 0 g* *bis (trifluoromethyl)phenyl)ethoxy)3(S)-(4fluorophenyl)4(3(5oxyphosphoyl-1 H-i 2,4- triazolo)methyl) morpholine; -(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)3(S)(4- fluorophenyl)-4-(3-( 1 -monophosphoryl-5-oxo-4H-1 2 ,4-triazolo)methyl)morpholine; 1 phenyl)ethoxy)-4-(4-N N-dimethylaminobut-2-yn-yl)-3-(S)-(4- fluorophenyl)morpholine; or a pharmaceutically acceptable salt thereof.
126. The NK-1 receptor antagonist and an anorectic agent when used according to any one of claims 111 to 125, wherein the NK-1 receptor antagonist is orally active, long acting and CNS- penetrant.
127. The NK-1 receptor antagonist and an anorectic agent when used according to any one of claims 111 to 126, wherein the anorectic agent is selected from aminorex, amphechloral, amphetamine, benzphetamine, chlorphentermine, clobenzorex, cloforex, clominorex, clortermine, cyclexedrine, dexfenfluramine, dextroamphetamine, diethylpropion, diphemethoxidine, N- ethyl amphetamine, fenbutrazate, fenfluramine, fenisorex, fenproporex, fludorex, fluminorex, fu rfu ryl methyl amphetamine, levamfetamine, levophacetoperane, mazindol, mefenorex, i~~ 35 metamfepramone, methamphetamine, norpseudoephedrine, pentorex, phendimetrazine, [1A:DayLib\LIBHj00830.doc:Ijg 136 phenmetrazine, phentermine, phenylpropanolamine picilorex and sibutramine; or a pharmaceutically acceptable salt thereof.
128. The NK-1 receptor antagonist and an anorectic agent when used according to any one of claims 115 to 127, wherein the anorectic agent is a halogenated amphetamine derivative.
129. The NK-1 receptor antagonist and an anorectic agent when used according to claim 128, wherein the amphetamine derivative is selected from chlorphentermine cloforex, clortermine, dexfenfluramine, fenfluramine, picilorex and sibutramine; or a pharmaceutically acceptable salt thereof.
130. The NK-1 receptor antagonist and an anorectic agent when used according to any one of claims 111 to 129, wherein the eating disorder results in or causes obesity.
131. The NK-1 receptor antagonist and an anorectic agent when used according to any one s: of claims 111 to 129, wherein the eating disorder is bulimia nervosa.
132. The NK-1 receptor antagonist and an anorectic agent when used according to any one of claims 111 to 129, wherein the eating disorder is a compulsive eating disorder. 15 133. A pharmaceutical composition for the treatment or prevention of eating disorders, said composition comprising a NK-1 receptor antagonist and an anorectic agent, together with at least one pharmaceutically acceptable carrier or excipient.
134. The composition according to claim 133, wherein the NK-1 receptor antagonist is a compound of formula I R3 X R 4 S I R 2 N) R S 20 R(I) wherein R 1 is selected from the group consisting of: C1-6alkyl, substituted with one or more of the substituents selected from: heterocycle, wherein the heterocycle is selected from the group Sconsisting of: benzimidazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, (F) pyrazinyl, pyrazolyl, pyridyl, pyrrolyl, tetrazolyl, thiadiazolyl, triazolyl, and (M) piperidinyl, and wherein the heterocycle is unsubstituted or substituted with one or more substituent(s) selected from: Ci-alkyl, unsubstituted or substituted with halo, -CF3, -OCH 3 or phenyl, (ii) Cl-6alkoxy, (iii) oxo, (iv) thioxo, cyano, (vi) -SCH 3 (vii) phenyl, (viii) hydroxy, (ix) trifluoromethyl, (CH 2 )mNR9RiO, wherein m is 0, 1 or 2, and R 9 and R 1 0 are independently selected from: hydrogen, (II) Ci-alkyl, (III) hydroxyCl6alkyl, and (IV) phenyl, (xi) -NR 9 COR 1 0 wherein R 9 and R 1 0 are as defined above, and (xii) -CONR9Ro 1 wherein R 9 and R 1 0 are as defined above, R 2 and R 3 are independently selected from the group consisting of: hydrogen; (2) [R:\LIBH]01012.doc:ljg I. t; I? 137 R6 R Cli-alkyl, C2-6alkenyl, and phenyl; X is R 4 is z R5 is phenyl, unsubstituted or substituted with halo; R 6 R 7 and R 8 are independently selected from the group consisting of: hydrogen, Ci.6alkyl, halo, and -CF 3 Y is and Z is hydrogen or C14alkyl; or a pharmaceutically acceptable salt thereof.
135. The composition according to claim 133, wherein the NK-1 receptor antagonist is a compound of formula Ila: A 1 0 O A 2 IO I *N o R6I, A (Ila) wherein A 1 is fluorine or CF 3 A 2 is fluorine or CF 3 A 3 is fluorine or hydrogen; X is an alkylene chain of 1 to 4 carbon atoms optionally substituted by oxo; Y is a C14alkyl group optionally substituted by a hydroxyl group; R 6 is a 5-membered or 6-membered heterocyclic ring containing 2 or 3 nitrogen atoms optionally substituted by =S or a C-4alkyl group, and optionally substituted by a group of the formula ZNR 7 R 8 where Z is Ci-ealkylene or C3-cycloalkylene; R 7 is hydrogen, C14alkyl, C3-7cycloalkyl or C3-7cycloalkylCl-4alkyl, or C2-4alkyl substituted by C14alkoxy or hydroxyl; R 8 is hydrogen,'C4alkyl, C37cycloalkyl or C37cycloalkylC-4alkyl, or C2-4alkyl substituted by one or two 1s 15 substituents selected from Ci4alkoxy, hydroxyl or a 4, 5 or 6 membered heteroaliphatic ring containing one or two heteroatoms selected from N, O and S; or R 7 R 8 and the nitrogen atom to which they are attached form a heteroaliphatic ring of 4 to 7 ring atoms, optionally substituted by a hydroxy group, and optionally containing a double bond, which ring may optionally contain an oxygen or sulphur ring atom, a group S(0) or S(0)2 or a second nitrogen atom which will be part of 20 a NH or NRc moiety where Rc is C14alkyl optionally substituted by hydroxy or C-4alkoxy; or R 7 R 8 and the nitrogen atom to which they are attached form a non-aromatic azabicyclic ring system of 6 to 12 ring atoms; or Z, R 7 and the nitrogen atom to which they are attached form a heteroaliphatic ring of 4 to 7 ring atoms which may optionally contain an oxygen ring atom; or a pharmaceutically acceptable salt thereof.
136. The composition according to claim 133, wherein the NK-1 receptor antagonist is a compound of formula III: [R:\LIBH]01012.doc:ljg b wherein: R 2 and R 3 are independently selected from the group consisting of: hydrogen; (2) Ci.6alkyl, C2-alkenyl, and phenyl; R 6 R 7 and R 8 are independently selected from the group consisting of: hydrogen, Ci-alkyl, fluoro, chloro, bromo, iodo, and -CF 3 R 11 R 12 and R 1 3 are independently selected from the group consisting of: fluoro, chloro, (3) bromo, and iodo; A is unsubstituted Ciealkyl; B is selected from the group consisting of: HN-N x'X, X\\NA N-N 0 N-M N-N '11N "k10 110 SI S N "-S x NO N 5 X H 6O S.* 0r S.. D S t. 0 S *0S6 S x N-N xN N-N A~S."x x N-N N-NN x N I x N-A x N H Il I N N S I II IA or A p is Oorl1; X is selected from: wherein M+ is a pharmaceutically monovalent counterion, (b) -PO(O-) 2 .2M, -PO(O-) 2 D2+, wherein D 2 is a pharmaceutically acceptable divalent counterion, -CH(R 4 wherein R 4 is hydrogen or Cl3alkyl, -CH(R 4 2 .2M+, CH(R 4 2 -CO-CH 2 CH 2 -CO 2 -CH(CH)-O-CO-R5, wherein R 5 is selected f e g p c n H2+Mo from the group consisting of: (ii)M( C0 2 -M+ 0 C02jM (v M~M c0- 2 NH 3 C02M+ C0 2 -M+ C02M+ "1 0) C0 M v (iii) (iv) I (vi) I (vii) C02jM+ 0- and Y is Z is hydrogen or Ci-.alkyl; or a pharmaceutically acceptable salt thereof. [R:\LIBH]01012.doc:Ijg 139
137. The composition according to claim 133, wherein the NK-1 receptor antagonist is a compound of formula IVa: A 1 SA 3 x (IVa) wherein A 1 is fluorine or CF3; A 2 is fluorine or CF3; A 3 is fluorine or hydrogen; X is a group of the formula NR 6 R 7 or a C- or N-linked imidazolyl ring; Y is hydrogen or C14alkyl optionally substituted by a hydroxy group; R 6 is hydrogen, Clealkyl, C3-7cycloalkyl, C3.7cycloalkylC14alkyl, phenyl, or C24alkyl substituted by Clialkoxy or hydroxy; R 7 is hydrogen, Clealkyl, C3.7cycloalkyl, C3-7cycloalkylCi4alkyl, phenyl, or C2Aalkyl substituted by one or two substituents selected from CClalkoxy, hydroxy or a 4, 5 or 6 membered heteroaliphatic ring containing one or two heteroatoms 1io selected from N, O and S; or R 6 and R 7 together with the nitrogen atom to which they are attached, form a saturated or partially saturated heterocyclic ring of 4 to 7 ring atoms, which ring may optionally contain in the ring one oxygen or sulphur atom or a group selected from NR 8 S(0) or S(0) 2 and which ring may be optionally substituted by one or two groups selected from hydroxy- C-4alkyl, ClAalkoxyCi4alkyl, oxo, CORa or CO 2 Ra where Ra is hydrogen or C14alkyl; or R 6 and R 7 together with the nitrogen atom to which they are attached, form a non-aromatic azabicyclic ring Ssystem of 6 to 12 ring atoms; and R 8 is hydrogen, C14alkyl, hydroxy CiAalkyl or C-4alkyl C14alkyl; S or a pharmaceutically acceptable salt thereof.
138. The composition according to claim 133, wherein the NK-1 receptor antagonist is a compound of formula V: 4 R7 R2 R 8 R6 (V) 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 (CH 2 )n may optionally be replaced by a carbon-carbon double bond, and (R:\LIBH]01012.doc:ljg D i 140 wherein any one of the carbon atoms of said (CH 2 )n may optionally be substituted with R 4 and wherein any one of the carbon atoms of said (CH 2 )m may optionally be substituted with R 7 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 R 1 is hydrogen or Ci-salkyl optionally substituted with hydroxy, C-4alkoxy or fluoro; R 2 is a radical selected from hydrogen, Ci1- straight or branched alkyl, C3-7cycloalkyl wherein one of the CH 2 groups in said cycloalkyl may optionally be replaced by NH, oxygen or sulphur; aryl selected from phenyl and naphthyl; heteroaryl selected from indanyl, thienyl, furyl, pyridyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl and quinolyl; phenyl-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, Ci-alkyl, Ci-6alkoxy, trifluoromethyl, amino, Cl.alkylamino, Cl.alkyl-O- CO, C1-6alkyl-O-CO-C-6alkyl, Cl-alkyl-O-CO, Cl-6alkyl-CO-Cl.ealkyl-O-, Cl-alkyl-CO, Ci.alkyl-CO- c. 15 NHClealkyl-, di-Ci.alkylamino, -CONH-C 1 ialkyl, C16alkyl-CO-NH-Clealkyl, -NHCOH and -NHCO- CI-6alkyl; and wherein one of the phenyl moieties of said benzhydryl may optionally be replaced by naphthyl, thienyl, furyl or pyridyl; R 5 is hydrogen, phenyl or Cl1-alkyl; or R 2 and R 5 together with the carbon to which they are attached, form a saturated ring having from 3 to 7 carbon atoms wherein one of the CH 2 groups in said ring may optionally be replaced by oxygen, NH or sulfur; R 3 is aryl selected from phenyl and naphthyl; heteroaryl selected from indanyl, thienyl, furyl, pyridyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl and quinolyl; and cycloalkyl having 3 to 7 Scarbon' atoms wherein one of the (CH 2 groups in said cycloalkyl may optionally be replaced by NH, oxygen or sulphur; wherein each of said aryl and heteroaryl groups may optionally be substituted with one or more substituents, and said C3.7cycloalkyl may optionally be substituted with one or two 25 substituents, each of said substituents being independently selected from halo, nitro, Ci-ealkyl, *0 C1i-alkoxy, trifluoromethyl, amino, Cl-alkylamino, -CO-NH-Cisalkyl, Cl-alkyl-CO-NH-C Ci-alkyl, -NHCOH and -NHCO- C1-6alkyl; R 4 and R 7 are each independently selected from hydroxy, halogen, halo, amino, oxo, cyano, methylene, hydroxymethyl, halomethyl, Cl6alkylamino, di-Ci-alkylamino, Ci6alkoxy, Ci-6alkyl-O-CO, Cl.6alkyl-O-CO-Cl6alkyl, C1.6alkyl-CO-O, Cl.alkyl-CO-Clsalkyl-O-, Cl-alkyl-CO-, Ciealkyl-CO-Ci.alkyl, and the radicals set forth in the definition of R 2 R 6 is -NHCOR9, -NHCH 2 R 9 S0 2 R 9 or one of the radicals set forth in any of the definitions of R 2 R 4 and R 7 R 8 is oximino (=NOH) or one of the radicals set forth in any of the definitions of R 2 R 4 and R 7 R9 is Ci6alkyl, hydrogen, phenyl or phenylCi-6alkyl; with the proviso that when m is 0, R 8 is CO ALi absent, when R 4 R 6 R 7 or R 8 is as defined in R 2 it cannot form together with the carbon to ws ich it is attached ,a ring with R 5 and when R 4 and R 7 are attached to the same carbon atom, [R:\LIBH]01012.doc:ljg e 141 when either each of R 4 and R 7 is independently selected from hydrogen, fluoro and Ci-alkyl, or R 4 and R 7 together with the carbon to which they are attached, for a C3-6saturated carbocyclic ring that forms a spiro compound with the nitrogen-containing ring to which they are attached; or a pharmaceutically acceptable salt thereof.
139. The composition according to claim 133, wherein the NK-1 receptor antagonist is a compound of formula VI: o R 0 R N R1 R3/ R4 R 2 R R R (VI) wherein: radicals R are phenyl radicals optionally 2- or 3-substituted by a halogen atom or a methyl radical; R 1 is optionally substituted phenyl, cyclohexadienyl, naphthyl, indenyl or optionally i 10 substituted heterocycle; R 2 is H, halogen, OH, alkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkyloxy, alkylthio, acyloxy, carboxy, optionally substituted alkyloxycarbonyl, benzyloxycarbonyl, amino or acylamino; R 3 is optionally 2-substituted phenyl; R 4 is OH or fluorine when R 5 is H; or R 4 and R 5 are OH; or R 4 and R 5 together form a bond; or a pharmaceutically acceptable salt thereof.
140. The composition according to claim 133, wherein the NK-1 receptor antagonist is a i5 compound of formula VII: R Q I I Ar-T-CO-N-CH 2 -C-CH 2 -CH 2 -Am+,A Ar' (VII) wherein: Ar represents an optionally substituted mono-, di- or tricyclic aromatic or heteroaromatic group; T represents a bond, a hydroxymethylene group, a CA1alkoxymethylene group or a Cl-salkylene group; Ar' represents a phenyl group which is unsubstituted or substituted by one or 20 more substituents selected from halogen, preferably chlorine or fluorine, trifluoromethyl, C-4alkoxy, Clialkyl 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, ClAalkyl, co-Ci alkoxy- Ci.4alkyl or co-C24alkanoyloxyC2alkyl; Q represents hydrogen; or Q and R together form a Xi /N@ 1,2-ethylene, 1,3-propylene or 1,4-butylene group; Am+ represents the radical x 3 X 2 in which X 1 X 2 and X 3 together with the nitrogen atom to which they are attached, form an azabicyclic or azatricyclic ring system optionally substituted by a phenyl or benzyl group; and A- represents a pharmaceutically acceptable anion.
141. The composition according to claim 133, wherein the NK-1 receptor antagonist is a S compound of formula VIII [R:\LIBH]O0112.doc:ljg J. 142 R3 R-N -X 2 -N-X 3 -R 4 R2-X 1 (VIII) wherein: R 1 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; R 2 represents cycloalkyl or an optionally substituted aryl or heteroaryl group; R 3 represents hydrogen, alkyl, carbamoyl or an alkanoyl or alkenoyl group optionally substituted by carboxy or esterified or amidated carboxy; R 4 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 10 hydroxymethylene group; X 2 represents alkylene, carbonyl or a bond; and X 3 represents carbonyl, oxo-lower alkyl, oxo(aza)-lower alkyl, or an alkyl group optionally substituted by phenyl, hydroxymethyl, optionally esterified or amidated carboxy, or (in other than the a-position) hydroxy; or a pharmaceutically acceptable salt thereof.
142. The composition according to claim 133, wherein the NK- 1 receptor antagonist is a 15 compound of formula IX: *00 R 2 O( 0 R A H N-R 0 R4 (IX) orx wherein: R 1 is aryl, or a group of the formula: X is CH or N; and Z is 0 or N-R 5 in which R 5 is hydrogen or lower alkyl; R 2 is hydroxy or lower alkoxy; R 3 is hydrogen or optionally substituted lower alkyl; R 4 is optionally substituted ar(lower)alkyl; A is carbonyl or 20 sulfonyl; and Y is a bond or lower alkenylene; or a pharmaceutically acceptable salt thereof.
143. The composition according to claim 133, wherein the NK-1 receptor antagonist is a compound of formula X: H I 1 N R KN...,R2 I H (X) wherein: R 1 is aryl selected from indanyl, phenyl and naphthyl; heteroaryl selected from 5 thienyl, furyl, pyridyl and quinolyl; and cycloalkyl having 3 to 7 carbon atoms, wherein one of said [R:\LIBH]01012.doc:ljg f 143 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 C3-7cycloalkyl 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.ioalkoxy optionally substituted with from one to three fluoro groups, amino, Ci-1oalkyl-S-, C.-loalkyl-S(O)-, C-.loalkyl-SO2-, phenyl, phenoxy, Ci-ioalkyl-SO 2 NH-, Cl-ioalkyl-SO 2 NH- Cl-loalkyl-, Cl-loalkylamino-diCi-loalkyl-, cyano, hydroxy, cycloalkoxy having 3 to 7 carbon atoms, Cl.-oalkylamino, Ci-6dialkylamino, HC(O)NH- and C.-ioalkyl-C(O)NH-; and R 2 is thienyl, benzhydryl, naphthyl or phenyl optionally substituted with from one to three substituents to independently selected from chloro, bromo, fluoro, iodo, cycloalkoxy having 3 to 7 carbon atoms, Ci-ioalkoxy optionally substituted with from one to three fluoro groups and Cl-ioalkyl optionally Ssubstituted with from one to three fluoro groups; or a pharmaceutically acceptable salt thereof.
144. The composition according to claim 133, wherein the NK- 1 receptor antagonist is a compound of formula XI: R 2 2 (CH 2 )x N R3 5 (XI) R 6 N wherein: R 1 is a C.4alkoxy group; R 2 is N-N R 3 is a hydrogen or halogen atom; S* R 4 and R 5 may each independently represent a hydrogen or halogen atom, or a C-4alkyl, Cl4alkoxy or trifluoromethyl group; R 6 is a hydrogen atom, a Ci-4alkyl, (CH2)mcyclopropyl, -S(O)nC-4alkyl, phenyl, NR 7 R 8 CH 2 C(O)CF 3 or trifluoromethyl group; R 7 and R 8 may each independently represent a hydrogen atom, or a C14alkyl or acyl group; x represents zero or 1; n represents zero, 1 or 2; and m represents zero or 1; or a pharmaceutically acceptable salt thereof.
145. The composition according to claim 133, wherein the NK-1 receptor antagonist is a compound of formula XII: [R:\LIBH]01012.doc:jg 0 4'i i 144 R-(CHl 2 H 2 -N-(cHt 2 )-R3 1 12 NH R (LC ;H 2 R 1 (XII) 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, Cl-3alkoxy, trifluoromethyl, C14alkyl, phenyl-Ci. 3 alkoxy, or C14alkanoyl groups; R 1 is trityl, phenyl, diphenylmethyl, phenoxy, phenylthio, piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, indolinyl, indolyl, benzothienyl, hexarnethyleneiminyl, benzofuranyl, tetrahydropyridinyl, quinolinyl, isoquinolinyl, reduced quinolinyl, reduced isoquinolinyl, phenyl-(Cl4alkyI)-, phenyl-(Cl.~alkoxy)-, quinolinyl-(Ci.4alkyl)-, isoquinolinyl-(Ci~alkyl)-, reduced quniolinyl-(Cl~alkyl)-, reduced isoquinolinyl-(Cl~alky)-, benzoyl-(Ci 3 alky)-, C14alkyl, or -NH-CH 2 i R 5 any one of which RI groups may be substituted with halo, Ct1ialkyl, CiAalkoxy, trifluoromethyl, amino, C14alkylamino, di(Cl~alkyI)amino, or Ci4alkanoylamino; or any one of which R 1 groups may be substituted with phenyl, piperazinyl, C3-8cycloalkyl, benzyl, C14alkyI, piperizlinyl, pyridinyl, pyrimidinyl, C2-6alkanoylamino, pyrrolidinyl, C2-6alkanoyI, or C14alkoxycarbonyl; any one of which groups may be substituted with halo, C14alkyl, C14alkoxy, trifluoromethyl, amino, Cl-4alkylamino, di(Cl~alkyI)amino, or C2.4alkanoyl amino; or R 1 is amino, a leaving group, hydrogen, Ci1salkylamino, or di(Cl~alkyl)amino; R 5 is pyridyl, anilino(Cl-3alkyI)-, or anilinocarbonyl; R 2 is hydrogen, C14alkyI, C14alkylsulfonyl, carboxy-(Cl-3alkyI)-, C1.3alkoxycarbonyl-(CI- 3 alkyl)-, or -CO-R 6 R 6 is hydrogen, Ci4alkyl, Cl-3haloalkyl, phenyl, C1l3alkoxy, Cl-3hydroxyalkyl, amino, Ci4alkylamino, di(Ciltalkyl) amino, or (CH2)q-R 7 q is zero to 3; R 7 is carboxy, Ci4alkoxycarbonyl, C14alkylcarbonyloxy, amino, S 20 C14alkylamino, di(Cl~alkyI) amino, Cl-6alkoxycarbonylamino, or phenoxy, phenylthio, piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, indolinyl, indolyl, benzothienyl, benzofuranyl, quinolinyl, OSSS phenYl-(Cl~alkyl)-, quinolinyl-(Ci 4alkyl)-, isoquinolinyl-(Cl~alkyl)-, reduced quinolinyl-(Cl~alkyl)-, reduced isoquinolinyl-(Cl~alkyl)-, benzoyl-C1.3alkyl; any one of which aryl or heterocyclic R 7 groups may be substituted with halo, tnfluoromethyl, C14alkoxy, Ci4alkyI, amino, C14~alkylamino, di(Ci~alkyl)amino, or C2Aalkanoylamlno; or any one of which R 7 groups may be substituted with phenyl piperazinyl, C3-8cycloalkyl, benzyl, piperidinyl, pyridinyl, pyrimidinyl pyrrolidinyl, C2-6alkanoyl, or Cl~alkoxycarbonyl; any of which groups may be substituted with halo, trifluoromethyl, amino, Cl-4alkoxy, C14alkyl, Ci-4talkylamino, di(Cl~alkyl)amino, or C24alkanoylamino; R 8 is hydrogen or i-alkyl; R 3 is phenyl, phenyI-(Cl-6alkyl)-, C3-8Cycloalkyl, C5-8cycloalkenyl, Ci-8alkyl, naphthyl, C248alkenyl, or hydrogen; any one or which groups except hydrogen may be substituted with one or [R:\LIBH]O 101 2.doc:Ijg 0O 0-6 0 0* 0 0 0 e.g a e a e 6060 'e.g 6 66O~ 0 0 I eeoc 0 60 0 B. a. .0 0060 0 0 6 60 c eec. *0 C O C J Ce two halo, Cl-3alkoxy, Cl-3alkylthio, nitro, trifluoromethyl, or C1-3alkyl groups; and R 4 is hydrogen or C1l3alkyl; with the proviso that if R 1 is hydrogen or halo, R 3 is phenyl, phenyl-(Cl- 6 alkyl)-, C3-8cycloalkyl, C5-8cycloalkenyl or naphthyl; or a pharmaceutically acceptable salt thereof.
146. The composition according to claim 133, 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.
147. The composition according to claim 133, wherein the NK-1 receptor antagonist is selected from 5-bis(tnfluoromethyl)benzyloxy-3(S)-(4 -fluorophenyl)-4-(3-(5-oxo-1H, 4H- 1 ,2,4-triazolo)methyl)morpholine; (trifluoromethyl)phenyl)ethoxy)-4-(3-(5-oxo- 1 H,4H-i ,2,4-triazolo)methyl)-3-(S)-phenyl-morpholine; 2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-4- (3-(5-oxo-1 H ,4H-1 ,2,4-triazolo)methyl)-3-(S)-phenyl-morpholine; 1 bi~rfurmty)pey~toy-3()(-loohnl--3(-x- H ,4H-1 ,2,4-triazolo)methyl)- morpholine; -(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(5(N ,N dimethylamino)methyl- 1 ,2,3-triazol-4-yl)methyl-3-(S)-phenylmorpholine; 1 (trifluoromethyl)phenyl)- 15ethoxy)-4-(5-(N ,N-dimethylamino)methyl-1 ,2,3-triazol-4-yl)methyl-3-(S)-(4-fluorophenyl)morpholine; 1 -(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3(S)(4fluorophenyl)4(3(4-monophosphoryl- 5-oxo-1 H-i ,2,4-triazolo)methyl)morpholine; (trifluoromethyl)phenyl)ethoxy)-3- (S)-(4-fluorophenyl)-4-(3-(1 -monophosphoryl-5-oxo-1 H-i ,2,4-triazolo)methyl)morpholine; 5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluoro phenyl)-4-(3-(2-monophosphoryl-5-oxo- 20 1 H-i ,2,4-triazolo)methyl)morpholine; (R)-(3,5-bis (trifluoromethyl)phenyl)ethoxy)-3-(S)-(4- fluorophenyl)-4-(3-(5-oxyphosphoryl-1 H-i ,2,4-triazolo)methyl) morpholine; bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-( I -monophosphory-5-oxo-4H- 1,2,4- triazolo)methyl)morpholine; 1 -(R)-(3,5-bis(tdfluoromethyl) phenyl)ethoxy)-4-(4-N ,N- dimethylaminobut-2-yn-yl)-3-(S)-(4-fluorophenyl)morpholine; or a pharmaceutically acceptable salt 25 thereof.
148. The composition according to claim 133, wherein the NK-1 receptor antagonist is orally active, long acting and CNS-penetrant.
149. The composition according to any one of claims 133 to 148, 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, metamfepramone, methamphetamine, norpseudoephedrine, pentorex, phendimetrazine, phenmetrazine, phentermine, phenylpropanolamine picilorex and sibutramine; or 3 5 a pharmaceutically acceptable salt thereof. [R:\UBH]O 101 2.doc:ljg 146
150. The composition according to any one of claims 133 to 149, wherein the anorectic agent is a halogenated amphetamine derivative.
151. The composition according to claim 150, wherein the amphetamine derivative is selected from chlorphentermine cloforex, clortermine, dexfenfluramine, fenfluramine, picilorex and sibutramine; or a pharmaceutically acceptable salt thereof.
152. The composition according to any one of claims 133 to 151, wherein the eating disorder results in or causes obesity. 152. The composition according to any one of claims 133 to 151, wherein the eating disorder is bulimia nervosa.
153. The composition according to any one of claims 133 to 151, wherein the eating disorder is a compulsive eating disorder. 00 Dated 18 December, 2001 Merck Sharp Dohme Limited S 1 5 Patent Attorneys for the Applicant/Nominated Person SPRUSON FERGUSON 000 0• [R:\LIBH]01012.doc:ljg
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GBGB9708289.5A GB9708289D0 (en) | 1997-04-24 | 1997-04-24 | Therapeutic use |
| GB9708289 | 1997-04-24 | ||
| GB9721265 | 1997-10-07 | ||
| GBGB9721265.8A GB9721265D0 (en) | 1997-10-07 | 1997-10-07 | Therapeutic use |
| PCT/GB1998/001161 WO1998047513A1 (en) | 1997-04-24 | 1998-04-22 | Use of nk-1 receptor antagonists for treating eating disorders |
Publications (2)
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| AU744261B2 true AU744261B2 (en) | 2002-02-21 |
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| AU70657/98A Ceased AU744261B2 (en) | 1997-04-24 | 1998-04-22 | Use of NK-1 receptor antagonists for treating eating disorders |
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| EP (1) | EP0977572A1 (en) |
| JP (1) | JP2001524960A (en) |
| AU (1) | AU744261B2 (en) |
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| WO (1) | WO1998047513A1 (en) |
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| MXPA01009404A (en) * | 1999-03-19 | 2004-03-19 | Abbott Gmbh & Co Kg | Method of treating eating disorders. |
| EP1220673A2 (en) * | 1999-10-13 | 2002-07-10 | Glaxo Group Limited | Morpholinol derivatives for the treatment of obesity |
| IL157456A0 (en) * | 2001-03-21 | 2004-03-28 | Pharmacopeia Inc Pharmacopeia | Aryl and biaryl compounds having mch modulatory activity |
| DE10311984A1 (en) * | 2003-03-12 | 2004-09-23 | Freie Universität Berlin | Using neutral endopeptidase-associated molecules for treatment, diagnosis, prophylaxis and monitoring of eating and metabolic disorders and dementia, also for drug development |
| CN106290894A (en) * | 2016-07-21 | 2017-01-04 | 浙江理工大学 | A kind of leukemia detection kit based on NK1R albumen |
Citations (3)
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|---|---|---|---|---|
| EP0577394A1 (en) * | 1992-06-29 | 1994-01-05 | Merck & Co. Inc. | Morpholine and thiomorpholine tachykinin receptor antagonists |
| WO1996024353A1 (en) * | 1995-02-10 | 1996-08-15 | Eli Lilly And Company | Methods of treating or preventing psychiatric disorders |
| WO1996037207A2 (en) * | 1995-05-25 | 1996-11-28 | Biofrontiers, Inc. | Pharmaceutical compositions containing calcium sulfate |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB8929070D0 (en) * | 1989-12-22 | 1990-02-28 | Fujisawa Pharmaceutical Co | Peptide compounds,processes for preparation thereof and pharmaceutical composition comprising the same |
| UA41251C2 (en) * | 1990-01-04 | 2001-09-17 | Пфайзер, Інк. | Hydrogenated nitrogen-containing heterocyclic substances, piperidine derivatives, pharmaceutical composition and method for inhibiting activity of p substance |
| SK284565B6 (en) * | 1991-03-26 | 2005-06-02 | Pfizer Inc. | A process for preparing substituted piperidines |
| MY110227A (en) * | 1991-08-12 | 1998-03-31 | Ciba Geigy Ag | 1-acylpiperindine compounds. |
| FR2689888B1 (en) * | 1992-04-10 | 1994-06-10 | Rhone Poulenc Rorer Sa | NOVEL PERHYDROISOINDOLE DERIVATIVES, THEIR PREPARATION AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM. |
| FR2696178B1 (en) * | 1992-09-30 | 1994-12-30 | Sanofi Elf | Quaternary basic amides, process for their preparation and pharmaceutical compositions containing them. |
| IS4208A (en) * | 1993-09-22 | 1995-03-23 | Glaxo Group Limited | 3- (tetrazolyl-benzyl) amino-piperadidine derivatives |
| US6403577B1 (en) * | 1993-11-17 | 2002-06-11 | Eli Lilly And Company | Hexamethyleneiminyl tachykinin receptor antagonists |
| IL112134A (en) * | 1993-12-29 | 1999-12-22 | Merck Sharp & Dohme | Substituted morpholine derivatives their preparation and pharmaceutical compositions containing them |
| IL112778A0 (en) * | 1994-03-04 | 1995-05-26 | Merck & Co Inc | Substituted heterocycles, their preparation and pharmaceutical compositions containing them |
| US5824678A (en) * | 1994-08-15 | 1998-10-20 | Merck Sharp & Dohme Ltd. | Morpholine derivatives and their use as therapeutic agents |
| EP0761219A1 (en) * | 1995-08-21 | 1997-03-12 | Eli Lilly And Company | 2-Acylaminopropanamines as growth hormone secretagogues |
| WO1997038692A1 (en) * | 1996-04-12 | 1997-10-23 | Eli Lilly And Company | Bisindoles for treating pain or nociception |
| EP0906315A1 (en) * | 1996-06-21 | 1999-04-07 | MERCK SHARP & DOHME LTD. | Spiro-piperidine derivatives and their use as therapeutic agents |
| GB9613969D0 (en) * | 1996-07-03 | 1996-09-04 | Merck Sharp & Dohme | Therapeutic agents |
-
1998
- 1998-04-22 JP JP54529098A patent/JP2001524960A/en active Pending
- 1998-04-22 CA CA002287487A patent/CA2287487A1/en not_active Abandoned
- 1998-04-22 WO PCT/GB1998/001161 patent/WO1998047513A1/en not_active Ceased
- 1998-04-22 EP EP98917425A patent/EP0977572A1/en not_active Withdrawn
- 1998-04-22 AU AU70657/98A patent/AU744261B2/en not_active Ceased
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0577394A1 (en) * | 1992-06-29 | 1994-01-05 | Merck & Co. Inc. | Morpholine and thiomorpholine tachykinin receptor antagonists |
| WO1996024353A1 (en) * | 1995-02-10 | 1996-08-15 | Eli Lilly And Company | Methods of treating or preventing psychiatric disorders |
| WO1996037207A2 (en) * | 1995-05-25 | 1996-11-28 | Biofrontiers, Inc. | Pharmaceutical compositions containing calcium sulfate |
Also Published As
| Publication number | Publication date |
|---|---|
| JP2001524960A (en) | 2001-12-04 |
| WO1998047513A1 (en) | 1998-10-29 |
| CA2287487A1 (en) | 1998-10-29 |
| AU7065798A (en) | 1998-11-13 |
| EP0977572A1 (en) | 2000-02-09 |
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| FGA | Letters patent sealed or granted (standard patent) | ||
| MK14 | Patent ceased section 143(a) (annual fees not paid) or expired |