AU7065798A - Use of nk-1 receptor antagonists for treating eating disorders - Google Patents

Use of nk-1 receptor antagonists for treating eating disorders Download PDF

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AU7065798A
AU7065798A AU70657/98A AU7065798A AU7065798A AU 7065798 A AU7065798 A AU 7065798A AU 70657/98 A AU70657/98 A AU 70657/98A AU 7065798 A AU7065798 A AU 7065798A AU 7065798 A AU7065798 A AU 7065798A
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Franz F Hefti
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Organon Pharma UK Ltd
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Merck Sharp and Dohme Ltd
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    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
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    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
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    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/438—The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A—HUMAN NECESSITIES
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/451—Non condensed piperidines, e.g. piperocaine having a carbocyclic group directly attached to the heterocyclic ring, e.g. glutethimide, meperidine, loperamide, phencyclidine, piminodine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
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    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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    • A61K31/66—Phosphorus compounds
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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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 5 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 10 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 15 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 20 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 25 Journal, 301:835-837 (1990). Bulimia nervosa is characterised by recurrent episodes of overeating, or binges, followed by severe dieting often associated with self induced vomiting, abuse of laxatives or diuretics, or excessive exercise to avoid weight gain. Frequent vomiting or purging may result in electrolyte 30 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 5 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 10 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, 15 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 20 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). 25 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 30 also provide for a rapid onset of action to combat eating disorders thereby enabling prescription on an "as-needed" basis.
WO 98/47513 PCT/GB98/01161 -3 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 a NK-1 5 receptor antagonist for the manufacture of a medicament for the treatment or prevention of eating disorders. The present invention also provides a method for the treatment or prevention of eating disorders, which method comprises administration to a patient in need of such treatment an effective amount of a NK-1 receptor 10 antagonist. In a further aspect of the present invention, there is provided a pharmaceutical composition for the treatment or prevention of eating disorders comprising a NK-1 receptor antagonist, together with at least one pharmaceutically acceptable carrier or excipient. 15 In a further embodiment of the present invention there is provided the use of a NK-1 receptor antagonist for the manufacture of a medicament for the treatment or prevention of obesity. The present invention also provides a method for the treatment or prevention of obesity, which method comprises administration to a patient 20 in need of such treatment an effective amount of a NK-1 receptor antagonist. In an alternative embodiment of the present invention there is provided the use of a NK-1 receptor antagonist for the manufacture of a medicament for the treatment or prevention of bulimia nervosa. 25 The present invention also provides a method for the treatment or prevention of bulimia nervosa, which method comprises administration to a patient in need of such treatment an effective amount of a NK-1 receptor antagonist. In a further embodiment of the present invention there is provided 30 the use of a NK-1 receptor antagonist for the manufacture of a WO 98/47513 PCT/GB98/01161 -4 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 5 administration to a patient in need of such treatment an effective amount of a NK-1 receptor antagonist. In an alternative embodiment of the present invention there is provided the use of a NK-1 receptor antagonist for the manufacture of a medicament for reducing the total body fat mass in an obese mammal, 10 especially a human. The present invention also provides a method for reducing the total body fat mass in an obese mammal, especially a human, which method comprises administration to a patient in need of such treatment an effective amount of a NK-1 receptor antagonist. 15 The present invention further provides the use of a NK-1 receptor antagonist and an anorectic agent for the manufacture of a medicament for the treatment or prevention of eating disorders. The present invention also provides a method for the treatment or prevention of eating disorders, which method comprises administration to 20 a patient in need of such treatment an amount of a NK-1 receptor antagonist and an amount of an anorectic agent, such that together they give effective relief. In a further aspect of the present invention, there is provided a pharmaceutical composition comprising a NK-1 receptor antagonist and an 25 anorectic agent, together with at least one pharmaceutically acceptable carrier or excipient. It will be appreciated that the NK-1 receptor antagonist and anorectic agent may be present as a combined preparation for simultaneous, separate or sequential use for the treatment or prevention 30 of eating disorders. Such combined preparations may be, for example, in the form of a twin pack.
WO 98/47513 PCT/GB98/01161 -5 In a further or alternative aspect of the present invention, there is therefore provided a product comprising a NK-1 receptor antagonist and an anorectic agent as a combined preparation for simultaneous, separate or sequential use in the treatment or prevention of eating disorders. 5 In a further embodiment of the present invention there is provided the use of a NK-1 receptor antagonist and an anorectic agent for the manufacture of a medicament for the treatment or prevention of obesity. The present invention also provides a method for the treatment or prevention of obesity, which method comprises administration to a patient 10 in need of such treatment an amount of a NK-1 receptor antagonist and an amount of an anorectic agent, such that together they give effective relief. It will be appreciated that the NK-1 receptor antagonist and anorectic agent may be present as a combined preparation for simultaneous, separate or sequential use for the treatment or prevention 15 of obesity. Such combined preparations may be, for example, in the form of a twin pack. In a further or alternative aspect of the present invention, there is therefore provided a product comprising a NK-1 receptor antagonist and an anorectic agent as a combined preparation for simultaneous, separate 20 or sequential use in the treatment or prevention of obesity. In an alternative embodiment of the present invention there is provided the use of a NK-1 receptor antagonist and an anorectic agent for the manufacture of a medicament for the treatment or prevention of bulimia nervosa. 25 The present invention also provides a method for the treatment or prevention of bulimia nervosa, which method comprises administration to a patient in need of such treatment an amount of a NK-1 receptor antagonist and an amount of an anorectic agent, such that together they give effective relief. 30 It will be appreciated that the NK-1 receptor antagonist and anorectic agent may be present as a combined preparation for WO 98/47513 PCT/GB98/01161 -6 simultaneous, separate or sequential use for the treatment or prevention of bulimia nervosa. Such combined preparations may be, for example, in the form of a twin pack. In a further or alternative aspect of the present invention, there is 5 therefore provided a product comprising a NK-1 receptor antagonist and an anorectic agent as a combined preparation for simultaneous, separate or sequential use in the treatment or prevention of bulimia nervosa. In a further embodiment of the present invention there is provided the use of a NK-1 receptor antagonist and an anorectic agent for the 10 manufacture of a medicament for the treatment or prevention of compulsive eating disorders. The present invention also provides a method for the treatment or prevention of compulsive eating disorders, which method comprises administration to a patient in need of such treatment an amount of a NK-1 15 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 20 of compulsive eating disorders. Such combined preparations may be, for example, in the form of a twin pack. In a further or alternative aspect of the present invention, there is therefore provided a product comprising a NK-1 receptor antagonist and an anorectic agent as a combined preparation for simultaneous, separate 25 or sequential use in the treatment or prevention of compulsive eating disorders. In an alternative embodiment of the present invention there is provided the use of a NK-1 receptor antagonist and an anorectic agent for the manufacture of a medicament for reducing the total body fat mass in 30 an obese mammal, especially a human.
WO 98/47513 PCT/GB98/01161 -7 The present invention also provides a method for reducing the total body fat mass in an obese mammal, especially a human, which method comprises administration to a patient in need of such treatment an amount of a NK-1 receptor antagonist and an amount of an anorectic 5 agent, such that together they give effective relief. It will be appreciated that the NK-1 receptor antagonist and anorectic agent may be present as a combined preparation for simultaneous, separate or sequential use for reducing the total body fat mass in an obese mammal, especially a human. Such combined 10 preparations may be, for example, in the form of a twin pack. In a further or alternative aspect of the present invention, there is therefore provided a product comprising a NK-1 receptor antagonist and an anorectic agent as a combined preparation for simultaneous, separate or sequential use in reducing the total body fat mass in an obese mammal, 15 especially a human. It will be appreciated that when using a combination of the present invention, both the NK-1 receptor antagonist and the anorectic agent will be administered to a patient, within a reasonable period of time. The compounds may be in the same pharmaceutically acceptable carrier and 20 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 25 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 30 10 seconds.
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 5 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. 10 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 15 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 20 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 25 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 30 treatment is expected to prevent, or to prevent the progression of, the medical sequelae of obesity, such as, e.g., arteriosclerosis, Type II diabetes, WO 98/47513 PCT/GB98/01161 -9 polycycstic ovarian disease, cardiovascular diseases, osteoarthritis, dermatological disorders, hypertension, insulin resistance, hypercholesterolemia, hypertriglyceridemia, and cholelithiasis. Thus, in one aspect, this invention relates to the inhibition and/or 5 complete suppression of lipogenesis in obese mammals, i.e., the excessive accumulation of lipids in fat cells, which is one of the major features of human and animal obesity, as well as loss of total body weight. In another aspect, the invention ameliorates the conditions that are a consequence of the disease, such as preventing or arresting the progression of polycystic 10 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, e.g., one with adult-onset diabetes or Type II diabetes. "Mammals" include animals of economic importance such as bovine, 15 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 20 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 25 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, 30 dextroamphetamine, diethylpropion, diphemethoxidine, N ethylamphetamine, fenbutrazate, fenfluramine, fenisorex, fenproporex, WO 98/47513 PCT/GB98/01161 - 10 fludorex, fluminorex, furfurylmethylamphetamine, levamfetamine, levophacetoperane, mazindol, mefenorex, metamfepramone, methamphetamine, norpseudoephedrine, pentorex, phendimetrazine, phenmetrazine, phentermine, phenylpropanolamine, picilorex and 5 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, 10 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 15 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 20 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, 25 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, 30 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, 5 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, 10 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 15 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 (I): 34 X R RxNR (i) 1 R N
R
5 20 R or a pharmaceutically acceptable salt thereof, wherein:
R
1 is selected from the group consisting of: (1) hydrogen; (2) Cl_6alkyl, unsubstituted or substituted with one or more of the 25 substituents selected from: (a) hydroxy, (b) oxo, (c) Ci-ealkoxy, WO 98/47513 PCT/GB98/01161 - 12 (d) phenyl-C1.3alkoxy, (e) phenyl, (f) -CN, (g) halo, 5 (h) -NR 9 R'o, wherein R 9 and R 1 O are independently selected from: (i) hydrogen, (ii) CI-Galkyl, (iii) hydroxy-C.Galkyl, and 10 (iv) phenyl, (i) -NR 9 COR1o, wherein R 9 and RI o are as defined above, (j) -NR 9
CO
2 R1O, wherein R 9 and RIO are as defined above, (k) -CONR 9
R
1 o, wherein R 9 and RI o are as defined above, (1) -COR 9 , wherein R 9 is as defined above, 15 (m) -CO 2
R
9 , wherein R 9 is as defined above, (n) heterocycle, wherein the heterocycle is selected from the group consisting of: (A) benzimidazolyl, (B) benzofuranyl, 20 (C) benzthiophenyl, (D) benzoxazolyl, (E) furanyl, (F) imidazolyl, (G) indolyl, 25 (H) isoxazolyl, (I) isothiazolyl, (J) oxadiazolyl, (K) oxazolyl, (L) pyrazinyl, 30 (M) pyrazolyl, (N) pyridyl, WO 98/47513 PCT/GB98/01161 - 13 (0) pyrimidyl, (P) pyrrolyl, (Q) quinolyl, (R) tetrazolyl, 5 (S) thiadiazolyl, (T) thiazolyl, (U) thienyl, (V) triazolyl, (W) azetidinyl, 10 (X) 1,4-dioxanyl, (Y) hexahydroazepinyl, (Z) oxanyl, (AA) piperazinyl, (AB) piperidinyl, 15 (AC) pyrrolidinyl, (AD) tetrahydrofuranyl, and (AE) tetrahydrothienyl, and wherein the heterocylcle is unsubstituted or substituted with one or more substituent(s) selected from: 20 (i) C1.
6 alkyl, unsubstituted or substituted with halo, -CF 3 ,
-OCH
3 , or phenyl, (ii) Cl.6alkoxy, (iii) oxo, (iv) hydroxy, 25 (v) thioxo, (vi) -SR 9 , wherein R 9 is as defined above, (vii) halo, (viii) cyano, (ix) phenyl, 30 (x) trifluoromethyl, WO 98/47513 PCT/GB98/01161 - 14 (xi) -(CH 2 )m-NR9R1O, wherein m is 0, 1 or 2, and R 9 and RiO are as defined above, (xii) -NR9COR1o, wherein R 9 and Rio are as defined above, (xiii) -CONR9R 1 o, wherein R 9 and RIO are as defined above, 5 (xiv) -CO 2
R
9 , wherein R 9 is as defined above, and (xv) -(CH2)m-OR 9 , wherein m and R 9 are as defined above; (3) C 2 -6alkenyl, unsubstituted or substituted with one or more of the substituent(s) selected from: (a) hydroxy, 10 (b) oxo, (c) Cl_6alkoxy, (d) phenyl-C1-3alkoxy, (e) phenyl, (f) -CN, 15 (g) halo, (h) -CONR 9
R
1 o, wherein R 9 and RIO are as defined above, (i) -COR 9 , wherein R 9 is as defined above, (j) -C0 2
R
9 , wherein R 9 is as defined above, (k) heterocycle, wherein the heterocycle is as defined 20 above; (4) C 2 -6alkynyl; (5) phenyl, unsubstitued or substituted with one or more of the substituent(s) selected from: (a) hydroxy, 25 (b) C1-6alkoxy, (c) C1-alkyl, (d) C2.5alkenyl, (e) halo, (f) -CN, 30 (g) -NO 2 , (h) -CF 3
,
WO 98/47513 PCT/GB98/01161 -15 (i) -(CH2)m-NR 9
R
1 0 , wherein m, R 9 and Rio 1 are as defined above, (j) -NR 9
COR
1 0 , wherein R 9 and RiO are as defined above, (k) -NR 9
CO
2
R
1 0 , wherein R 9 and RIO are as defined above, 5 (1) -CONR9R 1 o, wherein R 9 and RI o are as defined above, (m) -CO 2
NR
9 R1O, wherein R 9 and RI o are as defined above, (n) -COR 9 , wherein R 9 is as defined above, (0) -CO 2
R
9 , wherein R 9 is as defined above; 10 R 2 and R 3 are independently selected from the group consisting of: (1) hydrogen; (2) Ci- 6 alkyl, unsubstituted or substituted with one or more of the substituents selected from: (a) hydroxy, 15 (b) oxo, (c) Cl.-6alkoxy, (d) phenyl-Cl-3alkoxy, (e) phenyl, (f) -CN, 20 (g) halo, (h) -NR 9 R'o, wherein R 9 and RIO are independently selected from: (i) -NROCORIo, wherein R 9 and R 1 O are as defined above, (j) -NR 9
CO
2 RIO, wherein R 9 and Rio are as defined above, 25 (k) -CONR 9
R
1 o, wherein R 9 and RiO are as defined above, (1) -COR 9 , wherein R 9 is as defined above, and (m) -CO 2
R
9 , wherein R 9 is as defined above; (3) C2-6alkenyl, unsubstituted or substituted with one or more of the substituent(s) selected from: 30 (a) hydroxy, (b) oxo, WO 98/47513 PCT/GB98/01161 - 16 (c) C1.
6 alkoxy, (d) phenyl-Cl3.aalkoxy, (e) phenyl, (f) -CN, 5 (g) halo, (h) -CONR 9
R
1 o wherein R 9 and R 1 O are as defined above, (i) -COR 9 , wherein R 9 is as defined above, (j) -CO 2
R
9 , wherein R 9 is as defined above; (4) C 2
-
6 alkynyl; 10 (5) phenyl, unsubstituted or substituted with one or more of the substituent(s) selected from: (a) hydroxy, (b) C1.6alkoxy, (c) C1.calkyl, 15 (d) C 2 -5alkenyl, (e) halo, (f) -CN, (g) -NO 2 , (h) -CF 3 , 20 (i) -(CH 2 )m-NR 9
R
1 0 , wherein m, R 9 and RIO are as defined above, (j) -NR 9
COR
1 0 , wherein R 9 and R 1 O are as defined above, (k) -NR 9
CO
2 Rl 0 , wherein R 9 and R 1 O are as defined above, (1) -CONR 9 R1o, wherein R 9 and RIO are as defined above, 25 (m) -CO 2
NR
9 R1o, wherein R 9 and RIO are as defined above, (n) -COR 9 , wherein R 9 is as defined above, (0) -C0 2
R
9 , wherein R 9 is as defined above; and the groups R 1 and R 2 may be joined together to form a heterocyclic 30 ring selected from the group consisting of: (a) pyrrolidinyl, WO 98/47513 PCT/GB98/01161 - 17 (b) piperidinyl, (c) pyrrolyl, (d) pyridinyl, (e) imidazolyl, 5 (f) oxazolyl, and (g) thiazolyl, and wherein the heterocyclic ring is unsubstituted or substituted with one or more substituent(s) selected from: (i) C1-6alkyl, 10 (ii) oxo, (iii) C1.
6 alkoxy, (iv) -NR 9 R1O, wherein R 9 and R 10 are as defined above, (v) halo, and (vi) trifluoromethyl; 15 and the groups R 2 and R 3 may be joined together to form a carbocyclic ring selected from the group consisting of: (a) cyclopentyl, (b) cyclohexyl, 20 (c) phenyl, and wherein the carbocyclic ring is unsubstituted or substituted with one or more substituents selected from: (i) Ci-6alkyl, (ii) C1-6alkoxy, 25 (iii) -NR 9
R
1 o, wherein R 9 and R 10 are as defined above, (iv) halo, and (v) trifluoromethyl; and the groups R 2 and R 3 may be joined together to form a heterocyclic 30 ring selected from the group consisting of: (a) pyrrolidinyl, WO 98/47513 PCT/GB98/01161 - 18 (b) piperidinyl, (c) pyrrolyl, (d) pyridinyl, (e) imidazolyl, 5 (f) furanyl, (g) oxazolyl, (h) thienyl, and (i) thiazolyl, and wherein the heterocyclic ring is unsubstituted or substituted with one 10 or more substituent(s) selected from: (i) CI-6alkyl, (ii) oxo, (iii) Cl-6alkoxy, (iv) -NR9R1IO, wherein R 9 and Rio are as defined above, 15 (v) halo, and (vi) trifluoromethyl; X is selected from the group consisting of: (1) -0-, 20 (2) -S-, (3) -SO-, and (4) -SO 2 -;
R
4 is selected from the group consisting of: 25 (1)
R
6 Y\ Z R (2) -Y-CIsalkyl, wherein alkyl is unsubstituted or substituted with one or more of the substituents selected from: WO 98/47513 PCT/GB98/01161 - 19 (a) hydroxy, (b) oxo, (c) C1-6alkoxy, (d) phenyl-Cl-3alkoxy, 5 (e) phenyl, (f) -CN, (g) halo, (h) -NR 9 R10, wherein R 9 and RO10 are as defined above, (i) -NR9CORiO, wherein R 9 and Rio are as defined above, 10 (j) -NR9CO 2 RiO, wherein R 9 and Rio are as defined above, (k) -CONRR1O, wherein R 9 and Rio are as defined above, (1) -COR 9 , wherein R 9 is as defined above, (m) -C0 2
R
9 , wherein R 9 is as defined above; (3) -Y-C2-6alkenyl, wherein the alkenyl is unsubstituted or 15 substituted with one or more of the substituent(s) selected from: (a) hydroxy, (b) oxo, (c) CI-6alkoxy, (d) phenyl-Ci_ 3 alkoxy, 20 (e) phenyl, (f) -CN, (g) halo, (h) -CONRRO, wherein R 9 and Rio are as defined above, (i) -COR 9 , wherein R 9 is as defined above, 25 (j) -CO 2
R
9 , wherein R 9 is as defined above, (4) -O(CO)-phenyl, wherein the phenyl is unsubstituted or substituted with one or more of R 6 , R 7 and R 8 ;
R
5 is selected from the group consisting of: 30 (1) phenyl, unsubstituted or substituted with one or more of R 11 , R 12 and R 13
;
WO 98/47513 PCT/GB98/01161 - 20 (2) C1.salkyl, unsubstituted or substituted with one or more of the substituent(s) selected from: (a) hydroxy, (b) oxo, 5 (c) C1.6alkoxy, (d) phenyl-Ci.3alkoxy, (e) phenyl, (f) -CN, (g) halo, 10 (h) -NR 9
R
1 o, wherein R 9 and RI o are as defined above, (i) -NR9CORiO, wherein R 9 and Rio are as defined above, (j) -NR 9
CO
2
R
1 IO, wherein R 9 and RIO are as defined above, (k) -CONR 9 R'o, wherein R 9 and Rio are as defined above, (1) -COR 9 , wherein R 9 is as defined above, 15 (m) -CO 2
R
9 , wherein R 9 is as defined above; (3) C2-6alkenyl, unsubstituted or substituted with one or more of the substituent(s) selected from: (a) hydroxy, (b) oxo, 20 (c) CI-6alkoxy, (d) phenyl-C1-3alkoxy, (e) phenyl, (f) -CN, (g) halo, 25 (h) -CONR 9 RO, wherein R 9 and Rio are as defined above, (i) -COR 9 , wherein R 9 is as defined above, (j) -C0 2
R
9 , wherein R 9 is as defined above; (4) heterocycle, wherein the heterocycle is as defined above; 30 R 6 , R 7 and R 8 are independently selected from the group consisting of: (1) hydrogen; WO 98/47513 PCT/GB98/01161 -21 (2) C1.Galkyl, unsubstituted or substituted with one or more of the substituents selected from: (a) hydroxy, (b) oxo, 5 (c) C1-6alkoxy, (d) phenyl-Cl-3alkoxy, (e) phenyl, (f) -CN, (g) halo, 10 (h) -NR 9
R
1 o, wherein R 9 and R I0 are as defined above, (i) -NR 9 COR1o, wherein R 9 and R 1 0 are as defined above, (j) -NR 9
CO
2
R
1 O, wherein R 9 and R I0 are as defined above, (k) -CONR 9 R1O, wherein R 9 and R 1 0 are as defined above, (1) -COR 9 , wherein R 9 is as defined above, and 15 (m) -CO 2
R
9 , wherein R 9 is as defined above; (3) C2-6alkenyl, unsubstituted or substituted with one or more of the substituent(s) selected from: (a) hydroxy, (b) oxo, 20 (c) Cl-6alkoxy, (d) phenyl-Cl-3alkoxy, (e) phenyl, (f) -CN, (g) halo, 25 (h) -CONR 9
R
1 o wherein R 9 and R 1 0 are as defined above, (i) -COR 9 wherein R 9 is as defined above, (j) -CO 2
R
9 , wherein R 9 is as defined above; (4) C 2
-
6 alkynyl; (5) phenyl, unsubstituted or substituted with one or more of the 30 substituent(s) selected from: (a) hydroxy, WO 98/47513 PCT/GB98/01161 - 22 (b) C1.
6 alkoxy, (c) C1.6alkyl, (d) C2-5alkenyl, (e) halo, 5 (f) -CN, (g) -NO 2 , (h) -CFa, (i) -(CH2)m-NR 9
R
1 o, wherein m, R 9 and R
I
o are as defined above, 10 (j) -NR 9
COR
1 0 , wherein R 9 and RI o are as defined above, (k) -NR 9
CO
2
R
1 O, wherein R 9 and R 1 O are as defined above, (1) -CONR 9 Ro, wherein R 9 and RIO are as defined above, (m) -C0 2
NR
9
R
1 o, wherein R 9 and RIO are as defined above, (n) -COR 9 , wherein R 9 is as defined above; 15 (o) -CO 2
R
9 , wherein R 9 is as defined above; (6) halo, (7) -CN, (8) -CFa, (9) -NO 2 , 20 (10) -SR 14 , wherein R 14 is hydrogen or Cl5alkyl, (11) -SOR 14 , wherein R 14 is as defined above, (12) -SO 2 Rl 4 , wherein R 14 is as defined above, (13) NR 9 CORIO, wherein R 9 and RIO are as defined above, (14) CONR 9
COR
1 0 , wherein R 9 and RIO are as defined above, 25 (15) NR 9
R
1 o, wherein R 9 and R i o are as defined above, (16) NR 9
CO
2
R
1 0 , wherein R 9 and RIO are as defined above, (17) hydroxy, (18) C 1 .6alkoxy, (19) COR 9 , wherein R 9 is as defined above, 30 (20) CO 2
R
9 , wherein R 9 is as defined above, WO 98/47513 PCT/GB98/01161 - 23 R 11 , R 12 and R 13 are independently selected from the definitions of R 6 , R 7 and R s , or -OX; Y is selected from the group consisting of: 5 (1) a single bond, (2) -0-, (3) -S-, (4) -CO-, (5) -CH 2 -, 10 (6) -CHR 15 -, and (7) -CR1 5
RI
6 -, wherein R 1 5 and R 1 6 are independently selected from the group consisting of: (a) C1.
6 alkyl, unsubstituted or substituted with one or more of the substituents selected from: 15 (i) hydroxy, (ii) oxo, (iii) C1.6alkoxy, (iv) phenyl-C1-3alkoxy, (v) phenyl, 20 (vi) -CN, (vii) halo, (viii) -NR 9 R'o, wherein R 9 and R 1 O are as defined above, (ix) -NR 9 CORIO, wherein R 9 and R 1 O are as defined above, (x) -NR 9
CO
2
RI
o , wherein R 9 and Rio are as defined above, 25 (xi) -CONR 9
RI
o , wherein R 9 and R 1 O are as defined above, (xii) -COR 9 , wherein R 9 is as defined above, and (xiii) -C0 2
R
9 , wherein R 9 is as defined above; (b) phenyl, unsubstituted or substituted with one or more of the substituent(s) selected from: 30 (i) hydroxy, (ii) C1.calkoxy, WO 98/47513 PCT/GB98/01161 - 24 (iii) Ci1oalkyl, (iv) C2.
5 alkenyl, (v) halo, (vi) -CN, 5 (vii) -NO 2 , (viii) -CF 3 , (ix) -(CH2)m-NR 9
R
1 0 , wherein m, R 9 and R 1 O are as defined above, (x) -NR 9
COR
1 O, wherein R 9 and RIO are as defined above, 10 (xi) -NR 9 CO2R 10 , wherein R 9 and R 1 O are as defined above, (xii) -CONR 9 R'o, wherein R 9 and R 1 O are as defined above, (xiii) -CO 2 NR9Rlo, 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 R 9 is as defined above; 15 Z is selected from: (1) hydrogen, (2) C1- 4 alkyl, and (3) hydroxy, with the proviso that if Y is -0-, Z is other than 20 hydroxy, or if Y is -CHR 15 -, then Z and R 1 5 may be joined together to form a double bond. Particularly preferred compounds of formula (I) are those wherein:
R
1 is selected from the group consisting of: (1) C1.6alkyl, substituted with one or more of the substituents 25 selected from: (a) heterocycle, wherein the heterocycle is selected from the group consisting of: (A) benzimidazolyl, (B) imidazolyl, 30 (C) isoxazolyl, (D) isothiazolyl, WO 98/47513 PCT/GB98/01161 - 25 (E) oxadiazolyl, (F) pyrazinyl, (G) pyrazolyl, (H) pyridyl, 5 (I) pyrrolyl, (J) tetrazolyl, (K) thiadiazolyl, (L) triazolyl, and (M) piperidinyl, 10 and wherein the heterocycle is unsubstituted or substituted with one or more substituent(s) selected from: (i) Ci.
6 alkyl, unsubstituted or substituted with halo, -CF 3 ,
-OCH
3 , or phenyl, (ii) CI.6alkoxy, 15 (iii) oxo, (iv) thioxo, (v) cyano, (vi) -SCH 3 , (vii) phenyl, 20 (viii) hydroxy, (ix) trifluoromethyl, (x) -(CH 2 )m-NR 9
R
1 o, wherein m is 0, 1 or 2, and R 9 and RIO areindependently selected from: (I) hydrogen, 25 (II) C1.
6 alkyl, (III) hydroxyCl_<alkyl, and (IV) phenyl, (xi) -NR 9
COR
1 0 , wherein R 9 and R
I
O are as defined above, and 30 (xii) -CONR 9 RIo, wherein R 9 and RIO are as defined above,
R
2 and R 3 are independently selected from the group consisting of: WO 98/47513 PCT/GB98/01161 - 26 (1) hydrogen; (2) Cl-Galkyl (3) C2-6alkenyl, and (5) phenyl; 5 X is -O-;
R
4 is R Y~\ Z R8
R
5 is phenyl, unsubstituted or substituted with halo;
R
6 , R 7 and R 8 are independently selected from the group consisting of: 10 (1) hydrogen, (2) Cl-6alkyl, (3) halo, and (4) -CF 3 ; Y is -O-; and 15 Z is hydrogen or C1- 4 alkyl; and pharmaceutically acceptable salts thereof. Particularly preferred compounds of formula (I) are: 4-(3-(1,2,4-triazolo)methyl)-2(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3(S) phenyl-morpholine; 20 4-(3-(1,2,4-triazolo)methyl)-2(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3(R) phenyl-morpholine; 4-(3-(5-oxo- 1H,4H-1,2,4-triazolo)methyl)-2(S)-(3,5 bis(trifluoromethyl)benzyloxy)-3(S)-phenyl-morpholine; and 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl) 25 4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)morpholine; or a pharmaceutically acceptable salt thereof.
WO 98/47513 PCT/GB98/01161 - 27 Further preferred NK-1 receptor antagonists are those described in International (PCT) Patent Specification No. WO 95/18124, i.e. compounds of formula (II): R 9a 0 0 R3 R I IRR (II)
R
9 b N 4 R R 5 5 or a pharmaceutically acceptable salt or prodrug thereof, wherein
R
1 is hydrogen, halogen, C1.
6 alkyl, C1.6alkoxy, CF3, NO 2 , CN, SRa, SORa, SO 2 Ra, CO 2 Ra, CONRaRb, C2.6alkenyl, C2.Galkynyl or Cl-4alkyl substituted by Cl.4alkoxy, where Ra and Rb each independently represent 10 hydrogen or C1-4alkyl;
R
2 is hydrogen, halogen, C1.-6alkyl, C.6alkoxy substituted by C14alkoxy or CF 3 ;
R
3 is hydrogen, halogen or CF 3 ;
R
4 is hydrogen, halogen, C1-Galkyl, C1-6alkoxy, CF 3 , NO 2 , CN, SRa, 15 SORa, SO 2 Ra, CO 2 Ra, CONRaRb, C2-Galkenyl, C2-6alkynyl or C1.4alkyl substituted by Cl-4alkoxy, where Ra and Rb each independently represent hydrogen or CI.4alkyl;
R
5 is hydrogen, halogen, C1.cGalkyl, C1.alkoxy substituted by C1-4alkoxy or CF 3 ; 20 R G is a 5-membered or 6-membered heterocyclic ring containing 2 or 3 nitrogen atoms optionally substituted by =0, =S or a C1.4alkyl group, and optionally substituted by a group of the formula ZNRTR 8 where Z is C1.6alkylene or C3-6cycloalkylene;
R
7 is hydrogen, C1-4alkyl, Ca.-7cycloalkyl or C3-7cycloalkylC1.i 4 alkyl, or 25 C2.
4 alkyl substituted by C1-4alkoxy or hydroxyl; WO 98/47513 PCT/GB98/01161 - 28 R 8 is hydrogen, C1.4alkyl, C3-7cycloalkyl or C3-7cycloalkylCl-4alkyl, or
C
2
-
4 alkyl substituted by one or two substituents selected from C1-4alkoxy, hydroxyl or a 4, 5 or 6 membered heteroaliphatic ring containing one or two heteroatoms selected from N, 0 and S; 5 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 10 Rc is C1.4alkyl 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 ring of 4 to 7 ring atoms which may optionally contain an 15 oxygen ring atom; R9a and R9b are each independently hydrogen or C1- 4 alkyl, 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 20 by oxo; and Y is a C1-4alkyl group optionally substituted by a hydroxyl group; with the proviso that if Y is C1-4alkyl, R 6 is susbstituted at least by a group of formula ZNRTR 8 as defined above. Particularly preferred compounds of formula (II) are those of 25 formula (IHa) and pharmaceutically acceptable salts thereof: WO 98/47513 PCT/GB98/01161 - 29 A Y
K
0 0 A N
R
6
A
3 R 6'- x (IIa) wherein: A' is fluorine or CF 3 ;
A
2 is fluorine or CF 3 ; 5 A 3 is fluorine or hydrogen; and X, Y and R 6 are as defined in relation to formula (II). Particularly preferred compounds of formula (II) include: 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(5-(dimethylamino) methyl-1,2,3-triazol-4-yl)methyl-3-(S)-phenylmorpholine; 10 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(5-(dimethylamino) methyl-1,2,3-triazol-4-yl)methyl-3-(S)-(4-fluorophenyl)morpholine; and pharmaceutically acceptable salts thereof. Further preferred NK-1 receptor antagonists are those described in European Patent Specification No. WO 95/23798, i.e. compounds of 15 formula (III):
R
6 37 R X Y R R 8 2 Z R (III) R N -IR (O)p A
R
3
R'
2 B R or a pharmaceutically acceptable salt thereof, wherein: WO 98/47513 PCT/GB98/01161 - 30 R 2 and R 3 are independently selected from the group consisting of: (1) hydrogen, (2) C1.6alkyl, unsubstituted or substituted with one or more of the substituents selected from: 5 (a) hydroxy, (b) oxo, (c) Ci-6alkoxy, (d) phenyl-CIa-3alkoxy, (e) phenyl, 10 (f) -CN, (g) halo, (h) -NR 9
R
1 o, wherein R 9 and RIO are independently selected from: (i) hydrogen, 15 (ii) Ci-alkyl, (iii) hydroxy-C1.6alkyl, and (iv) phenyl, (i) -NR 9
COR
1 0 , wherein R 9 and R 1 O are as defined above, (j) -NRgCO 2 R1O, wherein R 9 and Rio are as defined above, 20 (k) -CONR 9 R1o, wherein R 9 and RIO are as defined above, (1) -COR 9 , wherein R 9 is as defined above, and (m) -C0 2
R
9 , wherein R 9 is as defined above; (3) C'2-6alkenyl, unsubstituted or substituted with one or more of the substituent(s) selected from: 25 (a) hydroxy, (b) oxo, (c) C1-alkoxy, (d) phenyl-Cl.aalkoxy, (e) phenyl, 30 (f) -CN, (g) halo, WO 98/47513 PCT/GB98/01161 -31 (h) -CONR 9
R
1 0 wherein R 9 and Rio are as defined above, (i) -COR 9 wherein R 9 is as defined above, (j) -CO 2
R
9 , wherein R 9 is as defined above; (4) C2-6alkynyl; 5 (5) phenyl, unsubstituted or substituted with one or more of the substituent(s) selected from: (a) hydroxy, (b) C1-galkoxy, (c) CI.6alkyl, 10 (d) C 2 -5alkenyl, (e) halo, (f) -CN, (g) -NO 2 , (h) -CFa, 15 (i) -(CH 2 )m-NR 9
R
1 O, wherein m, R 9 and RI 0 are as defined above, (j) -NR 9
COR
1 IO, wherein R 9 and R
I
O are as defined above, (k) -NR 9
CO
2 RlO, wherein R 9 and Rio are as defined above, (1) -CONR 9 Rio, wherein R 9 and RIO are as defined above, 20 (m) -CO 2 NR9Rlo, wherein R 9 and RI o are as defined above, (n) -COR 9 , wherein R 9 is as defined above, (o) -CO 2
R
9 , wherein R 9 is as defined above; and the groups R 2 and R 3 may be joined together to form a carbocyclic ring 25 selected from the group consisting of: (a) cyclopentyl, (b) cyclohexyl, (c) phenyl, and wherein the carbocyclic ring is unsubstituted or substituted with one 30 or more substituents selected from: (i) CI-Galkyl, WO 98/47513 PCT/GB98/01161 - 32 (ii) C1.6alkoxy, (iii) -NR 9 RIO, wherein R 9 and RiO are as defined above, (iv) halo, and (v) trifluoromethyl; 5 and the groups R 2 and R 3 may be joined together to form a heterocyclic ring selected from the group consisting of: (a) pyrrolidinyl, (b) piperidinyl, 10 (c) pyrrolyl, (d) pyridinyl, (e) imidazolyl, (f) furanyl, (g) oxazolyl, 15 (h) thienyl, and (i) thiazolyl, and wherein the heterocyclic ring is unsubstituted or substituted with one or more substituent(s) selected from: (i) C.-6alkyl, 20 (ii) oxo, (iii) C1_6alkoxy, (iv) -NR 9
R
1 o, wherein R 9 and RIO are as defined above, (v) halo, and (vi) trifluoromethyl; 25
R
6 , R 7 and R 8 are independently selected from the group consisting of: (1) hydrogen; (2) Ci.calkyl, unsubstituted or substituted with one or more of the substituents selected from: 30 (a) hydroxy, (b) oxo, WO 98/47513 PCT/GB98/01161 - 33 (c) C1-6alkoxy, (d) phenyl-Cl-3alkoxy, (e) phenyl, (f) -CN, 5 (g) halo, (h) -NR 9 R'o, wherein R 9 and R
I
O are as defined above, (i) -NR 9 CORi 1 o, wherein R 9 and RI o are as defined above, (j) -NR 9
CO
2
R
1 O, wherein R 9 and R
I
o are as defined above, (k) -CONR 9 R1O, wherein R 9 and Rio are as defined above, 10 (1) -COR 9 , wherein R 9 is as defined above, and (m) -CO 2
R
9 , wherein R 9 is as defined above; (3) C 2 -6alkenyl, unsubstituted or substituted with one or more of the substituent(s) selected from: (a) hydroxy, 15 (b) oxo, (c) C1.-6alkoxy, (d) phenyl-Cl- 3 alkoxy, (e) phenyl, (f) -CN, 20 (g) halo, (h) -CONR 9 R1O wherein R 9 and Rio are as defined above, (i) -COR 9 wherein R 9 is as defined above, (j) -CO2R 9 , wherein R 9 is as defined above; (4) C 2
-
6 alkynyl; 25 (5) phenyl, unsubstituted or substituted with one or more of the substituent(s) selected from: (a) hydroxy, (b) C1.6alkoxy, (c) C1.6alkyl, 30 (d) C2.5alkenyl, (e) halo, WO 98/47513 PCT/GB98/01161 - 34 (f) -CN, (g) -NO 2 , (h) -CF 3 , (i) -(CH2)m-NR 9
R
1 0 , wherein m, R 9 and RIO are as defined 5 above, (j) -NR9COR 1 0 , wherein R 9 and R 1 O are as defined above, (k) -NR 9
CO
2
R
l0 , wherein R 9 and R
I
o are as defined above, (1) -CONR 9 R'o, wherein R 9 and Rio are as defined above, (m) -CO 2
NR
9
R'
l0 , wherein R 9 and Rio are as defined above, 10 (n) -COR 9 , wherein R 9 is as defined above, (o) -C0 2
R
9 , wherein R 9 is as defined above; (6) halo, (7) -CN, (8) -CF 3 , 15 (9) -NO 2 , (10) -SR 14 , wherein R 14 is hydrogen or Ci5.salkyl, (11) -SOR 14 , wherein R 14 is as defined above, (12) -SO 2 Rl 4 , wherein R 14 is as defined above, (13) NR 9 CORIO, wherein R 9 and R 1 O are as defined above, 20 (14) CONR 9 CORIO, wherein R 9 and RIO are as defined above, (15) NR 9
R
1 o, wherein R 9 and RIO are as defined above, (16) NR 9
CO
2
R
1 o, wherein R 9 and R 1 O are as defined above, (17) hydroxy, (18) C 1 .6alkoxy, 25 (19) COR 9 , wherein R 9 is as defined above, (20) CO 2
R
9 , wherein R 9 is as defined above, (21) 2-pyridyl, (22) 3-pyridyl, (23) 4-pyridyl, 30 (24) 5-tetrazolyl, (25) 2-oxazolyl, and WO 98/47513 PCT/GB98/01161 - 35 (26) 2-thiazolyl;
R
1 , R 12 and R 13 are independently selected from the definitions of R 6 , R 7 and R 8 , or -OX; 5 A is selected from the group consisting of: (1) C1.
6 alkyl, unsubstituted or substituted with one or more of the substituents selected from: (a) hydroxy, 10 (b) oxo, (c) C1.6alkoxy, (d) phenyl-Cl_3alkoxy, (e) phenyl, (f) -CN, 15 (g) halo, wherein halo is fluoro, chloro, bromo or iodo, (h) -NR 9 RIO, wherein R 9 and R
I
o are as defined above, (i) -NR9COR1IO, wherein R 9 and RIO are as defined above, (j) -NR 9
CO
2
R
1 o, wherein R 9 and R
I
O are as defined above, (k) -CONR 9
R
1 o, wherein R 9 and R 1 O are as defined above, 20 (1) -COR 9 , wherein R 9 is as defined above, and (m) -C0 2
R
9 , wherein R 9 is as defined above; (2) C 2
-
6 alkenyl, unsubstituted or substituted with one or more of the substituent(s) selected from: 25 (a) hydroxy, (b) oxo, (c) C1-6alkoxy, (d) phenyl-C1.3alkoxy, (e) phenyl, 30 (f) -CN, (g) halo, WO 98/47513 PCT/GB98/01161 - 36 (h) -CONR 9
R
1 0 wherein R 9 and Rio are as defined above, (i) -COR 9 wherein R 9 is as defined above, and (j) -CO 2
R
9 , wherein R 9 is as defined above; and (3) C2-6alkynyl; 5 B is a heterocycle, wherein the heterocycle is selected from the group consisting of: NHN X X H X H N-N N-N N-N N N 0 N 0 N S X H N-N N-N N-N N / / I N S N 0 N ' X H N X N-N N-- N-N N-N N 'N N N N N N XXX WO 98/47513 PCT/GB98/01161 - 37 x H X N=N N O N N N 0 N NXS H X H H N H H / N NI N S NX/ ,X I N 0 N S X X NX N XN IN X N X N N N N I I I X X X and wherein the heterocycle may be substituted in addition to -X with one or more substituent(s) selected from: (i) C-1.6alkyl, unsubstituted or substituted with halo, -CF 3 , 5 -OCHa, or phenyl, (ii) C1.6alkoxy, (iii) oxo, (iv) hydroxy, (v) thioxo, 10 (vi) -SR 9 , wherein R 9 is as defined above, (vii) halo, (viii) cyano, (ix) phenyl, (x) trifluoromethyl, 15 (xi) -(CH 2 )m-NR9R1O, wherein m is 0, 1 or 2, and R 9 and R 1 0 are as defined above, WO 98/47513 PCT/GB98/01161 - 38 (xii) -NR 9 COR1o, wherein R 9 and RIO are as defined above, (xiii) -CONR 9 R'o, wherein R 9 and RIO are as defined above, (xiv) -CO 2
R
9 , wherein R 9 is as defined above, and (xv) -(CH2)m-OR 9 , wherein m and R 9 are as defined above; 5 p is 0 or 1; X is selected from: (a) -PO(OH)O- * M
+
, wherein M + is a pharmaceutically 10 acceptable monovalent counterion, (b) -PO(O-) 2 * 2M+, (c) -PO(O-) 2 * D 2+ , wherein D 2+ is a pharmaceutically acceptable divalent counterion, (d) -CH(R 4 )-PO(OH)O- * M+, wherein R 4 is hydrogen or C1.aalkyl, 15 (e) -CH(R4)-PO(O-) 2 2M +, (f) -CH(R4)-PO(O-) 2
D
2+ , (g) -S0 3 - * M+, (h) -CH(R 4
)-SO
3 - * M+, (i) -CO-CH 2
CH
2 -CO2 • M +, 20 (j) -CH(CH 3
)-O-CO-R
5 , wherein R 5 is selected from the group consisting of: WO 98/47513 PCT/GB98/01161 - 39 (ii) N N R 9 (iii) 0 CO 2
M
+
CO
2
M
+ (iv) O CO 2
M
+ o2' (v) _ +
NH
3
CO
2
M
+ (vi) - 0
CO
2
M
+ C02-M+
CO
2 M
CO
2 M (vii) 0 ; and (k) hydrogen, with the proviso that if p is 0 and none of R u , R12 or R 13 are -OX, then X is other than hydrogen; 5 Y is selected from the group consisting of: (1) a single bond, (2) -0O-, (3) -S-, (4) -CO-, WO 98/47513 PCT/GB98/01161 - 40 (5) -CH 2 -, (6) -CHRI 5 -, and (7) -CR 15
R
16 -, wherein R 15 and RI 6 are independently selected from the group consisting of: 5 (a) C1.
6 alkyl, unsubstituted or substituted with one or more of the substituents selected from: (i) hydroxy, (ii) oxo, (iii) C1.
6 alkoxy, 10 (iv) phenyl-C1.3alkoxy, (v) phenyl, (vi) -CN, (vii) halo, (viii) -NR 9 R'o, wherein R 9 and RIO are as defined above, 15 (ix) -NR9CORi 1 o, wherein R 9 and R 1 O are as defined above, (x) -NR 9
CO
2 R'o, wherein R 9 and Rio are as defined above, (xi) -CONR 9 R'o, 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; 20 (b) phenyl, unsubstituted or substituted with one or more of the substituent(s) selected from: (i) hydroxy, (ii) CI-ealkoxy, (iii) C1-calkyl, 25 (iv) C2-5alkenyl, (v) halo, (vi) -CN, (vii) -NO 2 , (viii) -CF 3 , 30 (ix) -(CH2)m-NR 9
R
1 0 , wherein mn, R 9 and RIO are as defined above, WO 98/47513 PCT/GB98/01161 - 41 (x) -NR9COR1IO, wherein R 9 and RIO are as defined above, (xi) -NR 9
CO
2 R1O, wherein R 9 and RIO are as defined above, (xii) -CONR9R1O, wherein R 9 and Rio are as defined above, (xiii) -CO 2 NR9R1O, wherein R 9 and RI o are as defined above, 5 (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: (1) hydrogen, 10 (2) CI.6alkyl, and (3) hydroxy, with the proviso that if Y is -0-, Z is other than hydroxy, or if Y is -CHR 15 -, then Z and R 15 may be joined together to form a double bond. Particularly preferred compounds of formula (III) are those wherein: 15 R 2 and R 3 are independently selected from the group consisting of: (1) hydrogen, (2) Ci-6alkyl, (3) C 2
_
6 alkenyl, and (4) phenyl; 20 R
G
, R 7 and R 8 are independently selected from the group consisting of: (1) hydrogen, (2) Ci-alkyl, (3) fluoro, (4) chloro, 25 (5) bromo, (6) iodo, and (7) -CF 3 ;
R
11 , R 12 and R 13 are independently selected from the group consisting of: (1) fluoro, 30 (2) chloro, (3) bromo, and WO 98/47513 PCT/GB98/01161 - 42 (4) iodo; A is unsubstituted 1icalkyl; B is selected from the group consisting of: NH X X H X H NN H H N N-N N-N N-N SN 0 N 0 N S X H H XH N-N H X N-N N-N N-N N N S N 0 N NXX X H N X N-N N N-N -/ N N N N x x x H x N- . - N 0 N N 0 I N S H X H H N H H SN N X N N N S 5 X p is 0 or 1; X is selected from: (a) -PO(OH)O- M
+
, wherein M is a pharmaceutically acceptable monovalent counterion, 10 (b) -PO(O-) 2 * 2M + , (c) -PO(O-) 2 * D 2 + , wherein D 2+ is a pharmaceutically acceptable divalent counterion, (d) -CH(R 4
)-PO(OH)O
-
* M
+
, wherein R 4 is hydrogen or C1 3 alkyl, WO 98/47513 PCT/GB98/01161 - 43 (e) -CH(R4)-PO(O-) 2 2M +, (f) -CH(R4)-PO(O-) 2
D
2+, (i) -CO-CH 2
CH
2 -C0 2 - M +, (j) -CH(CH 3
)-O-CO-R
5 , wherein R 5 is selected from the group 5 consisting of: (i) O NH3 + M H2 M (ii) o N OH ' (iii) 0 CO 2 M C02 M (iv) O CO 2
M
+ (v)
OC
O 2
NH
3 SCO 2
M
+ (vi) O
CO
2 M C0 2 M+ CO 2 M
CO
2" M (vii) and Y is -0O-; Z is hydrogen or C1-6alkyl; and pharmaceutically acceptable salts thereof.
WO 98/47513 PCT/GB98/01161 - 44 Particularly preferred compounds of formula (III) include: (1) 2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-4-(3-(5-oxo 1H,4H-1,2,4-triazolo)methyl)morpholine N-oxide; (2) 2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-4-(3-(4 5 (ethoxycarbonyloxy- 1-ethyl)-5-oxo- 1H- 1,2,4 triazolo)methyl)morpholine; (3) 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4 fluorophenyl)-4-(3-(4-monophosphoryl-5-oxo- 1H-1,2,4 triazolo)methyl)morpholine; 10 (4) 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4 fluorophenyl)-4-(3-(1-monophosphoryl-5-oxo- 1H-1,2,4 triazolo)methyl)morpholine; (5) 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4 fluorophenyl)-4-(3-(2-monophosphoryl-5-oxo- 1H-1,2,4 15 triazolo)methyl)morpholine; (6) 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4 fluorophenyl)-4-(3-(5-oxyphosphoryl- 1H-1,2,4 triazolo)methyl)morpholine; (7) 2-(S)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4 20 fluorophenyl)-4-(3-(1-monophosphoryl-5-oxo-4H-1,2,4 triazolo)methyl)morpholine; and pharmaceutically acceptable salts thereof. Further preferred NK-1 receptor antagonists are those described in European Patent Specification No. WO 96/05181, i.e. compounds of 25 formula (IV): WO 98/47513 PCT/GB98/01161 - 45 R y R2 Y\ R O R R N9b (IV)
R
4 R 5 X x wherein X is a group of the formula NRGR 7 or a C- or N-linked imidazolyl 5 ring; Y is hydrogen or C1.
4 alkyl optionally substituted by a hydroxy group;
R
1 is hydrogen, halogen, Ci-salkyl, C1.-alkoxy, CF 3 , NO 2 , CN, SRa, SORa, SO 2 Ra, CO 2 Ra, CONRaRb, C2-Galkenyl, C2-6alkynyl or C1-4alkyl 10 substituted by Cl- 4 alkoxy, wherein Ra and Rb each independently represent hydrogen or C 1
-
4 alkyl;
R
2 is hydrogen, halogen, C1.6alkyl, C1.
6 alkoxy substituted by C1.4alkoxy or CF 3 ;
R
3 is hydrogen, halogen or CF 3 ; 15 R 4 is hydrogen, halogen, C1.6alkyl, C1.6alkoxy, hydroxy, CF 3 , NO 2 , CN, SRa, SORa, SO 2 Ra, CO 2 Ra, CONRaRb, C2-6alkenyl, C2-6alkynyl or C1-4alkyl substituted by C1.4alkoxy, wherein Ra and Rb are as previously defined;
R
5 is hydrogen, halogen, C_6alkyl, Clcalkoxy substituted by 20 C1-4alkoxy or CF 3 ;
R
G is hydrogen, C1.-Galkyl, C3-7cycloalkyl, C3.7cycloalkylCi-4alkyl, phenyl, or C2.
4 alkyl substituted by C1-4alkoxy or hydroxy;
R
7 is hydrogen, Ci-6alkyl, C3.7cycloalkyl, C3-7cycloalkylC1.
4 alkyl, phenyl, or C24alkyl 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, 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 5 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 hydroxyCl-4alkyl, C1.4alkoxyC1-4alkyl, oxo, CORa or CO 2 Ra where Ra is as previously defined; 10 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, C1.4alkyl, hydroxyC1.4alkyl or C1-4alkoxyC1-4alkyl; and 15 R 9 a and R9b are each independently hydrogen or C1.4alkyl, or R 9 a and R9b are joined so, together with the carbon atoms to which they are attached, there is formed a C5- 7 ring; and pharmaceutically acceptable salts thereof. Particularly preferred compounds of formula (IV) are those of 20 formula (IVa) and pharmaceutically acceptable salts thereof: A' Y A 2 O 0(IVa) NZ A 3 x wherein A' is fluorine or CF 3
;
WO 98/47513 PCT/GB98/01161 - 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 (I). Specific compounds of formula (IV) of use in the present invention 5 include: 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl) 4-(4-morpholinobut-2-yn-yl)morpholine; 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(4-N,N dimethylaminobut-2-yn-yl)-3-(S)-(4-fluorophenyl)morpholine; 10 4-(4-azetidinylbut-2-yn-yl)-2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl) ethoxy)-3-(S)-(4-fluorophenyl)morpholine; 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl) 4-(4-imidazolylbut-2-yn-yl)morpholine; 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl) 15 4-(4-(N-methylpiperazinyl)but-2-yn-yl)morpholine; 4-(4-bis(2-methoxyethyl)aminobut-2-yn-yl)-2-(R)-(1-(R)-(3,5 bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)morpholine; 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl) 4-(4-pyrrolidinobut-2-yn-yl)morpholine; 20 3-(S)-(4-fluorophenyl)-2-(R)-(1-(R)-(3-fluoro-5-(trifluoromethyl)phenyl) ethoxy)-4-(4-morpholinobut-2-yn-yl)morpholine; 3-(S)-(4-fluorophenyl)-4-(4-morpholinobut-2-yn-yl)-2-(R)-(1-(R)-(3 (trifluoromethyl)phenyl)ethoxy)morpholine; 4-(4-azetidinylbut-2-yn-yl)-3-(S)-(4-fluorophenyl)-2-(R)-(1-(R)-(3 25 (trifluoromethyl)phenyl)ethoxy)morpholine; 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(4-(N-(2 methoxyethyl)-N-methyl)aminobut-2-yn-yl)-3-(S)-phenylmorpholine; 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(4-(N-cyclopropyl-N (2-methoxyethyl)amino)but-2-yn-yl)-3-(S)-phenylmorpholine; 30 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(4-(N-isopropyl-N-(2 methoxyethyl)amino)but-2-yn-yl)-3-(S)-phenylmorpholine; WO 98/47513 PCT/GB98/01161 - 48 4-(4-(N,N-dimethylamino)but-2-yn-yl)-3-(S)-(4-fluorophenyl)-2-(R)-(1-(S)-(3 fluoro-5-(trifluoromethyl)phenyl-2-hydroxyethoxy)morpholine; 4-(4-azetidinylbut-2yn-yl)-3-(S)-(4-fluorophenyl)-2-(R)-(1-(S)-(3-fluoro-5 (trifluoromethyl)phenyl)-2-hydroxyethoxy)morpholine; 5 2-(R)-(1-(S)-(3,5-bis(trifluoromethyl)phenyl)-2-hydroxyethoxy)-4-(4-(N,N dimethylamino)but-2-yn-yl)-3-(S)-(4-fluorophenyl)morpholine; 4-(4-azetidinylbut-2-yn-yl)-2-(R)-(1-(S)-(3,5-bis(trifluoromethyl)phenyl-2 hydroxyethoxy)-3-(S)-(4-fluorophenyl)morpholine; 4-(4-N-bis(2-methoxy)ethyl-N-methylamino)but-2-yn-yl)-2-(R)-(1-(R)-(3,5 10 bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)morpholine; 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl) 4-(4-(2-(S)-(methoxymethyl)pyrrolidino)but-2-yn-yl)morpholine; 4-(4-(7-azabicyclo[2.2.1]heptano)but-2-yn-yl)-2-(R)-(1-(R)-(3,5 bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)morpholine; 15 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(4 diisopropylaminobut-2-yn-yl)-3-(S)-(4-fluorophenyl)morpholine; 2-(R)-(1-(R)-(3-fluoro-5-(trifluoromethyl)phenyl)ethoxy)-4-(4-(2-(S) (methoxymethyl)pyrrolidino)but-2-yn-yl)-3-(S)-phenylmorpholine; 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl) 20 4-(4-(2-(S)-(hydroxymethyl)pyrrolidino)but-2-yn-yl)morpholine; and pharmaceutically acceptable salts thereof. Another class of NK-1 receptor antagonists of use in the present invention is that described in European Patent Specification No. 0 436 334, i.e. compounds of formula (V): 25 R R R YR 2 (V) N
R
5
R'
WO 98/47513 PCT/GB98/01161 - 49 or a pharmaceutically acceptable salt thereof, 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 5 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 (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 10 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
8 ;
R
1 is hydrogen or C1.salkyl optionally substituted with hydroxy, C1-4alkoxy or fluoro; 15 R 2 is a radical selected from hydrogen, C 1
_
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 20 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, C 1
.
6 alkyl, C1.6alkoxy, trifluoromethyl, amino, C1-6alkylamino, Cl-calkyl-O-CO, Ci-6alkyl-O-CO 25 Cl6alkyl, Ci.
6 alkyl-CO-O, C1-6alkyl-CO-CI-alkyl-O-, C1-Galkyl-CO,
C.
6 alkyl-CO-Cl.
6 alkyl-, di-CI.6alkylamino, -CONH-CI-Galkyl, CI.Galkyl-CO-NH-Cl.Galkyl, -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; 30 R 5 is hydrogen, phenyl or C1.6alkyl; WO 98/47513 PCT/GB98/01161 - 50 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; 5 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; 10 wherein each of said aryl and heteroaryl groups may optionally be substituted with one or more substituents, and said C3-7cycloalkyl may optionally be substituted with one or two substituents, each of said substituents being independently selected from halo, nitro, C1.6alkyl, C1.6alkoxy, trifluoromethyl, amino, CIocalkylamino, -CO-NH- C1-Galkyl, 15 C1.
6 alkyl-CO-NH-C1.6alkyl, -NHCOH and -NHCO-C1.Galkyl;
R
4 and R 7 are each independently selected from hydroxy, halogen, halo, amino, oxo, cyano, methylene, hydroxymethyl, halomethyl, C1-alkylamino, di-Ci-oalkylamino, C1-alkoxy, C1.6alkyl-O-CO, Cl-.alkyl-O-CO-C1-6alkyl, Cl6alkyl-CO-O, Cl.6alkyl-CO-CI.
6 alkyl-O-, 20 Cl.Galkyl-CO-, Cl.6alkyl-CO-CI.6alkyl, and the radicals set forth in the definition of R2;
R
6 is -NHCOR 9 , -NHCH 2
R
9 , S0 2
R
8 or one of the radicals set forth in any of the definitions of R 2 , R 4 and RT;
R
8 is oximino (=NOH) or one of the radicals set forth in any of the 25 definitions of R 2 , R 4 and RT;
R
9 is CI.
6 alkyl, hydrogen, phenyl or phenylC1.6alkyl; with the proviso that (a) when m is 0, R 8 is absent, (b) 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 (c) when R 4 and R 7 are attached to the 30 same carbon atom, then either each of R 4 and R 7 is independently selected from hydrogen, fluoro and C1-6ealkyl, or R 4 and R 7 , together with the carbon WO 98/47513 PCT/GB98/01161 -51 to which they are attached, for a C3.6 saturated carbocyclic ring that forms a spiro compound with the nitrogen-containing ring to which they are attached. A particularly preferred compound of formula (V) is (2S,3S)-cis-3-(2 5 methoxybenzylamino)-2-phenylpiperidine; or a pharmaceutically acceptable salt thereof. Another class of NK-1 receptor antagonists of use in the present invention is that described in International Patent Specification No. WO 93/21155, i.e. compounds of formula (VI): 10 R R 0 N CH-R 1 (VI) Rs1 R R3 R4 R R4 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; 15 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; 20 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. A particularly preferred compound of formula (VI) is (3aS, 4S, 7aS) 25 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-N-CH 2
-C-CH
2
-CH
2 -Am , A (VII) Ar ' 5 wherein Ar represents an optionally substituted mono-, di- or tricyclic aromatic or heteroaromatic group; T represents a bond, a hydroxymethylene group, a
C
1
-
4 alkoxymethylene group or a C1salkylene group; 10 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; 15 R represents hydrogen, C1.4alkyl, 0-Cl4alkoxyCl-4alkyl, or
-C
2
-
4 alkanoyloxyC2-4alkyl; Q represents hydrogen; or Q and R together form a 1,2-ethylene, 1,3-propylene or 1,4 butylene group; 20 Am + represents the radical 1
X
3 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 25 A- represents a pharmaceutically acceptable anion.
WO 98/47513 PCT/GB98/01161 - 53 A particularly preferred compound of formula (VII) is (+) 1-[2-[3 (3,4-dichlorophenyl)- 1- [(3-isopropoxyphenyl)acetyl] -3-piperidinyl] ethyl] -4 phenyl- 1-azabicyclo [2,2,2] octane; or a pharmaceutically acceptable salt, especially the chloride, thereof. 5 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
1 -N X -X- R 4 (VIII) R2-X or a pharmaceutically acceptable salt thereof, wherein 10 R 1 represents an optionally substituted aralkyl, aryloxyalykl, heteroaralkyl, aroyl, heteroaroyl, cycloalkylcarbonyl, aralkanoyl, heteroarylalkanoyl, aralkoxycarbonyl or arylcarbamoyl group or the acyl group of an cc-amino acid optionally N-substituted by a lower alkanoyl or carbamoyl-lower alkanoyl group; 15 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 20 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
X
3 represents carbonyl, oxo-lower alkyl, oxo(aza)-lower alkyl, or an 25 alkyl group optionally substituted by phenyl, hydroxymethyl, optionally esterified or amidated carboxy, or (in other than the a-position) hydroxy. A particularly preferred compound of formula (VIII) is (2R*, 4S*)-2 benzyl- 1-(3,5-dimethylbenzoyl)-N-(4-quinolinylmethyl)-4-piperidineamine; or a pharmaceutically acceptable salt thereof.
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 IR
R
1 -Y-A- N CONHCHCON (IX) R 5 or a pharmaceutically acceptable salt thereof, wherein RI is aryl, or a group of the formula: z Xis CH or N; and 10 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 15 Y is a bond or lower alkenylene. A particularly preferred compound of formula (IX) is the compound of formula (IXa) HO 0 C (IXa) 0 - CH 3 N 3C3 WO 98/47513 PCT/GB98/01161 -55 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 ,%\N R 1 N R H 5 (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 10 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 15 with from one to three fluoro groups, Ci-loalkoxy optionally substituted with from one to three fluoro groups, amino, Cl-ioalkyl-S-, Ci-oalkyl-S(O)-, Clloalkyl-SO2-, phenyl, phenoxy, C 1 .10alkyl-SO 2 NH-, Ci-.oalkyl-SO2NH-Cl-10akyl-, Ci-loalkylamino-diCi-loalkyl-, cyano, hydroxy, cycloalkoxy having 3 to 7 carbon atoms, CI.6alkylamino, C1.edialkylamino, 20 HC(O)NH- and C 1 .10alkyl-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, Cilioalkyl optionally substituted with from one to three fluoro groups and Ci -loalkoxy 25 optionally substituted with from one to three fluoro groups. A particularly preferred compound of formula (X) is (2S,3S)-3-(2 methoxy-5-trifluoromethoxybenzyl) -amino-2-phenylpiperidine; or a pharmaceutically acceptable salt thereof.
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 )x HI N R3 N H I R 4
R
5 (XI) 5 or a pharmaceutically acceptable salt thereof, wherein
R
1 is a CI- 4 alkoxy group;
R
2 is 6 N N NN
R
3 is a hydrogen or halogen atom; 10 R 4 and R may each independently represent a hydrogen or halogen atom, or a C14alkyl, C14alkoxy or trifluoromethyl group;
R
6 is a hydrogen atom, a C-4alkyl, (CH2)mcyclopropyl, -S(O)nC 1 . 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 15 CI- 4 alkyl or acyl group; x represents zero or 1; n represents zero, 1 or 2; and m represents zero or 1. Particularly preferred compounds of formula (XI) are (2-methoxy-5 20 tetrazol-1-yl-benzyl)-([2S,3S]-2-phenyl-piperidin-3-yl)-amine; and [2 methoxy-5-(5-trifluoromethyl-tetrazol-1-yl)-benzyl]-([2S,3S]-2-phenyl piperidin-3-yl)-amine; or a pharmaceutically acceptable salt thereof.
WO 98/47513 PCT/GB98/01161 - 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) R8 R4 R R R -(CH 2 n - C -CH2- N- (CH 2
)
o - R 3 I 12 NH R (CO)p I
(CH
2 ) m R1 (XII) R 5 or a pharmaceutically acceptable salt thereof, wherein m is zero, 1, 2 or 3; n is zero or 1; o is zero, 1 or 2; p is zero or 1; 10 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_ 3 alkoxy, trifluoromethyl, C1.
4 alkyl, phenyl-C1- 3 alkoxy, or C14alkanoyl groups; RI is trityl, phenyl, diphenylmethyl, phenoxy, phenylthio, 15 piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, indolinyl, indolyl, benzothienyl, hexamethyleneiminyl, benzofuranyl, tetrahydropyridinyl, quinolinyl, isoquinolinyl, reduced quinolinyl, reduced isoquinolinyl, phenyl-(Cl-4alkyl)-, phenyl-(C1.4alkoxy)-, quinolinyl-(C.1-4alkyl)-, isoquinolinyl-(C1- 4 alkyl)-, reduced quniolinyl-(C1-4alkyl)-, reduced 20 isoquinolinyl-(C1-4alkyl)-, benzoyl-(C1.3alkyl)-, C1-4alkyl, or -NH-CH 2
-R
5 ; any one of which R 1 groups may be substituted with halo, C14alkyl, C4alkoxy, trifluoromethyl, amino, C1-4alkylamino, di(C 1-4alkyl)amino, or C2-4alkanoylamino; or any one of which RI groups may be substituted with phenyl, 25 piperazinyl, C3-8cycloalkyl, benzyl, C14alkyl, piperidinyl, pyridinyl, WO 98/47513 PCT/GB98/01161 - 58 pyrimidinyl, C 2
-
6 alkanoylamino, pyrrolidinyl, C2-6alkanoyl, or C 1- 4 alkoxycarbonyl; any one of which groups may be substituted with halo, C1.4alkyl, C1.4alkoxy, trifluoromethyl, amino, C1.4alkylamino, di(C1-4alkyl)amino, or 5 C 2
.
4 alkanoylamino; or R 1 is amino, a leaving group, hydrogen, C1.4alkylamino, or di(C 1-.
4 alkyl) amino;
R
5 is pyridyl, anilino-(C1-3alkyl)-, or anilinocarbonyl;
R
2 is hydrogen, C1-4alkyl, C1-4alkylsulfonyl, carboxy-(C1-3alkyl)-, 10 C1- 3 alkoxycarbonyl-(C1-3alkyl)-, or -CO-R 6 ;
R
6 is hydrogen, C1-4alkyl, C1 3 haloalkyl, phenyl, C1-3alkoxy,
C
1
.
3 hydroxyalkyl, amino, C1.4alkylamino, di(C 1.4alkyl)amino, or -(CH2)q-R 7 ; q is zero to 3;
R
7 is carboxy, C1.4alkoxycarbonyl, C1-4alkylcarbonyloxy, amino, 15 C1.
4 alkylamino, di(C1.
4 alkyl)amino, C.l-6alkoxycarbonylamino, or phenoxy, phenylthio, piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, indolinyl, indolyl, benzothienyl, benzofuranyl, quinolinyl, phenyl-(C1-4alkyl)-, quinolinyl-(C1-4alkyl)-, isoquinolinyl-(C1-4alkyl)-, reduced quinolinyl (C1- 4 alkyl)-, reduced isoquinolinyl-(C1.4alkyl)-, benzoyl-C1-3alkyl; 20 any one of which aryl or heterocyclic R 7 groups may be substituted with halo, trifluoromethyl, C-l.4alkoxy, C1- 4 alkyl, amino, C-4alkylamino, di(C1- 4 alkyl)amino, or C2-4alkanoylamino; or any one of which R 7 groups may be substituted with phenyl, piperazinyl, C 3 .scycloalkyl, benzyl, piperidinyl, pyridinyl, pyrimidinyl, 25 pyrrolidinyl, C2- 6 alkanoyl, or C1-4alkoxycarbonyl; any of which groups may be substituted with halo, trifluoromethyl, amino, C1l4alkoxy, C1-4alkyl, C1.4alkylamino, di(C1.4alkyl)amino, or C2-4alkanoylamino;
R
8 is hydrogen or Cl_ 6 alkyl; 30 R 3 is phenyl, phenyl-(CiG6alkyl)-, C 3 scycloalkyl, C5-scycloalkenyl, C1 8 .salkyl, naphthyl, C 2 -8alkenyl, or hydrogen; WO 98/47513 PCT/GB98/01161 - 59 any one or which groups except hydrogen may be substituted with one or two halo, C1- 3 alkoxy, C1.3alkylthio, nitro, trifluoromethyl, or C1-3alkyl groups; and
R
4 is hydrogen or C1.3alkyl; 5 with the proviso that if R 1 is hydrogen or halo, R 3 is phenyl, phenyl-(Ci.-6alkyl)-, C3-8cycloalkyl, C5.8cycloalkenyl, or naphthyl. A particularly preferred compound of formula (XII) is [N-(2 methoxybenzyl)acetylamino]-3-(1H-indol-3-yl)-2-[N-(2-(4-piperidin- 1 yl)piperidin-1-yl)acetylamino]propane; or a pharmaceutically acceptable 10 salt thereof. The preferred compounds of formulae (I), (II), (III) and (IV) will have the 2- and 3-substituents on the morpholine ring in the cis arrangement, the preferred stereochemistry being as shown in the following general formula: 15 R Where the benzyloxy moiety is a-substituted, the preferred stereochemistry of the a-carbon is either (R) when the substituent is an 20 alkyl (e.g. methyl) group or (S) when the substituent is a hydroxyalkyl (e.g. hydroxymethyl) group. Unless otherwise defined herein, suitable alkyl groups include straight-chained and branched alkyl groups containing from 1 to 6 carbon atoms. Typical examples include methyl and ethyl groups, and straight 25 chained 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 - 60 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 5 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. 10 Unless otherwise defined herein, suitable aryl groups include phenyl and naphthyl groups. A particular aryl-C 1 6 alkyl, e.g. phenyl-C1.6alkyl, group is benzyl. Unless otherwise defined herein, suitable heteroaryl groups include pyridyl, quinolyl, isoquinolyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyranyl, 15 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 20 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 25 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 30 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 -61 carboxylic acid group, the present invention also contemplates salts thereof, preferably non-toxic pharmaceutically acceptable salts thereof, such as the sodium, potassium and calcium salts thereof. Suitable pharmaceutically acceptable salts of the anorectic agent of 5 use in the combinations of the present invention include those salts described above in relation to the salts of NK-1 receptor antagonists. The present invention accordingly provides the use of a NK-1 receptor antagonist selected from the compounds of formulae (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI) and (XII), for the manufacture of 10 a medicament for the treatment or prevention of eating disorders. The present invention also provides a method for the treatment or prevention of eating disorders, which method comprises administration to a patient in need of such treatment an effective amount of a NK-1 receptor antagonist selected from the compounds of formulae (I), (II), (III), (IV), (V), 15 (VI), (VII), (VIII), (IX), (X), (XI) and (XII). In a further aspect of the present invention, there is provided a pharmaceutical composition for the treatment or prevention of eating disorders comprising a NK-1 receptor antagonist selected from the compounds of formulae (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), 20 (XI) and (XII), together with at least one pharmaceutically acceptable carrier or excipient. It will be appreciated that the NK-1 receptor antagonist selected from the compounds of formulae (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI) and (XII) may be used in combination with an anorectic 25 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 30 selected from the compounds of formulae (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI) and (XII) and an anorectic agent as a combined WO 98/47513 PCT/GB98/01161 - 62 preparation for simultaneous, separate or sequential use in the treatment or prevention of eating disorders. In a preferred aspect, the present invention accordingly provides the use of a NK-1 receptor antagonist selected from the compounds of formulae 5 (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI) and (XII) and a halogenated amphetamine derivative for the manufacture of a medicament for the treatment or prevention of eating disorders. The present invention also provides a method for the treatment or prevention of eating disorders, which method comprises administration to 10 a patient in need of such treatment an amount of a NK-1 receptor antagonist selected from the compounds of formulae (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI) and (XII) and a halogenated amphetamine derivative such that together they give effective relief. In a further aspect of the present invention, there is provided a 15 pharmaceutical composition comprising a NK-1 receptor antagonist selected from the compounds of formulae (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI) and (XII) and a halogenated amphetamine derivative together with at least one pharmaceutically acceptable carrier or excipient. 20 In a further or alternative aspect of the present invention, there is provided a product comprising a NK-1 receptor antagonist selected from the compounds of formulae (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI) and (XII) and a halogenated amphetamine derivative as a combined preparation for simultaneous, separate or sequential use in the 25 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 30 compounds of formulae (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI) and (XII) and a halogenated amphetamine derivative selected from WO 98/47513 PCT/GB98/01161 - 63 the group consisting of fenfluramine and dexfenfluramine, for the manufacture of a medicament for the treatment or prevention of eating disorders. The present invention also provides a method for the treatment or 5 prevention of eating disorders, which method comprises administration to a patient in need of such treatment an amount of a NK-1 receptor antagonist selected from the compounds of formulae (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI) and (XII) and an amount of a halogenated amphetamine derivative selected from the group consisting of 10 fenfluramine and dexfenfluramine, such that together they give effective relief. In a further aspect of the present invention, there is provided a pharmaceutical composition comprising a NK-1 receptor antagonist selected from the compounds of formulae (I), (II), (III), (IV), (V), (VI), (VII), 15 (VIII), (IX), (X), (XI) and (XII) and a halogenated amphetamine derivative selected from the group consisting of fenfluramine and dexfenfluramine, together with at least one pharmaceutically acceptable carrier or excipient. In a further or alternative aspect of the present invention, there is 20 provided a product comprising a NK-1 receptor antagonist selected from the compounds of formulae (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI) and (XII) and a halogenated amphetamine derivative selected from the group consisting of fenfluramine and dexfenfluramine, as a combined preparation for simultaneous, separate or sequential use in the 25 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. 30 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 - 64 solutions or suspensions, or suppositories, for oral, parenteral or rectal administration, by inhalation or insufflation or administration by trans dermal patches or by buccal cavity absorption wafers. Oral dosage forms are particularly preferred (e.g. tablets, capsules, pills or wafers). 5 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 10 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 15 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 20 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 25 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 30 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 - 65 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 5 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 10 in the form of an emulsion (as a water-in-oil or oil-in-water emulsion). Suitable surface-active agents include, in particular, non-ionic agents, such as polyoxyethylenesorbitans (e.g. TweenTM 20, 40, 60, 80 or 85) and other sorbitans (e.g. Span T M 20, 40, 60, 80 or 85). Compositions with a surface-active agent will conveniently comprise between 0.05 and 15 5% surface-active agent, and preferably between 0.1 and 2.5%. It will be appreciated that other ingredients may be added, for example mannitol or other pharmaceutically acceptable vehicles, if necessary. Suitable emulsions may be prepared using commercially available fat emulsions, such as IntralipidTM, LiposynTM, InfonutrolTM, LipofundinTM 20 and Lipiphysan T M . The active ingredient may be either dissolved in a pre mixed emulsion composition or alternatively it may be dissolved in an oil (e.g. soybean oil, safflower oil, cottonseed oil, sesame oil, corn oil or almond oil) and an emulsion formed upon mixing with a phospholipid (e.g. egg phospholipids, soybean phospholipids or soybean lecithin) and water. It 25 will be appreciated that other ingredients may be added, for example glycerol or glucose, to adjust the tonicity of the emulsion. Suitable emulsions will typically contain up to 20% oil, for example, between 5 and 20%. The fat emulsion will preferably comprise fat droplets between 0.1 and 1.0pm, particularly 0.1 and 0.5pm, and have a pH in the range of 5.5 30 to 8.0.
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 (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI) and (XII) with IntralipidTM or the components thereof (soybean oil, egg 5 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. 10 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, 15 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 20 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 25 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 30 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 - 67 the NK-1 receptor antagonist and the anorectic agent will suitably be between 0.001 to 1 and 1000 to 1, and especially between 0.01 to 1 and 100 to 1. A suitable dosage level for the NK-1 receptor antagonist about 0.05 5 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 10 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 15 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 20 patient's physician or pharmacist. The compounds of formulae (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI) and (XII) may be prepared by the methods described in EP-A-0 577 394 (or WO 95/16679), WO 95/18124, WO 95/23798, WO 96/05181, EP-A-0 436 334, WO 93/21155, EP-A-0 591 040, 25 EP-A-0 532 456, EP-A-0 443 132, WO 92/17449, WO 95/08549 and WO 95/14017, respectively. Particularly preferred NK-1 receptor antagonists of the formulae (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI) and (XII) for use in the present invention are compounds which are potent NK-1 receptor 30 antagonists, i.e. compounds with an NK-1 receptor affinity (IC 5 0 ) 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 (IC 50 ) of less than 10nM, favourably less than 2nM and preferably less than InM. 5 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 10 NK-1 receptor binding assays are performed in intact Chinese hamster ovary (CHO) cells expressing the human NK-1 receptor using a modification of the assay conditions described by Cascieri et al, J. Pharmacol. Exp. Ther., 1992, 42, 458. Typically, the receptor is expressed at a level of 3x10 5 receptors per cell. Cells are grown in monolayer culture, 15 detached from the plate with enzyme-free dissociation solution (Speciality Media Inc.), and washed prior to use in the assay. 12 5 1 -Tyr 8 -substance P (0.1nM, 2000Ci/mmol; New England Nuclear) is incubated in the presence or absence of test compounds (dissolved in 5pd dimethylsulphoxide, DMSO) with 5x10 4 CHO cells. Ligand binding is performed in 0.25ml of 50mM 20 Tris-HC1, pH7.5, containing 5mM MnC1 2 , 150mM NaC1, 0.02% bovine serum albumin (Sigma), 50pg/ml chymostatin (Peninsula), 0. lnM phenylmethylsulphonyl fluoride, 2tg/ml pepstatin, 2pg/ml leupeptin and 2.8ptg/ml furoyl saccharine. The incubation proceeds at room temperature until equilibrium is achieved (>40 minutes) and the receptor-ligand 25 complex is harvested by filtration over GF/C filters pre-soaked in 0.1% polyethylenimine using a Tomtek 96-well harvester. Non-specific binding is determined using excess substance P (1ptM) 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 5 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 10 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 (e.g. pentagastrin) or a 15 selective NK-1 receptor agonist (e.g. GR73632 (d Ala[L-Pro 9 ,Me-LeulO] substance P-(7-11)) is infused directly into the cerebral ventricles (e.g. 3pmol in 5[d i.c.v., depending on test substance) by vertical insertion of a cuffed 27 gauge needle to a depth of 4.5mm below bregma. The scalp incision is closed and the animal allowed to recover from anaesthesia in a 20 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 25 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 30 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 - 70 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 5 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. 10 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 15 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 20 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 25 (or for up to 4 hours following an oral dose, dependent upon the oral pharmacokinetics of the test compound) before social isolation for 15 minutes as described above. The duration and/or number of vocalisation on drug treatment days may be expressed as a percentage of the pre treatment baseline value for each animal or compared with values 30 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 -71 compound at each dose tested. A suitable selection cascade for NK 1 antagonists of use according to the present invention is as follows: 5 (i) Determine affinity for human NK 1 receptor in radioligand binding studies (Assay 1); select compounds with IC 50 < 10nM, preferably
IC
50 so < 2nM, especially ICso _ InM. (ii) Determine ability of compounds to penetrate CNS by their ability to inhibit foot tapping in gerbils induced by central injection of an 10 NK 1 agonist (Assay 2); select compounds that inhibit foot tapping with
ID
50 so 3mg/kg i.v., and preferably ID 50 < Img/kg i.v. when administered immediately prior to central NK 1 agonist challenge, or IDoo 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 15 tapping assay following intravenous administration 24 hours prior to central NK 1 agonist challenge; select compounds showing _ 25-fold loss of potency compared with ID 50 determined in step (ii) above with the proviso that IDso 5 10mg/kg i.v., and preferably _ 5mg/kg i.v. after 24 hour pre-treatment. 20 (iv) Determine oral bioavailability of compounds by pharmacokinetic analysis, activity in gerbil foot tapping assay following oral administration and/or by ability to inhibit cisplatin-induced emesis in ferrets (Assay 3); select compounds with IDoo _ 3mg/kg p.o., and preferably
ID
0 - 1mg/kg p.o. 25 Particularly preferred compounds of use in the present invention are identified using steps (i) to (iv) followed by step (v): (v) Determine activity of compounds in assays sensitive to conventional serotonergic drugs (inhibition of pharmacologically evoked foot tapping in gerbils and/or inhibition of distress vocalisations in guinea- WO 98/47513 PCT/GB98/01161 - 72 pig pups (Assay 4)). Select compounds with ID 50 so 20mg/kg, and preferably
ID
50 < 10mg/kg. Yet further preferred compounds of use in the present invention may be selected from those compounds which satisfy the NK-1 5 receptor binding criteria of step (i) which, in addition, have _ 5-fold shift in affinity when incubated in the presence of human serum albumin (HSA) to show non-specific protein binding. One example of a NK-1 receptor antagonist of use in the present invention is the compound 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl) 10 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: IC5o0=0.lnM gerbil foot-tapping (5 mins.): IDso0=0.36mg/kg i.v. gerbil foot-tapping (24 hrs.): ID5o0=0.33mg/kg i.v. ferret emesis: IDgo<3mg/kg p.o. guinea-pig vocalisation ID 5 o0=0.73mg/kg p.o. (4hrs. pretreatment) 15 Another example of a NK-1 receptor antagonist of use in the present invention is the compound 2-(R)-(1-(R)-(3,5 bis(trifluoromethyl)phenyl)ethoxy)-4-(5-(N,N-dimethylamino)methyl-1,2,3 triazol-4-yl)methyl-3-(S)-phenylmorpholine, the preparation of which is 20 described in International Patent Specification No. WO 95/18124. In the aforementioned assays, this compound has the following activity: human NK-1 receptor binding: ICso0=0.25nM gerbil foot-tapping (5 mins.): ID5o0=0.12mg/kg i.v. gerbil foot-tapping (24 hrs.): ID5o0=0.17mg/kg i.v.
WO 98/47513 PCT/GB98/01161 - 73 guinea-pig vocalisation: ID5o=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. 5 Evaluation of the Interaction of NK-1 Antagonists and Anorectic Agents on Food Intake and Body Weight in Diet-Induced Obese Mice. Mice: 10 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 (70%:30%, vol:vol). Fresh wet chow was provided daily. These mice will be referred to as diet induced obese (DIO). The other half was maintained on just ground rodent 15 chow. These will be referred to as Non-Obese Littermates (NOL). Both food and water were supplied ad libitumn. 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 20 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: 25 (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 o0 = 3 mg/kg, ip). The combined effect that [2-methoxy-5-(5-trifluoromethyl-tetrazol-1-yl)-benzyl] 30 ([2S,3S]-2-phenyl-piperidin-3-yl)amine (GR205171) and dexfenfluramine WO 98/47513 PCT/GB98/01161 - 74 had on food consumption was examined by observing the resulting changes in food intake observed after treatment with dexfenfluramine, GR205171, or combinations of dexfenfluramine with decreasing doses of GR 205171. Mice were randomly assigned to one of the following treatment 5 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 10 * 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 15 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: 20 (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 25 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. 30 WO 98/47513 PCT/GB98/01161 - 75 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. 5 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 15mg of dexfenfluramine Amount mg NK-1 antagonist 50.0 100.0 300.0 dexfenfluramine 15.0 15.0 15.0 Microcrystalline cellulose 80.0 80.0 80.0 Modified food corn starch 80.0 80.0 80.0 Lactose 174.5 124.5 124.5 Magnesium Stearate 0.5 0.5 0.5 10 EXAMPLE 2 Tablets containing 50-300mg of NK-1 antagonist and 60mg of fenfluramine Amount mg NK-1 antagonist 50.0 100.0 300.0 fenfluramine 60.0 60.0 60.0 Microcrystalline cellulose 80.0 80.0 80.0 Modified food corn starch 80.0 80.0 80.0 Lactose 129.5 179.5 129.5 Magnesium Stearate 0.5 0.5 0.5 The active ingredients cellulose, lactose and a portion of the corn 15 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 - 76 then compressed into tablets containing 50mg, 100mg and 300mg of the NK-1 receptor antagonist per tablet. EXAMPLE 3 Parenteral infection 5 Amount Active Ingredients 10 to 300mg Citric Acid Monohydrate 0.75mg Sodium Phosphate 4.5mg Sodium Chloride 9mg 10 Water for injection to 10ml 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 (28)

1. Use of a NK-1 receptor antagonist for the manufacture of a medicament for the treatment or prevention of eating disorders. 5
2. Use according to claim 1 which further comprises the simultaneous, separate or sequential administration of an anorectic agent.
3. A pharmaceutical composition for the treatment or 10 prevention of eating disorders comprising a NK-1 receptor antagonist, together with at least one pharmaceutically acceptable carrier or excipient.
4. A composition according to claim 3 which further comprises 15 an anorectic agent.
5. A product comprising a NK-1 receptor antagonist and an anorectic agent as a combined preparation for simultaneous, separate or sequential use in the treatment or prevention of eating disorders. 20
6. A method for the treatment or prevention of eating disorders, which method comprises administration to a patient in need of such treatment of an effective amount of a NK-1 receptor antagonist. 25
7. A method for the treatment or prevention of eating disorders, which method comprises administration to a patient in need of such treatment of an amount of a NK-1 receptor antagonist and an amount of an anorectic agent, such that together they give effective relief.
8. A use according to claim 1 or 2, a composition according to 30 claim 3 or 4, a product according to claim 5 or a method according to claim 6 or 7 wherein the NK-1 receptor antagonist is a compound of formula I: WO 98/47513 PCT/GB98/01161 - 78 R 3 X R 4 R N R 5 R wherein R 1 is selected from the group consisting of: (1) CI-_alkyl, substituted with one or more of the substituents 5 selected from: (a) heterocycle, wherein the heterocycle is selected from the group consisting of: (A) benzimidazolyl, (B) imidazolyl, 10 (C) isoxazolyl, (D) isothiazolyl, (E) oxadiazolyl, (F) pyrazinyl, (G) pyrazolyl, 15 (H) pyridyl, (I) pyrrolyl, (J) tetrazolyl, (K) thiadiazolyl, (L) triazolyl, and 20 (M) piperidinyl, and wherein the heterocycle is unsubstituted or substituted with one or more substituent(s) selected from: (i) CI. 6 alkyl, unsubstituted or substituted with halo, -CF 3 , -OCH 3 , or phenyl, 25 (ii) CI.calkoxy, (iii) oxo, WO 98/47513 PCT/GB98/01161 - 79 (iv) thioxo, (v) cyano, (vi) -SCH 3 , (vii) phenyl, 5 (viii) hydroxy, (ix) trifluoromethyl, (x) -(CH2)m-NR 9 R 10 , wherein m is 0, 1 or 2, and R 9 and R I O areindependently selected from: (I) hydrogen, 10 (II) Cl-Galkyl, (III) hydroxyCi.oalkyl, and (IV) phenyl, (xi) -NR 9 COR 1 IO, wherein R 9 and RIO are as defined above, and 15 (xii) -CONR 9 R 1 o, wherein R 9 and R 1 O are as defined above, R 2 and R 3 are independently selected from the group consisting of: (1) hydrogen; (2) Ci. 6 alkyl (3) C 2 -6alkenyl, and 20 (5) phenyl; X is -O-; R 4 is R 6 I 8 z R R 5 is phenyl, unsubstituted or substituted with halo; 25 R 6 , R 7 and R 8 are independently selected from the group consisting of: (1) hydrogen, (2) Ci 6 alkyl, (3) halo, and WO 98/47513 PCT/GB98/01161 - 80 (4) -CF 3 ; Y is -O-; and Z is hydrogen or C1_ 4 alkyl; or a pharmaceutically acceptable salt thereof. 5
9. A use according to claim 1 or 2, a composition according to claim 3 or 4, a product according to claim 5 or a method according to claim 6 or 7 wherein the NK-1 receptor antagonist is a compound of formula IIa: A 1 O 00 A 2 NA Iy| R 6 A 10 (IIa) wherein: A' is fluorine or CF 3 ; A 2 is fluorine or CF 3 ; A 3 is fluorine or hydrogen; 15 R 6 is a 5-membered or 6-membered heterocyclic ring containing 2 or 3 nitrogen atoms optionally substituted by =0, =S or a C14alkyl group, and optionally substituted by a group of the formula ZNR 7 R 8 where Z is C1-6alkylene or C3-Gcycloalkylene; R 7 is hydrogen, C1- 4 alkyl, C3-7cycloalkyl or Ca3.7cycloalkylC1.4alkyl, or 20 C2-4alkyl substituted by C1.4alkoxy or hydroxyl; R 8 is hydrogen, C1-4alkyl, C3-7cycloalkyl or C3-7cycloalkylC1. 4 alkyl, or C2-4alkyl substituted by one or two substituents selected from Cl4alkoxy, hydroxyl or a 4, 5 or 6 membered heteroaliphatic ring containing one or two heteroatoms selected from N, O and S; WO 98/47513 PCT/GB98/01161 -81 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 5 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 Cl-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 10 heteroaliphatic ring of 4 to 7 ring atoms which may optionally contain an oxygen ring atom; or a pharmaceutically acceptable salt thereof.
10. A use according to claim 1 or 2, a composition according to 15 claim 3 or 4, a product according to claim 5 or a method according to claim 6 or 7 wherein the NK-1 receptor antagonist is a compound of formula III: R6 R 3 X Y R 7 R2 z R8 (III) (O)p A\ 113 R 12 BR 20 wherein: R 2 and R 3 are independently selected from the group consisting of: (1) hydrogen, (2) CI 6 alkyl, (3) C2- 6 alkenyl, and 25 (4) phenyl; WO 98/47513 PCT/GB98/01161 - 82 R 6 , R 7 and R8 are independently selected from the group consisting of: (1) hydrogen, (2) CI-6alkyl, (3) fluoro, 5 (4) chloro, (5) bromo, (6) iodo, and (7) -CFa; R 11 , R 12 and R 13 are independently selected from the group consisting of: 10 (1) fluoro, (2) chloro, (3) bromo, and (4) iodo; A is unsubstituted 16alkyl; 15 B is selected from the group consisting of: H N-N X X H X H N-N N-N N-N N N 0 N 0 N S X H NH X H X N-N N-N N-N N X X I N S N 0 N S X H N S /X N-N N N-N -N 1) N N N x x WO 98/47513 PCT/GB98/01161 - 83 X H X N N N I N S H X H H N H H N S N XN N N N S x p is 0 or 1; X is selected from: (a) -PO(OH)0- M , wherein M+ is a pharmaceutically 5 acceptable monovalent counterion, (b) -PO(O-) 2 * 2M+, (c) -PO(O-) 2 * D 2+ , wherein D 2 + is a pharmaceutically acceptable divalent counterion, (d) -CH(R 4 )-PO(OH)O- * M+, wherein R 4 is hydrogen or C1-3alkyl, 10 (e) -CH(R4)-PO(O-) 2 2M , (f) -CH(R4)-PO(O-)2 * D2+, (i) -CO-CH 2 CH 2 -CO2 * M +, (j) -CH(CH 3 )-O-CO-R5, wherein R 5 is selected from the group consisting of: WO 98/47513 PCT/GB98/01161 - 84 (i) \o NH 3 M H2 M" (ii) \O N OH ' (iii) O / CO 2 M 0 CO 2 C0 2 -M, (iv) 0 C0 2 M+ Co2 (v) 0 O NH 3 CO 2" M + (vi) - O0 CO 2 M CO 2 M + CO 2 M + (vii) ; and Y is -0O-; Z is hydrogen or C1. 6 alkyl; or a pharmaceutically acceptable salt thereof. 5
11. A use according to claim 1 or 2, a composition according to claim 3 or 4, a product according to claim 5 or a method according to claim 6 or 7 wherein the NK-1 receptor antagonist is a compound of formula IVa: WO 98/47513 PCT/GB98/01161 - 85 A Y \ A2 O .O (N (IVa) NZ / A x X wherein A 1 is fluorine or CFa; 5 A 2 is fluorine or CF 3 ; A 3 is fluorine or hydrogen; X is a group of the formula NRGR 7 or a C- or N-linked imidazolyl ring; Y is hydrogen or C1-4alkyl optionally substituted by a hydroxy 10 group; R 6 is hydrogen, Cl_6alkyl, C3.7cycloalkyl, C37cycloalkylC1-4alkyl, phenyl, or C2. 4 alkyl substituted by C1. 4 alkoxy or hydroxy; R 7 is hydrogen, C1-6alkyl, C3-7cycloalkyl, C3-7cycloalkylCl-4alkyl, phenyl, or C 2 4 alkyl substituted by one or two substituents selected from 15 C1-4alkoxy, hydroxy or a 4, 5 or 6 membered heteroaliphatic ring containing one or two heteroatoms selected from N, O and S; or R 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 20 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 hydroxyC1-4alkyl, C1.4alkoxyC1-4alkyl, oxo, CORa or CO 2 Ra where Ra is hydrogen or C1- 4 alkyl; WO 98/47513 PCT/GB98/01161 - 86 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, C1-4alkyl, hydroxyC1-4alkyl or Cl-4alkoxyC1-4alkyl; 5 or a pharmaceutically acceptable salt thereof.
12. A use according to claim 1 or 2, a composition according to claim 3 or 4, a product according to claim 5 or a method according to claim 6 or 7 wherein the NK-1 receptor antagonist is a compound of formula V: 10 R 7 R RI NN Rs5 R8 - (1) 16 R 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 15 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 RT; Z is (CH2)m wherein m is an integer from 0 to 6, and wherein any 20 one of the carbon-carbon single bonds of (CH 2 )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 Ci.salkyl optionally substituted with hydroxy, 25 C1- 4 alkoxy or fluoro; WO 98/47513 PCT/GB98/01161 - 87 R 2 is a radical selected from hydrogen, C1p- 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, 5 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 C 2 .6alkyl and benzhydryl may optionally be substituted with one or more substituents independently selected from halo, nitro, C1-6 alkyl, C1.6alkoxy, 10 trifluoromethyl, amino, Cl-6alkylamino, C1. 6 alkyl-O-CO, Cl6alkyl-O-CO Cl.6alkyl, C1- 6 alkyl-CO-O, C1.-6alkyl-CO-C1.6alkyl-O-, C-alkyl-CO, Ci.6alkyl-CO-CI- 6 alkyl-, di-Cl-6alkylamino, -CONH-CI-6alkyl, Cl 6 alkyl-CO-NH-C1.6alkyl, -NHCOH and -NHCO-C1. 6 alkyl; and wherein one of the phenyl moieties of said benzhydryl may optionally be replaced 15 by naphthyl, thienyl, furyl or pyridyl; R 5 is hydrogen, phenyl or C1.6alkyl; 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 20 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 25 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, ClI6alkyl, 30 Cp.6alkoxy, trifluoromethyl, amino, Cil 6 alkylamino, -CO-NH- Cic-6alkyl, C 1 6 alkyl-CO-NH-CI-6alkyl, -NHCOH and -NHCO-Ci. 6 alkyl; WO 98/47513 PCT/GB98/01161 - 88 R 4 and R 7 are each independently selected from hydroxy, halogen, halo, amino, oxo, cyano, methylene, hydroxymethyl, halomethyl, C1. 6 alkylamino, di-C1-6alkylamino, C.alkoxy, Ci.6alkyl-O-CO, Cl 6 alkyl-O-CO-C1-6alkyl, C1.6alkyl-CO-O, C1-6alkyl-CO-Cl. 6 alkyl-O-, 5 C1.6alkyl-CO-, Cl-6alkyl-CO-C1.6alkyl, and the radicals set forth in the definition of R 2 ; RG is -NHCOR 9 , -NHCH 2 R 9 , S0 2 R 8 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 10 definitions of R 2 , R 4 and RT; R 9 is Cl.6alkyl, hydrogen, phenyl or phenylC1.6alkyl; with the proviso that (a) when m is 0, R 8 is absent, (b) 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 (c) when R 4 and R 7 are attached to the 15 same carbon atom, then either each of R 4 and R 7 is independently selected from hydrogen, fluoro and Cl.6alkyl, or R 4 and R 7 , together with the carbon to which they are attached, for a C 3 .G saturated carbocyclic ring that forms a spiro compound with the nitrogen-containing ring to which they are attached; 20 or a pharmaceutically acceptable salt thereof.
13. A use according to claim 1 or 2, a composition according to claim 3 or 4, a product according to claim 5 or a method according to claim 6 or 7 wherein the NK-1 receptor antagonist is a compound of formula VI: 25 R R 0 N CH-R (VI) R2 R 3 R wherein: WO 98/47513 PCT/GB98/01161 - 89 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; 5 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; 10 or R 4 and R 5 are OH; or R 4 and R 5 together form a bond; or a pharmaceutically acceptable salt thereof.
14. A use according to claim 1 or 2, a composition according to 15 claim 3 or 4, a product according to claim 5 or a method according to claim 6 or 7 wherein the NK-1 receptor antagonist is a compound of formula VII: R Q Ar-T-CO- -CH 2 -C-CH 2 -CH 2 -Am , A - (VII) Ar ' wherein: 20 Ar represents an optionally substituted mono-, di- or tricyclic aromatic or heteroaromatic group; T represents a bond, a hydroxymethylene group, a C1- 4 alkoxymethylene group or a Cl.5alkylene group; 25 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, C 1 4alkyl where the said substituents may be the same or different; a thienyl group; a benzothienyl group; a naphthyl group; or an indolyl group; WO 98/47513 PCT/GB98/01161 - 90 R represents hydrogen, CI- 4 alkyl, co-C1. 4 alkoxyCl-4alkyl, or w -C 2 - 4 alkanoyloxyC2.4alkyl; Q represents hydrogen; or Q and R together form a 1,2-ethylene, 1,3-propylene or 1,4 5 butylene group; Am + represents the radical 2_ N X 3 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 10 substituted by a phenyl or benzyl group; and A- represents a pharmaceutically acceptable anion.
15. A use according to claim 1 or 2, a composition according to claim 3 or 4, a product according to claim 5 or a method according to claim 15 6 or 7 wherein the NK-1 receptor antagonist is a compound of formula VIII R3 R'-N (VIII) R1 - N Pf--N- Xi--- R'(II) R 2 _X 1 wherein: R 1 represents an optionally substituted aralkyl, aryloxyalykl, heteroaralkyl, aroyl, heteroaroyl, cycloalkylcarbonyl, aralkanoyl, 20 heteroarylalkanoyl, aralkoxycarbonyl or arylcarbamoyl group or the acyl group of an c-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; 25 R 3 represents hydrogen, alkyl, carbamoyl or an alkanoyl or alkenoyl group optionally substituted by carboxy or esterified or amidated carboxy; WO 98/47513 PCT/GB98/01161 -91 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; 5 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 t-position) hydroxy; or a pharmaceutically acceptable salt thereof. 10
16. A use according to claim 1 or 2, a composition according to claim 3 or 4, a product according to claim 5 or a method according to claim 6 or 7 wherein the NK-1 receptor antagonist is a compound of formula IX: 15 2 CH 2 IR R 1 -Y-A-N CONHCHCON (IX) R 4 wherein: R 1 is aryl, or a group of the formula: S X 20 Xis CHorN; 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; 25 A is carbonyl or sulfonyl; and WO 98/47513 PCT/GB98/01161 - 92 Y is a bond or lower alkenylene; or a pharmaceutically acceptable salt thereof.
17. A use according to claim 1 or 2, a composition according to 5 claim 3 or 4, a product according to claim 5 or a method according to claim 6 or 7 wherein the NK-1 receptor antagonist is a compound of formula X: H N "R 2 N)' /R2 H (X) wherein: 10 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 15 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, Cilloalkyl optionally substituted with from one to three fluoro groups, Ci-ioalkoxy optionally substituted with from one to three fluoro groups, amino, Ci-ioalkyl-S-, Ci-ioalkyl-S(O)-, 20 Cl.loalkyl-SO2-, phenyl, phenoxy, C1-loalkyl-SO2NH-, C 1 - 1 oalkyl-SO 2 NH-Ci-10oakyl-, C-lloalkylamino-diCi-loalkyl-, cyano, hydroxy, cycloalkoxy having 3 to 7 carbon atoms, C1.6alkylamino, Ci.edialkylamino, HC(O)NH- and C-o10alkyl-C(O)NH-; and R 2 is thienyl, benzhydryl, naphthyl or phenyl optionally substituted 25 with from one to three substituents independently selected from chloro, bromo, fluoro, iodo, cycloalkoxy having 3 to 7 carbon atoms, CIl-oalkyl optionally substituted with from one to three fluoro groups and Ci-loalkoxy optionally substituted with from one to three fluoro groups; WO 98/47513 PCT/GB98/01161 - 93 or a pharmaceutically acceptable salt thereof.
18. A use according to claim 1 or 2, a composition according to claim 3 or 4, a product according to claim 5 or a method according to claim 5 6 or 7 wherein the NK-1 receptor antagonist is a compound of formula XI: R 2 1 (CH 2 )x H N R R' N H I R4 R 5 (XI) wherein: R 1 is a C1. 4 alkoxy group; 10 R 2 is 6 N 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- 4 alkyl, C1-4alkoxy or trifluoromethyl group; 15 R 6 is a hydrogen atom, a C1. 4 alkyl, (CH2)mcyclopropyl, -S(O)nC 1 4alkyl, phenyl, NRTR 8 , 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; 20 n represents zero, 1 or 2; and m represents zero or 1; WO 98/47513 PCT/GB98/01161 - 94 or a pharmaceutically acceptable salt thereof.
19. A use according to claim 1 or 2, a composition according to claim 3 or 4, a product according to claim 5 or a method according to claim 5 6 or 7 wherein the NK-1 receptor antagonist is a compound of formula XII: R8 R4 R R R-(CH 2 ) n - C-CH2- N-(CH 2 )o-- R 3 NH R I (CO)p (CH 2 ) 1 (XII) R wherein: m is zero, 1, 2 or 3; 10 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; 15 which R groups may be substituted with one or two halo, CI-3alkoxy, trifluoromethyl, C1. 4 alkyl, phenyl-Cl-3alkoxy, or C1-4alkanoyl groups; RI is trityl, phenyl, diphenylmethyl, phenoxy, phenylthio, piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, indolinyl, indolyl, benzothienyl, hexamethyleneiminyl, benzofuranyl, tetrahydropyridinyl, 20 quinolinyl, isoquinolinyl, reduced quinolinyl, reduced isoquinolinyl, phenyl-(Cl.14alkyl)-, phenyl-(C1.4alkoxy)-, quinolinyl-(C1-4alkyl)-, isoquinolinyl-(C 14alkyl)-, reduced quniolinyl-(C1.4alkyl)-, reduced isoquinolinyl-(C 1 -4alkyl)-, benzoyl-(C1. 3 alkyl)-, C1.4alkyl, or -NH-CH2-R; WO 98/47513 PCT/GB98/01161 - 95 any one of which RI groups may be substituted with halo, C-4alkyl, C1.4alkoxy, trifluoromethyl, amino, C1.4alkylamino, di(C1-4alkyl)amino, or C 2 - 4 alkanoylamino; or any one of which RI groups may be substituted with phenyl, 5 piperazinyl, C 3 scycloalkyl, benzyl, C1. 4 alkyl, piperidinyl, pyridinyl, pyrimidinyl, C 2 -6alkanoylamino, pyrrolidinyl, C2-6alkanoyl, or C 1 -4alkoxycarbonyl; any one of which groups may be substituted with halo, C1- 4 alkyl, C 1 - 4 alkoxy, trifluoromethyl, amino, C1.4alkylamino, di(C1-4alkyl)amino, or 10 C 2 . 4 alkanoylamino; or R 1 is amino, a leaving group, hydrogen, C1.4alkylamino, or di(C 1-4alkyl) amino; R 5 is pyridyl, anilino-(C1.3alkyl)-, or anilinocarbonyl; R 2 is hydrogen, C1.4alkyl, C1.4alkylsulfonyl, carboxy-(Cl -3alkyl)-, 15 C 1 - 3 alkoxycarbonyl-(C1-3alkyl)-, or -CO-R 6 ; R 6 is hydrogen, C1-4alkyl, C1.3haloalkyl, phenyl, C1-3alkoxy, CI.- 3 hydroxyalkyl, amino, C1.4alkylamino, di(C 14alkyl)amino, or -(CH2)q-R 7 ; q is zero to 3; R 7 is carboxy, C1-4alkoxycarbonyl, Cl-4alkylcarbonyloxy, amino,
20 C1l4alkylamino, di(C1. 4 alkyl)amino, C1.6alkoxycarbonylamino, or phenoxy, phenylthio, piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, indolinyl, indolyl, benzothienyl, benzofuranyl, quinolinyl, phenyl-(C1.4alkyl)-, quinolinyl-(C1-4alkyl)-, isoquinolinyl-(C1-4alkyl)-, reduced quinolinyl (C1.4alkyl)-, reduced isoquinolinyl-(Cl-4alkyl)-, benzoyl-C1.3alkyl; 25 any one of which aryl or heterocyclic R 7 groups may be substituted with halo, trifluoromethyl, C1-4alkoxy, C1.4alkyl, amino, Cl-4alkylamino, di(C1-4alkyl)amino, or C2-4alkanoylamino; or any one of which R 7 groups may be substituted with phenyl, piperazinyl, C3-8cycloalkyl, benzyl, piperidinyl, pyridinyl, pyrimidinyl, 30 pyrrolidinyl, C 2 - 6 alkanoyl, or C1-4alkoxycarbonyl; WO 98/47513 PCT/GB98/01161 - 96 any of which groups may be substituted with halo, trifluoromethyl, amino, C1.4alkoxy, C1-4alkyl, C1.4alkylamino, di(C1-4alkyl)amino, or C 2 - 4 alkanoylamino; R 8 is hydrogen or C1.Galkyl; 5 R 3 is phenyl, phenyl-(C1.6alkyl)-, C3.8cycloalkyl, C5-8cycloalkenyl,_ Cs-8alkyl, naphthyl, C 2 -8alkenyl, or hydrogen; any one or which groups except hydrogen may be substituted with one or two halo, C 1 . 3 alkoxy, C1.3alkylthio, nitro, trifluoromethyl, or C1-3alkyl groups; and 10 R 4 is hydrogen or C-3alkyl; with the proviso that if R 1 is hydrogen or halo, R 3 is phenyl, phenyl-(C1.6alkyl)-, C3-8cycloalkyl, C5-s.8cycloalkenyl, or naphthyl; or a pharmaceutically acceptable salt thereof. 15 20. A use, composition, product or method according to any one of the preceding claims wherein the NK-1 receptor antagonist is orally active, long acting and CNS-penetrant.
21. A use according to claim 1 or 2, a composition according to 20 claim 3 or 4, a product according to claim 5 or a method according to claim 6 or 7 wherein the NK-1 receptor antagonist is selected from the classes of compounds described in EP-A-0577394, WO-A-9508549, WO-A-9518124, WO-A-9523798 and WO-A-9605181. 25
22. A use according to claim 1 or 2, a composition according to claim 3 or 4, a product according to claim 5 or a method according to claim 6 or 7 wherein the NK-1 receptor antagonist is selected from 2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3(S)-(4-fluorophenyl)-4-(3-(5-oxo 1H,4H-1,2,4-triazolo)methyl)morpholine; 30 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(3-(5-oxo- 1H,4H 1,2,4-triazolo)methyl)-3-(S)-phenyl-morpholine; WO 98/47513 PCT/GB98/01161 - 97 2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-4-(3-(5-oxo- 1H,4H- 1,2,4 triazolo)methyl)-3-(S)-phenyl-morpholine; 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl) 4-(3-(5-oxo- 1H,4H-1,2,4-triazolo)methyl)morpholine; 5 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(5-(N,N dimethylamino)methyl-1,2,3-triazol-4-yl)methyl-3-(S)-phenylmorpholine; 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(5-(N,N dimethylamino)methyl- 1,2,3-triazol-4-yl)methyl-3-(S)-(4 fluorophenyl)morpholine; 10 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl) 4-(3-(4-monophosphoryl-5-oxo- 1H-1,2,4-triazolo)methyl)morpholine; 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl) 4-(3-(1-monophosphoryl-5-oxo- 1H- 1,2,4-triazolo)methyl)morpholine; 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl) 15 4-(3-(2-monophosphoryl-5-oxo- 1H- 1,2,4-triazolo)methyl)morpholine; 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl) 4-(3-(5-oxyphosphoryl- 1H- 1,2,4-triazolo)methyl)morpholine; 2-(S)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl) 4-(3- (1-monophosphoryl-5-oxo-4H- 1,2,4-triazolo)methyl)morpholine; 20 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(4-N,N dimethylaminobut-2-yn-yl)-3-(S)-(4-fluorophenyl)morpholine; or a pharmaceutically acceptable salt thereof.
23. A use, composition, product or method according to any one of 25 the preceding claims wherein the anorectic agent is selected from aminorex, amphechloral, amphetamine, benzphetamine, chlorphentermine, clobenzorex, cloforex, clominorex, clortermine, cyclexedrine, dexfenfluramine, dextroamphetamine, diethylpropion, diphemethoxidine, N-ethylamphetamine, fenbutrazate, fenfluramine, 30 fenisorex, fenproporex, fludorex, fluminorex, furfurylmethylamphetamine, levamfetamine, levophacetoperane, mazindol, mefenorex, WO 98/47513 PCT/GB98/01161 - 98 metamfepramone, methamphetamine, norpseudoephedrine, pentorex, phendimetrazine, phenmetrazine, phentermine, phenylpropanolamine, picilorex and sibutramine; or a pharmaceutically acceptable salt thereof. 5
24. A use, composition, product or method according to any one of the preceding claims wherein the anorectic agent is a halogenated amphetamine derivative.
25. A use, composition, product or method according to claim 24 10 wherein the amphetamine derivative is selected from chlorphentermine, cloforex, clortermine, dexfenfluramine, fenfluramine, picilorex and sibutramine; or a pharmaceutically acceptable salt thereof.
26. A use, composition, product or method according to any one of 15 claims 1 to 25 wherein the eating disorder is obesity.
27. A use, composition, product or method according to any one of claims 1 to 25 wherein the eating disorder is bulimia nervosa. 20
28. A use, composition, product or method according to any one of claims 1 to 25 wherein the eating disorder is a compulsive eating disorder.
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CA2287487A1 (en) 1998-10-29
AU744261B2 (en) 2002-02-21

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