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WO1999064006A1 - Utilisation d'antagonistes du recepteur nk-1 dans le traitement des troubles psychiatriques - Google Patents

Utilisation d'antagonistes du recepteur nk-1 dans le traitement des troubles psychiatriques Download PDF

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Publication number
WO1999064006A1
WO1999064006A1 PCT/GB1999/001797 GB9901797W WO9964006A1 WO 1999064006 A1 WO1999064006 A1 WO 1999064006A1 GB 9901797 W GB9901797 W GB 9901797W WO 9964006 A1 WO9964006 A1 WO 9964006A1
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Prior art keywords
disorders
anxiety
stress
treatment
disorder
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PCT/GB1999/001797
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English (en)
Inventor
Nadia Melanie Rupniak
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Merck Sharp & Dohme Limited
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Publication date
Priority claimed from GBGB9812616.2A external-priority patent/GB9812616D0/en
Priority claimed from GBGB9812618.8A external-priority patent/GB9812618D0/en
Priority claimed from GBGB9812666.7A external-priority patent/GB9812666D0/en
Priority claimed from GBGB9812620.4A external-priority patent/GB9812620D0/en
Application filed by Merck Sharp & Dohme Limited filed Critical Merck Sharp & Dohme Limited
Priority to AU42781/99A priority Critical patent/AU4278199A/en
Priority to CA002334611A priority patent/CA2334611A1/fr
Priority to EP99955423A priority patent/EP1085873A1/fr
Priority to JP2000553075A priority patent/JP2002517446A/ja
Publication of WO1999064006A1 publication Critical patent/WO1999064006A1/fr

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    • 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
    • A61K31/535—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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • This invention relates to the treatment or prevention of certain depressive disorders, severe anxiety disorders, depressive disorders when present with anxiety, and stress disorders, by the administration of a NK- 1 receptor antagonist, in particular, 2-(R)-(l-(S)-(3,5- bis(trifluoromethyl)phenyl)-2-hydroxyethoxy)-3-(S)-(4-fluorophenyl)-4- (l,2,4-triazol-3-yl)methylmorpholine, or a pharmaceutically acceptable salt thereof.
  • a NK- 1 receptor antagonist in particular, 2-(R)-(l-(S)-(3,5- bis(trifluoromethyl)phenyl)-2-hydroxyethoxy)-3-(S)-(4-fluorophenyl)-4- (l,2,4-triazol-3-yl)methylmorpholine, or a pharmaceutically acceptable salt thereof.
  • a major depressive episode has been defined as being a period of at least two weeks during which, for most of the day and nearly every day, there is either depressed mood or the loss of interest or pleasure in all, or nearly all activities.
  • the individual may also experience changes in appetite or weight, sleep and psychomotor activity; descreased energy; feelings of worthlessness or guilt; difficulty thinking, concentrating or making decisions; and recurrent thoughts of death or suicidal ideation, plans or attempts.
  • One or more major depressive episodes may give rise to a diagnosis of major depressive disorder (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, American Psychiatric Association, 1994) .
  • Anxiety is an emotional condition characterised by feelings such as apprehension and fear accompanied by physical symptoms such as tachycardia, increased respiration, sweating and tremor. It is a normal emotion but when it is severe and disabling it becomes pathological.
  • the condition of an individual suffering from a major depressive disorder is sometimes complicated by the fact that the individual is also suffering from anxiety.
  • the patient may show signs of excessive or uncontrolled worry, irritability, feelings of tension, fears, restlessness and insomnia, difficulty in concentrating, and multiple somatic complaints such as pains and aches, twitching, stiffness, my oclonic jerks, tinnitus, blurred vision, hot and cold flushes, etc., all of which add to the individual's social and occupational impairment.
  • Stressors have been described as physiological or psychological perturbances which disrupt an individual's homeostatic balance, and the stress-response is the set of neural and endocrine adaptations that come into effect to reestablish homeostasis (R.M. Sapolsky, "Stress, the Aging Brain, and the Mechanisms of Neuron Death", the MIT Press, Cambridge, Massachusetts. 1992).
  • the stress-response is surprisingly convergent in that stressors as diverse as injury, starvation, temperature extremes and anxiety will provoke similar stress-responses. With prolonged stress, however, the stress-response can become as damaging as the stressor itself.
  • chronic overactivation of the stress-response may lead to stress-related conditions including myopathy, steroid diabetes, hypertension, peptic ulcers, reproductive impairment, psychogenic dwarfism and immunosuppression.
  • Stress disorders may result from over-exposure to a stressor, an adjustment reaction (for example, to serious illness or breavement) or in response to an exceptionally stressful trauma.
  • Treatment regimens for depressive disorders commonly include the use of tric tambo-depressants (TCAs), monoamrne oxidase inhibitors MAOIs), some psychotropic drugs, lithium carbonate, and electroconvulsive therapy (ECT) (see R. J. Baldessarini in Goodman & Gilman's The Pharmacological Basis of Therapeutics, 9th Edition, Chapter 19, McGraw-Hill, 1996 for a review). More recently, new classes of anti- depressant drugs are being developed including selective serotonin reuptake inhibitors (SSRIs), specific monoamine reuptake inhibitors and 5-HTIA receptor agonists and antagonists. The most established drug treatment for the management of depressive illness are the tricyclic anti-depressants.
  • tricyclic anti-depressants such as amitriptyline
  • amitriptyline for other patients, less sedating compounds such as imipramine or desipramine can be used.
  • tricyclic anti-depressants also possess antagonist properties at a variety of neurotransmitter receptors, including muscarinic cholinergic receptors, ⁇ i-adrenoceptors and Hi-histamine receptors.
  • receptor antagonist effects account for much of the side-effect profile of the tricyclic anti-depressants, and in particular, their anticholinergic side-effects which are particularly troublesome in patients with prostatic enlargement or glaucoma.
  • Other side-effects include dry mouth, tachycardia, difficulty in visual accommodation, constipation, urinary retention, sexual dysfunction, cognitive impairment, postural hypotension, and weight gain.
  • Monoamine oxidase inhibitors are generally prescribed for patients who have failed to respond to tricyclic anti-depressants or electroconvulsive therapy.
  • SSRIs such as fluoxetine, fluvoxamine, sertraline and paroxetine are generally non-sedating. Furthermore. SSRIs do not stimulate appetite and may therefore be appropriate in patients in whom weight gain would be undesirable.
  • SSRIs are not without their own side-effects, including nausea, diarrhoea, dry mouth, reduced appetite, dyspepsia, vomiting, headache, nervousness, insomnia, anxiety, tremour, dizziness, fatigue, decreased libido, pharyngitis, dyspnoea, skin rash and sexual dysfunction.
  • TCAs Tricyclic antidepressants
  • amitriptyline which have both anxiolytic and antidepressant actions may also be used.
  • 5-HTIA receptor agonists and antagonists may also have useful anxiolytic and other psychotropic activity (see R. J. Baldessarini in Goodman & Gilman's The Pharmacological Basis of Therapeutics, 9th
  • SSRIs selective serotonin reuptake inhibitors
  • benzodiazepines are also associated with a number of side-effects including increased hostility and irritability, vivid or disturbing dreams, weight gain, skin rash, nausea, headache, impairment of sexual function, vertigo, and lightheadedness. Difficulties may also arise with the use of tricyclic antidepressants, in particular, due to their anticholinergic side-effects which are particularly troublesome in patients with prostatic enlargement or glaucoma.
  • Other side-effects of tricyclic antidepressants include dry mouth, tachycardia, difficulty in visual accomodation, constipation, urinary retention, sexual dysfunction, cognitive impairment, postural hypotension, and weight gain.
  • SSRIs are not without their own side-effects, including nausea, diarrhoea, dry mouth, reduced appetite, dyspepsia, vomiting, headache, nervousness, insomnia, anxiety, tremour, dizziness, fatigue, decreased libido, pharyngitis, dyspnoea, skin rash and sexual dysfunction.
  • treatment of stress disorders may include the use of anxiolytic drugs such as benzodiazepines or tricyclic antidepressants, or hypnotic drugs.
  • anxiolytic drugs such as benzodiazepines or tricyclic antidepressants, or hypnotic drugs.
  • Potent benzodiazepines should not be prescribed for more than 3 or 4 weeks, however, due to the risks described above.
  • difficulties may also arise with the use of tricyclic antidepressants (TCAs).
  • SSRIs selective serotonin reuptake inhibitors
  • Neurokinin 1 (NK-1; substance P) receptor antagonists are being developed for the treatment of a number of physiological disorders associated with an excess or imbalance of tachykinins, and in particular substance P. Examples of conditions in which substance P has been implicated include disorders of the central nervous system such as anxiety, depression and psychosis (see, for instance, International (PCT) patent specification Nos. WO 95/16679, WO 95/18124 and WO 95/23798).
  • European Patent Specification No. 0 286 928 describes inhibitors of the enzyme prolyl-endopeptidase, which enzyme degrades neuropeptides such as substance P, the enzyme inhibitors having an antipsychotic, anxiolytic and antidepressant action.
  • degrading substance P or reducing the action of substance P in some other way e.g. antagonism at its preferred NK-1 receptor
  • the present invention provides the use of the NK-1 receptor antagonist 2-(R)-(l-(S)-(3,5-bis(trifluoromethyl)phenyl)-2-hydroxyethoxy)- 3-(S)-(4-fluorophenyl)-4-(l,2,4-triazol-3-yl)methylmorphohne, or a pharmaceutically acceptable salt thereof for the treatment of major depressive disorders, severe anxiety, depressive disorders when present with anxiety and stress disorders.
  • the compounds of this class advantageously exhibit a rapid onset of action and a reduced side-effect profile when compared against conventional antidepressant, anti-anxiety and anti-stress agents.
  • the exceptional pharmacology of the NK- 1 receptor antagonist of use in the present invention enables the treatment of major depressive disorders, severe anxiety, depressive disorders when present with anxiety and stress disorders, without the need for concomitant therapy using tricyclic antidepressants or monoamine oxidase inhibitors or, in particular, without the need for concomitant use of a serotonin agonist or antagonist or an SSRI. Furthermore, the exceptional pharmacology of the NK-1 receptor antagonist of use in the present invention results in a rapid onset of action.
  • the present invention accordingly provides the use of 2-(R)-(l-(S)- (3,5-bis(trifluoromethyl)phenyl)-2-hydroxyethoxy)-3-(S)-(4-fluorophenyl)-4- (l,2,4-triazol-3-yl)methylmorpholine, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment or prevention of major depressive disorders, severe anxiety disorders, depressive disorders when present with anxiety and stress disorders without concomitant therapy with other antidepressant, anti-anxiety and anti-stress agents.
  • the present invention also provides a method for the treatment or prevention of major depressive disorders, severe anxiety disorders, depressive disorders when present with anxiety and stress disorders without concomitant therapy with other antidepressant, anti-anxiety and anti-stress agents, which method comprises the administration to a patient in need of such treatment of an effective amount of 2-(R)-(l-(S)- (3,5-bis(trifluoromethyl)phenyl)-2-hydroxyethoxy)-3-(S)-(4-fluorophenyl)-4- (l,2,4-triazol-3-yl)methylmorpholine, or a pharmaceutically acceptable salt thereof.
  • an pharmaceutical composition for the treatment of major depressive disorders, severe anxiety disorders, depressive disorders when present with anxiety and stress disorders which comprises essentially 2-(R)-(l-(S)- (3,5-bis(trifluoiOmethyl)phenyl)-2-hydroxyethoxy)-3-(S)-(4-fluorophenyl)-4- (l,2,4-triazol-3-yl)methylmorphohne, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier or excipient.
  • the compound 2-(R)-(l-(S)-(3,5-bis(trifluoromethyl)- phenyl)-2-hydroxyethoxy)-3-(S)-(4-fluorophenyl)-4-(l,2,4-triazol-3- yl)methylmorpholine, or a pharmaceutically acceptable salt thereof is presented in a pharmaceutical composition adapted for oral administration .
  • the compound 2-(R)-(l-(S)-(3,5-bis(trifiuoromethyl)- phenyl)-2-hydroxyethoxy)-3-(S)-(4-fluorophenyl)-4-(l,2,4-triazol-3- yl)methylmorpholine, or a pharmaceutically acceptable salt thereof is administered once-a-day.
  • the present invention accordingly provides the use of 2-(R)-(l-(S)- (3,5-bis(trifluoromethyl)phenyl)-2-hydroxyethoxy)-3-(S)-(4-fluorophenyl)-4- (l,2,4-triazol-3-yl)methylmorpholine, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment or prevention of major depressive disorders, severe anxiety disorders, depressive disorders when present with anxiety and stress disorders without concomitant therapy with other antidepressant, anti-anxiety and anti-stress agents in a patient who is non-responsive to heterocyclic antidepressants (TCAs, tetracychcs, and the hke), SSRIs, mixed serotonin and norepinephrine selective reuptake inhibitors, dopamine reuptake inhibitors or MAOIs, or for whom heterocyclic antidepressants (TCAs, tetracychcs, and the hke), SSRI
  • the present invention also provides a method for the treatment or prevention of major depressive disorders, severe anxiety disorders, depressive disorders when present with anxiety and stress disorders without concomitant therapy with other antidepressant, anti-anxiety and anti-stress agents in a patient who is non-responsive to heterocyclic antidepressants (TCAs, tetracychcs, and the hke), SSRIs, mixed serotonin and norepinephrine selective reuptake inhibitors, dopamine reuptake inhibitors or MAOIs, or for whom heterocyclic antidepressants (TCAs, tetracychcs, and the hke), SSRIs, mixed serotonin and norepinephrine selective reuptake inhibitors, dopamine reuptake inhibitors or MAOIs are contraindicated, which method comprises administration to TCAs, tetracychcs, and the hke), SSRIs, mixed serotonin and norepinephrine selective reup
  • the present invention accordingly provides the use of 2-(R)-(l-(S)- (3,5-bis(trifluoromethyl)phenyl)-2-hydroxyethoxy)-3-(S)-(4-fluorophenyl)-4- (l,2,4-triazol-3-yl)methylmorphohne, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment or prevention of major depressive disorders, severe anxiety disorders, depressive disorders when present with anxiety and stress disorders without concomitant therapy with other antidepressant, anti-anxiety or anti-stress agents in a patient who is non-responsive to SSRIs or serotonin agonists or antagonists or for whom SSRIs or serotonin agonists or antagonists are contraindicated.
  • the present invention also provides a method for the treatment or prevention of major depressive disorders, severe anxiety disorders, depressive disorders when present with anxiety and stress disorders without concomitant therapy with other antidepressant, anti-anxiety or anti-stress agents in a patient who is non-responsive to SSRIs or serotonin agonists or antagonists or for whom SSRIs or serotonin agonists or antagonists are contraindicated, which method comprises administration to the patient in need of such treatment of an effective amount of 2-(R)-(l- (S)-(3,5-bis(trifluoromethyl)phenyl)-2-hydroxyethoxy)-3-(S)-(4- fluorophenyl)-4-(l,2,4-triazol-3-yl)methylmorpholine, or a pharmaceutically acceptable salt thereof.
  • severe anxiety disorders and stress disorders are inadequately treated with benzodiazepines.
  • some patients may be adversely affected by the side-effects of benzodiazepines.
  • the present invention accordingly provides the use of 2-(R)-(l-(S)- (3,5-bis(trifluoromethyl)phenyl)-2-hydroxyethoxy)-3-(S)-(4-fluorophenyl)-4- (l,2,4-triazol-3-yl)methylmorphohne, or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment or prevention of severe anxiety disorders or stress disorders, without concomitant therapy with other anti-anxiety or anti-stress agents, in a patient who is non-responsive to benzodiazepines or for whom benzodiazepines are contraindicated.
  • the present invention also provides a method for the treatment or prevention of severe anxiety disorders or stress disorders, without concomitant therapy with other anti-anxiety or anti-stress agents, in a patient who is non-responsive to benzodiazepines or for whom benzodiazepines are contraindicated, which method comprises administration to the patient in need of such treatment of an effective amount of 2-(R)-(l-(S)-(3,5-bis(trifluoromethyl)phenyl)-2-hydroxyethoxy)-3- (S)-(4-fluorophenyl)-4-(l,2,4-triazol-3-yl)methylmorphohne, or a pharmaceutically acceptable salt thereof.
  • severe anxiety disorders are inadequately treated with tricychc antidepressants.
  • some patients may be adversely affected by the side-effects of tricychc antidepressants.
  • the present invention accordingly provides the use of 2-(R)-(l-(S)- (3,5-bis(trifluoromethyl)phenyl)-2-hydroxyethoxy)-3-(S)-(4- ⁇ luorophenyl)-4- (l,2,4-triazol-3-yl)methylmorphohne, or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment or prevention of severe anxiety disorders, without concomitant therapy with other anti-anxiety agents, in a patient who is non-responsive to tricychc antidepressants or for whom tricychc antidepressants are contraindicated.
  • the present invention also provides a method for the treatment or prevention of severe anxiety disorders, without concomitant therapy with other anti-anxiety agents, in a patient who is non-responsive to tricychc antidepressants or for whom tricychc antidepressants are contraindicated, which method comprises administration to the patient in need of such treatment of an effective amount of 2-(R)-(l-(S)-(3,5- bis(trifluoromethyl)phenyl)-2-hydroxyethoxy)-3-(S)-(4-fluorophenyl)-4- (l,2,4-triazol-3-yl)methylmorpholine, or a pharmaceutically acceptable salt thereof.
  • non-responsive in relation to major depressive disorder means patients who have not had a reasonable clinical response (e.g. a 50% reduction in Hamilton Depression Scale (HAM-D) from a patient's baseline score after treatment with one or more chnical courses of conventional antidepressants).
  • HAM-D Hamilton Depression Scale
  • non-responsive in relation to severe anxiety disorders means patients who have not had a reasonable clinical response (e.g. a 50% reduction in Hamilton Anxiety Scale (HAM- A) from a patient's basehne score after treatment with one or more chnical courses of conventional anxiolytics).
  • HAM- A Hamilton Anxiety Scale
  • major depressive disorder includes single or recurrent major depressive episodes, with or without psychotic features, catatonic features, melanchohc features, atypical features or postpartum onset and. in the case of recurrent episodes, with or without interepisode recovery and with or without seasonal pattern.
  • Major depressive disorder include dysthymic disorder with early or late onset and with or without atypical features; dementia of the Alzheimer's type, with early or late onset, with depressed mood; vascular dementia with depressed mood; mood disorders induced by alcohol, amphetamines, cocaine, hallucinogens, inhalants, opioids, phencyclidine, sedatives, hypnotics, anxiolytics and other substances; schizo affective disorder of the depressed type; and adjustment disorder with depressed mood.
  • Major depressive disorders may also result from a general medical condition including, but not hmited to, myocardial infarction, diabetes, miscarriage or abortion, etc.
  • a "major depressive episode” is defined as at least two weeks of depressed mood or loss of interest, which may be accompanied by other symptoms of depression. The symptoms must persist for most of the day (i.e. for at least two thirds of the patients' waking hours), nearly every day (i.e. for at least ten out of fourteen days) for at least two consecutive weeks.
  • a "depressed mood” is often described by the patient as feehng sad, hopeless, helpless or worthless. The patient may also appear sad to an observer, for example, through facial expression, posture, voice and tearfulness. In children and adolescents, the mood may be irritable.
  • a 'loss of interest is often described by the patient as feehng less interested in hobbies or not feehng any enjoyment in activities that were previously considered to be pleasurable.
  • a major depressive episode may be accompanied by other symptoms of depression including significant weight loss when not dieting or weight gain (e.g. a change of more than 5% body weight in one month), or decrease or increase in appetite; insomnia or hypersomnia; psychomotor agitation or retardation; fatigue or loss of energy; feelings of worthlessness or excessive or inappropriate guilt; diminished ability to think or concentrate; or indecisiveness; and recurrent thoughts of death, recurrent suicidal ideation with or without a specific plan, or a suicide attempt.
  • weight gain e.g. a change of more than 5% body weight in one month
  • migraine anxiety disorders includes panic disorder with or without agoraphobia, agoraphobia without history of panic disorder, specific phobias, social phobias and obsessive-compulsive disorder.
  • Panic disorder is defined as the presence of recurrent panic attacks followed by at least one month of persistent concern about having another panic attack.
  • a “panic attack” is a discrete period in which there is a sudden onset of intense apprehension, fearfulness or terror.
  • the individual may experience a variety of symptoms including palpitations, sweating, trembhng, shortness of breath, chest pain, nausea and dizziness.
  • Panic disorder may occur with or without agoraphobia.
  • “Phobias” includes agoraphobia, specific phobias and social phobias.
  • Agoraphobia is characterised by an anxiety about being in places or situations from which escape might be difficult or embarrassing or in which help may not be available in the event of a panic attack.
  • Agoraphobia may occur without history of a panic attack.
  • a "specific phobia” is characterised by clinically significant anxiety provoked by exposure to a specific feared object or situation.
  • Specific phobias include the following subtypes: animal type, cued by animals or insects; natural environment type, cued by objects in the natural environment, for example storms, heights or water; blood-injection-injury type, cued by the sight of blood or an injury or by seeing or receiving an injection or other invasive medical procedure; situational type, cued by a specific situation such as pubhc transportation, tunnels, bridges, elevators, flying, driving or enclosed spaces; and other type where fear is cued by other stimuh.
  • Specific phobias may also be referred to as simple phobias.
  • a "social phobia” is characterised by clinically significant anxiety provoked by exposure to certain types of social or performance circumstances. Social phobia may also be referred to as social anxiety disorder.
  • “Obsessive-compulsive disorder” is characterised by recurrent obsessions or compulsions that are severe enough to be time consuming (i.e. they take at least one hour a day) or cause marked distress or significant impairment. At some point during the course of the disorder, the patient should recognise that the obsessions or compulsions are excessive or unreasonable.
  • Other anxiety disorders encompassed within the term “severe anxiety disorders” include anxiety disorders induced by alcohol, amphetamines, caffeine, cannabis, cocaine, hallucinogens, inhalants, phencychdine, sedatives, hypnotics, anxiolytics and other substances, and adjustment disorders with anxiety.
  • stress disorders includes acute stress disorder, adjustment disorder and acute, chronic or delayed onset post- traumatic stress disorder.
  • treatment refers both to the treatment and to the prevention or prophylactic therapy of the aforementioned conditions.
  • the NK-1 receptor antagonist of use in the present invention is the compound 2-(R)-(l-(S)-(3,5-bis(trifluoromethyl)phenyl)-2- hydroxyethoxy)-3-(S)-(4-fluorophenyl)-4-(l,2,4-triazol-3- yl)methylmorpholine, or a pharmaceutically acceptable salt thereof.
  • Suitable pharmaceutically acceptable salts of the NK-1 receptor antagonist of use in the present invention include acid addition salts which may. for example, be formed by mixing a solution of the compound with a solution of a pharmaceutically acceptable non-toxic acid such as hydrochloric acid, fumaric acid, maleic acid, succinic acid, acetic acid, citric acid, tartaric acid, carbonic acid, phosphoric acid or sulphuric acid.
  • Salts of amine groups may also comprise the quaternary ammonium salts in which the amino nitrogen atom carries an alkyl, alkenyl, alkynyl or aralkyl group.
  • compositions containing the NK- 1 receptor antagonist of use according to the present invention are in unit dosage forms such as tablets, pills, capsules, wafers and the hke.
  • the NK-1 receptor antagonist of use according to the present invention may be presented as granules or powders for extemporaneous formulation as volume defined solutions or suspensions.
  • the NK-1 receptor antagonist of use according to the present invention may be presented in ready-prepared volume defined solutions or suspensions.
  • Preferred forms are tablets and capsules.
  • sohd 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 sohd preformulation composition containing a homogeneous mixture of a compound of the present invention, or a non-toxic pharmaceutically acceptable salt thereof.
  • 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
  • preformulation compositions when referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. This sohd preformulation composition is then subdivided into unit dosage forms of the type described above containing from 0.1 to about 500 mg of the active ingredient of the present invention.
  • the tablets or pills of the novel composition can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action.
  • the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former.
  • the two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release.
  • 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.
  • compositions of the present invention may be incorporated for administration orally include aqueous solutions, suitably flavoured syrups, aqueous or oil suspensions, and flavoured emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil, peanut oil or soybean oil, as weU as elixirs and similar pharmaceutical vehicles.
  • Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth. acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinyl-pyrrohdone or gelatin.
  • Compositions of the present invention may also be administered via the buccal cavity using conventional technology, for example, absorption wafers.
  • compositions in the form of tablets, pills, capsules or wafers for oral administration are particularly preferred.
  • a minimum dosage level for the NK-1 receptor antagonist is about lmg per day, preferably about 5mg per day and especially about lOmg per day.
  • a maximum dosage level for the NK-1 receptor antagonist is about 1500mg per day, preferably about lOOOm per day and especially about 500mg per day.
  • the compounds are administered once a day. It will be appreciated that the amount of the NK-1 receptor antagonist required for use in the treatment or prevention of major depressive disorders will vary not only with the particular compounds or compositions selected but also with the route of administration, the nature of the condition being treated, and the age and condition of the patient, and will ultimately be at the discretion of the patient's physician or pharmacist.
  • NK- 1 receptor antagonists of use in the present invention may be measured using of the following assays:
  • ASSAY 1 NK-1 Receptor binding
  • NK-1 receptor binding assays are performed in intact Chinese hamster ovary (CHO) cells expressing the human NK- 1 receptor using a modification of the assay conditions described by Cascieri et al, J.
  • the receptor is expressed at a level of 3xl0 5 receptors per ceU.
  • Cells are grown in monolayer culture. detached from the plate with enzyme-free dissociation solution (Speciality Media Inc.), and washed prior to use in the assay.
  • 125 I-Tyr 8 -substance P O. lnM, 2000Ci/mmol; New England Nuclear
  • DMSO dimethylsulphoxide
  • Ligand binding is performed in 0.25ml of 50mM Tris-HCl, pH7.5, containing 5mM MnCl 2 , 150mM NaCl, 0.02% bovine serum albumin (Sigma), 50 ⁇ g/ml chymostatin (Peninsula), O.lnM phenylmethylsulphonyl fluoride, 2 ⁇ g/ml pepstatin, 2 ⁇ g/ml leupeptin and 2.8 ⁇ g/ml furoyl saccharine.
  • the incubation proceeds at room temperature until equilibrium is achieved (>40 minutes) and the receptor-hgand 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 (l ⁇ M) and represents ⁇ 10% of total binding.
  • CNS-penetrant NK-1 receptor antagonists for use in the present invention can be identified by their ability to inhibit foot tapping in gerbils induced by anxiogenic agents (such as pentagastrin) or central infusion of NK-1 receptor agonists such as GR73632. or caused by aversive stimulation such as foot shock or single housing, based on the method of Rupniak & Williams, Eur. J. Pharmacol, 1994, 265, 179.
  • Male or female Mongohan gerbils (35-70g) are anaesthetised by inhalation of an isoflurane/oxygen mixture to permit exposure of the jugular vein in order to permit administration of test compounds or vehicle in an injection volume of 5ml/kg i.v.
  • 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
  • a selective NK-1 receptor agonist e.g.
  • GR73632 (d Ala[L-Pro 9 ,Me-Leu 10 ] -substance P-(7- ll)) is infused directly into the cerebral ventricles (e.g. 3pmol in 5 ⁇ l 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 clear perspex observation box (25cm x 20cm x 20cm). The duration and/or intensity of hind foot tapping is then recorded continuously for approximately 5 minutes. Alternatively, the ability of test compounds to inhibit foot tapping evoked by aversive stimulation, such as foot shock or single housing, may be studied using a similar method of quantification.
  • ASSAY 3 Ferret Emesis Individually housed male ferrets (1.0 -2.5 kg) are dosed orally by gavage with test compound. Ten minutes later they are fed with approximately lOOg of tinned cat food. At 60 minutes following oral dosing, cisplatin (lOmg/kg) is given i.v. via a jugular vein catheter inserted under a brief period of halothane anaesthesia. The catheter is then removed, the jugular vein hgated and the skin incision closed. The ferrets recover rapidly from the anaesthetic and are mobile within 10-20 minutes.
  • the animals are observed continuously during recovery from the anaesthetic and for 4 hours following the cisplatin injection, after which time the animals are killed humanely.
  • the numbers of retches and vomits occurring during the 4 hours after cisplatin administration are recorded by trained observers.
  • ASSAY 4 Separation-Induced Vocalisation
  • mice Male and female guinea-pigs pups are housed in family groups with their mothers and httermates throughout the study. Experiments are commenced after weaning when the pups are 2 weeks old. Before entering an experiment, the pups are screened to ensure that a vigorous vocalisation response is reproducibly ehcited following maternal separation. The pups are placed individually in an observation cage (55cm x 39cm x 19cm) in a room physicaUy isolated from the home cage for 15 minutes and the duration of vocalisation during this basehne period is recorded. Only animals which vocalise for longer than 5 minutes are employed for drug challenge studies (approximately 50% of available pups may fail to reach this criterion).
  • each pup On test days each pup receives an oral dose or an s.c. or i.p. injection of test compound or vehicle and is then immediately returned to the home cage with its mother and siblings for 30 to 60 minutes (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 of vocalisation on drug treatment days is expressed as a percentage of the pre-treatment basehne value for each animal.
  • the same subjects are retested once weekly for up to 6 weeks. Between 6 and 8 animals receive each test compound at each dose tested.
  • CNS-penetrant refers to NK-1 receptor antagonists which are able to inhibit NK-1 receptor antagonist-induced foot-tapping in the gerbil as hereinafter defined.
  • hind foot-tapping in the gerbil induced by infusion of the NK-1 receptor agonist, GR73632 (d Ala[L-Pro 9 ,Me-Leu 10 ]-substance P- (7-11)), under anaesthesia, directly into the central ventricles is inhibited when a CNS-penetrant NK-1 receptor antagonist is administered intravenously immediately prior to GR73632 challenge, wherein hind foot- tapping over a period of five minutes following recovery from the anaesthesia is inhibited with an ID50 ⁇ 3mg/kg, and preferably with an IDso ⁇ lmg/kg.
  • the NK-1 receptor antagonist is administered orally, 1 hour prior to GR73632 challenge, wherein the foot- tapping over a period of five minutes following recovery from anaesthesia is inhibited with an ID5o ⁇ 30mg/kg, and preferably with an IDso ⁇ lOmg/kg.
  • CNS-penetrant NK-1 receptor antagonists of use in the present invention are also effective in the attenuation of separation-induced vocalisations by guinea-pig pups as hereinafter defined.
  • a vocalisation response in guinea-pig pups is induced by isolation from their mothers and littermates, which response is attenuated when a CNS-penetrant NK-1 receptor antagonist is administered subcutaneously 30 minutes prior to isolation, wherein vocalisations during the first 15 minutes of isolation are attenuated with an ID ⁇ o ⁇ 20mg/kg, preferably with an IDso ⁇ lOmg/kg, and especially with an IDso ⁇ mg/kg.
  • the NK-1 receptor antagonist is administered orally, 4 hours prior to isolation, wherein vocalisations during the first 15 minutes of isolation are attenuated with an ID ⁇ o ⁇ 20mg/kg, preferably with an IDso ⁇ lOmg/kg, and especially with an
  • a suitable selection cascade for NKi antagonists of use according to the present invention is as follows:
  • Particularly preferred compounds of use in the present invention are identified using steps (i) to (iv) followed by step (v): (v) Determine activity of compounds in assays sensitive to conventional antipsychotic drugs (inhibition of distress vocalisations in guinea-pig pups (Assay 4)). Select compounds with ID50 ⁇ 20mg/kg, and preferably ID50 ⁇ lOmg/kg.
  • Yet further preferred compounds of use in the present invention may be selected from those compounds which satisfy the NK-1 receptor binding criteria of step (i) which, in addition, have ⁇ 5-fold shift in affinity when incubated in the presence of human serum albumin (HSA) to show non-specific protein binding.
  • HSA human serum albumin
  • the NK-1 receptor antagonist of use in the present invention is the compound 2-(R)-(l-(S)-(3,5-bis(trifiuoromethyl)phenyl)-2-hydroxyethoxy)-3- (S)-(4-fluorophenyl)-4-(l,2,4-triazol-3-yl)methylmorphohne, the preparation of which is described in International Patent Specification No. WO 95/18124 and US Patent No. 5,612,337. In the aforementioned assays, this compound has the following activity:
  • ID50 0.91 mg/kg p.o.
  • the active ingredient, cellulose, lactose and a portion of the corn starch are mixed and granulated with 10% corn starch paste.
  • the resulting granulation is sieved, dried and blended with the remainder of the corn starch and the magnesium stearate.
  • the resulting granulation is then compressed into tablets containing 50mg, lOOmg and 300mg of the NK-1 receptor antagonist per tablet.

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Abstract

La présente invention a pour objet l'utilisation d'un antagoniste du récepteur NK-1 dans la fabrication d'un médicament prévu pour être administré pour traiter ou prévenir les troubles dépressifs majeurs, les troubles anxieux sévères, les troubles dépressifs majeurs avec les troubles anxieux et les états de stress, sans thérapie parallèle par d'autres agents antidépressifs, anxiolytiques ou antistress. L'invention concerne également des procédés de traitement à l'aide d'un antagoniste du récepteur NK-1 et de compositions pharmaceutiques comprenant cet antagoniste.
PCT/GB1999/001797 1998-06-11 1999-06-08 Utilisation d'antagonistes du recepteur nk-1 dans le traitement des troubles psychiatriques WO1999064006A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
AU42781/99A AU4278199A (en) 1998-06-11 1999-06-08 Use of a nk-1 receptor antagonist for treating psychiatric disorders
CA002334611A CA2334611A1 (fr) 1998-06-11 1999-06-08 Utilisation d'antagonistes du recepteur nk-1 dans le traitement des troubles psychiatriques
EP99955423A EP1085873A1 (fr) 1998-06-11 1999-06-08 Utilisation d'antagonistes du recepteur nk-1 dans le traitement des troubles psychiatriques
JP2000553075A JP2002517446A (ja) 1998-06-11 1999-06-08 精神障害の治療のためのｎｋ−１受容体アンタゴニストの使用

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GBGB9812616.2A GB9812616D0 (en) 1998-06-11 1998-06-11 Therapeutic use
GBGB9812618.8A GB9812618D0 (en) 1998-06-11 1998-06-11 Therapeutic use
GBGB9812666.7A GB9812666D0 (en) 1998-06-11 1998-06-11 Therapeutic use
GB9812666.7 1998-06-11
GBGB9812620.4A GB9812620D0 (en) 1998-06-11 1998-06-11 Therapeutic use
GB9812620.4 1998-06-11
GB9812616.2 1998-06-11
GB9812618.8 1998-06-11

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002016343A1 (fr) * 2000-08-22 2002-02-28 Merck Sharp & Dohme Limited Derives tetrahydropyranes en tant qu'antagonistes de recepteur nk-1
WO2004026296A1 (fr) * 2002-09-18 2004-04-01 Ajinomoto Co., Inc. Composition pour lutter contre des maladies liees au stress

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995018124A1 (fr) * 1993-12-29 1995-07-06 Merck Sharp & Dohme Limited Derives de morpholine substitues et une utilisation en tant qu'agents therapeutiques
WO1998015277A2 (fr) * 1996-10-07 1998-04-16 Merck Sharp & Dohme Limited Antagoniste du recepteur nk-1 utilise comme antidepresseur et/ou agent anxiolytique
WO1998024438A1 (fr) * 1996-12-02 1998-06-11 Merck Sharp & Dohme Limited Utilisation d'antagonistes du recepteur nk-1 dans le traitement des etats depressifs majeurs
WO1998024441A1 (fr) * 1996-12-02 1998-06-11 Merck Sharp & Dohme Limited Utilisation d'antagonistes du recepteur nk-1 dans le traitement des etats depressifs majeurs accompagnes d'anxiete
WO1998024440A1 (fr) * 1996-12-02 1998-06-11 Merck Sharp & Dohme Limited Utilisation d'antagonistes du recepteur nk-1 dans le traitement des etats de stress
WO1998024439A1 (fr) * 1996-12-02 1998-06-11 Merck Sharp & Dohme Limited Utilisation d'antagonistes du recepteur nk-1 dans le traitement des etats anxieux severes
WO1998024444A1 (fr) * 1996-12-02 1998-06-11 Merck Sharp & Dohme Limited Utilisation d'antagonistes du recepteur nk-1 dans le traitement des troubles du sevrage

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995018124A1 (fr) * 1993-12-29 1995-07-06 Merck Sharp & Dohme Limited Derives de morpholine substitues et une utilisation en tant qu'agents therapeutiques
WO1998015277A2 (fr) * 1996-10-07 1998-04-16 Merck Sharp & Dohme Limited Antagoniste du recepteur nk-1 utilise comme antidepresseur et/ou agent anxiolytique
WO1998024438A1 (fr) * 1996-12-02 1998-06-11 Merck Sharp & Dohme Limited Utilisation d'antagonistes du recepteur nk-1 dans le traitement des etats depressifs majeurs
WO1998024441A1 (fr) * 1996-12-02 1998-06-11 Merck Sharp & Dohme Limited Utilisation d'antagonistes du recepteur nk-1 dans le traitement des etats depressifs majeurs accompagnes d'anxiete
WO1998024440A1 (fr) * 1996-12-02 1998-06-11 Merck Sharp & Dohme Limited Utilisation d'antagonistes du recepteur nk-1 dans le traitement des etats de stress
WO1998024439A1 (fr) * 1996-12-02 1998-06-11 Merck Sharp & Dohme Limited Utilisation d'antagonistes du recepteur nk-1 dans le traitement des etats anxieux severes
WO1998024444A1 (fr) * 1996-12-02 1998-06-11 Merck Sharp & Dohme Limited Utilisation d'antagonistes du recepteur nk-1 dans le traitement des troubles du sevrage

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002016343A1 (fr) * 2000-08-22 2002-02-28 Merck Sharp & Dohme Limited Derives tetrahydropyranes en tant qu'antagonistes de recepteur nk-1
WO2002016344A1 (fr) * 2000-08-22 2002-02-28 Merck Sharp & Dohme Limited Derives de tetrahydropyrane utilises comme antagonistes du recepteur de nk-1
WO2004026296A1 (fr) * 2002-09-18 2004-04-01 Ajinomoto Co., Inc. Composition pour lutter contre des maladies liees au stress

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JP2002517446A (ja) 2002-06-18
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EP1085873A1 (fr) 2001-03-28

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