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WO1999064010A1 - Utilisation d'un antagoniste du recepteur nk-1 dans le traitement des troubles psychiatriques - Google Patents

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

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Publication number
WO1999064010A1
WO1999064010A1 PCT/GB1999/001819 GB9901819W WO9964010A1 WO 1999064010 A1 WO1999064010 A1 WO 1999064010A1 GB 9901819 W GB9901819 W GB 9901819W WO 9964010 A1 WO9964010 A1 WO 9964010A1
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WO
WIPO (PCT)
Prior art keywords
treatment
disorders
pharmaceutically acceptable
triazol
hydroxyethoxy
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PCT/GB1999/001819
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English (en)
Inventor
Nadia Melanie Rupniak
Original Assignee
Merck Sharp & Dohme Limited
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Priority claimed from GBGB9812669.1A external-priority patent/GB9812669D0/en
Priority claimed from GBGB9812661.8A external-priority patent/GB9812661D0/en
Priority claimed from GBGB9812663.4A external-priority patent/GB9812663D0/en
Application filed by Merck Sharp & Dohme Limited filed Critical Merck Sharp & Dohme Limited
Priority to AU42796/99A priority Critical patent/AU4279699A/en
Priority to CA002334609A priority patent/CA2334609A1/fr
Priority to JP2000553079A priority patent/JP2002517448A/ja
Priority to EP99955427A priority patent/EP1085875A1/fr
Publication of WO1999064010A1 publication Critical patent/WO1999064010A1/fr

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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535Heterocyclic 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
    • A61K31/53751,4-Oxazines, e.g. morpholine
    • A61K31/53771,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/18Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • This invention relates to the treatment or prevention of certain schizophrenic disorders, certain substance use disorders, and movement disorders by the administration of a NK- 1 receptor antagonist, in particular, 2-(R)-(l-(S)-(3,5-bis(tri_Quoromethyl)phenyl)-2-hydroxyethoxy)- 3-(S)-(4-fluorophenyl)-4-(l,2,4-triazol-3-yl)methylmorphohne, or a pharmaceutically acceptable salt thereof.
  • a NK- 1 receptor antagonist in particular, 2-(R)-(l-(S)-(3,5-bis(tri_Quoromethyl)phenyl)-2-hydroxyethoxy)- 3-(S)-(4-fluorophenyl)-4-(l,2,4-triazol-3-yl)methylmorphohne, or a pharmaceutically acceptable salt thereof.
  • the essential features of schizophrenia are a mixture of characteristic signs and symptoms (both positive and negative) which are present in an individual for a significant portion of
  • active-phase symptoms include delusions, hallucinations, disorganised speech, disorganised or catatonic behaviour and negative symptoms (e.g. affective flattening, alogia and avolition).
  • Some patients have only a single episode of the illness, but most have either recurrent episodes or chronic illness.
  • schizophrenic patients The care of schizophrenic patients is a major part of the work of psychiatrists.
  • the long-term care of schizophrenic patients is complicated, however, generally symptoms can at least be kept under control if patients with chronic schizophrenia receive long-term treatment with an antipsychotic drug.
  • schizophrenic symptoms cannot be controlled without invoking extrapyramidal side-effects. Consequently, antiparkinsonian drugs may also be prescribed to reduce these side-effects, however, the use of anticholinergic drugs may actually increase the risk of tardive dyskinesia (a late and sometimes irreversible side-effect of prolonged treatment with antipyschotic drugs).
  • Treatment of schizophrenia with antipsychotic (or neuroleptic) agents is typically associated with a number of side-effects, including extrapyramidal symptoms, acute dystonias, tardive dyskinesias, akathesia, tremor, tachycardia, drowsiness, confusion, postural hypotension, blurring of vision, precipitation of glaucoma, dry mouth, constipation, urinary hesitance and impaired sexual function.
  • side-effects are often debilitating and contribute considerably to a patient's non-compliance with prescribed treatment. They may also hinder a patient's social rehabilitation.
  • a common, though not inevitable, outcome of long-term drug use is the occurrence of a withdrawal response, which occurs either when the drug is withdrawn or when an antagonist is given and which usually takes the form of some sort of adverse reaction.
  • a withdrawal syndrome occurs in opiate addicts when the opiate is withdrawn or when an antagonist, such as naloxone, is given.
  • the symptoms consist of yawning, rhinorrhoea, and sweating, followed by the so-called cold turkey, in which there is shivering and goose flesh. Later, nausea, vomiting, diarrhoea, and hypertension may occur.
  • the acute syndrome subsides within a week, but the addict may have anxiety and sleep disturbances for several weeks or months after.
  • This syndrome can be avoided by introducing increasing doses of methadone as the opiate is withdrawn, as the later withdrawal of methadone, which has a much longer duration of action than morphine, may not result in this syndrome.
  • Delirium tremens may occur on withdrawal of alcohol from chronic alcoholics. This syndrome consists of disorientation and visual hallucinations.
  • the pharmacological management of drug withdrawal disorders is not always effective and is often hampered by the addictive potential of many of the drugs which are prescribed to treat withdrawal symptoms.
  • Diseases of the extrapyramidal motor systems cause either a loss of movement (akinesia) accompanied by an increase in muscle tone (rigidity) or abnormal involuntary movements (dyskinesias) often accompanied by a reduction in muscle tone.
  • the akinetic-rigid syndrome called parkinsonism, and the dyskinesias represent opposite ends of the spectrum of movement disorders (for review see C. D. Marsden in Oxford Textbook of Medicine, 3rd Edition, Oxford University Press, 1996, vol. 3, pages 3998-4022).
  • Treatment of akinetic-rigid conditions such as parkinsonism typically involves the use of levodopa, anticholinergics or dopamine agonists.
  • Levodopa is converted into dopamine in the brain by the enzyme dopa decarboxylase.
  • this enzyme is also present in the gut wall, liver, kidney and cerebral capillaries, thus the peripheral formation of levodopa metabolites may give rise to side-effects such as nausea, vomiting, cardiac dysrhythmias and postural hypotension.
  • This peripheral decarboxylation is largely prevented by the addition of a selective extracerebral decarboxylase inhibitor, such as carbidopa or benserazide, which themselves do not penetrate the brain.
  • Levodopa combined with carbidopa (SINEMET TM ) or benserazide (MADOPAR TM ) is now the treatment of choice when levodopa is indicated. Even then, this combination therapy may be associated with side-effects such as dyskinesias and psychiatric disturbances.
  • anticholinergic such as benzhexol or orphenadrine may be used, however, anticholinergics cause peripheral parasympathetic blockade which may cause dry mouth, blurred vision and constipation, and they may also precipitate glaucoma, urinary retention and a toxic confusional state.
  • Dopamine agonists such as bromocriptine (PARLODEL TM ), lisuride and pergolide (CELANCE TM ) act directly on dopamine receptors and have a similar side-effect profile to levodopa.
  • PARLODEL TM bromocriptine
  • CELANCE TM pergolide
  • the dyskinesias are treated with a variety of pharmacological agents.
  • tremor may be treated with benzodiazepines such as diazepam
  • chorea may be treated with diazepam, a phenothiazide or haloperidol, or tetrabenazine
  • tics may be controlled with neuroleptics such as haloperidol or pimozide
  • dystonias tend to be treated with levodopa
  • benzodiazepines such as diazepam
  • anticholinergics such as benzhexol
  • phenothiazines and other neuroleptics such as haloperidol, and tetrabenazine.
  • Treatment of psychotic disorders with neuroleptic agents may be at the expense of a number of side-effects, including extrapyramidal symptoms, acute dystonias, tardive dyskinesias, akathesia, tremor, tachycardia, drowsiness, confusion, postural hypotension, blurring of vision, precipitation of glaucoma, dry mouth, constipation, urinary hesitance and impaired sexual function.
  • 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 might be expected to be detrimental to the treatment of psychoses such as schizophrenic disorders.
  • the present invention provides the use of 2-(R)-(l-(S)-(3,5- bis(tr ⁇ _luoromethyl)phenyl)-2-hydroxyethoxy)-3-(S)-(4-fluorophenyl)-4- (l,2,4-triazol-3-yl)methylmorpholine, or a pharmaceutically acceptable salt thereof, in an oral, once-a-day medicament for the treatment of schizophrenic disorders, substance use disorders, and movement disorders.
  • the compounds of this class advantageously exhibit a rapid onset of action and a reduced side-effect profile when compared against conventional antipsychotic agents.
  • the exceptional pharmacology of the NK- 1 receptor antagonist of use in the present invention enables the treatment of schizophrenic disorders, substance use disorders, and movement disorders, without the need for concomitant therapy and in particular, without the need for concomitant therapy.
  • 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 adapted for oral administration for the treatment or prevention of schizophrenic disorders, substance use disorders, and movement disorders.
  • the present invention also provides a method for the treatment or prevention of schizophrenic disorders, substance use disorders, and movement disorders, which method comprises the oral administration to a patient in need of such treatment of an effective amount of 2-(R)-(l-(S)-
  • an oral pharmaceutical composition for the treatment of schizophrenic disorders, substance use disorders, and movement disorders which comprises 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, together with a pharmaceutically acceptable carrier or excipient.
  • the present invention also provides a method for the treatment or prevention of schizophrenic disorders in a patient who is non-responsive to antipsychotic agents, or for whom antipsychotic agents are contraindicated, which method comprises oral 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.
  • a combination of a conventional antipsychotic drug with a NK-1 receptor antagonist may provide an enhanced effect in the treatment of schizophrenic disorders.
  • Such a combination would be expected to provide for a rapid onset of action to treat schizophrenic symptoms thereby enabling prescription on an "as needed basis".
  • such a combination may enable a lower dose of the antipsychotic agent to be used without compromising the efficacy of the antipsychotic agent, thereby minimising the risk of adverse side-effects.
  • a yet further advantage of such a combination is that, due to the action of the NK- 1 receptor antagonist, adverse side-effects caused by the antipsychotic agent such as acute dystonias, dyskinesias, akathesia and tremor may be reduced or prevented.
  • the present invention also provides a method for the treatment or prevention of schizophrenic disorders, which method comprises administration to a patient in need of such treatment of an amount of 2- (R)-(l-(S)-(3,5-bis(tr ⁇ luoromethyl)phenyl)-2-hydroxyethoxy)-3-(S)-(4- fluorophenyl)-4-(l,2,4-triazol-3-yl)methylmorpholine, or a pharmaceutically acceptable salt thereof, and an amount of an antipsychotic agent, such that together they give effective relief.
  • NK-1 receptor antagonist and the antipsychotic agent may be present as a combined preparation for simultaneous, separate or sequential use for the treatment or prevention of schizophrenic disorders.
  • Such combined preparations may be, for example, in the form of a twin pack.
  • 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 adapted for oral administration for the treatment or prevention of dyskinesias in a patient who is non-responsive to neuroleptic agents, or for whom neuroleptic agents are contraindicated.
  • the present invention also provides a method for the treatment or prevention of dyskinesias in a patient who is non -responsive to neuroleptic agents, or for whom neuroleptic agents are contraindicated, which method comprises oral 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.
  • Such a combination may enable a lower dose of the antiparkinsonian agent to be used without compromising the efficacy of the antiparkinsonian agent, thereby minimising the risk of adverse side-effects.
  • the present invention also provides a method for the treatment or prevention of akinetic-rigid disorders, which method comprises administration to a patient in need of such treatment of an 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, and an amount of an antiparkinsonian agent, such that together they give effective relief.
  • composition comprising 2-(R)-(l-(S)-(3,5- bis(tri uoromethyl)phenyl)-2-hydroxyethoxy)-3-(S)-(4-fluorophenyl)-4-
  • NK-1 receptor antagonist and the antiparkinsonian agent may be present as a combined preparation for simultaneous, separate or sequential use for the treatment or prevention of akinetic-rigid disorders.
  • Such combined preparations may be, for example, in the form of a twin pack.
  • a product comprising 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 and an antiparkinsonian agent as a combined preparation for simultaneous, separate or sequential use in the treatment or prevention of akinetic-rigid disorders.
  • a combination of a conventional neuroleptic drug with 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 may provide an enhanced effect in the treatment of dyskinesias.
  • Such a combination may enable a lower dose of the neuroleptic agent to be used without compromising the efficacy of the neuroleptic agent, thereby minimising the risk of adverse side-effects.
  • a yet further advantage of such a combination is that, due to the action of the NK- 1 receptor antagonist, adverse side-effects caused by the neuroleptic agent such as acute dystonias, dyskinesias, akathesia and tremor may be reduced or prevented.
  • the present invention also provides a method for the treatment or prevention of dyskinesias, which method comprises administration to a patient in need of such treatment of an amount of 2-(R)-(l-(S)-(3,5- bis(trifl.uoromethyl)phenyl)-2-hydroxyethoxy)-3-(S)-(4-fluorophenyl)-4- (l,2,4-triazol-3-yl)methylmorpholine, or a pharmaceutically acceptable salt thereof, and an amount of a neuroleptic agent, such that together they give effective relief.
  • a pharmaceutical composition comprising 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, and a neuroleptic agent, together with at least one pharmaceutically acceptable carrier or excipient.
  • NK- 1 receptor antagonist and the neuroleptic agent may be present as a combined preparation for simultaneous, separate or sequential use for the treatment or prevention of dyskinesias.
  • Such combined preparations may be, for example, in the form of a twin pack.
  • a product comprising 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, and an neuroleptic agent as a combined preparation for simultaneous, separate or sequential use in the treatment or prevention of dyskinesias.
  • the NK-1 receptor antagonist and the antipsychotic, antiparkinsonian, or neuroleptic agent may be in the same pharmaceutically acceptable carrier and therefore administered simultaneously. They may be in separate pharmaceutical carriers such as conventional oral dosage forms which are taken simultaneously.
  • the term “combination” also refers to the case where the compounds are provided in separate dosage forms and are administered sequentially. Therefore, by way of example, the antipsychotic, antiparkinsonian, or neuroleptic 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.
  • a fast-dissolving oral formulation is meant, an oral delivery form which when placed on the tongue of a patient, dissolves within about 10 seconds.
  • schizophrenic disorders includes paranoid, disorganised, catatonic, undifferentiated and residual schizophrenia; schizophreniform disorder; schizoaffective disorder; delusional disorder; brief psychotic disorder; shared psychotic disorder; substance-induced psychotic disorder; and psychotic disorder not otherwise specified.
  • schizophrenic disorders include self-injurious behaviour (e.g. Lesch-Nyhan syndrome) and suicidal gestures.
  • substance use disorders includes substance dependence or abuse with or without physiological dependence.
  • the substances associated with these disorders are: alcohol, amphetamines (or amphetamine-like substances), caffeine, cannabis, cocaine, hallucinogens, inhalants, nicotine, opioids, phencyclidine (or phencychdine-like compounds), sedative-hypnotics or benzodiazepines, and other (or unknown) substances and combinations of all of the above.
  • the term "substance use disorders” includes drug withdrawal disorders such as alcohol withdrawal with or without perceptual disturbances; alcohol withdrawal delirium; amphetamine withdrawal; cocaine withdrawal; nicotine withdrawal; opioid withdrawal; sedative, hypnotic or anxiolytic withdrawal with or without perceptual disturbances; sedative, hypnotic or anxiolytic withdrawal delirium; and withdrawal symptoms due to other substances. It will be appreciated that reference to treatment of nicotine withdrawal includes the treatment of symptoms associated with smoking cessation.
  • substance use disorders include substance-induced anxiety disorder with onset during withdrawal; substance-induced mood disorder with onset during withdrawal; and substance-induced sleep disorder with onset during withdrawal.
  • movement disorders includes akinesias and akinetic-rigid syndromes, dyskinesias and medication-induced parkinsonism (such as neuroleptic-induced parkinsonism, neuroleptic malignant syndrome, neuroleptic-induced acute dystonia, neuroleptic - induced acute akathisia, neuroleptic-induced tardive dyskinesia and medication-induced postural tremor).
  • akinetic-rigid syndromes include Parkinson's disease, drug-induced parkinsonism, postencephalitic parkinsonism, progressive supranuclear palsy, multiple system atrophy, corticobasal degeneration, parkinsonism -ALS dementia complex and basal gangha calcification.
  • Examples of “dyskinesias” include tremor (including rest tremor, postural tremor and intention tremor), chorea (such as Sydenham's chorea, Huntington's disease, benign hereditary chorea, neuroacanthocytosis, symptomatic chorea, drug- induced chorea and hemiballism), myoclonus (including generalised myoclonus and focal myoclonus), tics (including simple tics, complex tics and symptomatic tics), and dystonia (including generalised dystonia such as iodiopathic dystonia, drug-induced dystonia, symptomatic dystonia and paroxymal dystonia, and focal dystonia such as blepharospasm, oromandibular dystonia, spasmodic dysphonia, spasmodic torticollis, axial dystonia, dystonic writer's cramp and hemiplegic dystonia).
  • chorea such as Sydenham's chorea, Hunt
  • 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(trifiuoromethyl)phenyl)-2- hydroxyethoxy)-3-(S)-(4-fluorophenyl)-4-(l,2,4-triazol-3- yl)methylmorpholine, or a pharmaceutically acceptable salt thereof.
  • Full descriptions of the preparation of the NK-1 receptor antagonist which may be employed in the present invention may be found in International Patent Specification No. WO 95/18124 and US Patent No. 5,612,337.
  • Suitable antipsychotic agents of use in combination with the NK-1 receptor antagonist include the phenothiazine, thioxanthene, heterocyclic dibenzazepine, butyrophenone, diphenylbutylpiperidine and indolone classes of antipsychotic agent.
  • Suitable examples of phenothiazines include chlorpromazine, mesoridazine, thioridazine, acetophenazine, fluphenazine, perphenazine and trifluoperazine.
  • Suitable examples of thioxanthenes include chlorprothixene and thiothixene.
  • dibenzazepines include clozapine and olanzapine.
  • An example of a butyrophenone is haloperidol.
  • An example of a diphenylbutylpiperidine is pimozide.
  • An example of an indolone is molindolone.
  • Other antipsychotic agents include loxapine, sulpiride and risperidone.
  • the antipsychotic agents when used in combination with the NK- 1 receptor antagonist may be in the form of a pharmaceutically acceptable salt, for example, chlorpromazine hydrochloride, mesoridazine besylate, thioridazine hydrochloride, acetophenazine maleate, fluphenazine hydrochloride, flurphenazine enathate, fluphenazine decanoate, trifluoperazine hydrochloride, thiothixene hydrochloride, haloperidol decanoate, loxapine succinate and molindone hydrochloride.
  • Perphenazine, chlorprothixene, clozapine, olanzapine, haloperidol, pimozide and risperidone are commonly used in a non-salt form.
  • NK- 1 receptor antagonists include dopamine receptor antagonists, especially D2, D3 and D4 dopamine receptor antagonists, and muscarinic ml receptor agonists.
  • D3 dopamine receptor antagonist is the compound PNU-99194A.
  • D4 dopamine receptor antagonist is PNU-101387.
  • a muscarinic ml receptor agonist is xanomeline.
  • Another class of antipsychotic agent of use in combination with the NK-1 receptor antagonist is the 5-HT 2 A receptor antagonists, examples of which include MDL100907 and fananserin.
  • 5-HT 2 A receptor antagonists examples of which include MDL100907 and fananserin.
  • SDAs serotonin dopamine antagonists
  • olanzapine and zip erasi done examples of which include olanzapine and zip erasi done.
  • Suitable antiparkinsonian agents of use in combination with the NK-1 receptor antagonist include levodopa (with or without a selective extracerebral decarboxylase inhibitor such as carbidopa or benserazide), anticholinergics such as biperiden (optionally as its hydrochloride or lactate salt) and trihexyphenidyl (benzhexol) hydrochloride, and dopamine agonists such as alentemol, bromocriptine, fenoldopam, lisuride, naxagolide, pergolide and pramipexole.
  • levodopa with or without a selective extracerebral decarboxylase inhibitor such as carbidopa or benserazide
  • anticholinergics such as biperiden (optionally as its hydrochloride or lactate salt) and trihexyphenidyl (benzhexol) hydrochloride
  • dopamine agonists such as al
  • the dopamine agonist may be in the form of a pharmaceutically acceptable salt, for example, alentemol hydrobromide, bromocriptine mesylate, fenoldopam mesylate, naxagohde hydrochloride and pergolide mesylate. Lisuride and pramipexol are commonly used in a non-salt form.
  • Suitable neuroleptic agents of use in combination with the NK- 1 receptor antagonist include the phenothiazine, thioxanthene, heterocyclic dibenzazepine, butyrophenone, diphenylbutylpiperidine and indolone classes of neuroleptic agent.
  • Suitable examples of phenothiazines include chlorpromazine, mesoridazine, thioridazine, acetophenazine, fluphenazine, perphenazine and trifluoperazine.
  • Suitable examples of thioxanthenes include chlorprothixene and thiothixene.
  • An example of a dibenzazepine is clozapine.
  • An example of a butyrophenone is haloperidol.
  • An example of a diphenylbutylpiperidine is pimozide.
  • An example of an indolone is molindolone.
  • Other neuroleptic agents include loxapine, sulpiride and risperidone.
  • the neuroleptic agents when used in combination with the NK-1 receptor antagonist may be in the form of a pharmaceutically acceptable salt, for example, chlorpromazine hydrochloride, mesoridazine besylate, thioridazine hydrochloride, acetophenazine maleate, fluphenazine hydrochloride, flurphenazine enathate, fluphenazine decanoate, trifluoperazine hydrochloride, thiothixene hydiOchloride, haloperidol decanoate, loxapine succinate and molindone hydrochloride.
  • Perphenazine, chlorprothixene, clozapine, haloperidol, pimozide and risperidone are commonly used in a non-salt form.
  • 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.
  • Suitable pharmaceutically acceptable salts of the antipsychotic, antiparkinsonian, or neuroleptic agents used in combination with the NK- 1 receptor antagonist according to the present invention include those salts described above in relation to the salts of the NK-1 receptor antagonist.
  • the antipsychotic agent carries an acidic group, for example a carboxylic acid group
  • the present invention also contemplates the use of salts thereof, preferably non-toxic pharmaceutically acceptable salts thereof, such as the sodium, potassium and calcium salts thereof.
  • the 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 like.
  • 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.
  • 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 p reformulation 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
  • a pharmaceutical carrier e.g. conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalc
  • This solid preformulation composition is then subdivided into unit dosage forms of the type described above containing from 0.1 to about 500 mg of the active ingredient of the present invention.
  • the tablets or pills of the novel composition can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action.
  • 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 well as elixirs and similar pharmaceutical vehicles.
  • Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinyl-pyrrolidone or gelatin.
  • 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.
  • the present invention further provides a process for the preparation of a pharmaceutical composition comprising the compound 2-(R)-(l-(S)- (3,5-bis(trifluoromethyl)phenyl)-2-hydiOxyethoxy)-3-(S)-(4-fluorophenyl)-4- (l,2,4-triazol-3-yl)methylmorpholine, or a pharmaceutically acceptable salt thereof, and an antipsychotic, antiparkinsonian, or neuroleptic agent, which process comprises bringing 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 and an antipsychotic, antiparkinsonian, or neuroleptic agent
  • the NK-1 receptor antagonist and an antipsychotic, antiparkinsonian, or neuroleptic agent are presented in a ratio which is consistent with the manifestation of the desired effect.
  • the ratio by weight of the NK-1 receptor antagonist and the antipsychotic, antiparkinsonian, or neuroleptic 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 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 lOOOmg per day and especially about
  • the compounds are administered one to three times daily, preferably once a day.
  • a minimum dosage level for the antipsychotic agent will vary depending upon the choice of agent, but is typically about 0.5mg per day for the most potent compounds or about 20mg per day for less potent compounds.
  • a maximum dosage level for the antipsychotic agent is typically 30mg per day for the most potent compounds or 200mg per day for less potent compounds. The compounds are administered one to three times daily, preferably once a day.
  • a minimum dosage level for the antiparkinsonian agent will vary depending upon the choice of agent, but is typically about 0.05mg per day for the most potent compounds or about 20mg per day for less potent compounds.
  • a maximum dosage level for the antipsychotic agent is typically 30mg per day for the most potent compounds or 500mg per day for less potent compounds.
  • the compounds are administered one to three times daily, preferably once or twice a day, and especially once a day.
  • a minimum dosage level for the neuroleptic agent will vary depending upon the choice of agent, but is typically about 0.5mg per day for the most potent compounds or about 20mg per day for less potent compounds.
  • a maximum dosage level for the neuroleptic agent is typically 30mg per day for the most potent compounds or 200mg per day for less potent compounds.
  • the compounds are administered one to three times daily, preferably once or twice a day, and especially once a day.
  • the amount of the NK-1 receptor antagonist required for use in the treatment or prevention of schizophrenic diosrders will vary not only with the particular compounds or compositions selected but also with the route of administration, the nature of the condition being treated, and the age and condition of the patient, and will ultimately be at the discretion of the patient's physician or pharmacist.
  • the amount of the NK-1 receptor antagonist and the antipsychotic agent required for use in the treatment or prevention of schizophrenic disorders will vary not only with the particular compounds or compositions selected but also with the route of administration, the nature of the condition being treated, and the age and condition of the patient, and will ultimately be at the discretion of the patient's physician or pharmacist.
  • the amount of the NK-1 receptor antagonist and the antiparkinsonian or neuroleptic agent required for use in the treatment or prevention of movement 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 the following assays: ASSAY 1: NK-1 Receptor binding
  • NK-1 receptor binding assays are performed in intact Chinese hamster ovary (CHO) cells expressing the human NK-1 receptor using a modification of the assay conditions described by Cascieri et al, J. Pharmacol. Exp. Ther., 1992, 42, 458. Typically, the receptor is expressed at a level of 3xl0 5 receptors per cell. Cells are grown in monolayer culture, detached from the plate with enzyme-free dissociation solution (Speciality Media Inc.), and washed prior to use in the assay.
  • 125 I-Tyr 8 -substance P (O.lnM, 2000Ci/mmol; New England Nuclear) is incubated in the presence or absence of test compounds (dissolved in 5 ⁇ l dimethylsulphoxide, DMSO) with 5xl0 4 CHO cells.
  • 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-ligand complex is harvested by filtration over GF/C filters pre-soaked in 0.1% polyethylenimine using a Tomtek 96-well harvester. Non-specific binding is determined using excess substance P (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.
  • test compounds Male or female Mongolian gerbils (35-70g) are anaesthetised by inhalation of an isoflurane/oxygen mixture to permit exposure of the jugular vein in order to permit administration of test compounds or vehicle in an injection volume of 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[ ⁇ _-Pro 9 ,Me-Leu 10 ]-substance P-(7- 11)) 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.
  • mice 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 2 weeks old. Before entering an experiment, the pups are screened to ensure that a vigorous vocalisation response is reproducibly elicited following maternal separation. The pups are placed individually in an observation cage (55cm x 39cm x 19cm) in a room physically isolated from the home cage for 15 minutes and the duration of vocalisation during this baseline 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). On test days each pup receives an oral dose or an s.c. or i.p.
  • test compound or vehicle 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 baseline 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 ID ⁇ o ⁇ 3mg/kg, and preferably with an
  • 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 ID ⁇ o ⁇ 30mg/kg, and preferably with an ID ⁇ o ⁇ 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 ID5o ⁇ 20mg/kg, preferably with an IDso ⁇ lOmg/kg, and especially with an IDso ⁇ 5mg/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 ID5o ⁇ 20mg/kg, preferably with an ID ⁇ o ⁇ lOmg/kg, and especially with an IDso ⁇ mg/kg.
  • a suitable selection cascade for NKi antagonists of use according to the present invention is as follows:
  • Yet further preferred compounds of use in the present invention may be selected from those compounds which satisfy the NK-1 20 receptor binding criteria of step (i) which, in addition, have ⁇ ⁇ -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, ⁇ -bis(trifluoromethyl)phenyl)-2-hydroxyethoxy)-3- 2 ⁇ (S)-(4-fluorophenyl)-4-(l,2 ) 4-triazol-3-yl)methylmorpholine, the preparation of which is described in International Patent Specification No. WO 9 ⁇ /18124 and US Patent No. ⁇ ,612,337.
  • 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
  • compositions comprising a combination of a NK-1 receptor antagonist and an antipsychotic agent may be prepared with l ⁇ separate active ingredients or with a combination of active ingredients in one composition. In such combined preparations, the ratio of the NK-1 receptor antagonist and the antipsychotic agent will depend upon the choice of active ingredients.
  • NK-1 antagonist ⁇ .0 50.0 100.0 100.0 300.0 300.0 haloperidol ⁇ .O 10.0 ⁇ .O 10.0 ⁇ .O 10.0
  • the active ingredients, cellulose, lactose and a portion of the corn starch are mixed and granulated with 10% corn starch paste.
  • the resulting granulation is sieved, dried and blended with the remainder of the corn starch and the magnesium stearate.
  • the resulting granulation is then compressed into tablets containing ⁇ Omg, lOOmg and 300mg of the NK-1 receptor antagonist per tablet.
  • compositions comprising a combination of the NK- 1 receptor antagonist and a neuroleptic agent may be prepared with separate active ingredients or with a combination of active ingredients in one composition. In such combined preparations, the ratio of the NK-1 receptor antagonist and the neuroleptic agent will depend upon the choice of active ingredients.
  • NK-1 antagonist ⁇ .0 ⁇ .0 100.0 100.0 300.0 300.0 haloperidol ⁇ .O 10.0 5.0 10.0 5.0 10.0
  • the active ingredients, cellulose, lactose and a portion of the corn starch are mixed and granulated with 10% corn starch paste.
  • the resulting granulation is sieved, dried and blended with the remainder of the corn starch and the magnesium stearate.
  • the resulting granulation is 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 concerne l'utilisation d'un antagoniste du récepteur NK-1 (neurokinine 1) pour la fabrication d'un médicament, administrable par voie orale, intervenant dans le traitement ou la prévention de troubles schizophréniques, de troubles liés à l'utilisation de certaines substances et de troubles de la mobilité ainsi que des techniques de traitement médical au moyen d'un tel antagoniste du récepteur NK-1 et des compositions pharmaceutiques et des produits renfermant ledit antagoniste.
PCT/GB1999/001819 1998-06-11 1999-06-08 Utilisation d'un antagoniste du recepteur nk-1 dans le traitement des troubles psychiatriques WO1999064010A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
AU42796/99A AU4279699A (en) 1998-06-11 1999-06-08 Use of a nk-1 receptor antagonist for treating psychiatric disorders
CA002334609A CA2334609A1 (fr) 1998-06-11 1999-06-08 Utilisation d'un antagoniste du recepteur nk-1 dans le traitement des troubles psychiatriques
JP2000553079A JP2002517448A (ja) 1998-06-11 1999-06-08 精神障害の治療用nk−1受容体アンタゴニストの使用
EP99955427A EP1085875A1 (fr) 1998-06-11 1999-06-08 Utilisation d'un antagoniste du recepteur nk-1 dans le traitement des troubles psychiatriques

Applications Claiming Priority (6)

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GBGB9812669.1A GB9812669D0 (en) 1998-06-11 1998-06-11 Therapeutic use
GB9812669.1 1998-06-11
GBGB9812661.8A GB9812661D0 (en) 1998-06-11 1998-06-11 Therapeutic use
GBGB9812663.4A GB9812663D0 (en) 1998-06-11 1998-06-11 Therapeutic use
GB9812663.4 1998-06-11
GB9812661.8 1998-06-11

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Cited By (4)

* 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
US6620438B2 (en) 2001-03-08 2003-09-16 Boehringer Ingelheim Pharma Kg Pharmaceutical compositions based on anticholinergics and NK1-receptor antagonists
WO2002069944A3 (fr) * 2001-03-08 2003-10-02 Boehringer Ingelheim Pharma Nouvelles compositions medicamenteuses a base d'anticholinergiques et d'antagonistes de recepteurs nk1
WO2009109001A1 (fr) * 2008-03-04 2009-09-11 Adelaide Research & Innovation Pty Ltd Procédé de prévention et/ou de traitement d’une maladie, d’une condition ou d’un état associés à une fonction réduite des neurones dopaminergiques

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060030600A1 (en) * 2004-08-06 2006-02-09 Patrick Schnider Dual NK1/NK3 receptor antagonists for the treatment of schizophrenia
WO2006043532A1 (fr) * 2004-10-19 2006-04-27 Ono Pharmaceutical Co., Ltd. Agent thérapeutique pour la maladie de parkinson

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WO1995018124A1 (fr) * 1993-12-29 1995-07-06 Merck Sharp & Dohme Limited Derives de morpholine substitues et une utilisation en tant qu'agents therapeutiques
WO1997018206A1 (fr) * 1995-11-14 1997-05-22 Merck Sharp & Dohme Limited Derives de la morpholine et leur utilisation comme agents therapeutiques
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
WO1998024445A1 (fr) * 1996-12-02 1998-06-11 Merck Sharp & Dohme Limited Utilisation d'antagonistes du recepteur nk-1 dans le traitement des troubles schizophreniques
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
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
WO1998024443A1 (fr) * 1996-12-02 1998-06-11 Merck Sharp & Dohme Limited Utilisation d'antagonistes du recepteur nk-1 dans le traitement des troubles bipolaires
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
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

Patent Citations (9)

* 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
WO1997018206A1 (fr) * 1995-11-14 1997-05-22 Merck Sharp & Dohme Limited Derives de la morpholine et leur utilisation comme agents therapeutiques
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
WO1998024445A1 (fr) * 1996-12-02 1998-06-11 Merck Sharp & Dohme Limited Utilisation d'antagonistes du recepteur nk-1 dans le traitement des troubles schizophreniques
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
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
WO1998024443A1 (fr) * 1996-12-02 1998-06-11 Merck Sharp & Dohme Limited Utilisation d'antagonistes du recepteur nk-1 dans le traitement des troubles bipolaires
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
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

Cited By (5)

* 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
US6620438B2 (en) 2001-03-08 2003-09-16 Boehringer Ingelheim Pharma Kg Pharmaceutical compositions based on anticholinergics and NK1-receptor antagonists
WO2002069944A3 (fr) * 2001-03-08 2003-10-02 Boehringer Ingelheim Pharma Nouvelles compositions medicamenteuses a base d'anticholinergiques et d'antagonistes de recepteurs nk1
WO2009109001A1 (fr) * 2008-03-04 2009-09-11 Adelaide Research & Innovation Pty Ltd Procédé de prévention et/ou de traitement d’une maladie, d’une condition ou d’un état associés à une fonction réduite des neurones dopaminergiques

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