Note: Descriptions are shown in the official language in which they were submitted.
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USE OF A NK-1 RECEPTOR ANTAGONIST FOR TREATING
PSYCHIATRIC DISORDERS
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,)-(1-(S)-(3,5-bis(trifluoromethyl)phenyl)-2-hydroxyethoxy)-
3-(S)-(4-ffuorophenyl)-4-(1,2,4-triazol-3-yl)methylmorpholine, 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 time over at least one
month. The so-called "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.
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. Frequently, 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, such as haloperidol and chlorpromazine, is typically associated
with a number of side-effects, including extrapyramidal symptoms, acute
dystonias, tardive dyskinesias, akathesia, tremor, tachycardia, drowsiness,
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confusion, postural hypotension, blurring of vision, precipitation of
glaucoma, dry mouth, constipation, urinary hesitance and impaired sexual
function. Such 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.
Withdrawal of benzodiazepines after long-term therapy may result
in a disturbance of sleep pattern (rebound insomnia assicated with
abnormal sleep patterns), agitation, restlessness, and occasionally
epileptic convulsions.
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)
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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. However, 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'"~ or benserazide (MADOPA.R,"~ 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.
An 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 (PAR,LODELT'~, lisuride
and pergolide (CELANCE~ act directly on dopamine receptors and have a
similar side-effect profile to levodopa.
The dyskinesias, notably tremor, chorea, myoclonus, tics and
dystonias, are treated with a variety of pharmacological agents. Thus, for
example, tremor may be treated with benzodiazepines such as diazepam;
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chorea may be treated with diazepam, a phenothiazide or haloperidol, or
tetrabenazine; tics may be controlled with neuroleptics such as haloperidol
or pimozide; and 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, such as
haloperidol 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 95/1GG79, WO 95/18124 and WO 95/23798).
On the other hand, 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. Thus, degrading
substance P or reducing the action of substance P in some other way (e.g.
antagonism at its preferred NK-1 receptor) might be expected to be
detrimental to the treatment of psychoses such as schizophrenic disorders.
More recently, International (PCT) patent specification No. WO
96/24353 (published 15th August 199G) suggests that a more efficacious
and safe treatment of psychiatric disorders would be achieved using a
combination of a tachykinin antagonist and a serotonin agonist or selective
serotonin reuptake inhibitor (SSRI).
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It has been reported that central (i.c.v.) injection of RP67580 could
attenuate naloxone-precipitated withdrawal signs in rats receiving
morphine for five days (Maldonado et al, Neurosci. Letts., 156:135, 1993).
This study resembles an earlier report using guinea-pigs showing that the
morphine withdrawal response was inhibited by i.c.v. injection of peptide
substance P antagonists (Johnston & Chahl, Arch. Pharrnacol., 343:283,
1991). These investigators subsequently attempted to block the
withdrawal response in guinea-pigs using systemic administration of
CP-96,345, and found that only high doses (20mglkg) were active, and this
could therefore not be attributed with confidence to a specific blockage of
NK-1 receptors (Chahl & Johnston, Regul. Pept. Suppl. 1, 543, 1992).
In view of the short-comings of existing antipsychotic therapy, there
is a need for new, safe and effective treatment for schizophrenic disorders,
substance use disorders, and movement disorders.
The present invention provides the use of 2-(R,)-(1-(S)-(3,5-
bis(triffuoromethyl)phenyl)-2-hydroxyethoxy)-3-(S)-(4-fluorophenyl)-4-
(1,2,4-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.
Furthermore, the exceptional pharmacology of the NK-1 receptor
antagonist of use in the present invention results in a rapid onset of
action.
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The present invention accordingly provides the use of 2-(R,)-(1-(S)-
(3,5-bis(triffuoromethyl)phenyl)-2-hydroxyethoxy)-3-(S)-(4-fluorophenyl)-4-
(1,2,4-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,)-(1-(S)-
(3,5-bis(trifluoromethyl)phenyl)-2-hydroxyethoxy)-3-(S)-(4-fluorophenyl)-4-
(1,2,4-triazol-3-yl)methylmorpholine, or a pharmaceutically acceptable salt
thereof_
In a further aspect of the present invention, there is provided an
oral pharmaceutical composition for the treatment of schizophrenic
disorders, substance use disorders, and movement disorders which
comprises 2-(R,)-(1-(S)-(3,5-bis(triffuoromethyl)phenyl)-2-hydroxyethoxy)-3-
(S)-(4-ffuorophenyl)-4-(1,2,4-triazol-3-yl)methylmorpholine, or a
pharmaceutically acceptable salt thereof, together with a pharmaceutically
acceptable carrier or excipient.
There exists a patient population in whom schizophrenic disorders
are inadequately treated with existing antipsychotic therapy.
Furthermore, some patients may be adversely affected by the side-effects
of antipsychotic drugs.
The present invention accordingly provides the use of 2-(R,)-(1-(S)-
(3,5-bis(trifluoromethyl)phenyl)-2-hydroxyethoxy)-3-(S)-(4-fluorophenyl)-4-
(1,2,4-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
in a patient who is non-responsive to antipsychotic agents, or for whom
antipsychotic agents are contraindicated.
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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 oxal administration to the
patient in need of such treatment of an effective amount of 2-(R,)-(1-(S)-
(3, 5-bis(triffuoromethyl)phenyl)-2-hydroxyethoxy)-3-(S)-(4-fluorophenyl)-4-
(1,2,4-triazol-3-yl)methylmorpholine, or a pharmaceutically acceptable salt
thereof.
Whilst it is envisaged that 2-(R.)-(1-(S)-(3,5-
bis(trifluoromethyl)phenyl)-2-hydroxyethoxy)-3-(S)-(4-fluorophenyl)-4-
(1,2,4-triazol-3-yl)methylmorpholine, or a pharmaceutically acceptable salt
thereof, will be useful alone in the treatment of schizophrenic disorders, it
will be appreciated that 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".
Furthermore, 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.
Thus, according to a further aspect of the present invention there is
provided the use of 2-(R,)-(1-(S)-(3,5-bis(trifluoromethyl)phenyl)-2-
hydroxyethoxy)-3-(S)-(4-fluorophenyl)-4-(1,2,4-triazol-3-
yl)methylmorpholine, or a pharmaceutically acceptable salt thereof, and
an antipsychotic agent for the manufacture of a medicament for the
treatment or prevention of schizophrenic disorders.
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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,)-{1-(S)-(3,5-bis(triffuoromethyl)phenyl)-2-hydroxyethoxy)-3-(S)-(4-
ffuorophenyl)-4-(1,2,4-triazol-3-yl)methylmorpholine, or a
pharmaceutically acceptable salt thereof, and an amount of an
antipsychotic agent, such that together they give effective relief.
It will be appreciated that the 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.
In a further or alternative aspect of the present invention, there is
therefore provided a product comprising 2-(R)-(1-(S)-(3,5-
bis(triffuoromethyl)phenyl)-2-hydroxyethoxy)-3-(S)-(4-fluorophenyl)-4-
(1,2,4-triazol-3-yl)methylmorpholine, or a pharmaceutically acceptable salt
thereof, and an antipsychotic agent as a combined preparation for
simultaneous, separate or sequential use in the treatment or prevention of
schizophrenic disorders.
There also exists a patient population in whom dyskinesias are
inadequately treated with existing neuroleptic therapy. Furthermore,
some patients may be adversely affected by the side-effects of neuroleptic
drugs.
The present invention accordingly provides the use of 2-(R.)-(1-(S)-
(3,5-bis(triffuoromethyl)phenyl)-2-hydroxyethoxy)-3-(S)-(4-ffuorophenyl)-4-
(1,2,4-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.
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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,)-(1-(S)-(3,5-bis(trifluoromethyl)phenyl)-2-
hydroxyethoxy)-3-(S)-(4-ffuorophenyl)-4-( 1,2,4-triazol-3-
yl)methylmorpholine, or a pharmaceutically acceptable salt thereof.
Whilst it is envisaged that 2-(R,)-(1-(S)-{3,5-
bis(trifluoromethyl)phenyl)-2-hydroxyethoxy)-3-(S)-(4-fluorophenyl)-4
(1,2,4-triazol-3-yl)methylmorpholine, or a pharmaceutically acceptable salt
thereof, will be useful alone in the treatment of movement disorders, it
will be appreciated that a combination of a conventional antiparkinsonian
drug with 2-(R,)-(1-(S)-(3,5-bis(trifluoromethyl)phenyl)-2-hydroxyethoxy)-3-
(S)-(4-fluorophenyl)-4-(1,2,4-triazol-3-yl)methylmorpholine, or a
pharmaceutically acceptable salt thereof, may provide an enhanced effect
in the treatment of akinetic-rigid disorders such as parkinsonism. 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.
Thus, according to a further aspect of the present invention there is
provided the use of 2-(R,)-(1-(S)-(3,5-bis(trifluoromethyl)phenyl)-2-
hydroxyethoxy)-3-{S)-(4-fluorophenyl)-4-(1,2,4-triazol-3-
yl)methylmorpholine, or a pharmaceutically acceptable salt thereof, and
an antiparkinsonian agent for the manufacture of a medicament for the
treatment or prevention of akinetic-rigid disorders.
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,)-(1-(S)-(3,5-bis(trifluoromethyl)phenyl)-2-hydroxyethoxy)-3-(S)-(4-
fluorophenyl)-4-(1,2,4-triazol-3-yl)methylmorpholine, or a
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pharmaceutically acceptable salt thereof, and an amount of an
antiparkinsonian agent, such that together they give effective relief.
In a further aspect of the present invention, there is provided a
pharmaceutical composition comprising 2-(R,)-(1-(S)-(3,5-
bis(triffuoromethyl)phenyl)-2-hydroxyethoxy)-3-(S)-(4-fluorophenyl)-4-
{1,2,4-triazol-3-yl)methylmorpholine, or a pharmaceutically acceptable salt
thereof, and an antiparkinsonian agent, together with at least one
pharmaceutically acceptable carrier or excipient.
It will be appreciated that the 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.
In a further or alternative aspect of the present invention, there is
therefore provided a product comprising 2-(R,)-(1-(S)-(3,5-
bis(triffuoromethyl)phenyl)-2-hydroxyethoxy)-3-(S)-(4-fluorophenyl)-4-
(1,2,4-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.
It will be further appreciated that a combination of a conventional
neuroleptic drug with 2-(R,)-(1-(S)-(3,5-bis(trifluoromethyl)phenyl)-2-
hydroxyethoxy)-3-(S)-(4-fluorophenyl)-4-( 1,2,4-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
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acute dystonias, dyskinesias, akathesia and tremor may be reduced or
prevented.
Thus, according to a further aspect of the present invention there is
provided the use of 2-(R)-(1-(S)-(3,5-bis(triffuoromethyl)phenyl)-2-
hydroxyethoxy)-3-(S)-(4-fluorophenyl)-4-(1,2,4-triazol-3-
yl)methylmorpholine, or a pharmaceutically acceptable salt thereof, and a
neuroleptic agent for the manufacture of a medicament for the treatment
or prevention of dyskinesias.
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.)-(1-(S)-(3,5-
bis(trifluoromethyl)phenyl)-2-hydroxyethoxy)-3-(S)-(4-ffuorophenyl)-4-
(1,2,4-triazol-3-yl)methylmorpholine, or a pharmaceutically acceptable salt
thereof, and an amount of a neuroleptic agent, such that together they give
effective relief.
In a further aspect of the present invention, there is provided a
pharmaceutical composition comprising 2-(R,)-(1-(S)-(3,5-
bis(trifluoromethyl)phenyl)-2-hydroxyethoxy)-3-(S)-(4-ffuorophenyl)-4-
(1,2,4-triazol-3-yl)methylmorpholine, or a pharmaceutically acceptable salt
thereof, and a neuroleptic agent, together with at least one
pharmaceutically acceptable carrier or excipient.
It will be appreciated that the 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.
In a further or alternative aspect of the present invention, there is
therefore provided a product comprising 2-(R,)-(1-(S)-(3,5-
bis(trifluoromethyl)phenyl)-2-hydroxyethoxy)-3-(S)-(4-fluorophenyl)-4
(1,2,4-triazol-3-yl)methylmorpholine, or a pharmaceutically acceptable salt
thereof, and an neuroleptic agent as a combined preparation for
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simultaneous, separate or sequential use in the treatment or prevention of
dyskinesias.
It will be appreciated that when using a combination of the present
invention, 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. By a
"fast-dissolving oral formulation" is meant, an oral delivery form which
when placed on the tongue of a patient, dissolves within about 10 seconds.
As used herein, the term "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
sp ecified.
Other conditions commonly associated with schizophrenic disorders
include self injurious behaviour (e.g. Lesch-Nyhan syndrome) and suicidal
gestures.
As used herein, the term "substance use clisorders" 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
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phencyclidine-like compounds), sedative-hypnotics or benzodiazepines, and
other (or unknown) substances and combinations of all of the above.
In particular, 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.
Other "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.
As used herein, the term "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). Examples of "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 ganglia 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
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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).
Another "movement disorder" which may be treated according to the
present invention is Gilles de la Tourette's syndrome, and the symptoms
thereof.
As used herein, the term "treatment" refers both to the treatment
and to the prevention or prophylactic therapy of the aforementioned
conditions.
In particular, the NK-1 receptor antagonist of use in the present
invention is the compound 2-(R,)-(1-(S)-(3,5-bis(triffuoromethyl)phenyl)-2-
hydroxyethoxy)-3-(S)-(4-ffuorophenyl)-4-(1,2,4-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 triffuoperazine. Suitable examples of
thioxanthenes include chlorprothixene and thiothixene. Suitable
examples of 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, sulpirzde and
risperidone. It will be appreciated that the antipsychotic agents when
used in combination with the NK-1 receptor antagonist may be in the form
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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.
Other classes of antipsychotic agnet of use in combination with the
NK-1 receptor antagonist include dopamine receptor antagonists,
especially D2, D3 and D4 dopamine receptor antagonists, and muscarinic
m1 receptor agonists. An example of a D3 dopamine receptor antagonist is
the compound PNU-99194A. An example of a D4 dopamine receptor
antagonist is PNU-101387. An example of a muscarinic ml receptor
agonist is xanomeline.
Another class of antipsychotic agent of use in combination with the
NK-I receptor antagonist is the 5-HTzn receptor antagonists, examples of
which include MDL100907 and fananserin. Also of use in combination
with a NK-1 receptor antagonist are the serotonin dopamine antagonists
(SDAs) which are believed to combine 5-HTzA and dopamine receptor
antagonist activity, examples of which include olanzapine and
ziperasidone.
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. It will be appreciated that the
dopamine agonist may be in the form of a pharmaceutically acceptable
salt, for example, alentemol hydrobromide, bromocriptine mesylate,
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fenoldopam mesylate, naxagolide 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
r eceptor 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. It will be appreciated that 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 hydrochloride, 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, malefic acid, succinic acid, acetic acid,
citric
acid, tartaric acid, carbonic acid, phosphoric acid or sulphuric acid. Salts
of amine groups may also comprise the quaternary ammonium salts in
which the amino nitrogen atom carries an alkyl, alkenyl, alkynyl or
aralkyl group.
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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. Where 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.
Preferably 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. Additionally,
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. Alternatively, 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.
For preparing solid compositions such as tablets, the principal
active ingredient is mixed with a pharmaceutical carrier, e.g. conventional
tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc,
stearic acid, magnesium stearate, dicalcium phosphate or gums, and other
pharmaceutical diluents, e.g. water, to form a solid preformulation
composition containing a homogeneous mixture of a compound of the
present invention, or a non-toxic pharmaceutically acceptable salt thereof.
When referring to these preformulation compositions as homogeneous, it is
meant that the active ingredient is dispersed evenly throughout the
composition so that the composition may be readily subdivided into equally
effective unit dosage forms such as tablets, pills and capsules. This solid
preformulation composition is then subdivided into unit dosage forms of
the type described above containing from 0.1 to about 500 mg of the active
ingredient of the present invention. The tablets or pills of the novel
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composition can be coated or otherwise compounded to provide a dosage
form affording the advantage of prolonged action. For example, the tablet
or pill can comprise an inner dosage and an outer dosage component, the
latter being in the form of an envelope over the former. The two
components can be separated by an enteric layer which serves to resist
disintegration in the stomach and permits the inner component to pass
intact into the duodenum or to be delayed in release. A variety of
materials can be used for such enteric layers or coatings, such materials
including a number of polymeric acids and mixtures of polymeric acids
with such materials as shellac, cetyl alcohol and cellulose acetate.
The liquid forms in which the novel compositions of the present
invention may be incorporated for administration orally 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,
metbylcellulose, 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,)-(1-(S)-
(3,5-bis(trifluoromethyl)phenyl)-2-hydroxyethoxy)-3-(S)-(4-fluorophenyl)-4-
(1,2,4-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,)-(1-(S)-(3,5-
bis(trifluoromethyl)phenyl)-2-hydroxyethoxy)-3-(S)-(4-fluorophenyl)-4-
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(1,2,4-triazol-3-yl)methylmorpholine, or a pharmaceutically acceptable salt
thereof and an antipsychotic, antiparkinsonian, or neuroleptic agent, into
association with a pharmaceutically acceptable carrier or excipient.
When administered in combination, either as a single or as separate
pharmaceutical composition(s), the NK-1 receptor antagonist and an
antipsychotic, antiparkinsonian, or neuroleptic agent are presented in a
ratio which is consistent with the manifestation of the desired effect. In
particular, 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 l0mg per
day. A maximum dosage level for the NK-1 receptor antagonist is about
1500mg per day, preferably about 1000mg per day and especially about
500mg per day. 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.
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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.
It will be appreciated that 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.
When used in combination, it will be appreciated that 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.
When used in combination, it will be appreciated that 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.
The activity of the NK-1 receptor antagonists of use in the present
invention may be measured using the following assays:
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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 3x105 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. Iz5I_Tyr$-substance P
(0. lnM, 2000Ci/mmol; New England Nuclear) is incubated in the presence
or absence of test compounds (dissolved in 5Nl dimethylsulphoxide, DMSO)
with 5x104 CHO cells. Ligand binding is performed in 0.25m1 of 50mM
Tris-HCI, pH7.5, containing 5mM MnCla, 150mM NaCI, 0.02% bovine
serum albumin (Sigma), 50~g/ml chymostatin (Peninsula), 0.lnM
phenylmethylsulphonyl fluoride, 2~.g/ml pepstatin, 2~.g/ml leupeptin and
2.8pg/ml furoyl saccharine. The incubation proceeds at room temperature
until equilibrium is achieved (>40 minutes) and the receptor-ligand
complex is harvested by filtration over GF/C filters pre-soaked in 0.1%
polyethylenimine using a Tomtek 9G-well harvester. Non-specific binding
is determined using excess substance P (1~ and represents <10% of
total binding.
ASSAY 2: Gerbil Foot-Tapping
CNS-penetrant NK-1 receptor antagonists for use in the present
invention can be identifiied 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. Phczrmacol., 1994, 265, 179.
Male or female Mongolian gerbils (35-70g) are anaesthetised by
inhalation of an isoffuraneloxygen mixture to permit exposure of the
jugular vein in order to permit administration of test compounds or vehicle
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in an injection volume of 5m1/kg i.v. Alternatively, test compounds may be
administered orally or by subcutaneous or intraperitoneal routes. A skin
incision is then made in the midline of the scalp to expose the skull. An
anxiogenic agent {e.g. pentagastrin) or a selective NK-1 receptor agonist
(e.g. GR73632 (d Ala[L-Pro9,Me-Leu»~-substance P-(7-11)) is infused
directly into the cerebral ventricles (e.g. 3pmo1 in 5~1 i.c.v., depending on
test substance) by vertical insertion of a cuffed 27 gauge needle to a depth
of 4.5mm below bregma. The scalp incision is closed and the animal
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 100g of tinned cat food. At 60 minutes following oral
dosing, cisplatin (l0mg/kg) is given i.v. uia a jugular vein catheter
inserted under a brief period of halothane anaesthesia. The catheter is
then removed, the jugular vein ligated and the skin incision closed. The
ferrets recover rapidly from the anaesthetic and are mobile within 10-20
minutes. The animals are observed continuously during recovery from the
anaesthetic and for 4 hours following the cisplatin injection, after which
time the animals are killed humanely. The numbers of retches and vomits
occurring during the 4 hours after cisplatin administration are recorded by
trained observers.
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ASSAY 4: Separation-Induced Vocalisation
Male and female guinea-pigs pups are housed in family groups with
their mothers and littermates throughout the study. Experiments are
commenced after weaning when the pups are 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 l9cm) 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. injection of test compound or vehicle and is then
immediately returned to the home cage with its mother and siblings for 30
to GO 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 G weeks. Between 6 and 8 animals receive each test compound at each
dose tested.
As used herein, the term "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.
Essentially, hind foot-tapping in the gerbil induced by infusion of
the NK-1 receptor agonist, GR73632 (d Ala[L-Pro~,Me-Leulfl]-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
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anaesthesia is inhibited with an ID~o<_3mg/kg, and preferably with an
IDso<_ lmg/kg.
In an alternative method, 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 IDso<_30mg/kg, and preferably with an IDsoslOmg/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.
Essentially, 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 IDso<_20mg/kg,
preferably with an IDso<_lOmg/kg, and especially with an IDso<_5mg/kg.
In an alternative method, 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
IDSO<_20mg/kg, preferably with an ID~o<_lOmg/kg, and especially with an
IDso__<5mg/kg.
A suitable selection cascade for NKi antagonists of use according to
the present invention is as follows:
(i) Determine amity for human NKi receptor in radioligand
binding studies (Assay 1); select compounds with ICso <_ IOnM, preferably
ICso <_ 2nM, especially ICso _< lnM.
(ii) Determine ability of compounds to penetrate CNS by their
ability to inhibit foot tapping in gerbils induced by central injection of an
NK~ agonist (Assay 2); select compounds that inhibit foot tapping with
IDso <_ 3mg/kg i.v., and preferably ID;o <_ lmg/kg i.v. when administered
immediately prior to central NK~ agonist challenge, or IDso <_ 30mg/kg p.o.,
and preferably ID:;o < l0mg/kg p.o. 1 hour prior to challenge.
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(iii) Determine central duration of action of compounds in gerbil foot
tapping assay following intravenous administration 24 hours prior to
central NK1 agonist challenge; select compounds showing _< 25-fold loss of
potency compared with IDso determined in step (ii) above with the proviso
that IDso s l0mg/kg i.v., and preferably s 5mg/kg i.v. after 24 hour
pre-treatment.
(iv) Determine oral bioavailability of compounds by pharmacoki.netic
analysis, activity in gerbil foot tapping assay following oral administration
and/or by ability to inhibit cisplatin-induced emesis in ferrets (Assay 3);
select compounds with IDso s 3mg/kg p.o., and preferably ID~o <_ lmg/kg
p.o.
Particularly preferred compounds of use in the present invention
are identified using steps (i) to (iv) followed by step (v).
(v) Determine activity of compounds in assays sensitive to
conventional antipsychotic drugs (inhibition of distress vocalisations in
guinea-pig pups (Assay 4)). Select compounds with IDso <_ 20mg/kg, and
preferably IDso <_ lOmg/kg.
Yet further preferred compounds of use in the present
invention may be selected from those compounds which satisfy the NK-1
receptor binding criteria of step (i) which, in addition, have <_ 5-fold shift
in
affinity when incubated in the presence of human serum albumin (HSA) to
show non-specific protein binding.
The NK-1 receptor antagonist of use in the present invention is the
compound 2-(R,)-(1-(S)-(3,5-bis(trifluoromethyl)phenyl)-2-hydroxyethoxy)-3-
(S)-(4-fluorophenyl)-4-(1,2,4-triazol-3-yl)methylmorpholine, 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:
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human NK-1 receptor binding: ICso= 0.12 nM
gerbil foot-tapping (5 mins.): ID~a = 0.38 mg/kg i.v.
gerbil foot-tapping (24 hrs.): IDSO = 2.2 mg/kg i.v.
ferret emesis: IDso = 1 mg/kg p.o.
guinea-pig vocalisation
(4 hr. pre-treatment): IDso = 0.91 mg/kg p.o.
The following example illustrates pharmaceutical compositions
according to the invention.
EXAMPLE 1 Tablets containing 50-300mg of NK-1 antagonist
Amount m~
NK-1 antagonist 50.0 100.0 300.0
Microcrystalline cellulose80.0 80.0 80.0
Modified food corn starch80.0 80.0 80.0
Lactose 189.5 139.5 139.5
Magnesium Stearate 0.5 0.5 0.5
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, 100mg and 300mg of the
NK-1 receptor antagonist per tablet.
Pharmaceutical compositions comprising a combination of a NK-1
receptor antagonist and an antipsychotic 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 antipsychotic agent will depend upon the
choice of active ingredients.
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EXAMPLE 2 Tablets containing 50-300mg of NK-1 antagonist and
5-10m~ of haloperidol
Amount
m~
NK-1 antagonist 50.0 50.0 100.0 100.0 300.0 300.0
haloperidol 5.0 10.0 5.0 10.0 5.0 10.0
Microcrystalline cellulose80.0 80.0 80.0 80.0 80.0 80.0
Modified food corn 80.0 80.0 80.0 80.0 80.0 80.0
starch
Lactose 184.5 179.5 134.5 129.5 134.5 129.5
Magnesium Stearate 0.5 0.5 0.5 0.5 0.5 0.5
EXAMPLE 3 Tablets containing 50-300mg of NK-1 antagonist and 25m~
of chlorpromazine hydrochloride
Amount
m~
NK-1 antagonist 50.0 100.0 300.0
chlorpromazine hydrochloride25.0 25.0 25.0
Microcrystalline cellulose80.0 80.0 80.0
Modified food corn starch80.0 80.0 80.0
Lactose 164.5 114.5 114.5
Magnesium Stearate 0.5 0.5 0.5
The active ingredients, cellulose, lactose and a portion of the corn
starch are mixed and granulated with 10% corn starch paste. The
resulting granulation is sieved, dried and blended with the remainder of
the corn starch and the magnesium stearate. The resulting granulation is
then compressed into tablets containing 50mg, 100mg and 300mg of the
NK-1 receptor antagonist per tablet.
Pharmaceutical 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
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receptor antagonist and the neuroieptic agent will depend upon the choice
of active ingredients.
EXAMPLE 4 Tablets containing 50-300mg of NK-1 antagonist and
5-lOmg of haloperidol
Amount
ma
NK-1 antagonist 50.0 50.0 100.0 100.0 300.0 300.0
haloperidol 5.0 10.0 5.0 10.0 5.0 10.0
Microcrystalline cellulose80.0 80.0 80.0 80.0 80.0 80.0
Modified food corn 80.0 80.0 80.0 80.0 80.0 80.0
starch
Lactose 184.5 179.5 134.5 129.5 134.5 129.5
Magnesium Stearate 0.5 0.5 0.5 0.5 0.5 0.5
The active ingredients, cellulose, lactose and a portion of the corn
starch are mixed and granulated with 10% corn starch paste. The
resulting granulation is sieved, dried and blended with the remainder of
the corn starch and the magnesium stearate. The resulting granulation is
then compressed into tablets containing 50mg, 100mg and 300mg of the
NK-1 receptor antagonist per tablet.
