JP2002517448A - Use of NK-1 receptor antagonist for the treatment of mental disorders - Google Patents

Abstract

  (57) [Summary] The present invention relates to the use of an NK-1 receptor antagonist for the manufacture of a medicament suitable for oral administration for the treatment or prevention of schizophrenia, substance use disorder and dyskinesia. The present invention relates to a method of treatment using a receptor antagonist, as well as pharmaceutical compositions and products containing said antagonist.

Description

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to NK-1 receptor antagonists, particularly 2- (R)-(1- (S)-
(3,5-bis (trifluoromethyl) phenyl) -2-hydroxyethoxy)
-3- (S)-(4-Fluorophenyl) -4- (1,2,4-triazole-3
-Yl) The treatment or prevention of certain schizophrenia, certain substance use disorders and movement disorders by administration of methylmorpholine or a pharmaceutically acceptable salt thereof.

An essential feature of schizophrenia is the combination of characteristic signs and symptoms (positive and negative) found in a patient for a period of at least one month. So-called "active" symptoms include delusions, hallucinations, incoherent language, incoherent or tense behavior,
And negative symptoms (eg, flattening of emotions, aphasia and lethargy). Some patients have only a single episode of disease, while many patients have repeated episodes or chronic illness.

The care of schizophrenics is a major part of the work of psychiatrists. Although long-term care of schizophrenic patients is complex, chronic schizophrenic patients who take antipsychotics for extended periods of time can usually at least control their symptoms. Schizophrenic symptoms often cannot be controlled without manifesting extrapyramidal side effects. Thus, antiparkinson drugs can be prescribed to reduce the above side effects, but the use of anticholinergic drugs can cause delayed onset dyskinesia (a side effect that is delayed and sometimes irreversible when treated with antipsychotic drugs for a long time) D) may actually increase.

[0004] Treatment of schizophrenia with antipsychotics (or neuroleptics), such as haloperidol or chlorpromacidine, usually results in extrapyramidal symptoms, acute dystonia, delayed abnormal movements, inability to sit, tremors, Numerous side effects occur, including tachycardia, somnolence, confusion, postural hypotension, blurred eyes, sudden glaucomatous onset, dry mouth, constipation, dysuria and sexual dysfunction. These side effects often debilitate patients, and these side effects are a major reason for patients not following their prescribed treatment. The side effects may also delay the patient's return to society.

[0005] Symptoms commonly (but not always) seen with prolonged use of the drug occur when the drug is stopped or the antagonist is administered, and withdrawal can usually occur in the form of certain side effects. It is a reaction.

[0006] Withdrawal symptoms occur in opiate addicts when opiate is discontinued or an antagonist such as naloxone is administered. The symptoms consist of abscission, rhinorrhea and sweating, followed by so-called narcotic residual symptoms with chills and goose bumps. Then nausea,
Vomiting, diarrhea and hypertension may occur. Acute symptoms subside within one week, but addicts may complain of anxiety and sleep disorders for weeks or months thereafter. This condition can be avoided by administering high doses of methadone when opiates are discontinued. Subsequent discontinuation of methadone, which has a much longer duration of action than morphine, does not cause the above symptoms.

[0007] Tremor delirium can occur when drinking is prohibited from chronic alcoholics. The symptoms consist of disorientation and visual hallucinations.

Discontinuation of benzodiazepines after prolonged treatment can result in impaired sleep patterns (rebound insomnia associated with abnormal sleep patterns), sway, anxiety, and sometimes epileptic seizures.

[0009] Drug treatment of drug withdrawal disorders is not always effective, and many drugs prescribed to treat withdrawal symptoms are often hampered by the potential for addiction.

[0010] Diseases of the extrapyramidal motor system are a lack of movement with increased muscle tone (rigidity) (akinesia)
Or it causes abnormal involuntary movements (dyskinesias), often with decreased muscle tone. The akinesia-rigid syndrome, called Parkinson's syndrome, and dyskinesia are at the extremes of the spectrum of movement disorders (for reference, see CD Marsden, Oxf
ord Textbook of Medicine, 3rd edition, Oxford
University Press (1996), vol. 3, p. 3998-4
022).

For the treatment of akinesia-rigid conditions such as Parkinson's syndrome, levodopa, anticholinergics or dopamine agonists are commonly used. Levodopa is converted to dopamine in the brain by the enzyme dopa decarboxylase. However, this enzyme is also present in the intestinal wall, liver, kidney and brain capillaries, thus producing side effects such as nausea, vomiting, irregular heart rhythm and postural hypotension due to the peripheral formation of levadopa metabolites Sometimes. This peripheral decarboxylation is substantially prevented by the addition of selective extracerebral decarboxylase inhibitors that do not themselves penetrate the brain, such as carbidopa or benserazide. When applying levadopa, the combination of levodopa with carbidopa (SINEMET ™) or benserazide (MADOPAR ™) is the currently selected treatment. Even with this combination therapy, side effects such as dyskinesia and psychiatric disorders can be seen.

[0012] Anticholinergics such as benzhexol or orphenadrine can be used, but anticholinergics can cause peripheral parasympathetic blockade, which can lead to dry mouth, blurred vision and constipation. Anticholinergics can also suddenly cause glaucoma, urinary retention and confusion.

[0013] Bromocriptine (PARLODEL ™), lisuride and pergolide (
Dopamine agonists such as CELANCE ™ act directly on dopamine receptors and have a side effect profile similar to levadopa.

[0014] Dyskinesias, especially tremor, chorea, myoclonus, tics and dystonia, have been treated with various drugs. For example, tremor can be treated with a benzodiazepine, such as diazepam. Chorea can be treated with diazepam, phenothiazide or haloperidol or tetrabenazine. Ticks can be treated with a neuroleptic such as haloperedol or pimozide. Also, dystonia is levadopa, benzodiazepines (eg, diazepam), anticholinergics (eg, benzhexol)
, Phenothiazines and other neuroleptics such as haloperidol and tetrabenazine.

[0015] Treating a mental disorder with a neuroleptic, such as haloperidol, involves extrapyramidal symptoms, acute dystonia, tardive dyskinesia, inability to sit, tremor, tachycardia, somnolence, confusion,
It can be done at the expense of a number of side effects including orthostatic hypotension, blurred vision, sudden onset of glaucoma, dry mouth, constipation, dysuria and sexual dysfunction.

[0016] Neurokinin 1 (NK-1; substance P) receptor antagonists have been developed to treat a number of physiological abnormalities associated with tachykinins, especially substance P excess or imbalance. Examples of symptoms in which substance P is involved include central nervous system abnormalities such as anxiety, depression, and psychosis (for example, WO 95/16679, 95/1).
No. 8124 and No. 95/23798).

EP 0 286 928 describes inhibitors of the enzyme prolyl-endopeptidase, which degrades neuropeptides such as substance P, which have antipsychotic, anti-anxiety and antidepressant effects. . Other methods (eg, preferred NK
Antagonism at the -1 receptor) or substance P
Is expected to be detrimental to the treatment of psychoses such as schizophrenia.

More recently, International Patent Application Publication No. 96/1996, published August 15, 1996,
No. 24353 suggests that a combination of a tachykinin antagonist and a serotonin agonist or a selective serotonin reuptake inhibitor (SSRI) may be used to more effectively and safely treat mental disorders.

Central injection of RP67580 (ic) in rats treated with morphine for 5 days
. v. ) Has been reported to attenuate naloxen sudden onset signs (M
aldonado et al., Neurosci. Letts. , 156: 135 (19
93)). This study shows that morphine withdrawal response is a peptidic substance P antagonist i. c. v. Similar to previous reports with guinea pigs showing inhibition by injection (Johnston & Chahl, Arch. Pharma.
col. , 343: 283 (1991)). These investigators have subsequently attempted to block the withdrawal response in guinea pigs by systemic administration of CP-96,345, and only high doses (20 mg / kg) were active, which was a specific blocking of the NK-1 receptor. The effect could not be confirmed (Chahl & Johnso
n, Regul. Pept. Suppl. 1, S43 (1992)).

Due to the shortcomings of existing antipsychotic treatments, there is a need for new safe and effective treatments for schizophrenia, substance use disorders and movement disorders.

The present invention is directed to a method for treating schizophrenia, substance use disorders and movement disorders.
2- (R)-(1- (S)-(3,5-bis (trifluoromethyl) phenyl) -2-hydroxyethoxy) -3- (S)-in a drug administered orally once a day
Provided is the use of (4-fluorophenyl) -4- (1,2,4-triazol-3-yl) methylmorpholine or a pharmaceutically acceptable salt thereof. This class of compounds advantageously exhibits a rapid onset of action and a reduced side effect profile compared to conventional antipsychotics.

The very good pharmacological action of the NK-1 receptor antagonists used in the present invention makes it possible to treat schizophrenia, substance use disorders and movement disorders without the need for combination therapy.

Furthermore, the action is rapidly manifested by the very good pharmacological action of the NK-1 receptor antagonist used in the present invention.

Accordingly, the present invention provides 2- (R)-(1) for the manufacture of a medicament suitable for oral administration for the treatment or prevention of schizophrenia, substance use disorders and movement disorders.
-(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.

The present invention also provides a method for treating or preventing schizophrenia, substance use disorder and dyskinesia, the method comprising administering to a patient in need of such treatment 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 schizophrenia, substance use disorders and movement disorders, the composition comprising 2- (R)-(1- (S )-(3
, 5-Bis (trifluoromethyl) phenyl) -2-hydroxyethoxy) -3
A pharmaceutically acceptable carrier or excipient comprising-(S)-(4-fluorophenyl) -4- (1,2,4-triazol-3-yl) methylmorpholine or a pharmaceutically acceptable salt thereof; Include with.

[0027] Many schizophrenic patients are not adequately treated with existing antipsychotic treatments. In some patients, the adverse effects of antipsychotics may worsen the adverse effects.

Thus, the present invention is directed to the manufacture of a medicament suitable for oral administration for the treatment or prevention of schizophrenia in a patient that does not respond to or is contraindicated in antipsychotics. 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.

The present invention also provides a method for treating or preventing schizophrenia in a patient who does not respond to or is contraindicated in an antipsychotic drug, which method is effective for a patient in need of the treatment. Amount of 2- (R)-(1- (S)-(3,5-bis (trifluoromethyl) phenyl) -2-hydroxyethoxy) -3- (S)-(4-fluorophenyl) -4- Orally administering (1,2,4-triazol-3-yl) methylmorpholine or a pharmaceutically acceptable salt thereof.

2- (R)-(1- (S)-(3,5-bis (trifluoromethyl) phenyl) -2-hydroxyethoxy) -3- (S)-(4-fluorophenyl) -4 −
Although (1,2,4-triazol-3-yl) methylmorpholine or a pharmaceutically acceptable salt thereof is considered to be useful alone for the treatment of schizophrenia,
It has been found that combining NK-1 receptor antagonists with conventional antipsychotics has a high effect in treating schizophrenia. The combination is expected to produce an immediate effect for the treatment of schizophrenia so that it can be prescribed on an as needed basis. Furthermore, by the combination,
Low doses of antipsychotics can be used without diminishing the effects of the antipsychotics,
This can minimize the risk of side effects. Another advantage of the combination is that it can reduce or prevent side effects caused by antipsychotics, such as acute dystonia, dyskinesia, restlessness and tremor, due to the action of NK-1 receptor antagonists. is there.

Thus, according to a further aspect of the present invention, 2- (R)-(1- (S)-(3,5-bis) for the manufacture of a medicament for the treatment or prevention of schizophrenia. (Trifluoromethyl) phenyl) -2-hydroxyethoxy) -3- (S)-(4-fluorophenyl) -4- (1,2,4-triazol-3-yl) methylmorpholine or a pharmaceutically acceptable salt thereof Provided are salts and antipsychotics that can be used.

The present invention also provides a method for treating or preventing schizophrenia, the method comprising in combination with a patient in need of such treatment in an amount that effectively improves the symptoms.
(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.

It is contemplated that the NK-1 receptor antagonist and the antipsychotic can be present as a combined preparation for simultaneous, separate or sequential use in the treatment or prevention of schizophrenia. The above-mentioned composite preparation can take the form of, for example, two packs.

In another or alternative embodiment of the present invention, 2- (R)-(1- (S) is a combined preparation for simultaneous, separate or sequential use in the treatment or prevention of schizophrenia.
)-(3,5-Bis (trifluoromethyl) phenyl) -2-hydroxyethoxy) -3- (S)-(4-fluorophenyl) -4- (1,2,4-triazol-3-yl) There is provided a product comprising methylmorpholine or a pharmaceutically acceptable salt thereof and an antipsychotic.

[0035] Many dyskinetic patients are not well treated with existing neuroleptic treatments. In some patients, the adverse effects of neuroleptics may adversely affect the patient.

Accordingly, the present invention provides a method for the preparation of a medicament suitable for oral administration for the treatment or prevention of dyskinesias in patients who do not respond to or are contraindicated in neuroleptics. (R)-(1- (S)-(3,5-bis (trifluoromethyl)
Use of phenyl) -2-hydroxyethoxy) -3- (S)-(4-fluorophenyl) -4- (1,2,4-triazol-3-yl) methylmorpholine or a pharmaceutically acceptable salt thereof I will provide a.

The invention also provides a method for treating or preventing abnormal dyskinesia in a patient that does not respond to or is contraindicated in a neuroleptic drug, the method comprising administering an effective amount to a patient in need of such treatment. Of 2- (R)-(1- (S)-(3,5-bis (trifluoromethyl) phenyl) -2-hydroxyethoxy) -3- (S)-(4-fluorophenyl) -4- ( Oral administration of 1,2,4-triazol-3-yl) methylmorpholine or a pharmaceutically acceptable salt thereof.

2- (R)-(1- (S)-(3,5-bis (trifluoromethyl) phenyl) -2-hydroxyethoxy) -3- (S)-(4-fluorophenyl) -4 −
Although (1,2,4-triazol-3-yl) methylmorpholine or a pharmaceutically acceptable salt thereof is considered to be useful alone for the treatment of movement disorders, 2- (R
)-(1- (S)-(3,5-bis (trifluoromethyl) phenyl) -2-hydroxyethoxy) -3- (S)-(4-fluorophenyl) -4- (1,2,2
Combination of 4-triazol-3-yl) methylmorpholine or a pharmaceutically acceptable salt thereof with conventional anti-Parkinsonian drugs results in immobility such as Parkinsonism.
It is recognized that high effects are obtained in the treatment of stiffness disorders. The combination allows for the use of low doses of the antiparkinsonian without diminishing the efficacy of the antiparkinsonian, thereby minimizing the risk of side effects.

According to another aspect of the present invention, 2- (R)-(1- (S)-(3,5-bis (tri-) is used for the manufacture of a medicament for treating or preventing akinesia-rigidity disorder. (Fluoromethyl) phenyl) -2-hydroxyethoxy) -3- (S)-(4-fluorophenyl)-
Provided is the use of 4- (1,2,4-triazol-3-yl) methylmorpholine or a pharmaceutically acceptable salt thereof and an antiparkinsonian.

The present invention also provides a method for treating or preventing akinesia-rigidity disorder, the method comprising the step of improving the symptoms of 2- (R) in combination with a patient in need of such treatment.
)-(1- (S)-(3,5-bis (trifluoromethyl) phenyl) -2-hydroxyethoxy) -3- (S)-(4-fluorophenyl) -4- (1,2,2
4-triazol-3-yl) methylmorpholine or a pharmaceutically acceptable salt thereof and an anti-Parkinson agent.

According to another aspect of the present invention, 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 at least one antiparkinsonian drug
A pharmaceutical composition is provided that comprises together with two pharmaceutically acceptable carriers or excipients.

It is also envisioned that the NK-1 receptor antagonist and anti-parkinsonian agent may be present as a combined preparation for simultaneous, separate or sequential use in the treatment or prevention of akinesia-rigidity disorder. The above-mentioned composite preparation can take the form of, for example, two packs.

According to another or alternative embodiment of the present invention, 2- (R)-(1- (1-) is a combined preparation for simultaneous, separate or sequential use in the treatment or prevention of akinesia-rigid disorder.
(S)-(3,5-bis (trifluoromethyl) phenyl) -2-hydroxyethoxy) -3- (S)-(4-fluorophenyl) -4- (1,2,4-triazol-3- Yl) A product comprising methylmorpholine or a pharmaceutically acceptable salt thereof and an antiparkinsonian agent is provided.

2- (R)-(1- (S)-(3,5-bis (trifluoromethyl) phenyl) -2-hydroxyethoxy) -3- (S)-(4-fluorophenyl) -4 −
It has been found that the combination of (1,2,4-triazol-3-yl) methylmorpholine or a pharmaceutically acceptable salt thereof with conventional neuroleptics has a high effect in the treatment of dyskinesia. . The combination allows for the use of lower doses of the neuroleptic without diminishing the efficacy of the neuroleptic, thereby minimizing the risk of side effects. Said combination offers the advantage that, due to the action of NK-1 receptor antagonists, side effects caused by antipsychotics such as acute dystonia, dyskinesia, restlessness and tremor can be reduced or prevented.

Further, according to another aspect of the present invention, 2- (R)-(1- (S)-(3,5-bis (tri) is used for the manufacture of a medicament for treating or preventing dyskinesia. (Fluoromethyl) phenyl) -2-hydroxyethoxy) -3- (S)-(4-fluorophenyl)
Provided is the use of -4- (1,2,4-triazol-3-yl) methylmorpholine or a pharmaceutically acceptable salt thereof and a neuroleptic.

The present invention also provides a method of treating or preventing dyskinesia, the method comprising an amount of 2- (R) effective to ameliorate the symptoms together for a patient in need of such treatment.
-(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 a neuroleptic.

According to a further aspect of the present invention, 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 a neuroleptic at least one pharmaceutically acceptable carrier or excipient There is provided a pharmaceutical composition comprising the agent.

It is contemplated that the NK-1 receptor antagonist and the neuroleptic may be present as a combined preparation for simultaneous, separate or sequential use in the treatment or prevention of dyskinesia. The above-mentioned composite preparation can take the form of, for example, two packs.

According to another or alternative aspect of the present invention, 2- (R)-(1- (S) is a combined preparation for simultaneous, separate or sequential use in the treatment or prevention of dyskinesia.
)-(3,5-Bis (trifluoromethyl) phenyl) -2-hydroxyethoxy) -3- (S)-(4-fluorophenyl) -4- (1,2,4-triazol-3-yl) There is provided a product comprising methylmorpholine or a pharmaceutically acceptable salt thereof and a neuroleptic.

When using the combinations of the present invention, the NK-1 receptor antagonist and the antipsychotic, antiparkinsonian or neuroleptic agent may be present in the same pharmaceutically acceptable carrier and, therefore, administered simultaneously. Conceivable. The compounds may be present in separate pharmaceutical carriers such as conventional oral dosage forms that are taken simultaneously. The term "combination" also refers to the case where the compounds are in separate dosage forms and are administered sequentially. Thus, for example, an antipsychotic, antiparkinsonian or neuroleptic is administered as a tablet, and then within a reasonable time the NK-1 receptor antagonist is administered as an oral dosage form, such as a tablet, or in a rapidly dissolving oral dosage form. May be. By "quickly dissolving oral composition" is meant an oral dosage form that dissolves within about 10 seconds when placed on the patient's tongue.

As used herein, the term “schizophrenia” includes delusional schizophrenia, disorganized schizophrenia,
Catatonic schizophrenia, undifferentiated schizophrenia, residual schizophrenia, schizophrenia dysfunction, schizophrenia, dysbiosis, short-term psychiatric disorders, shared psychiatric disorders, substance-induced psychiatric disorders And psychiatric disorders that have not been otherwise identified.

[0052] Other conditions commonly associated with schizophrenia include self-harm (eg, Lesch-Nyhan syndrome) and suicide.

As used herein, “abnormal substance use” includes substance dependence or abuse with or without physiological dependence. Substances related to the above abnormal symptoms are alcohol, amphetamine (or amphetamine-like substance), caffeine, timer, cocaine, hallucinogen, inhalant, nicotine, opioid, phencyclidine (or phencyclidine-like substance), sedative hypnotic , Benzodiazepines and other (unknown) substances, and combinations thereof.

In particular, the term “substance use disorder symptoms” includes drug abstinence, such as alcohol withdrawal with or without sensory impairment, alcohol withdrawal delirium, amphetamine withdrawal, cocaine withdrawal, nicotine withdrawal, opioid withdrawal, sensory impairment Or withdrawal of analgesics, hypnotics or anxiolytics without abstinence, withdrawal of analgesics, hypnotics or anxiolytics and withdrawal symptoms due to other substances. Treatment of nicotine withdrawal may include treatment of symptoms associated with smoking cessation.

Other “substance use disorders” include substance-induced anxiety disorders that occur during withdrawal, substance-induced emotional disorders that occur during withdrawal, and substance-induced sleep disorders that occur during withdrawal.

As used herein, the term “kinetic disorder” includes akinesia, akinesia-rigid syndrome, dyskinesia, and drug-induced Parkinson's syndrome (eg, neuroleptic-induced Parkinson's syndrome, neuroleptic malignant syndrome) , Neuroleptic-induced acute dystonia, neuroleptic-induced acute restlessness, neuroleptic-induced late-onset dyskinesia and pharmacotherapy-induced postural tremor). Examples of "akinesia-rigid syndrome" include Parkinson's disease, drug-induced Parkinson's syndrome, post-encephalitis Parkinson's syndrome, progressive supranuclear palsy, multiple system atrophy, cortical basal degeneration, Parkinson's syndrome-ALS dementia complex syndrome and basal ganglia Calcification. Examples of "abnormal dyskinesia" include tremor (including rest tremor, postural tremor, and intentional tremor), sydnymian chorea, Huntington's chorea, benign chronic hereditary chorea, and spiny erythrocytes Chorea, including polycythemia, symptomatic chorea, drug-induced chorea and unilateral ballism, myoclonus (including systemic and localized myoclonus), (including simple tic, complex tic and symptomatic tic) Tic, and (systemic dystonia such as idiopathic dystonia, drug-induced dystonia, symptomatic dystonia and paroxysmal dystonia, and blepharospasm, stomatognathic dystonia,
Dystonia (including spastic vocalizations, spastic torticollis, axial dystonia, localized tonic dystonias such as myotonic spasticity and paraplegic dystonia).

Another “dyskinesia” that can be treated with the present invention is Jill de la Tourette syndrome and its symptoms.

As used herein, the term “treatment” refers to the treatment of the conditions described above and to prophylactic or preventative treatment.

In particular, the NK-1 receptor antagonist used in the present invention is compound 2- (R
)-(1- (S)-(3,5-bis (trifluoromethyl) phenyl) -2-hydroxyethoxy) -3- (S)-(4-fluorophenyl) -4- (1,2,2
4-triazol-3-yl) methylmorpholine or a pharmaceutically acceptable salt thereof.

For the production of NK-1 receptor antagonists that can be used in the present invention, see WO 95/18124 and US Pat. No. 5,612,3.
No. 37 describes this in detail.

Suitable antipsychotics for use with the NK-1 receptor antagonist include phenothiazine, thioxanthene, heterocyclic dibenzazepine, butyrophenone, diphenylbutylpiperidine and the indolone class of antipsychotics. Preferred examples of phenothiazines include chlorpromazine, mesoridazine, thioridazine, acetophenazine, fluphenazine, perphenazine and trifluoperazine. Suitable examples of thioxanthenes include chlorprothixene and thiothixene. Preferred examples of dibenzazepine include clozapine and olanzapine. An example of butyrophenone is haloperidol. An example of diphenylbutyl biperidine is pimozide. An example of an indolone is Moringdon. Other antipsychotics include loxapine, sulpiride and risperidone. NK
When used in combination with -1 receptor antagonists, the antipsychotics are pharmaceutically acceptable salts such as chlorpromazine hydrochloride, mesoridazine besylate, thioridazine hydrochloride, acetophenazine maleate, fluphenazine hydrochloride, fluphenazine enanthate, decanoic acid It is believed that it may be in the form of fluphenazine, trifluoperazine hydrochloride, thiothixene hydrochloride, haloperidol decanoate, loxapine succinate and morindone hydrochloride. Perphenazine, chlorprothixene, clozapine, olanzapine, haloperidol, pimozide and risperidone are commonly used in non-salt form.

[0062] Other classes of antipsychotics used in combination with NK-1 receptor antagonists include dopamine receptor antagonists, particularly D2, D3 and D4 dopamine receptor antagonists, and muscarinic m1 receptor agonists. An example of a D3 dopamine receptor antagonist is compound PNU-99194A. An example of a D4 dopamine receptor antagonist is PNU-101387. An example of a muscarinic m1 receptor agonist is xanomeline.

Another class of antipsychotics used in combination with NK-1 receptor antagonists is 5-H
T _2A is a receptor antagonist, examples of which include MDL 100907 and fananserin. Serotonin dopamine antagonists (SDAs) that are thought to combine 5-HT _2A and dopamine receptor antagonist activity, such as olanzapine and diperacidone, are also used in combination with the NK-1 receptor antagonist.

Suitable anti-Parkinson drugs for use in combination with an NK-1 receptor antagonist include (
Levodopa (optionally with a selective extracerebral decarboxylase inhibitor such as carbidopa or benserazide), biperiden (optionally as hydrochloride or lactate) and anticholinergic drugs such as trihexyphenidyl hydrochloride (benzhexal), and Dopamine agonists such as arentemol, bromocriptine, fenoldopam, lisuride, naxagolide, pergolide and pramipexole are included. It is envisioned that the dopamine agonist may be used in the form of a pharmaceutically acceptable salt such as alentemol hydrobromide, bromocriptine mesylate, fenoldopam mesylate, naxagolide hydrochloride and pergolide mesylate. Lisuride and pramipexole are commonly used in a non-salt form.

Suitable neuroleptics used in combination with NK-1 receptor antagonists include phenothiazine, thioxanthene, heterocyclic dibenzazepine, butyrophenone, diphenylbutylpiperidine and the indolone class of antipsychotics. Preferred 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 butyrophenone is haloperidol. An example of diphenylbutyl biperidine is pimozide. An example of an indolone is Moringdon. Other neuroleptic agents include loxapine, sulpiride and risperidone. When used in combination with an NK-1 receptor antagonist, the psycholeptic is a pharmaceutically acceptable salt such as chlorpromazine hydrochloride, mesoridazine besylate, thioridazine hydrochloride, acetophenazine maleate, fluphenazine hydrochloride, fluphenazine enanthate, decane. It is contemplated that it may be used in the form of fluphenazine acid, trifluoperazine hydrochloride, thiothixene hydrochloride, haloperidol decanoate, loxapine succinate and morindone hydrochloride. Perphenazine, chlorprothixene, clozapine, haloperidol, pimozide and risperidone will normally be used in non-salt form.

Suitable pharmaceutically acceptable salts of NK-1 receptor antagonists for use in the present invention include, for example, solutions of the compound in a pharmaceutically acceptable non-toxic acid (eg, hydrochloric acid, fumaric acid, Acid addition salts which can be formed by mixing with solutions of maleic acid, succinic acid, acetic acid, citric acid, tartaric acid, carbonic acid, phosphoric acid or sulfuric acid). The salt of an amine group may consist of a quaternary ammonium salt wherein the amino nitrogen atom has an alkyl, alkenyl, alkynyl or aralkyl group.

Suitable pharmaceutically acceptable salts of antipsychotic, antiparkinsonian or neuroleptic agents for use in combination with NK-1 receptor antagonists according to the present invention include those described above for salts of NK-1 receptor antagonists Contains salt. If the antipsychotic has an acid group, such as a carboxylic acid group, the present invention may also use its salts, preferably non-toxic pharmaceutically acceptable salts, such as sodium, potassium and calcium salts. Conceivable.

Preferably, the composition comprising the NK-1 receptor antagonist used according to the present invention is in unit dosage form, for example, a tablet, pill, capsule, cachet, and the like.
Also, the NK-1 receptor antagonist used in accordance with the present invention may be present in the form of granules or powders for extemporaneous compositions as volume defined solutions or suspensions. Alternatively, the NK-1 receptor antagonist used in accordance with the present invention may be in the form of a ready prepared volume of solution or suspension. Preferred forms are tablets and capsules.

For preparing solid compositions such as tablets, the principal active ingredient is a pharmaceutical carrier, such as a common tableting ingredient such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, stearic acid. Magnesium, dicalcium phosphate or gum) and other pharmaceutical excipients (e.g., water) to form a solid premix containing a homogeneous mixture of a compound of the present invention or a non-toxic pharmaceutically acceptable salt thereof. Form the prepared composition. When this pre-prepared composition is said to be homogeneous, it means that the active ingredient is homogeneously dispersed in the composition and the composition is easily and evenly effective in unit dosage forms, such as tablets, pills and capsules Means that it can be subdivided into The solid preparative composition described above is then subdivided into unit dosage forms of the type described above containing 0.1 to about 500 mg of the active ingredient of the present invention. Tablets or pills of the novel compositions can be coated or otherwise compounded into dosage forms having the advantage of long duration of action. For example, a tablet or pill consists of an inner dosage component and an outer dosage component, the latter being in the form of an envelope on the inner dosage component. The two components may be separated by an enteric layer that acts to prevent degradation in the stomach and allows the inner component to pass intact to the duodenum or delay release. A variety of materials can be used for the enteric layer or coating, including a number of high molecular weight acids and mixtures of high molecular weight acids with materials such as shellac, cetyl alcohol and cellulose acetate. .

The liquid forms in which the novel compositions of the present invention can be formulated for oral administration include aqueous solutions,
Includes suitably seasoned syrups, aqueous or oily suspensions, and seasoned emulsions containing edible oils such as cottonseed oil, sesame oil, coconut oil, peanut oil or soybean oil, elixir and similar pharmaceutical vehicles. Suitable dispersing or suspending agents for aqueous suspensions include synthetic or natural gums, for example, tragacanth, gum arabic, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinyl-pyrrolidone or gelatin.

The compositions of the present invention can also be administered via the buccal cavity using common methods (eg, an absorbing wafer).

Compositions in the form of tablets, pills, capsules or cachets for oral administration are particularly preferred.

Furthermore, the present invention relates to a compound 2- (R)-(1- (S)-(3,5-bis (trifluoromethyl) phenyl) -2-hydroxyethoxy) -3- (S)-(4 Preparation of a pharmaceutical composition comprising -fluorophenyl) -4- (1,2,4-triazol-3-yl) methylmorpholine or a pharmaceutically acceptable salt thereof and an antipsychotic, antiparkinsonian or neuroleptic agent A method is provided wherein the method comprises compound 2- (R)-
(1- (S)-(3,5-bis (trifluoromethyl) phenyl) -2-hydroxyethoxy) -3- (S)-(4-fluorophenyl) -4- (1,2,4-
Triazole-3-yl) methylmorpholine or a pharmaceutically acceptable salt thereof and an antipsychotic, antiparkinson or neuroleptic in a pharmaceutically acceptable carrier or excipient.

When a combination of an NK-1 receptor antagonist and an antipsychotic, antiparkinson or neuroleptic is administered as a single or separate pharmaceutical composition, the NK-1 receptor antagonist and antipsychotic, antiparkinson The drug or neuroleptic is present in a ratio that produces the desired effect. In particular, the weight ratio of NK-1 receptor antagonist to antipsychotic, antiparkinsonian or neuroleptic is preferably from 0.001: 1 to 1000: 1, especially from 0.01: 1 to 100: 1.

[0075] The lowest dose level of an NK-1 receptor antagonist is about 1 mg / day, preferably about 5 mg / day, especially about 10 mg / day. The highest dose level of the NK-1 receptor antagonist is about 1500 mg / day, preferably about 1000 mg / day, especially about 5 mg / day.
00 mg / day. The compounds are administered one to three times a day, preferably once a day.

The minimum dosage level of an antipsychotic varies with the type of drug, but is usually about 0.5 mg / day for the most potent compounds and about 20 mg / day for less potent compounds. The highest dose levels of antipsychotics are usually about 30 mg / day for the most potent compounds and about 200 mg / day for less potent compounds. The compounds are administered one to three times a day, preferably once a day.

The minimum dose level of an antiparkinsonian drug will vary with the type of drug, but is usually about 0.05 mg / day for the most potent compounds and about 20 mg / day for less potent compounds. The highest dose level of antiparkinsonian is usually about 30 mg with the most potent compound
/ Day, about 500 mg / day for less potent compounds. The compound may be used once a day
It is administered up to 3 times, preferably 1 to 2 times a day, especially once a day.

The lowest dose level of a neuroleptic varies with the type of drug, but is usually about 0.5 mg / day for the most potent compounds and about 20 mg / day for less potent compounds. The highest dose levels of neuroleptics are usually about 30 mg / day for the most potent compounds and about 200 mg / day for less potent compounds. The compounds are administered 1 to 3 times a day, preferably 1 to 2 times a day, especially once a day.

The amount of the NK-1 receptor antagonist required for use in the treatment or prevention of schizophrenia will depend not only on the particular compound or composition selected, but also on the route of administration, the type of condition being treated and the patient's condition. It will vary with age and condition, and will ultimately be determined by the patient's physician or pharmacist.

When the NK-1 receptor antagonist and the antipsychotic are used in combination, the amount of the NK-1 receptor antagonist and the antipsychotic required for use in the treatment or prevention of schizophrenia is determined by the specific agent selected. It will vary with the compound or composition, as well as the route of administration, the type of condition being treated and the age and condition of the patient, and will ultimately be determined by the patient's attending physician or pharmacist.

When an NK-1 receptor antagonist and an antiparkinson or neuroleptic are used in combination, the NK-1 receptor antagonist and antiparkinson or neuroleptic required for use in the treatment or prevention of dyskinesia are used. The amount will vary depending upon the particular compound or composition selected, as well as the route of administration, the type of condition being treated and the age and condition of the patient, and will ultimately be determined by the patient's attending physician or pharmacist.

The activity of the NK-1 receptor antagonist used in the present invention can be determined by the following assay.

[0083]Assay 1: NK-1 receptor binding  The NK-1 receptor binding assay is described in Cascieri et al. Pharmaco
l. Exp. Ther. , 42: 458 (1992).
Intact Chinese Hams expressing human NK-1 receptor under modified conditions
It is performed on ovarian (CHO) cells. Typically, 3 × 10⁵Receiving
Express at the container / cell level. Cells are grown in monolayer culture and digested without enzymes.
Separation solution (Specialty Media Inc.) from plate
Separate, wash and use for assay.¹²⁵I-Tyr⁸-Substance
P (0.1 nM, 2000 Ci / mmol; New England Nucl
ear) in a test compound (dissolved in 5 μl dimethyl sulfoxide (DMSO))
5 × 10 in the presence or absence of objects⁴Incubate with CHO cells. Re
Gand binding is 5 mM MnCl₂, 150 mM NaCl, 0.02% bovine
Serum albumin (Sigma), 50 μg / ml chymostatin (Penins
ula), 0.1 nM phenylmethylsulfonyl fluoride, 2 μg / ml
Pustatin, 2 μg / ml leupeptin and 2.8 μg / ml
Run in 0.25 ml of 50 mM Tris-HCl (pH 7.5) containing kalin.
Give. Incubation was performed at room temperature until equilibrium was reached (> 40 minutes),
Receptor-ligand complexes were analyzed using a Tomtek-96 well harvester for 0.1% po.
Filter and collect with a GF / C filter pre-soaked in ethyleneimine. Non
Specific binding was determined using excess substance P (1 μM) and <10% of total binding
%.

[0084]Assay 2: gerbil limb tapping  CNS permeable NK-1 receptor antagonists for use in the present invention are Ru
pniak & Williams, Eur. J. Pharmacol. , 26
5: 176 (1994).
genic agent) (eg, pentagasulin) or NK-1 receptor agonist (eg,
For example, triggered by central infusion of GR73632) or
Is due to its ability to suppress limb tapping caused by aversive stimuli such as private rooms.
Can be identified.

Male or female Mongolian gerbils (35-70 g) are anesthetized by inhaling an isoflurane / oxygen mixture and anaesthetized at 5 mg / kg i.v. v. The jugular vein is exposed to administer the test compound or vehicle at an injection volume of. Alternatively, test compounds may be administered orally, subcutaneously or intraperitoneally. Thereafter, a skin incision is made at the center of the scalp to expose the skull. Anxiety agents (eg, pentagasulin) or selective NK-
1 receptor agonists (for example, GR73632 (d Ala [L-Pro ⁹ , M
e-Leu ¹⁰ ] -Substance P- (7-11)) is injected directly into the ventricle by inserting a cuffed 27 gauge needle vertically to a depth of 4.5 mm below the bregma (eg, test substance) 3 pmol in 5 μl icv). Close the scalp incision and place the animal in a clear perspex observation box (25 cm × 20 cm × 2
At 0 cm). Thereafter, the time and / or intensity of hind limb tapping is continuously recorded for about 5 minutes. Alternatively, the ability of the test compound to inhibit limb tapping caused by aversive stimuli, such as limb shock or cubicles, can be determined using similar quantification methods.

[0086]Assay 3: Ferret vomiting  Gavage the test compound to male ferrets (1.0-2.5 kg) in each hut
Oral administration via a menu. After 10 minutes, give the animal about 100g of canned cat food
give. 60 minutes after oral administration, cisplatin (10 mg / kg) was
I. Via a jugular vein catheter inserted under rotary anesthesia. v. Administer. Next
Then, the catheter is removed, the jugular vein is ligated, and the skin incision is closed. Ferret
Immediately recover from anesthesia and begin to move within 10-20 minutes. Time from anesthesia to animal
Observation was made continuously for the recovery period and 4 hours after cisplatin injection.
Slaughter. Specializes in the number of nausea and vomiting that occurred during 4 hours after cisplatin administration
The house records.

[0087]Assay 4: Isolation-induced vocalization  Male and female guinea pig offspring were allowed to bring their mothers and litters together in small families during the experiment.
Put in the shop. The experiment is started after weaning when the child is two weeks old. Before entering the experiment
In some cases, children who have repeated violent vocal responses after isolating them from their mothers
Screen. Observation cables in a room physically separated from the home cage
Pages (55 cm x 39 cm x 19 cm) individually for 15 minutes during this reference period
Record the utterance time of. Only animals vocalized for more than 5 minutes are used for drug attack tests
(Approximately 50% of children obtained may not meet this standard). On the test day,
Each child is orally administered a test compound or vehicle or s. c. Or i. p.
Inject and immediately return to home cage with mother and siblings for 30-60 minutes
(Or up to 4 hours after oral administration, depending on the oral pharmacokinetics of the test compound)
And then socially isolated for 15 minutes as described above. Drug treatment for each animal
The daily vocalization time is displayed as a percentage of the pre-treatment reference value. The same subject
Retest once a week for a maximum of 6 weeks. Each test compound is applied to 6 to 8 animals.
Administer these test doses.

As used herein, the term “CNS permeability” refers to NK-
Refers to NK-1 receptor antagonists that can suppress 1 receptor antagonist induced limb tapping.

Essentially, the NK-1 receptor agonist GR73632 (
d Ala [L-Pro ⁹ , Me-Leu ¹⁰ ] -substance P- (7-11
Hind limb tapping induced by injecting)) directly into the central ventricle under anesthesia is suppressed when a CNS permeable NK-1 receptor antagonist is administered intravenously immediately prior to GR73632 challenge. In this case, hind limb tapping for 5 minutes after recovery from anesthesia is suppressed at ID ₅₀ ≦ 3 mg / kg, preferably at ID ₅₀ ≦ 1 mg / kg.

Alternatively, when NK-1 antagonist was administered orally 1 hour before GR73632 challenge, limb tapping for 5 minutes after recovery from anesthesia had an ID ₅₀ ≦ 30.
mg / kg, preferably at an ID ₅₀ ≦ 10 mg / kg.

The CNS permeable NK-1 receptor antagonist used in the present invention is also effective at attenuating the isolation-induced vocalizations by guinea pig children described above.

Essentially, the vocal response in guinea pig offspring was elicited by sequestration from mothers and siblings, but this response was observed when a CNS permeable NK-1 receptor antagonist was administered subcutaneously 30 minutes prior to isolation. descend. In this case, the first quarantine
Vocalization for 5 minutes is ID ₅₀ ≦ 20 mg / kg, preferably ID ₅₀ ≦ 10 mg / k
g, especially when ID ₅₀ ≦ 5 mg / kg.

[0093] Alternatively, the NK-1 receptor antagonist was given orally 4 hours before sequestration.
During this time, the first 15 minutes of the quarantine are ID₅₀≦ 20mg / kg, preferably ID ₅₀ ≦ 10mg / kg, especially ID₅₀≤5 mg / kg.

[0094] Suitable selection procedure for NK ₁ antagonists of use according to the present invention are as follows: (i) in the radioligand binding studies to determine the affinity for the human NK ₁ receptor (Assay 1): _{IC 50} Compounds having ≦ 10 nM, preferably IC ₅₀ ≦ 2 nM, especially IC ₅₀ ≦ 1 nM are selected. Measuring the CNS penetration ability of the compounds by their ability to inhibit induced the limb tapped by central injection of NK ₁ agonist (ii) in gerbils (Assay 2): ID ₅₀ when administered immediately prior to central NK ₁ agonist attack ≦ 3mg /
kgi. v. , Preferably ID ₅₀ ≦ 1 mg / kg i. v. To select a compound that suppresses limb tapping. Or, when administered 1 hour before challenge, ID ₅₀ ≦ 3
0 mg / kg p. o. , Preferably ID ₅₀ ≦ 10 mg / kg p. o. To select a compound that suppresses limb tapping. (Iii) examining the center duration of action of compounds in tapping assay limb in gerbil after intravenous administration 24 hours prior to central NK ₁ agonist Attack: is ≦ 25 times more potent as compared with ID ₅₀ measured in step (ii) Select fewer compounds. However, after 24 hours of pretreatment, ID ₅₀ ≦ 10 mg / kg i. v.
, Preferably ≦ 5 mg / kg i. v. It is. (Iv) Examining oral bioavailability of compounds by pharmacokinetic analysis after oral administration and by activity in gerbil limb tapping assays and / or by their ability to suppress cisplatin-induced emesis in ferrets (Assay 3):
ID ₉₀ ≦ 3 mg / kg p. o. , Preferably ID ₉₀ ≦ 1 mg / kg p. o.
Is selected.

A particularly preferred compound for use in the present invention is that after steps (i) to (iv) (
(v) Determine the activity of the compound in a conventional antipsychotic susceptibility assay (suppress harmful stress vocalization in guinea pig children (assay 4)): ID ₅₀ ≦
Compounds with 20 mg / kg, preferably with ID ₅₀ ≦ 10 mg / kg are selected.

Further preferred compounds for use in the present invention meet the NK-1 receptor binding criteria of step (i) and have an affinity ≦ 5-fold when incubated in the presence of human serum albumin (HSA), It may be selected from compounds that show non-specific protein binding.

The NK-1 receptor antagonist used in the present invention is 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 Application Publication No. 9
No. 5,18,124 and US Pat. No. 5,612,337. In the above assay, this compound has the following activities: human NK-receptor binding: IC ₅₀ = 0.12 nM, gerbil limb tapping (5 min): ID ₅₀ = 0.38 mg / kg i. v. Gerbil limb tapping (24 hours): ID ₅₀ = 2.2 mg / kg i. v. Vomiting: ferret vomiting: ID ₉₀ = 1 mg / kg p. o. Guinea pig vocalization (pretreatment for 4 hours): ID ₅₀ = 0.91 mg / kg p. o. Having.

The following examples illustrate the pharmaceutical compositions of the present invention.

Example 1 Tablet Containing 50-300 mg of NK-1 Antagonist

[0100]

[Table 1]

The active ingredient, cellulose, lactose and part of corn starch are mixed and
Granulate with% corn starch paste. The resulting granules are sieved, dried and
Mix with the rest of the corn starch and magnesium stearate. The resulting granules are then compressed into 50 mg, 100 mg and 300 mg NK-1 per tablet.
Tablets containing the receptor antagonist.

Pharmaceutical compositions comprising an NK-1 receptor antagonist and an antipsychotic can be manufactured with the individual active ingredients or with multiple active ingredients in one composition.
In the combination preparation, the ratio of NK-1 receptor antagonist and antipsychotic depends on the active ingredient chosen.

Example 2 50-300 mg of NK-1 antagonist and 5-10 mg of NK-1 antagonist
Tablets containing loperidol

[0104]

[Table 2]

Example 3 50-300 mg of NK-1 antagonist and 25 mg of hydrochloric acid hydrochloride
Tablets containing lorpromazine

[0106]

[Table 3]

The active ingredient, cellulose, lactose and part of corn starch were mixed and
Granulate with% corn starch paste. The resulting granules are sieved, dried and
Mix with the rest of the corn starch and magnesium stearate. The resulting granules are then compressed into 50 mg, 100 mg and 300 mg NK-1 per tablet.
Tablets containing the receptor antagonist.

Pharmaceutical compositions comprising an NK-1 receptor antagonist and a neuroleptic can be prepared with the individual active ingredients or with multiple active ingredients in one composition.
In the combination preparation, the ratio of the NK-1 receptor antagonist to the neuroleptic depends on the active ingredient chosen.

Example 4 50-300 mg of NK-1 antagonist and 5-10 mg of NK-1 antagonist
Tablets containing loperidol

[0110]

[Table 4]

The active ingredient, cellulose, lactose and part of corn starch are mixed and
Granulate with% corn starch paste. The resulting granules are sieved, dried and
Mix with the rest of the corn starch and magnesium stearate. The resulting granules are then compressed into 50 mg, 100 mg and 300 mg NK-1 per tablet.
Tablets containing the receptor antagonist.

────────────────────────────────────────────────── ─── Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) // A61K 31/445 A61K 31/445 C07D 413/06 C07D 413/06 (31) Priority claim number 9812663. 4 (32) Priority date June 11, 1998 (June 11, 1998) (33) Priority country United Kingdom (GB) (81) Designated country EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, SD, SL, SZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ , TM), AE, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, CA, CH, CN, CU, CZ, DE, DK, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MD, MG, MK , MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, UA, UG, US, UZ, VN, YU, ZA, ZW F term (reference) 4C063 AA01 BB03 CC54 DD41 EE01 4C086 AA01 AA02 BC73 GA07 GA09 MA01 MA04 MA52 NA14 ZA02 ZA15 ZA18 ZA22 ZA24 ZC39 ZC42

Claims (28)

[Claims] 1. A method for the preparation of a medicament suitable for oral administration for the treatment or prevention of schizophrenia, substance use disorder or dyskinesia.
-(S)-(3,5-bis (trifluoromethyl) phenyl) -2-hydroxyethoxy) -3- (S)-(4-fluorophenyl) -4- (1,2,4-triazol-3 -Yl) Use of methylmorpholine or a pharmaceutically acceptable salt thereof. 2. (R) for the manufacture of a medicament suitable for oral administration for the treatment or prevention of schizophrenia in patients who do not respond to or are contraindicated in antipsychotics. )-(1- (S)-(3,5-bis (trifluoromethyl) phenyl) -2-hydroxyethoxy) -3- (S)-(4-fluorophenyl) -4- (1,2,4 Use of -triazol-3-yl) methylmorpholine or a pharmaceutically acceptable salt thereof. 3. 2- (R)-(1- (S)-(3,5-bis (trifluoromethyl) phenyl)-for the manufacture of a medicament for treating or preventing schizophrenia. 2-hydroxyethoxy) -3- (S)-(4-fluorophenyl) -4
-Use of (1,2,4-triazol-3-yl) methylmorpholine or a pharmaceutically acceptable salt thereof and an antipsychotic. 4. A 2- (R)-preparation for the manufacture of a medicament suitable for oral administration for the treatment or prevention of dyskinesias in patients who do not respond to or are contraindicated in neuroleptics. (1- (S)-(3,5-bis (trifluoromethyl) phenyl) -2-hydroxyethoxy) -3- (S)-(4-fluorophenyl)
Use of 4- (1,2,4-triazol-3-yl) methylmorpholine or a pharmaceutically acceptable salt thereof. 5. (2-)-(1- (S)-(3,5-bis (trifluoromethyl) phenyl)-) for the manufacture of a medicament for the treatment or prevention of akinesia-rigidity disorder. 2-hydroxyethoxy) -3- (S)-(4-fluorophenyl) -4-
Use of (1,2,4-triazol-3-yl) methylmorpholine or a pharmaceutically acceptable salt thereof and an antiparkinsonian. 6. A method for the manufacture of a medicament for the treatment or prevention of dyskinesia.
-(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 use of a neuroleptic. 7. 2- (R)-(1- (S)-(3,5-bis (trifluoromethyl) phenyl) -2-hydroxyethoxy) -3- (S)-(4-fluorophenyl) Schizophrenia, substance use abnormality comprising -4- (1,2,4-triazol-3-yl) methylmorpholine or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier or excipient Oral pharmaceutical composition for the treatment of sickness or movement disorders. 8. (R)-(1- (S)-(3,5-bis (trifluoromethyl) phenyl) -2-hydroxyethoxy) -3- (S)-(4-fluorophenyl) Pharmaceutical composition comprising 4- (1,2,4-triazol-3-yl) methylmorpholine or a pharmaceutically acceptable salt thereof and an anti-parkinsonian drug with at least one pharmaceutically acceptable carrier or excipient object. 9. 2- (R)-(1- (S)-(3,5-bis (trifluoromethyl) phenyl) -2-hydroxyethoxy) -3- (S)-(4-fluorophenyl) Pharmaceutical composition comprising 4- (1,2,4-triazol-3-yl) methylmorpholine or a pharmaceutically acceptable salt thereof and a neuroleptic with at least one pharmaceutically acceptable carrier or excipient object. 10. A composite preparation for simultaneous, separate or sequential use in the treatment or prevention of schizophrenia, as 2- (R)-(1- (S)-(3,5).
-Bis (trifluoromethyl) phenyl) -2-hydroxyethoxy) -3- (
S)-(4-Fluorophenyl) -4- (1,2,4-triazol-3-yl)
A product comprising methylmorpholine or a pharmaceutically acceptable salt thereof and an antipsychotic. 11. A combined preparation for simultaneous, separate or sequential use in the treatment or prevention of akinesia-rigidity disorder as 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 product comprising a pharmaceutically acceptable salt thereof and an antiparkinson agent. 12. A combined preparation for simultaneous, separate or sequential use in the treatment or prevention of dyskinesia as 2- (R)-(1- (S)-(3,5-bis (trifluoromethyl)). Phenyl) -2-hydroxyethoxy) -3- (S)-
A product comprising (4-fluorophenyl) -4- (1,2,4-triazol-3-yl) methylmorpholine or a pharmaceutically acceptable salt thereof and a neuroleptic. 13. A method for treating or preventing schizophrenia, substance use disorder or dyskinesia, comprising administering to a patient in need of such treatment an effective amount of 2- (R)-.
(1- (S)-(3,5-bis (trifluoromethyl) phenyl) -2-hydroxyethoxy) -3- (S)-(4-fluorophenyl) -4- (1,2,4-
Triazole-3-yl) methylmorpholine or a pharmaceutically acceptable salt thereof, which is administered orally. 14. A method for treating or preventing schizophrenia in a patient that does not respond to or is contraindicated in an antipsychotic drug, the method comprising administering an effective amount of 2- (R) to a patient in need of such treatment. )-(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, which is administered orally. 15. A method for treating or preventing schizophrenia, comprising an amount of 2- (R)-which, together with a patient in need of such treatment, effectively improves the symptoms.
(1- (S)-(3,5-bis (trifluoromethyl) phenyl) -2-hydroxyethoxy) -3- (S)-(4-fluorophenyl) -4- (1,2,4-
Triazole-3-yl) methylmorpholine or a pharmaceutically acceptable salt thereof and said method comprising administering an amount of an antipsychotic. 16. A method for treating or preventing dyskinesia in a patient who does not respond to or is contraindicated in a neuroleptic drug, the method comprising administering an effective amount of 2- (R)- (1- (S)-(3,5-bis (trifluoromethyl) phenyl) -2-hydroxyethoxy) -3- (S)-(4-fluorophenyl) -4- (1,2,4-triazole -3-yl) The above method comprising orally administering methylmorpholine or a pharmaceutically acceptable salt thereof. 17. A method of treating or preventing akinesia-rigid disorder, comprising an amount of 2- (R)-() that, together with a patient in need of such treatment, effectively improves symptoms.
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 the method comprising administering an amount of an antiparkinsonian drug. 18. A method for treating or preventing dyskinesia, comprising an amount of 2- (R)-(1-
(S)-(3,5-bis (trifluoromethyl) phenyl) -2-hydroxyethoxy) -3- (S)-(4-fluorophenyl) -4- (1,2,4-triazol-3- Il) The method comprising administering methylmorpholine or a pharmaceutically acceptable salt thereof and an amount of a neuroleptic. 19. The schizophrenia is paranoid schizophrenia, disorganized schizophrenia, catatonic schizophrenia, undifferentiated schizophrenia, residual schizophrenia, schizophrenia dysplasia, schizophrenia Claims 1 to 6 selected from: mnemonic disorders, short-term psychiatric disorders, shared psychiatric disorders, substance-induced psychiatric disorders, and psychiatric disorders not otherwise specified. The use according to any one of claims, the composition according to any one of claims 7 to 9, the product according to any one of claims 10 to 12, Or the method according to any one of claims 13 to 18. 20. The use according to any one of claims 1 to 6, wherein the schizophrenia is associated with self-harm, Resh-Nyhan syndrome and suicide. The composition according to any one of claims 7 to 9, the product according to any one of claims 10 to 12, or the product according to claims 13 to 18. A method according to any one of the preceding claims. 21. The use according to any one of claims 1 to 6, wherein the substance use disorder is selected from substance dependence or abuse with or without physiological dependence. The composition according to any one of claims 7 to 9, the product according to any one of claims 10 to 12, or the product according to claims 13 to 18. A method according to any one of the preceding claims. 22. The substance related to the substance use disorder is alcohol, amphetamine (or amphetamine-like substance), caffeine, timer, cocaine, hallucinogen, inhalant, nicotine, opioid, phencyclidine (or phencyclidine-like). 22. The use, composition, product or method of claim 21 which is a sedative-hypnotic, a benzodiazepine and other (unknown) substances, and combinations thereof. 23. A substance use disorder wherein the substance withdrawal is drug withdrawal, amphetamine withdrawal, cocaine withdrawal, nicotine withdrawal, opioid withdrawal, analgesic with or without paresthesia, hypnotic or anxiolytic withdrawal, analgesic, hypnotic or The use according to any one of claims 1 to 6, which is selected from anxiolytic drug withdrawal forgetfulness and withdrawal symptoms due to other substances, any one of claims 7 to 9 A composition according to claim 1, a product according to any one of claims 10 to 12, or a method according to any one of claims 13 to 18. 24. The substance selected from the group consisting of substance-induced anxiety disorder that occurs during withdrawal, substance-induced emotional disorder that occurs during withdrawal, and substance-induced sleep disorder that occurs during withdrawal. The use according to any one of claims 1 to 6, the composition according to any one of claims 7 to 9, and the compositions according to claims 10 to 12.
A product according to any one of the preceding claims, or a method according to any one of claims 13 to 18. 25. The movement disorder is akinesia, akinesia-rigid syndrome, abnormal dyskinesia, drug-induced Parkinson's syndrome, neuroleptic-induced Parkinson's syndrome, neuroleptic malignant syndrome, neuroleptic-induced acute dystonia, neuroleptic The use according to any one of claims 1 to 6, wherein the use is selected from induced acute static immobility, neuroleptic drug-induced late abnormal dyskinesia, and pharmacotherapy-induced postural tremor. The composition according to any one of claims 7 to 9, the product according to any one of claims 10 to 12, or the product according to claims 13 to 18. A method according to any one of the preceding claims. 26. The akinetic-rigid syndrome is Parkinson's disease, drug-induced Parkinson's syndrome, post-encephalitis Parkinson's syndrome, progressive supranuclear palsy, multiple system atrophy, cortical basal degeneration, Parkinson's syndrome-ALS dementia complex syndrome and basal ganglia 26. Use, composition, product or method according to claim 25 selected from calcification. 27. The abnormal dyskinesia includes tremor, stationary tremor, postural tremor, intentional tremor,
Chorea, Sydenham's chorea, Huntington's chorea, benign chronic hereditary chorea, neurogenic spiny erythrocytosis, symptomatic chorea, drug-induced chorea, unilateral ballism, myoclonus, systemic myoclonus, localized myoclonus, tic, Simple tics, complex tics, symptomatic tics, dystonias, systemic dystonias, idiopathic dystonias, drug-induced dystonias, symptomatic dystonias, paroxysmal dystonias, localized dystonias,
26. Use, composition, product or method according to claim 25, selected from blepharospasm, oral and mandibular dystonia, spastic dysphonia, spastic torticollis, axial dystonia, myotonic writing spasticity and half body paralysis dystonia. 28. The use according to any one of claims 1 to 6, wherein the movement disorder is Jill de la Tourette syndrome and symptoms thereof.
A composition according to any one of claims 9 to 9, a product according to any one of claims 10 to 12, or a product according to claims 13 to 18. 2. The method according to item 1.