CN1230164C - Combinations of(S)-2-(benzylamino-methyl)-2,3,8,9-tetrahydro-7H-1,4-dioxion[2,3-e]indol-8-one and neuroleptics - Google Patents
Combinations of(S)-2-(benzylamino-methyl)-2,3,8,9-tetrahydro-7H-1,4-dioxion[2,3-e]indol-8-one and neuroleptics Download PDFInfo
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- CN1230164C CN1230164C CNB008169527A CN00816952A CN1230164C CN 1230164 C CN1230164 C CN 1230164C CN B008169527 A CNB008169527 A CN B008169527A CN 00816952 A CN00816952 A CN 00816952A CN 1230164 C CN1230164 C CN 1230164C
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- antipsychotic drug
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/404—Indoles, e.g. pindolol
- A61K31/4045—Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
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Abstract
Therapeutic combinations useful in the treatment or prevention of psychotic disorders, to pharmaceutical compositions containing said combinations, and to their use in the treatment or prophylaxis of prevention disorders are provided.
Description
Field of the present invention
The present invention relates to dopamine D 2/D3 acceptor portion agonist (S)-2-(benzylamino-methyl)-2,3,8,9-tetrahydrochysene-7H-1, the 4-bioxin is (dioxino) [2 also, 3-e] being used for the treatment of or preventing psychotic therapeutic agent compositions of indol-8-ones and Antipsychotic drug, comprise the pharmaceutical composition and the application in treatment or prevention psychosis thereof of described compositions.
Background of the present invention
Psychosis is serious psychotic disorder, it is characterized in that lacking or loses and the contacting of reality.The feature of these diseases comprises various symptoms, and described symptom is divided into the positive symptom (chaotic thinking, hallucination and vain hope), negative symptoms (withdrawing from society and bradykinesia) and cognitive not enough.
Tranquilizer or Antipsychotic drug can be used for treating the schizophrenia psychotic disorder relevant with other by dopaminergic neurotransmission among the blocking-up central nervous system.Antipsychotic drug is widely used for treating schizoid " positive " symptom.Yet think that in these medicines is invalid and in fact aspect schizoid " feminine gender " symptom in treatment a lot, because the dopaminergic blocking-up relevant with its action mechanism may make these symptoms aggravations.Also believe relevant with schizophrenia cognitive not enough as distractibility and carry out the negativity that technical ability such as working memory and projected capacity blocks by dopamine receptor and influence.
In addition, these Antipsychotic drugs have important side effect as cathisophobia, dystonia, the parkinson dyskinesia and the retardance dyskinesia etc., they are all caused by the blocking-up dopaminergic neurotransmission.
Anticholinergic such as Cogentin
Be used to reduce the side effect of parkinson sample, but also caused side effect such as spiritual and/or infliction of body, tachycardia, dysuria and gastrointestinal syndrome.
Some dopamine partial agonist with high relatively intrinsic activity has shown the effect with schizophrenia negative symptoms.Supposed what need aspect this it is to make the effect optimization of treatment negative symptoms make minimized some intrinsic activity of side effect simultaneously.Lindenmayer，J.P.，Acta?Psychiatrica?Scand.1995：91(supp.388)：15-19。
Yet along with the increase of intrinsic activity, the effect that the positive symptom is treated in the higher level of dopamine transmission and therefore may causing is lower.
Have now found that the side effect that has been used to reverse traditional Antipsychotic drug to dopamine partial agonist such as preclamol, pramipexole and the terguride of high intrinsic activity in having.These reports show that the higher effect that causes alleviating the side effect relevant with motor dysfunction of intrinsic activities is bigger.People such as Svensson, Neuropharmacology, 32 (10): 1037-1045 (1993).
New rem compositions can be used for patient's treatment.Special requirement are two kinds of character optimizations that medicine is useful, and relevant side effect minimizes when giving separately with described medicine simultaneously.The applicant has found to be used for the treatment of psychotic therapeutic agent compositions.
The accompanying drawing summary
Fig. 1 be diagrammatize after Drug therapy 60 minutes the time, (S)-2-(benzylamino-methyl)-2,3,8,9-tetrahydrochysene-7H-1,4-bioxin also [2,3-e] indol-8-ones (medicine) to the effect of the inductive rat catalepsy of haloperidol, under the subcutaneous dosage that gives 0.003-3mg medicine/kg, the time point of greatest reversal of catalepsy is with second measuring.Described data are meansigma methods ± SEM.
Fig. 2 is (the S)-2-(benzylamino-methyl)-2 that diagrammatizes, 3,8,9-tetrahydrochysene-7H-1,4-bioxin also [2,3-e] indol-8-ones (medicine) induces the ability of rat catalepsy, under the subcutaneous dosage that gives 0.003-3mg medicine/kg, with a persistent period of second measuring catalepsy.Described data are meansigma methods ± SEM.
Fig. 3 is (the S)-2-(benzylamino-methyl)-2,3,8 that diagrammatizes, and 9-tetrahydrochysene-7H-1,4-bioxin also [2,3-e] indol-8-ones (medicine) reverse the hyperactive effect of the inductive mice of d-amphetamine.Give under 8 0.0001-1mg medicine/kg dosage subcutaneous, the percent of viewed level of activation when described data are treated separately with the d-amphetamine (horizontal anomalous movement calculating) is represented.Described data are meansigma methods ± SEM.
The present invention describes in detail
The invention provides and comprise (S)-2-(benzylamino-methyl)-2,3,8,9-tetrahydrochysene-7H-1,4-bioxin be the compositions of [2,3-e] indol-8-ones or its officinal salt and one or more Antipsychotic drugs also.
(S)-and 2-(benzylamino-methyl)-2,3,8,9-tetrahydrochysene-7H-1,4-bioxin also [2,3-e] indol-8-ones are a kind of D2 partial agonists, it is disclosed in United States Patent (USP) 5,756, in 532.Unless otherwise indicated, employed (the S)-2-of this paper (benzylamino-methyl)-2,3,8,9-tetrahydrochysene-7H-1,4-bioxin also [2,3-e] indol-8-ones comprise its officinal salt.
Officinal salt comprises acid-addition salts example hydrochloric acid, fumaric acid, maleic acid, citric acid or succinic acid addition salts.
Term Antipsychotic drug or tranquilizer comprise the Antipsychotic drug that those work as the complete antagonist of d2 dopamine receptor and comprise typical and atypical Antipsychotic drug.Representational Antipsychotic drug that obtain by the commercial channel or that prepare by method known to those skilled in the art includes, but are not limited to:
United States Patent (USP) 2,645, the chlorpromazine or the 2-chloro-N that describe in 640, N-dimethyl-10H-phenothiazine-10-propylamine is incorporated herein it for reference in full.
United States Patent (USP) 3,084, mesoridazine or 10-[2-(1-methyl-2-piperidyl) ethyl described in 161]-2-(methylsulfinyl)-10H-phenothiazine, be incorporated herein it for reference in full.
Collect.Czech.Chem.Commun., 1990,55, thioridazine or 10-[2-(1-methyl-2-piperidyl) ethyl described in the 1586-1601]-2-(methyl mercapto)-10H-phenothiazine, be incorporated herein it for reference in full.
GB829, fluphenazine described in 246 or 4-[3-[2-(trifluoromethyl)-10H-phenothiazine-10-yl] propyl group]-1-piperazine alcohol, be incorporated herein it for reference in full.
GB813, trifluoperazine described in 816 or 10-[3-(4-methyl isophthalic acid-piperazinyl)-propyl group]-2-(trifluoromethyl)-10H-phenothiazine, be incorporated herein it for reference in full.
United States Patent (USP) 2,766, perphenazine described in 235 or 4-[3-(2-chloro-10H-phenothiazine-1-yl) propyl group]-1-piperazine alcohol, be incorporated herein it for reference in full.
United States Patent (USP) 3,539, clozapine described in 573 or 8-chloro-11-(4-methyl isophthalic acid-piperazinyl)-5H-dibenzo [b, e]-[1,4]-diazepine is incorporated herein it for reference in full.
United States Patent (USP) 3,438, haloperidol described in 991 or 4-[4-(4-chlorphenyl)-4-hydroxyl-piperidino]-1-(4-fluorophenyl)-1-butanone, be incorporated herein it for reference in full.
United States Patent (USP) 3,546, loxapine described in 226 or 2-chloro-11-(4-methyl isophthalic acid-piperazinyl)-dibenzo [b, f] [1,4]-oxygen azatropylidene is incorporated herein it for reference in full.
United States Patent (USP) 3,491, molindone described in 093 or 3-ethyl-1,5,6,7-tetrahydrochysene-2-methyl-5-(4-morpholinyl methyl)-4H-indyl-4-ketone is incorporated herein it for reference in full.
United States Patent (USP) 3,310, tiotixene described in 553 or N, N-dimethyl-9-[3-(4-methyl isophthalic acid-piperazinyl)-propylidene-9H-thioxanthene-2-sulfonamide (sulfanamide) is incorporated herein it for reference in full.
United States Patent (USP) 3,342, sulpiride described in 826 or 5-(amino-sulfonyl)-N-[(1-ethyl-2-pyrrolidinyl) methyl]-the 2-methoxy benzamide, be incorporated herein it for reference in full.
United States Patent (USP) 4,401, amisulpride described in 822 or 4-amino-N-[(1-ethyl-2-pyrrolidinyl) methyl]-5-(ethylsulfonyl)-2-methoxy benzamide, be incorporated herein it for reference in full.
United States Patent (USP) 4,804, risperidone described in 663 or 3-[2-[4-(6-fluoro-1,2-benzoisoxazole-3-yl) piperidines alcohol]-ethyl]-imidazoline-2-ketone, be incorporated herein it for reference in full.
Seroquel described in the EP 240228 (Seroquel) or 11-[4-[2-(2-hydroxyl-oxethyl) ethyl]-the 1-piperazinyl] dibenzo [b, f]-[1,4] sulfur azatropylidene, be incorporated herein it for reference in full.
United States Patent (USP) 5,229, the olanzapine described in 382 or 2-methyl-4-(4-methyl isophthalic acid-piperazinyl)-10H-thieno [2.3-b] [1,5] benzodiazepine is incorporated herein it for reference in full.
Unite with one or more Antipsychotic drugs and to give (S)-2-(benzylamino-methyl)-2,3,8,9-tetrahydrochysene-7H-1,4-bioxin also [2,3-e] indol-8-ones is used for the treatment of or prevention is relevant with the neurotransmitter activity change of dopaminergic system among the central nervous system psychosis such as schizophrenia, schizoaffective psychosis, acute mania and have the depression of psychotic features, eliminate simultaneously or with the independent side effect relevant when oral of some and described Antipsychotic drug as cathisophobiaing, dystonia, the parkinson dyskinesia and the retardance dyskinesia etc. ease down to minimum.
The present invention also provides-kind of product as a combined preparation, and it comprises (S)-2-(benzylamino-methyl)-2,3,8,9-tetrahydrochysene-7H-1,4-bioxin also [2,3-e] indol-8-ones and Antipsychotic drug and be used for simultaneously, respectively or sequential administration treat and suffer from psychotic patient.
(S)-and 2-(benzylamino-methyl)-2,3,8,9-tetrahydrochysene-7H-1, the 4-bioxin is the compositions of [2,3-e] indol-8-ones and one or more Antipsychotic drugs also, and hereinafter being called " compositions " can be with identical or different pharmaceutical preparatioies simultaneously or sequential administration.Certainly, the interval of sequential administration should keep the beneficial effect of compositions and described interval to be determined by skilled doctor.
The therapeutic dose that is appreciated that described compositions preferably has than giving Antipsychotic drug side effect still less separately for treating, suppress, prevent or improve the amount of one or more described psychotic symptoms.In compositions, concrete psychosis and patient's body weight, age and response type must be determined and will be depended on to the dosage of each medicine by the doctor.This paper provides dosage guideline.For compositions, should consider the dosage guideline of each medicine in the compositions.
Usually, (S)-2-(benzylamino-methyl)-2,3,8,9-tetrahydrochysene-7H-1,4-bioxin also [2,3-e] indol-8-ones appropriate dosage scope are about 0.5-100mg every day, and more preferably every day about 1-50mg.
The scope that the Antipsychotic drug appropriate dosage will be recommended at Producer.For some preferred Antipsychotic drug of the present invention, this paper provides following index:
Chlorpromazine: every day about 300-800mg;
Mesoridazine: every day about 100-400mg;
Thioridazine: every day about 200-600mg;
Fluphenazine: every day about 2-5mg;
Trifluoperazine: every day about 6-20mg;
Perphenazine: every day about 8-40mg;
Clozapine: every day about 300-600mg;
Haloperidol: every day about 1-20mg;
Loxapine: every day about 60-100mg;
Molindone: every day about 15-225mg;
Tiotixene: every day about 20-30mg;
Risperidone: every day about 4-20mg;
Seroquel: every day about 15-750mg; With
Olanzapine: every day about 10-20mg.
Although the active component of compositions can give with unprocessed chemical drugs form, preferably exist with pharmaceutical dosage forms.Pharmaceutical preparation of the present invention comprises the present composition, one or more pharmaceutically suitable carrier or excipient and dispensable other therapeutic agent.Described carrier must with the prescription in other component compatibility.When each component of giving respectively in the compositions, they exist with pharmaceutical dosage forms usually separately.
(S)-and 2-(benzylamino-methyl)-2,3,8,9-tetrahydrochysene-7H-1,4-the bioxin also compositions of [2,3-e] indol-8-ones and Antipsychotic drug can be present in the single dosage form with pharmaceutical dosage forms easily.It respectively is 0.1mg-1g that a kind of single-dose preparations easily comprises, for example the active component of 5mg-100mg amount.For example, typical unit doses can comprise (S)-2-(benzylamino-methyl)-2,3 of about 0.5-100mg, 8,9-tetrahydrochysene-7H-1,4-bioxin be [2,3-e] indol-8-ones also, and (S)-2-(benzylamino-methyl)-2 of 1mg-50mg preferably approximately, 3,8,9-tetrahydrochysene-7H-1, the 4-bioxin is [2,3-e] indol-8-ones also.
Pharmaceutical preparation can be prepared at unitary package and be generally " patient's bag " form that comprises whole dosage schedule in the bleb packing.Patient's bag has the benefit that surpasses the tradition prescription, and the pharmacists tells the medicine that is supplied to the patient from large quantities of supply bottles, and wherein, the patient has the right to use to the description that is comprised in patient's bag, and this does not have in the tradition prescription.Content in the description has shown to have to be improved the patient doctor is instructed the effect of compliance.
Be appreciated that giving the present composition by the mode that contains the single patient bag that instructs the patient correctly to use present composition description or each preparation patient bag is another feature of the present invention.
The present invention further provides and comprise at least a active component and the patient's bag that instructs present composition operation instructions in the present composition.
Preparation comprises those preparations that are applicable to oral, rectum, nose, part (comprising transdermal, oral cavity and Sublingual), vagina or parenteral route (comprising subcutaneous, intramuscular, intravenous and intradermal) administration.Described preparation can pass through the pharmaceutical field known method, for example by using method as people such as Gennaro, Remington ' s Pharmaceutical Sciences (18
ThEd., Mack Publishing Company is 1990, especially referring to Paft 8:PharmaceuticalPreparations and thir Manufacture) described in the method preparation.Described method comprises active component and the blended step of carrier that constitutes one or more helper components.Described helper component comprise this area conventional use those as filler, binding agent, diluent, disintegrating agent, lubricant, coloring agent, correctives and wetting agent.
The preparation that is applicable to oral administration can be respectively to comprise discrete unit such as pill, tablet or the capsule of measured quantity active component in advance; Can be powder or granule; Can be solution or suspension.Described active component also can be concentrated medicine mass or paste, perhaps can be included in the liposome.
The preparation of rectally can be suppository or enema.
In parenteral administration, suitable preparation comprises water and non-water aseptic parenteral solution.Described preparation may reside in single dose or multi-dose container, for example in Mi Feng bottle or the ampoule, and can only need add sterile liquid carrier before use, for example stores under the lyophilization of water (lyophilizing) condition.
Be applicable to that the preparation of going into administration by snuffing comprises powder or mist that pressurised aerosol, aerosol apparatus or the insufflator of available dosing produce.
Chemical compound in the present composition can obtain in a usual manner according to method well known in the art.
The following example only is used for explanation, and does not limit the present invention in any way scope.
As shown in following embodiment, with (S)-2-(benzylamino-methyl)-2,3,8,9-tetrahydrochysene-7H-1,4-bioxin also [2,3-e] indol-8-ones merging use have changed the side effect that is caused by the haloperidol treatment.
According to the people such as Svensson that change, Neuropharmacology, 1993, the 32:1037-1045 method is tested the reverse of the inductive rat catalepsy of haloperidol.Rat (200-250g) is transferred to laboratory and stays this there until off-test always from colony room.To be dissolved in 0.25% Tween 80
In haloperidol give all animals with the dosage i.p. of 3mg/kg.After 60 minutes, will also be dissolved in 0.25% Tween 80
In (S)-2-(benzylamino-methyl)-2,3,8,9-tetrahydrochysene-7H-1,4-bioxin also [2,3-e] indol-8-ones give with 4 dosage level s-c-, 6 male Sprague-Dawley Mus of each dosage level.With (S)-2-(benzylamino-methyl)-2,3,8,9-tetrahydrochysene-7H-1,4-bioxin be matched group injection equal-volume (1ml/kg) 0.25% Tween 80 estimated simultaneously of [2,3-e] indol-8-ones treatment group also
Carrier (VEH).After administration 30,60,90 and 120 minutes, be placed on ligneous cube by fore paw and (estimate the catalepsy of animal on 8 * 8 * 8cm) animal.Measure animal and keep the time of at least one fore paw on cube (maximum=60 second).Test righting reflex then and be used for eliminating abirritative and tried body.Utilize two factor variance analyses and single repeated measure to come analytical data.Use with controlled trial and compare minimum effective dose (MED) and the onset time that gained least significant difference (p＜0.05) determines to reverse the inductive catalepsy of haloperidol.Use trend test to determine dose-effect time point (if any) then.From these points, utilize the point that shows maximal reversal degree (having minimum catalepsy scoring) to calculate ED
50(dosage that makes maximum reaction reduce at 50% o'clock) and 95% confidence interval.These can utilize nonlinear regression analysis, and backward prediction is carried out then.
Fig. 1 be diagrammatize after Drug therapy, be time point of greatest reversal in 60 minutes the time, (S)-2-(benzylamino-methyl)-2,3,8,9-tetrahydrochysene-7H-1,4-bioxin also [2,3-e] indol-8-ones (medicine) to the effect of the inductive rat catalepsy of haloperidol.Described data are meansigma methods ± SEM.As shown in the figure, observing time that the catalepsy posture continues is dose dependent and reduces.The MED that is calculated by these results is 0.3mg/kg and ED
50Be 0.08mg/kg.
Embodiment 2
Except not giving the haloperidol, test (S)-2-(benzylamino-methyl)-2,3,8 according to embodiment 1 described similar method, 9-tetrahydrochysene-7H-1,4-bioxin also [2,3-e] indol-8-ones induce the probability of rat catalepsy.
Fig. 2 is (the S)-2-(benzylamino-methyl)-2,3,8 that diagrammatizes, and 9-tetrahydrochysene-7H-1,4-bioxin also [2,3-e] indol-8-ones (medicine) induce the ability of rat catalepsy.Described data are meansigma methods ± SEM.As shown in the figure, 60 minutes the time, described medicine lacks the ability of inducing the rat catalepsy significantly after with the dosage s.c. administration of 0.003-3mg/kg.Observe similar result at other testing time point.
Embodiment 3
According to the Riffee and Wilcox that changes, Psychopharmacology, 1985, the 85:97-101 method is tested the inductive hyperkinetic ability of antagonism amphetamine.Mice (25-30g) is transferred to laboratory and stays this there until off-test always from colony room.Before test, (open place is 8 * 8in.) 60 minutes to allow animal be familiar with the exercise test chamber.During being familiar with, i.p. gives all animals with d-amphetamine (2.5mg/kg solution is in distilled water).After 15 minutes, will be dissolved in 0.25% Tween 80
In test compound give 8 mices of each dosage level with 8 dosage level s.c..The carrier of the matched group injection equal-volume of estimating simultaneously with medication therapy groups (10ml/kg).After giving test compound, immediately animal is put into gymnasium separately.Utilize Omnitech Digiscan
(the monitoring situation is 30 minutes under turning on light for Columbus, Ohio) ir supervisor.Count the interruption of each infrared beam and with 10 minutes interval calculation sums by automatic system.The horizontal anomalous movement counting of collecting in after described on-test 10-20 minute is carried out one way analysis of variance, carrying out Student-Newman-Keuls check (p＜0.05) then determines to compare the effective dosage of the inductive hyperkinesia of test compound antagonism d-amphetamine with the vehicle treatment group.Analyze the average level activity count by nonlinear regression, calculate ED by backward prediction then
50(making the movable dosage that reduces at 50% o'clock) and 95% confidence interval (CI) and slope and minimum level of activation.
Fig. 3 is (the S)-2-(benzylamino-methyl)-2,3,8 that diagrammatizes, and 9-tetrahydrochysene-7H-1,4-bioxin also [2,3-e] indol-8-ones (medicine) reverse the hyperactive effect of the inductive mice of d-amphetamine.Described data are to represent from the percent of the independent observed level of activation of mice with d-amphetamine treatment and with meansigma methods ± SEM.As shown in the figure, observing the inductive hyperkinesia of d-amphetamine is dose dependent and reduces.ED by these results' calculating
50Be 0.002mg/kg.
Therefore, it is the side effect of model representation with the catalepsy that the present composition reduces inductive by haloperidol, is the ability of the schizophrenia positive symptom of model and do not reduce the haloperidol treatment with the inductive hyperkinesia of amphetamine.
Claims (22)
1, a kind ofly be used for the treatment of psychotic pharmaceutical composition, it comprises (S)-2-(benzylamino-methyl)-2,3,8, and 9-tetrahydrochysene-7H-1,4-bioxin be [2,3-e] indol-8-ones and Antipsychotic drug also.
2, the pharmaceutical composition of claim 1, it also comprises one or more pharmaceutical carriers.
3, claim 1 or 2 pharmaceutical composition, wherein said Antipsychotic drug is atypical Antipsychotic drug.
4, claim 1 or 2 pharmaceutical composition, wherein said Antipsychotic drug is typical Antipsychotic drug.
5, claim 1 or 2 pharmaceutical composition, wherein said Antipsychotic drug is selected from chlorpromazine, mesoridazine, thioridazine, fluphenazine, trifluoperazine, perphenazine, clozapine, haloperidol, loxapine, molindone, tiotixene, risperidone, Seroquel and olanzapine.
6, right claim 1 or 2 pharmaceutical composition, it is a peroral dosage form.
7, claim 1 or 2 pharmaceutical composition, it contains the Antipsychotic drug of 0.1mg-1g.
8, (S)-2-(benzylamino-methyl)-2,3,8,9-tetrahydrochysene-7H-1,4-bioxin also [2,3-e] indol-8-ones and Antipsychotic drug are used for the treatment of application in the insane medicine in preparation.
9, the application of claim 8, wherein said Antipsychotic drug are atypical Antipsychotic drug.
10, the application of claim 8, wherein said Antipsychotic drug are typical Antipsychotic drug.
11, the application of claim 8, wherein said Antipsychotic drug is selected from chlorpromazine, mesoridazine, thioridazine, fluphenazine, trifluoperazine, perphenazine, clozapine, haloperidol, loxapine, molindone, tiotixene, risperidone, Seroquel and olanzapine.
12, each application among the claim 8-11, wherein said medicine is a peroral dosage form.
13, the application of claim 8, wherein said psychosis is a schizophrenia.
14, the application of claim 8, wherein said psychosis is a schizoaffective psychosis.
15, the application of claim 8, wherein said psychosis is a depression.
16, the application of claim 8, wherein said medicine contains the Antipsychotic drug of 0.1mg-1g.
17, a kind ofly be used for the treatment of psychotic product as a combined preparation, it comprises, and is used for simultaneously, respectively or (the S)-2-(benzylamino-methyl)-2,3,8 of sequential administration, and 9-tetrahydrochysene-7H-1,4-bioxin be [2,3-e] indol-8-ones and Antipsychotic drug also.
18, the product of claim 17, wherein said Antipsychotic drug are atypical Antipsychotic drug.
19, the product of claim 17, wherein said Antipsychotic drug are typical Antipsychotic drug.
20, the product of claim 17, wherein said Antipsychotic drug is selected from chlorpromazine, mesoridazine, thioridazine, fluphenazine, trifluoperazine, perphenazine, clozapine, haloperidol, loxapine, molindone, tiotixene, risperidone, Seroquel and olanzapine.
21, each product among the claim 17-20, this product is a peroral dosage form.
22, a kind of patient bag, it comprise among the claim 1-7 each pharmaceutical composition or claim 17-21 in each product as a combined preparation, and comprise and instruct the description that active component is used in described compositions or the product.
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|---|---|---|---|
| US45860799A | 1999-12-10 | 1999-12-10 | |
| US09/458,607 | 1999-12-10 |
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| EP (1) | EP1235570A2 (en) |
| JP (1) | JP5557409B2 (en) |
| KR (1) | KR100772854B1 (en) |
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| AR (1) | AR026756A1 (en) |
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| CZ (1) | CZ20021880A3 (en) |
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| TW (1) | TWI222864B (en) |
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| WO2005044262A1 (en) | 2003-10-29 | 2005-05-19 | Wyeth | Sustained release pharmaceutical compositions comprising aplindore and derivatives thereof |
| EP1856126A2 (en) | 2005-02-17 | 2007-11-21 | Wyeth a Corporation of the State of Delaware | Cycloalkylfused indole, benzothiophene, benzofuran and indene derivatives |
| RU2481123C2 (en) * | 2008-02-13 | 2013-05-10 | Таргасепт, Инк. | Combination of alpha 7 nicotinic receptor agonists and antipsychotic agents |
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| JP2987484B2 (en) * | 1995-03-16 | 1999-12-06 | 大塚製薬 株式会社 | Method for producing carbostyril derivative |
| US5756532A (en) * | 1995-11-06 | 1998-05-26 | American Home Products Corporation | Aminomethyl-2 3 8 9-tetrahydro-7H-1 4-dioxino 2 3-E!-indol-8-ones and derivatives |
| GB9627005D0 (en) * | 1996-12-27 | 1997-02-12 | Knoll Ag | Therapeutic agents |
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| CN1409633A (en) | 2003-04-09 |
| EA200200656A1 (en) | 2002-12-26 |
| AR026756A1 (en) | 2003-02-26 |
| MXPA02005649A (en) | 2004-09-10 |
| TWI222864B (en) | 2004-11-01 |
| CA2396351A1 (en) | 2001-06-14 |
| KR100772854B1 (en) | 2007-11-02 |
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| IL149669A (en) | 2006-06-11 |
| CA2396351C (en) | 2009-11-10 |
| IL149669A0 (en) | 2002-11-10 |
| EA005002B1 (en) | 2004-10-28 |
| CZ20021880A3 (en) | 2002-08-14 |
| HK1045942A1 (en) | 2002-12-20 |
| ZA200205484B (en) | 2003-12-31 |
| EP1235570A2 (en) | 2002-09-04 |
| WO2001041750A3 (en) | 2002-02-14 |
| AU1949001A (en) | 2001-06-18 |
| PL355292A1 (en) | 2004-04-05 |
| HUP0203309A2 (en) | 2003-01-28 |
| NZ519381A (en) | 2004-04-30 |
| NO20022739L (en) | 2002-06-07 |
| NO20022739D0 (en) | 2002-06-07 |
| HUP0203309A3 (en) | 2004-12-28 |
| WO2001041750A2 (en) | 2001-06-14 |
| JP2003516350A (en) | 2003-05-13 |
| BR0016168A (en) | 2002-08-20 |
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