EA005002B1 - NOVEL THERAPEUTIC COMBINATIONS OF (S)-2(BENZYLAMINO-METHYL)-2,3,8,9-TETRAHYDRO-7H-1,4-DIOXINO(2,3-e)-INDOL-8-ONE AND NEUROLEPTICS FOR TREATING OR PREVENTION OF PSYCHOTIC DISORDERS - Google Patents

Abstract

1. A composition comprising (S)-2-(benzylamino-methyl)-2,3,8,9-tetrhydro-7H-1,4-dioxino [2,3-e] indol-8-one and an antipsychotic agent. 2. A pharmaceutical composition comprising (S)-2-(benzylaminomethyl)-2,3,8,9-tetrahydro-7H-1,4-dioxino [2,3-e] indol-8-one, an antipsychotic agent, and one or more pharmaceutical carriers therefor. 3. A pharmaceutical composition for treating a patient suffering from a psychotic disorder comprising an effective amount of (S)-2-(benzylamino-methyl)-2,3,8,9-tetrahydro-7H-1,4-dioxino [2,3-e] indol-8-one, in combination with an effective amount of an antipsychotic agent. 4. A composition according to any one of Claims 1 to 3 wherein the antipsychotic agent is an atypical antipsychotic. 5. A composition according to any one of Claims 1 to 3 wherein the antipsychotic agent is a typical antipsychotic. 6. A composition according to any one of Claims 1 to 3 wherein the antipsychotic agent is selected from chlorpromazine, mesoridazine, thioridazine, fluphenazine, trifluoperazine, perphenazine, clozapine, haloperidol, loxapine, molindone, thiothixene, risperidone, seroquel, and olanzapine. 7. A composition according to any one of Claims 1 to 6 wherein the composition is adapted for oral administration. 8. A composition according to any one of Claims 1 to 7 wherein the composition is adapted to administer the antipsychotic in the amount of about 10 mg to about 1000 mg per day. 9. A method of treating a patient suffering from a psychotic disorder comprising administering to said patient an effective amount of (S)-2-(benzylaminomethyl)-2,3,8,9-tetrahydro-7H-1,4-dioxino [2,3-e] indol-8-one, in combination with an effective amount of an antipsychotic agent. 10. The method of Claim 9 wherein the antipsychotic agent is an atypical antipsychotic. 11. The method of Claim 9 wherein the antipsychotic agent is a typical antipsychotic. 12. The method of Claim 9 wherein the antipsychotic agent is selected from the group consisting of chlorpromazine, mesoridazine, thioridazine, fluphenazine, trifluoperazine, perphenazine, clozapine, haloperidol, loxapine, molindone, thiothixene, risperidone, seroquel, and olanzapine. 13. The method of any one of Claims 9 to 12 wherein administration of the compounds is oral. 14. The method of Claim 9 wherein the patient is suffering from schizophrenia. 15. The method of Claim 9 wherein the patient is suffering from schizoaffective disorder. 16. The method of Claim 9 wherein the patient is suffering from depression. 17. The method of Claim 9 wherein the antipsychotic is administered in the amount of about 10 mg to about 1000 mg per day. 18. A product comprising (S)-2-(benzylaminomethyl)-2,3,8,9-tetrahydro-7H-1,4-dioxino [2,3-e] indol-8-one and an antipsychotic agent as a combined preparation for simultaneous, separate or sequential administration to treat a patient suffering from a psychotic disorder. 19. A product according to Claim 18 wherein the antipsychotic agent is an atypical antipsychotic. 20. A product according to Claim 18 wherein the antipsychotic agent is a typical antipsychotic. 21. A product according to Claim 18 wherein the antipsychotic agent is selected from chlorpromazine, mesoridazine, thioridazine, fluphenazine, trifluoperazine, perphenazine, clozapine, haloperidol, loxapine, molindone, thiothixene, risperidone, seroquel, and olanzapine. 22. A product according to any one of Claims 18 to 21 which is adapted for oral administration. 23. A product according to Claim 18 for treating schizophrenia. 24. A product according to Claim 18 for treating schizoaffective disorder. 25. A product according to Claim 18 for treating depression. 26. A patient pack comprising at least one active ingredient selected from (S)-2-(benzylamino-methyl)-2,3,8,9-tetrahydro-7H-1,4-dioxino [2,3-e] indol-8-one and an antipsychotic agent, and comprising an information insert containing directions on the use of the active ingredient or active ingredients in a combination comprising (S)-2-(benzylamino-methyl)-2,3,8,9-tetrahydro-7H-1,4-dioxino [2,3-e] indol-8-one and an antipsychotic agent.

Description

Field of Invention

The present invention relates to therapeutic combinations of (8) -2- (benzylaminomethyl) -2,3,8,9-tetrahydro-7H-1,4-dioxin [2,3-e] indol-8-one, a partial dopamine agonist Ό2 / Ο3 receptors, and antipsychotic agents for the treatment or prevention of psychotic disorders, to pharmaceutical compositions containing these combinations, and to their use in the treatment or prevention of psychotic disorders.

State of the art

Psychoses are severe mental illness characterized by impaired or lost contact with reality. These disorders are characterized by a variety of symptoms, which are classified as positive symptoms (impaired thinking, hallucinations and mania), negative symptoms (social autism and areactivity) and cognitive deficits.

Antipsychotics or antipsychotics can be used to treat schizophrenia and other related psychotic disorders by blocking dopaminergic neurotransmission in the central nervous system. Antipsychotics are widely used to treat “positive” symptoms of schizophrenia. However, many of these drugs are not considered effective in treating the "negative" symptoms of schizophrenia and may in fact exacerbate these symptoms due to dopaminergic blockade associated with their mechanism of action. It is believed that cognitive deficits associated with schizophrenia, such as pathological increased distractibility, and executive skills, such as working memory and the ability to plan, are also adversely affected by blockade of dopamine receptors.

In addition, these antipsychotics have important side effects, such as akathisia, dystonia, parkinsonism dyskinesia and tardive dyskinesia and the like, which are caused by blocking dopaminergic neurotransmission.

Anticholinergic agents such as cohentin® have been used to reduce Parkinson's-like side effects, but they also cause side effects such as mental and / or physical upset, tachycardia, dysuria, and gastrointestinal symptoms.

It has been shown that some partial dopamine agonists with relatively high endogenous activity are effective against negative symptoms of schizophrenia. It has been hypothesized that, in this regard, some endogenous activity is desirable to optimize the treatment of negative symptoms while minimizing side effects (Lysbept, BR.

However, with increased internal activity, dopamine transmission levels are higher, and therefore, treatment of positive symptoms may be less effective.

It was found that partial dopamine agonists having moderate to high endogenous activity, such as preclamol, pramipexole and terguride, have been used to eliminate the side effects of traditional antipsychotics. These reports show that higher internal activity leads to greater efficacy in alleviating the side effects associated with impaired motor function (8yep88op, e1 a1., #Igoryagtasodu 32 (10): 1037-1045 (1993)).

For the treatment of patients, new types of combination drug therapy can be used. It is highly desirable to optimize the beneficial properties of both drugs while minimizing the side effects associated with the drugs when used separately. Applicants have discovered a therapeutic combination that can be used to treat psychotic disorders.

Brief Description of the Drawings

Figure 1 is a schematic representation of the action of (8) -2- (benzylaminomethyl) -2,3,8,9-tetrahydro-7H-1,4-dioxin [2,3-e] indol-8-one (agent) for catalepsy caused by haloperidol in rats 60 minutes after drug treatment, the time point of maximum elimination, according to the measurement of time in seconds spent in catalepsy, in the dose range from 0.003 to 3 mg / kg of the agent subcutaneously. Data are mean values ± standard deviation.

FIG. 2 is a schematic representation of the ability of (8) -2- (benzylaminomethyl) -2,3,8,9-tetrahydro-7H-1,4-dioxin [2,3-e] indol-8-one (agent) to cause catalepsy in rats, according to the measurement of time in seconds spent in catalepsy, subcutaneously in the dose range from 0.003 to 3 mg / kg of agent. Data are mean values ± standard deviation.

Figure 3 is a schematic representation of the action of (8) -2- (benzylaminomethyl) -2,3,8,9-tetrahydro-7H-1,4-dioxin [2,3-e] indol-8-one (agent) aimed at eliminating hyperactivity in mice caused by 6amphetamine. Data are expressed as a percentage of the activity level (horizontal activity calculations) observed in mice treated with 6-amphetamine alone for eight doses of the agent in the range of 0.0001 to 1 mg / kg subcutaneously. Data are mean values ± standard deviation.

DETAILED DESCRIPTION OF THE INVENTION

In accordance with the present invention, there is provided a composition comprising (8) -2- (benzylaminomethyl) -2,3,8,9-tetrahydro 3

7H-1,4-dioxin [2,3-e] indol-8-one or its pharmaceutical salts and one or more antipsychotic agents.

(8) -2- (benzylaminomethyl) -2,3,8,9-tetrahydro-7H-1,4-dioxin [2,3-e] indol-8-one, partial agonist No. 2, disclosed in US patent No. 5756532 Unless otherwise indicated, the (8) -2- (benzylaminomethyl) 2,3,8,9-tetrahydro-7H-1,4-dioxin [2,3-e] indol8-one used includes its pharmaceutical salts.

Pharmaceutically acceptable salts include acid addition salts such as hydrochloric, fumaric, maleic, citric or succinic.

The term “antipsychotic agent” or “antipsychotic agent” includes antipsychotics that work as a complete antagonist of the dopamine Ό2 receptor and includes both typical and atypical antipsychotics. Representative antipsychotic agents that are commercially available or known to specialists in this field include (but are not limited to):

chlorpromazine or 2-chloro-HH-dimethyl10H-phenothiazine-10-propanamine, described in US patent No. 2645640, which is fully incorporated into the description by reference;

mesoridazine or 10- [2- (1-methyl-2-piperidinyl) ethyl] -2- (methylsulfinyl) -10H-phenothiazine, described in US patent No. 3084161, which is fully incorporated into the description by reference;

thioridazine or 10- [2- (1-methyl-2-piperidinyl) ethyl] -2- (methylthio) -10H-phenothiazine described in Sobes !. S / he. Siet. Sottip., 1990, 55, 1586-1601, which is incorporated herein by reference in its entirety;

fluphenazine or 4- [3- [2- (trifluoromethyl) 10H-phenothiazin-10-yl] propyl] -1-piperazineethanol described in CB 829246, which is incorporated herein by reference in its entirety;

trifluperazine or 10- [3- (4-methyl-1-piperazinyl) propyl] -2- (trifluoromethyl) -10H-phenothiazine, described in CB 813861, which is fully incorporated into the description by reference;

perphenazine or 4- [3- (2-chloro-10H-phenothiazin-1-yl) propyl] -1-piperazine ethanol described in US patent No. 27 66235, which is fully incorporated into the description by reference;

clozapine or 8-chloro-11- (4-methyl-1-piperazinyl) -5H-dibenzo [e, e] - [1,4] diazepine described in US patent No. 3539573, which is fully incorporated into the description by reference;

haloperidol or 4- [4- (4-chlorophenyl) -4-hydroxy-1-piperidinyl] -1 - (4-fluorophenyl) -1-butanone as described in US Pat. No. 3,438,991, which is incorporated herein by reference in its entirety. ;

loxapine or 2-chloro-11- (4-methyl-1-piperazinyl) dibenz | L.G | - [1,4] oxazepine described in US patent No. 3546226, which is fully incorporated into the description by reference;

molindone or 3-ethyl-1,5,6,7-tetrahydro-2methyl-5- (4-morpholinylmethyl) -4H-indol-4-one, as described in US Pat. No. 3,491,093, which is incorporated herein by reference in its entirety;

thiotixen or NY-dimethyl-9-3- (4-methyl-

1-piperazinyl) propylidene-9H-thioxanthene-2sulfanamide, described in US patent No. 3310553, which is fully incorporated into the description by reference;

sulpiride or 5- (aminosulfonyl) -Y - [(1-ethyl-2-pyrrolidinyl) methyl] -2-methoxybenzamide, described in US patent No. 3342826, which is fully incorporated into the description by reference;

amisulpiride or 4-amino-S - [(1-ethyl-2pyrrolidinyl) methyl] -5 (ethylsulfonyl) -2-methoxybenzamide as described in US Pat. No. 4,401,822, which is incorporated herein by reference in its entirety;

risperidone or 3- [2- [4- (6-fluoro-1,2-benzisoxazol-3-yl) piperidino] ethyl] imidazolidine-

2- it is described in US patent No. 4804663, which is fully incorporated into the description by reference;

seroquel or 11- [4- [2- (2-hydroxyethoxy) ethyl] -1-piperazinyl] dibenzo [b, G] - [1,4] thiazepine, the preparation described in EP 240228, which is fully incorporated into the description by reference ;

olanzapine or 2-methyl-4- (4-methyl-1-piperazinyl) -10H-thieno [2,3-b] [1,5] benzodiazepine described in US patent No. 5229382, which is fully incorporated into the description by links.

Introduction (8) -2 - (benzylaminomethyl) -2,3,8,9-tetrahydro-7H-1,4-dioxin [2,3-e] indol-8-one in combination with one or more antipsychotic agents for the treatment or prevention of psychotic disorders associated with impaired activity of the neurotransmission of the dopaminergic system in the central nervous system, such as schizophrenia, schizoaffective disorder, acute manic psychosis and depression with psychotic symptoms, while at the same time eliminating or minimizing certain side effects associated with indicated antipsychotic drugs when used separately, such as akathasia, dystonia, parkinsonism dyskinesia, tardive dyskinesia, and the like.

This invention also provides a product comprising (8) -2- (benzylaminomethyl) -2,3,8,9-tetrahydro-7H-1,4-dioxin [2,3-e] indol-8-one and an antipsychotic agent in as a combined preparation for simultaneous, separate or sequential administration for the treatment of a patient suffering from a psychotic disorder.

Combinations of (8) -2- (benzylaminomethyl) 2,3,8,9-tetrahydro-7H-1,4-dioxin [2,3-e] indol8-one and one or more antipsychotics, hereinafter referred to as “combinations”, may be administered simultaneously, in the same or in different pharmaceutical formulations, or sequentially. Of course, the determination of the time of sequential administration should preserve the advantageous effects of the combination, and the specified determination of time can be performed by a person skilled in the art.

By a therapeutically acceptable amount of a combination is meant an amount that treats, inhibits, prevents or alleviates one or more symptoms of the psychotic disorder in question, preferably with fewer side effects than that associated with the administration of a single antipsychotic agent. Dosages of each of the drugs in combination should be determined by the doctor and will depend on the specific psychotic disorder, as well as body size, age and type of patient response. Dosage guidance is provided. For the combination, the guidelines for determining the dosage of each drug in the combination should be taken into account.

In general, suitable doses of (8) -2- (benzylaminomethyl) -2,3,8,9-tetrahydro-7H-1,4-dioxin [2,3-e] indol-8-one are in the range from about 0 5 mg / day to about 100 mg / day, and more preferably from about 1 to about 50 mg / day.

A suitable dose of antipsychotic agent should be in the range recommended by the manufacturer. For certain preferred antipsychotics of the present invention, the following directions for use are provided:

chlorpromazine: from about 300 to about 800 mg / day;

mesoridazine: from about 100 to about 400 mg / day;

thioridazine: from about 200 to about 600 mg / day;

fluphenazine: from about 2 to about 5 mg / day;

trifluperazine: from about 6 to about 20 mg / day;

perphenazine: from about 8 to about 40 mg / day;

clozapine: from about 300 to about 600 mg / day;

haloperidol: from about 1 to about 20 mg / day;

loxapine: from about 60 to about 100 mg / day;

molindone: from about 15 to about 225 mg / day;

thiotixen: from about 20 to about 30 mg / day;

risperidone: from about 4 to about 20 mg / day;

seroquel: from about 15 to about 750 mg / day; and olanzapine: from about 10 to about 20 mg / day.

Although the active ingredients of the combination can be administered as a chemical compound, it is preferable to present them in the form of a pharmaceutical formulation. Pharmaceutical formulations in accordance with the present invention include a combination in accordance with the invention together with one or more pharmaceutically acceptable carriers or excipients and, optionally, other therapeutic agents. Carriers should be acceptable in the sense of compatibility with other ingredients in the formulation. With the separate administration of the individual components of the combination, each of them is generally presented in the form of a pharmaceutical formulation.

The combination of (8) -2- (benzylaminomethyl) 2,3,8,9-tetrahydro-7H-1,4-dioxin [2,3-e] indol8-one and an antipsychotic agent can be conveniently presented as a pharmaceutical preparative forms in unit dosage form. A convenient unit dosage form contains each active ingredient in amounts of from 0.1 mg to 1 g, for example, from 5 mg to 100 mg. Typical dosage forms may, for example, contain from about 0.5 to about 100 mg of (8) -2- (benzylaminomethyl) -2,3,8,9-tetrahydro-7H-1,4-dioxin [2,3- e] indol-8-one, and preferably from about 1 mg to about 50 mg of (8) -2- (benzylaminomethyl) 2,3,8,9-tetrahydro-7H-1,4-dioxin [2,3-e ] indol8-she.

Pharmaceutical formulations may be formulated as “patient packs” containing a complete course of treatment in one package, usually in a blister pack. Patient packages have an advantage over traditional prescriptions, in which the pharmacist separates the amount of pharmaceuticals due to the patient, in that the patient always has access to the insert contained in the patient packaging, which is usually not found in traditional prescriptions. The inclusion of the package insert in the package has been shown to improve patient compliance with medical instructions.

It should be understood that the introduction of a combination of the invention by means of a single package for a patient or packaging for a patient of each formulation with a package insert instructing the patient on the correct use of the invention is a desirable additional feature of the present invention.

In accordance with a further aspect of the invention, there is provided a package for a patient comprising at least one active ingredient of a combination of the invention and an information leaflet containing instructions for using the combination of the invention.

Formulations include preparations suitable for oral, rectal, intranasal, topical (including transdermal, buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration. The formulations may be prepared by any methods well known in the art of pharmacy, for example, using methods such as those described in the publication of Osipa c1 a1., Keshshdop'k Ryattaseibsa1 8s1epse5 ^(18,411 ee., Musk RiYMnpd Sotrapu 1990 , see, in particular, Paradise 8: Ryattaseibs1 RTeratabopk apb ΙΗοιγ MapiGasShte). Such methods include the step of combining the active ingredient with a carrier, which is one or more accessory ingredients. Such additive ingredients include ingredients commonly used in the art, such as fillers, binders, diluents, disintegrants, lubricants, colorants, flavoring agents and wetting agents.

Formulations suitable for oral administration may be presented as discrete units, such as pills, tablets or capsules, each of which contains a certain amount of the active ingredient; in the form of powder or granules; in the form of a solution or suspension. The active ingredient may also be present as a bolus or paste, or may be contained within the liposome.

Formulations for rectal administration may be presented as a suppository or enema.

Suitable formulations for parenteral administration are aqueous or non-aqueous sterile injectable solution. Formulations can be presented in containers with a standard dosage form or in multiple doses, for example, in hermetically sealed vials or sealed ampoules, and can be stored in a lyophilized state, requiring only sterile liquid carrier, for example, water, to be added before use.

Formulations suitable for administration by nasal inhalation include fine powders or aerosols, which can be obtained by compressing aerosol containers, nebulizers or insufflators providing a predetermined dose of aerosol.

The compounds of the composition of the present invention can be obtained in the usual way using methods known in this field.

The following examples are intended to be illustrative only and in no way intended to limit the scope of the invention.

As shown by the following examples, the side effects caused by haloperidol treatment are affected by the simultaneous treatment of (8) 2- (benzylaminomethyl) -2,3,8,9-tetrahydro-7H1,4-dioxin [2,3-e] indole-8 -on.

Example 1

Tests to eliminate the catalepsy caused in haloperidol in rats were carried out in accordance with the change in the methods of 8sep55op e1 a1., Igoryattasodu, 1993, 32: 1037-1045.

Rats (200-250 g) were transported from the room where the colony was kept to the experimental room and kept there for the duration of the experiment. Haloperidol, dissolved in 0.25% T \ sepep 80®, was administered intraperitoneally to all animals at a dose of 3 mg / kg. After 60 minutes, (8) -2- (benzylaminomethyl) -2,3,8,9-tetrahydro-7H-1,4-dioxin [2,3-e] indol-8-one, also dissolved in 0.25% Tetheep 80 ^® , in 4 dose levels, 6 male rats 8rtadie-OaMeu were administered intraperitoneally for each dose level. The control group, which was evaluated simultaneously with the groups treated with (8) -2- (benzylaminomethyl) -2,3,8,9-tetrahydro-7H-1,4-dioxin [2,3-e] indol-8-one , an injection of equal volumes (1 ml / kg) of the carrier (UEN) of 0.25% T \ sep 80® was performed. The animals were evaluated for catalepsy 30, 60, 90, and 120 minutes after drug administration by placing the animal's front paws on a wooden cube (8x8x8 cm). The time during which the animal remained with at least one of the forepaws on the cube (maximum = 60 s) was measured. The rectification reflex was then examined and used to weed out animals with a sedative effect. Data was analyzed using a two-way analysis of variance with one repeated measurement. The subsequent minimum statistically significant difference with the control test (p <0.05) was used to determine the minimum effective dose (MEI) to eliminate catalepsy caused by haloperidol, and to determine the start time. A trend test was then used to determine at what time points (if any) a dose-dependent effect was observed. At these time points, a point showing the maximum degree of elimination (having the lowest catalepsy score) was used to calculate the EI ₅₀ (dose causing a 50% decrease in maximal response) and 95% confidence intervals. This was carried out using nonlinear regression analysis followed by a reverse forecast.

FIG. 1 is a schematic representation of the effect of (8) -2- (benzylaminomethyl) -2,3,8,9-tetrahydro-7H-1,4-dioxin [2,3-e] indol-8-one (agent) on catalepsy caused by haloperidol in rats 60 minutes after drug treatment, the time point of maximum elimination. Data are mean values ± standard deviation. As shown in the drawing, a dose-dependent decrease in time spent in a cataleptic position was observed. According to these data, ΜΕΌ 0.3 mg / kg and ΕΌ ₅₀ 0.08 mg / kg were calculated.

Example 2

Testing of the cataleptogenic potential of (8) -2- (benzylaminomethyl) -2,3,8,9-tetrahydro 7H-1,4-dioxin [2,3-e] indol-8-one in rats was carried out by a method similar to the method described in example 1, except that haloperidol was not administered.

FIG. 2 is a schematic representation of the ability of (8) -2- (benzylaminomethyl) -2,3,8,9-tetrahydro-7H-1,4-dioxin [2,3-e] indol-8-one (agent) to cause catalepsy in rats. Data are mean values ± standard deviation. As shown in the drawing, the agent is not able to cause significant catalepsy in rats at a dose range of 0.003 to 3 mg / kg subcutaneously 60 minutes after administration. Similar results were observed at other time points tested.

Example 3

The ability to counteract the excessive motor activity caused by amphetamine was tested in accordance with a modified version of the Ktje apb \ νί1οοχ methods. P8syoryoryattasodu, 1985, 85: 97-101. Mice (25-30 g) were transported from the room where the colony was kept to the experimental room and kept there for the duration of the experiment. Before the test, the animals adapted for 60 minutes in the chambers for testing the motor function (open area 20.32 x 20.32 cm). After a period of adaptation, b-amphetamine (2.5 mg / kg intraperitoneally dissolved in distilled water) was administered to all animals. After 15 minutes, 8 mice were injected subcutaneously at 8 dose levels at each dose level with test compounds dissolved in 0.25% Teteep 80®. The control group, which was evaluated simultaneously with the groups treated with the drug, received an injection of equal volumes of the carrier (10 ml / kg). Immediately after administration of the test compound, the animals were individually housed in chambers to study motor activity. Activity was monitored for 30 minutes with the light turned on using Infrared Sensors® infrared monitors (Cli8i, Oio). Each interruption of the infrared ray was counted by an automated device and added up at 10-minute intervals. Quantitative assessments of horizontal activity, collected from 10 to 20 minutes after the start of the test session, were subjected to a one-way analysis of variance, followed by the criterion 81ibep1-YetetapKeyik (p <0.05) to determine the doses that were effective in counteracting excessive motor activity caused by bamphetamine, relative to the control group receiving the carrier. Average values of horizontal activity were analyzed by nonlinear regression followed by a reverse forecast to calculate ΕΌ ₅₀ (the dose causing a decrease in the maximum response by 50%) and 95% confidence intervals (CI), as well as the steepness of the curve and the minimum level of activity.

FIG. 3 is a schematic representation of the action of (8) -2- (benzylaminomethyl) 2,3,8,9-tetrahydro-7H-1,4-dioxin [2,3-e] indole-8one (agent) aimed at eliminating hyperactivity in mice caused by b-amphetamine. Data are expressed as a percentage of the level of activity observed in mice treated with b-amphetamine alone and are presented as mean values ± standard deviation. As shown in the drawing, there was a dose-dependent decrease in hyperactivity caused by bamphetamine. According to these results, ΕΌ ₅₀ 0.002 mg / kg was calculated.

Thus, the formulations of the present invention reduce the side effects caused by haloperidol, as evidenced by the catalepsy model, while at the same time not reducing the ability of haloperidol to treat positive symptoms of schizophrenia, as evidenced by the amphetamine-induced hyperactivity model.

Claims (26)

CLAIM 1. A composition comprising (8) -2- (benzylaminomethyl) -2,3,8,8-tetrahydro-7H-1,4-dioxin [2,3-e] indol-8-one and an antipsychotic agent. 2. A pharmaceutical composition comprising (8) -2 - (benzylaminomethyl) -2,3,8,9 -tetrahydro-7H-1,4-dioxin [2,3-e] indol-8-one, an antipsychotic agent and one or several pharmaceutical carriers. 3. Pharmaceutical composition for treating a patient suffering from a psychotic disorder, comprising an effective amount of (8) -2- (benzylaminomethyl) -2,3,8,9-tetrahydro-7H-1,4-dioxin [2,3-e] indole -8-it in combination with an effective amount of an antipsychotic agent. 4. Composition according to any one of claims 1 to 3, in which the antipsychotic agent is an atypical antipsychotic agent. 5. Composition according to any one of claims 1 to 3, in which the antipsychotic agent is a typical antipsychotic agent. 6. A composition according to any one of claims 1 to 3, in which the antipsychotic agent is selected from chlorpromazine, mezoridazine, thioridazine, flufenazine, trifluperazine, perphenazine, clozapine, haloperidol, loxapine, molindone, thiotixen, serperidone, serocol ally, seroconidine, haloperidol, loxapine, molindone, thiotixen, risperidone, seroperidine, haloperidol, loxapine, molindone, thiouxesen, serotridine 7. Composition according to any one of claims 1 to 6, adapted for oral administration. 8. Composition according to any one of claims 1 to 7, which is adapted to administer an antipsychotic in an amount from about 10 mg to about 1000 mg / day. 9. A method of treating a patient suffering from a psychotic disorder, comprising administering to said patient an effective amount of (8) -2 - (benzylaminomethyl) -2,3,8,9 tetrahydro-7H-1,4-dioxin [2,3-e] indole 8-it in combination with an effective amount of an antipsychotic agent. 10. The method of claim 9, wherein the antipsychotic agent is an atypical antipsychotic agent. 11. The method of claim 9, wherein the antipsychotic agent is a typical antipsychotic agent. 12. The method according to claim 9, wherein the antipsychotic agent is selected from chlorpromazine, mezoridazine, thioridazine, flufenazine, trifluperazine, perphenazine, clozapine, haloperidol, loxapine, molindone, thiothixen, risperidone, seroquel and olanapina, serpentine. 13. The method according to any of paragraphs.9-12, in which the administration of the compounds is carried out orally. 14. The method according to claim 9, in which the patient suffers from schizophrenia. 15. The method according to claim 9, in which the patient suffers from schizoaffective disorder. 16. The method according to claim 9, in which the patient suffers from depression. 17. The method of claim 9, wherein the antipsychotic agent is administered in an amount from about 10 mg to about 1000 mg / day. 18. The product, including (8) -2- (benzylaminomethyl) -2,3,8,9-tetrahydro-7H-1,4-dioxin [2,3-e] indol-8-one and antipsychotic agent, in the form a combined preparation for simultaneous, separate or sequential administration for the treatment of a patient suffering from a psychotic disorder. 19. A product according to claim 18, wherein the antipsychotic agent is an atypical antipsychotic agent. 20. A product according to claim 18, wherein the antipsychotic agent is a typical antipsychotic agent. 21. The product of claim 18, wherein the antipsychotic agent is selected from chlorpromazine, mezoridazine, thioridazine, flufenazine, trifluperazine, perphenazine, clozapine, haloperidol, loxapine, molindone, thiothixen, risperidone, seroquel, and olanapina. 22. Product according to any one of claims 18-21, which is adapted for oral administration. 23. A product according to claim 18 for the treatment of schizophrenia. 24. A product according to claim 18 for the treatment of schizoaffective disorder. 25. Product according to claim 18 for the treatment of depression. 26. A patient package containing at least one active ingredient selected from (8) -2- (benzylaminomethyl) -2,3,8,9 tetrahydro-7H-1,4-dioxin [2,3-e] indole 8-and antipsychotic agent, and includes an information insert containing instructions for using the active ingredient or active ingredients in a combination containing (8) -2- (benzylaminomethyl) -2,3,8,9-tetrahydro-7H-1,4 -dioxin [2,3-e] indole-8-one and antipsychotic agent.