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

Abstract

The present invention provides therapeutic compositions for treating or preventing mental illness, pharmaceutical compositions comprising said compositions, and their use in treating or preventing said illness.

Description

(S)-2-(Benzylaminomethyl)-2,3,8,9-tetrahydro-7H-1,4-dioxino[2,3-e]indol-8-one and spirit Novel therapeutic composition of inhibitory drugs for the treatment or prevention of psychosis

Field of the invention

The present invention relates to dopamine D2/D3 receptor partial agonist (S)-2-(benzylaminomethyl)-2,3,8,9-tetrahydro-7H-1,4-dioxino [2,3-e] A therapeutic agent composition of indol-8-one and an antipsychotic for the treatment or prevention of psychosis, a pharmaceutical composition comprising the composition, and its use in the treatment or prevention of psychosis.

Background of the invention

Psychosis is a serious mental illness characterized by a lack or loss of contact with reality. These disorders are characterized by a variety of symptoms grouped into positive symptoms (confused thinking, hallucinations, and delusions), negative symptoms (social withdrawal and unresponsiveness), and cognitive deficits.

Tranquilizers or antipsychotics are used to treat schizophrenia and other related psychiatric disorders by blocking dopaminergic neurotransmitters in the central nervous system. Neuroleptics are widely used to treat the "positive" symptoms of schizophrenia. However, many of these drugs are believed to be ineffective in treating the "negative" symptoms of schizophrenia and, in fact, may exacerbate these symptoms because of dopaminergic blockade associated with their mechanism of action. It is also believed that cognitive deficits associated with schizophrenia such as distraction and executive skills such as working memory and planning ability are negatively affected by dopamine receptor blockade.

In addition, these antipsychotics have important side effects such as akathisia, dystonia, parkinsonian dyskinesia and delayed dyskinesia, etc., which are all caused by blocking dopaminergic neurotransmitters.

Anticholinergics such as Cogentin( ^R) have been used to reduce Parkinson-like side effects, but also cause side effects such as mental and/or physical damage, tachycardia, dysuria and gastrointestinal syndrome.

Certain dopamine partial agonists with relatively high intrinsic activity have been shown to have efficacy against the negative symptoms of schizophrenia. It has been postulated that what is needed in this regard is some inherent activity that optimizes the effect of treating negative symptoms while minimizing side effects. Lindenmayer, J.P., Acta Psychiatrica Scand. 1995:91(supp.388):15-19.

However, with increased intrinsic activity, higher levels of dopamine delivery may result in less efficacy in treating positive symptoms.

It has now been found that dopamine partial agonists with moderate to high intrinsic activity such as propacramole, pramipexole and terguride have been used to reverse the side effects of traditional neuroleptics. These reports show that higher intrinsic activity leads to greater efficacy in alleviating side effects associated with dyskinesias. Svensson et al., Neuropharmacology, 32(10): 1037-1045 (1993).

Novel pharmaceutical therapeutic agent compositions are available for the treatment of patients. It is particularly desirable to optimize the beneficial properties of the two drugs while minimizing the side effects associated with the drugs when administered alone. Applicants have discovered compositions of therapeutic agents useful in the treatment of psychosis.

Brief description of the drawings

Figure 1 is a graphical representation of (S)-2-(benzylaminomethyl)-2,3,8,9-tetrahydro-7H-1,4-dioxin Effect of [2,3-e]indol-8-one (drug) on haloperidol-induced catalepsy in rats with maximal reversal of catalepsy at doses of 0.003-3 mg drug/kg administered subcutaneously Time points are measured in seconds. The data are means ± SEM.

Figure 2 is a schematic representation of (S)-2-(benzylaminomethyl)-2,3,8,9-tetrahydro-7H-1,4-dioxino[2,3-e]ind Indol-8-one (drug) ability to induce catalepsy in rats, duration of catalepsy measured in seconds at doses of 0.003-3 mg drug/kg administered subcutaneously. The data are means ± SEM.

Figure 3 is a schematic representation of (S)-2-(benzylaminomethyl)-2,3,8,9-tetrahydro-7H-1,4-dioxino[2,3-e]ind Indol-8-one (drug) reverses the effects of d-amphetamine-induced hyperactivity in mice. The data are expressed as a percentage of the activity level (calculated as horizontal activity) observed with d-amphetamine alone at eight subcutaneous doses of 0.0001-1 mg drug/kg. The data are means ± SEM.

Detailed description of the invention

The present invention provides a compound comprising (S)-2-(benzylaminomethyl)-2,3,8,9-tetrahydro-7H-1,4-dioxino[2,3-e]indole-8 - A combination of a ketone or a pharmaceutically acceptable salt thereof and one or more neuroleptics.

(S)-2-(Benzylaminomethyl)-2,3,8,9-tetrahydro-7H-1,4-dioxino[2,3-e]indol-8-one is a A D2 partial agonist disclosed in US Patent No. 5,756,532. As used herein, unless otherwise stated, (S)-2-(benzylaminomethyl)-2,3,8,9-tetrahydro-7H-1,4-dioxino[2,3-e] Indol-8-ones include their pharmaceutically acceptable salts.

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

The term neuroleptic or antipsychotic includes those neuroleptics that act as full dopamine D2 receptor antagonists and includes both typical and atypical neuroleptics. Representative antipsychotics that are commercially available or prepared by methods known to those skilled in the art include, but are not limited to:

Chlorpromazine or 2-chloro-N,N-dimethyl-10H-phenothiazine-10-propylamine are described in US Patent 2,645,640, which is incorporated herein by reference in its entirety.

Mesoridazine or 10-[2-(1-methyl-2-piperidinyl)ethyl]-2-(methylsulfinyl)-10H-phenothiazine described in U.S. Patent 3,084,161, which It is incorporated herein by reference in its entirety.

Thioridazine or 10-[2-(1-methyl-2-piperidinyl)ethyl]-2-(methyl Thio)-10H-phenothiazine, which is incorporated herein by reference in its entirety.

Fluphenazine or 4-[3-[2-(trifluoromethyl)-10H-phenothiazin-10-yl]propyl]-1-piperazinol described in GB829,246, the full text of which This article is incorporated by reference.

Trifluoperazine or 10-[3-(4-methyl-1-piperazinyl)-propyl]-2-(trifluoromethyl)-10H-phenothiazine described in GB813,816, will It is incorporated herein by reference in its entirety.

Perphenazine or 4-[3-(2-chloro-10H-phenothiazin-1-yl)propyl]-1-piperazinol are described in US Patent 2,766,235, which is incorporated herein by reference in its entirety.

Clozapine or 8-chloro-11-(4-methyl-1-piperazinyl)-5H-dibenzo[b,e]-[1,4]-diazepine as described in U.S. Patent 3,539,573 Zhuo, which is incorporated herein by reference in its entirety.

Haloperidol or 4-[4-(4-chlorophenyl)-4-hydroxy-1-piperidinyl]-1-(4-fluorophenyl)-1-butanone as described in U.S. Patent 3,438,991 , which is incorporated herein by reference in its entirety.

Loxapine or 2-chloro-11-(4-methyl-1-piperazinyl)-dibenzo[b,f][1,4]-oxazepine described in U.S. Patent 3,546,226, will It is incorporated herein by reference in its entirety.

Molindinone or 3-ethyl-1,5,6,7-tetrahydro-2-methyl-5-(4-morpholinylmethyl)-4H-indolyl- as described in U.S. Patent 3,491,093 4-keto, which is incorporated herein by reference in its entirety.

Thiothioxanthene or N,N-dimethyl-9-[3-(4-methyl-1-piperazinyl)-propylene-9H-thioxanthene-2-sulfo as described in U.S. Patent No. 3,310,553 Sulfanamide, which is incorporated herein by reference in its entirety.

Sulpiride or 5-(aminosulfonyl)-N-[(1-ethyl-2-pyrrolidinyl)methyl]-2-methoxybenzamide as described in U.S. Patent 3,342,826, which is incorporated herein in its entirety for reference.

Amisulpride or 4-amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzyl as described in U.S. Patent No. 4,401,822 amides, which are incorporated herein by reference in their entirety.

Risperidone or 3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidinol]-ethyl]-imidazoline as described in U.S. Patent 4,804,663 2-Keto, which is incorporated herein by reference in its entirety.

Seroquel (Seroquel) or 11-[4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl]dibenzo[b,f]-[1 , 4] Thiazepine, which is incorporated herein by reference in its entirety.

Olanzapine or 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2.3-b][1,5]benzodiazepine as described in U.S. Patent 5,229,382 , which is incorporated by reference in its entirety.

(S)-2-(benzylaminomethyl)-2,3,8,9-tetrahydro-7H-1,4-dioxino[2, 3-e]indol-8-one for the treatment or prophylaxis of psychotic disorders associated with altered neurotransmitter activity of the dopaminergic system in the central nervous system such as schizophrenia, schizoaffective psychosis, acute mania and psychotic Depression, and at the same time eliminate or minimize certain side effects associated with the oral administration of the antipsychotic drugs alone, such as akathisia, dystonia, Parkinson's syndrome dyskinesia and delayed dyskinesia, etc.

The present invention also provides a combined preparation product comprising (S)-2-(benzylaminomethyl)-2,3,8,9-tetrahydro-7H-1,4-dioxino[2 ,3-e]indol-8-one and an antipsychotic for simultaneous, separate or sequential administration to treat a patient suffering from psychosis.

(S)-2-(Benzylaminomethyl)-2,3,8,9-tetrahydro-7H-1,4-dioxino[2,3-e]indol-8-one and a Combinations of one or more neuroleptic drugs, hereinafter referred to as "compositions", may be administered simultaneously or sequentially in the same or different pharmaceutical formulations. The time interval for sequential administration should, of course, maintain the beneficial effects of the composition and can be determined by the skilled physician.

It is understood that a therapeutic amount of the composition is an amount that treats, inhibits, prevents or ameliorates one or more of the psychotic symptoms, preferably with fewer side effects than administration of the neuroleptic drug alone. The dosage of each drug in the composition must be determined by the physician and will depend on the particular psychiatric disorder as well as the patient's weight, age and response pattern. Dosage indicators are provided herein. For compositions, the dosage index of each drug in the composition should be considered.

Typically, (S)-2-(benzylaminomethyl)-2,3,8,9-tetrahydro-7H-1,4-dioxino[2,3-e]indol-8-one A suitable dosage range is about 0.5-100 mg per day, and more preferably about 1-50 mg per day.

Appropriate doses of neuroleptics will be within the range recommended by the manufacturer. For certain preferred antipsychotics of the present invention, the following indicators are provided herein:

Chlorpromazine: about 300-800mg per day;

Mesoridazine: about 100-400mg per day;

Thioridazine: about 200-600mg per day;

Fluphenazine: about 2-5mg per day;

Trifluoperazine: about 6-20mg per day;

Perphenazine: about 8-40mg per day;

Clozapine: about 300-600mg per day;

Haloperidol: about 1-20mg per day;

Loxapine: about 60-100mg per day;

Molindone: about 15-225mg per day;

Thiothixene: about 20-30mg per day;

Risperidone: about 4-20mg per day;

Seroquel: about 15-750mg per day; and

Olanzapine: about 10-20mg per day.

Although the active ingredient of the composition may be administered in raw chemical form, it is preferably presented as a pharmaceutical formulation. The pharmaceutical formulation of the present invention comprises the composition of the present invention, one or more pharmaceutically acceptable carriers or excipients and optionally other therapeutic agents. The carrier must be compatible with the other ingredients of the formulation. When the components of the composition are administered separately, they are usually each in the form of a pharmaceutical formulation.

(S)-2-(Benzylaminomethyl)-2,3,8,9-tetrahydro-7H-1,4-dioxino[2,3-e]indol-8-one and spirit The combination of inhibitory drugs may conveniently be presented as a pharmaceutical formulation in a single dosage form. A convenient single dose formulation contains the active ingredient in amounts of 0.1 mg to 1 g, for example 5 mg to 100 mg, each. For example, a typical unit dose may contain about 0.5-100 mg of (S)-2-(benzylaminomethyl)-2,3,8,9-tetrahydro-7H-1,4-dioxino[2 , 3-e] indol-8-one, and preferably about 1 mg-50 mg of (S)-2-(benzylaminomethyl)-2,3,8,9-tetrahydro-7H-1,4- Dioxino[2,3-e]indol-8-one.

Pharmaceutical formulations may be prepared in the form of "patient packs" containing the entire course of dosage in a single package, usually a blister pack. Patient packs have the advantage over traditional prescriptions that a pharmacist dispenses a supply of medication to a patient from a bulk supply vial, wherein the patient has access to the instructions contained in the patient pack, which is not available in traditional prescriptions. The content of the labeling has been shown to have the effect of improving patient compliance with physician orders.

It will be appreciated that it is another feature of the invention to administer the compositions of the invention in a single patient pack or individual patient packs containing instructions to instruct the patient on the proper use of the compositions of the invention.

The invention further provides patient packs comprising at least one active ingredient of the compositions of the invention and instructions for use of the compositions of the invention.

Formulations include those suitable for oral, rectal, nasal, topical (including transdermal, buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration. Said formulation may be by methods well known in the field of pharmacy, for example by using methods as described in Gennaro et al., Remington's Pharmaceutical Sciences (18 ^th ed., Mack Publishing Company, 1990, see in particular Paft 8: Pharmaceutical Preparations and thir Manufacture). Method preparation. Such methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients. The auxiliary components include those conventionally used in the art such as fillers, binders, diluents, disintegrants, lubricants, colorants, flavoring agents and wetting agents.

Formulations suitable for oral administration may be discrete units such as pills, tablets or capsules each containing a predetermined amount of the active ingredient; may be a powder or granules; may be a solution or a suspension. The active ingredient may also be presented as a concentrated bolus or paste, or it may be contained within liposomes.

Formulations for rectal administration may be presented as suppositories or enemas.

For parenteral administration, suitable formulations include aqueous and non-aqueous sterile injection solutions. The formulations may be presented in unit-dose or multi-dose containers, such as sealed vials or ampoules, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of a sterile liquid carrier, eg, water, prior to use.

Formulations suitable for administration by nasal inhalation include powders or mists available in metered dose pressurized aerosols, nebulisers or insufflators.

The compounds in the compositions of the present invention may be obtained in a conventional manner according to methods well known in the art.

The following examples are for illustration only and do not limit the scope of the invention in any way.

As shown in the following examples, with (S)-2-(benzylaminomethyl)-2,3,8,9-tetrahydro-7H-1,4-dioxino[2,3-e] The concomitant use of indol-8-one modifies the side effects caused by haloperidol treatment.

Example 1

The reversal of haloperidol-induced catalepsy in rats was tested following a modification of the method of Svensson et al., Neuropharmacology, 1993, 32: 1037-1045. Rats (200-250 g) were transferred from the colony room to the laboratory and remained there until the end of the experiment. Haloperidol dissolved in 0.25% Tween 80 ^(R) was administered ip at a dose of 3 mg/kg to all animals. After 60 minutes, (S)-2-(benzylaminomethyl)-2,3,8,9-tetrahydro-7H-1,4-dioxin, also dissolved in 0.25% Tween ^80® And[2,3-e]indol-8-one was administered sc-at 4 dose levels, 6 male Sprague-Dawley rats per dose level. Treatment with (S)-2-(benzylaminomethyl)-2,3,8,9-tetrahydro-7H-1,4-dioxino[2,3-e]indol-8-one The control group, which was evaluated at the same time, was injected with an equal volume (1 ml/kg) of 0.25% Tween ^80® vehicle (VEH). At 30, 60, 90 and 120 minutes after dosing, the animals were assessed for catalepsy by placing the animal's forepaws on a wooden cube (8 x 8 x 8 cm). The time that the animals keep at least one front paw on the cube is measured (maximum = 60 seconds). The righting reflex is then tested and used to weed out sedated subjects. Data were analyzed using two-way ANOVA with single repeated measures. The minimum effective dose (MED) and time to onset for reversing haloperidol-induced catalepsy were determined using the least significant difference (p<0.05) compared to the control trial. A trend test is then used to determine dose-response time points, if any. From these points, the _ED50 (the dose that reduces the maximum response by 50%) and the 95% confidence interval are calculated using the point showing the greatest degree of reversal (with the lowest catalepsy score). These can be performed using nonlinear regression analysis followed by backward forecasting.

Figure 1 is a graphical representation of (S)-2-(benzylaminomethyl)-2,3,8,9-tetrahydro-7H-1,4 at the time point of maximum reversal 60 minutes after drug treatment - Effect of dioxino[2,3-e]indol-8-one (drug) on haloperidol-induced catalepsy in rats. The data are means ± SEM. As shown, a dose-dependent decrease in the duration of catalepsy postural duration was observed. The MED calculated from these results was 0.3 mg/kg and the _ED50 was 0.08 mg/kg.

Example 2

(S)-2-(Benzylaminomethyl)-2,3,8,9-tetrahydro-7H-1,4 was tested in a similar manner to that described in Example 1, except that haloperidol was not administered. - Potential for dioxino[2,3-e]indol-8-one to induce catalepsy in rats.

Figure 2 is a schematic representation of (S)-2-(benzylaminomethyl)-2,3,8,9-tetrahydro-7H-1,4-dioxino[2,3-e]ind Indol-8-one (drug) ability to induce catalepsy in rats. The data are means ± SEM. As shown, the drug lacked significant ability to induce catalepsy in rats at 60 minutes after administration s.c. at doses of 0.003-3 mg/kg. Similar results were observed at other time points tested.

Example 3

The ability to antagonize amphetamine-induced hyperlocomotion was tested following a modified procedure of Riffee and Wilcox, Psychopharmacology, 1985, 85: 97-101. Mice (25-30 g) were transferred from the colony room to the laboratory and remained there until the end of the experiment. Animals were allowed to familiarize themselves with the exercise chamber (8 x 8 in. open field) for 60 minutes prior to testing. During the familiarization period, d-amphetamine (2.5 mg/kg solution in distilled water) was administered ip to all animals. After 15 minutes, test compound dissolved in 0.25% Tween 80( ^R) was administered sc at 8 dose levels, 8 mice per dose level. The control group, which was evaluated at the same time as the drug-treated group, was injected with an equal volume (10 ml/kg) of vehicle. Animals were individually placed in the exercise room immediately after administration of the test compound. Activity was monitored for 30 minutes with lights on using an Omnitech Digiscan( ^R) (Columbus, Ohio) infrared monitor. Breaks in each infrared beam were counted by an automated system and totaled at 10 minute intervals. The horizontal activity counts collected within 10-20 minutes after the start of the test were subjected to one-way analysis of variance followed by the Student-Newman-Keuls test (p<0.05) to determine whether the test compound antagonized d- Effective dose for amphetamine-induced hyperlocomotion. Mean level activity counts were analyzed by non-linear regression, followed by backward prediction to calculate _ED50 (dose at which activity was reduced by 50%) and 95% confidence intervals (CI), as well as slope and minimum activity level.

Figure 3 is a schematic representation of (S)-2-(benzylaminomethyl)-2,3,8,9-tetrahydro-7H-1,4-dioxino[2,3-e]ind Indol-8-one (drug) reverses the effects of d-amphetamine-induced hyperactivity in mice. The data are expressed as a percentage of the activity level observed for mice treated with d-amphetamine alone and are presented as mean ± SEM. As shown, a dose-dependent reduction in d-amphetamine-induced hyperactivity was observed. The _ED50 calculated from these results was 0.002 mg/kg.

Thus, the compositions of the present invention reduce the side effects expressed by haloperidol-induced catalepsy without reducing the positive effects of haloperidol on the treatment of schizophrenia modeled by amphetamine-induced hyperactivity. capacity for symptoms.

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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