Blend containing carbamate compound for prevention, mitigation, or treatment of schizophrenia

Abstract

To provide a combination and a pharmaceutical composition that exhibit an improved effect in the prevention, alleviation or treatment of schizophrenia without increasing side effects.SOLUTION: There are provided a blend and a pharmaceutical composition, comprising a carbamate compound represented by the following formula and aripiprazole. (In the formula, R1 and R2 are each independently selected from the group consisting of hydrogen, halogen, C1-C8 alkyl, halo-C1-C8 alkyl, C1-C8 thioalkoxy, and C1-C8 alkoxy; and one of A1 and A2 is CH, and the other is N).SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to a formulation for preventing, reducing or treating schizophrenia, which contains a carbamate compound represented by the following formula (1):

Chem.

Background Art

[0002] Schizophrenia, a representative psychotic disorder, is a syndrome of various psychiatric symptoms in which the main pathological condition is a thought disorder, and complex symptoms appear in various areas such as speech, behavior, emotion, and cognition related to or caused by such thought disorders. It has been a series of symptoms that have long been called madness in the history of humanity.

[0003] Generally, the prevalence of schizophrenia is about 1% of the world's population, and it has been observed to be constant regardless of population characteristics, regional and cultural differences such as Western and Eastern, and developed and developing countries. Although the cause of schizophrenia is not clear, it is said that genetic factors or environmental factors such as problems during pregnancy, rearing environment, and stress increase the likelihood of its onset.

[0004] The symptoms of schizophrenia are classified into positive symptoms, negative symptoms, cognitive symptoms, residual symptoms, etc. Positive symptoms are externally manifested abnormal and strange symptoms, symptoms of mental illness not seen in healthy humans, including sensory abnormalities such as auditory hallucinations and illusions. Abnormal thinking such as unrealistic and strange delusions, and disorders of the thinking process where abnormalities occur in the flow of thinking. Negative symptoms refer to phenomena where normal emotional reactions and behaviors decrease, resulting in a state of boredom, showing poverty of thought content, decreased motivation, social withdrawal, etc. Negative symptoms generally have a worse drug treatment response than positive symptoms. Cognitive symptoms refer to symptoms where it is difficult to maintain concentration, and the ability to learn new information or organize thoughts decreases. These symptoms prevent the patient from performing tasks they were previously good at, significantly reducing their memory and problem-solving abilities, thereby reducing the patient's social and occupational functions, preventing the patient from returning to society, causing unemployment, and leading to feelings of frustration. Cognitive symptoms refer to symptoms where it is difficult to maintain concentration, and the ability to learn new information or organize thoughts decreases. The patient is unable to perform tasks they were previously good at, showing a significant decrease in memory and problem-solving abilities. Cognitive symptoms are not prominent but reduce the social and occupational functions of schizophrenia patients, preventing the patients from returning to society and causing feelings of frustration.

[0005] Schizophrenia may appear in various forms according to the symptoms and signs as described above. Schizophrenia includes not only paranoid schizophrenia, disorganized schizophrenia, catatonic schizophrenia, and undifferentiated schizophrenia, but also post-schizophrenic depression, residual schizophrenia, simple schizophrenia, and specified non-organic type schizophrenia. In addition, schizophreniform disorder, schizoaffective disorder, delusional disorder, brief psychotic disorder, shared psychotic disorder, psychotic disorder due to other medical conditions, substance / medication-induced psychotic disorder, or psychotic disorder of unknown etiology are included in schizophrenia in a broad sense.

[0006] Representative antipsychotics such as haloperidol and chlorpromazine, and atypical antipsychotics such as aripiprazole, risperidone, and clozapine have been developed, and these drugs are known to be particularly effective for the positive symptoms of schizophrenia. When a patient starts taking the medication, acute psychomotor excitement, hallucinations, etc. generally improve within a few days, and delusions also improve within a few weeks. In most patients, it is known that when appropriate dosing is maintained at an appropriate dose for 6 - 8 weeks, a significant portion of the acute phase symptoms are improved. However, when taking antipsychotics for the first time, many of them experience drowsiness and dizziness, and often experience visual disturbances, palpitations, menstrual changes, and skin rashes.

[0007] Conventional antipsychotics reduce or eliminate a patient's symptoms and improve the quality of life, but this does not induce complete cure and their use is limited due to side effects. Therefore, these drugs have limited therapeutic value in the management of schizophrenia, and there is a need to develop new drugs with improved efficacy and fewer side effects. In particular, there are currently no satisfactory drugs for treating the negative or cognitive symptoms of schizophrenia, and the situation where development is urgent.

Summary of the Invention

Problems to be Solved by the Invention

[0008] An object of the present invention is to provide a formulation and a pharmaceutical composition that exhibit improved effects without increasing side effects in the prevention, reduction, or treatment of schizophrenia.

Means for Solving the Problems

[0009] The present inventor considered that when combining a conventional (existing) antipsychotic such as aripiprazole with a drug having a different mechanism of action, it is possible to reduce the side effects while maintaining or improving the efficacy of the conventional antipsychotic by reducing the dose required for its efficacy, and conducted intensive research.

[0010] Therefore, the inventors selected, as a drug having a mechanism of action different from that of conventional antipsychotics, a carbamate compound represented by the following formula (1) [Chemical formula] (1) (In the formula, R1 and R2 are each independently selected from the group consisting of hydrogen, halogen, C1-C8 alkyl, halo C1-C8 alkyl, C1-C8 thioalkoxy, and C1-C8 alkoxy, and one of A1 and A2 is CH and the other is N.), or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0011] In addition, the inventors selected, as conventional antipsychotic drugs, atypical antipsychotics selected from the group consisting of aripiprazole, asenapine, clozapine, iloperidone, olanzapine, lurasidone, paliperidone, quetiapine, risperidone, and ziprasidone. In one embodiment of the present invention, the atypical antipsychotic is aripiprazole.

[0012] Accordingly, in a specific aspect, the present invention provides a formulation for preventing, reducing, or treating schizophrenia, comprising: (a) a carbamate compound of formula (1), or a pharmaceutically acceptable salt, solvate, or hydrate thereof; and (b) aripiprazole, or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0013] The present invention also provides a pharmaceutical composition for preventing, reducing, or treating schizophrenia, comprising, as an active ingredient: (a) a carbamate compound of formula (1), or a pharmaceutically acceptable salt, solvate, or hydrate thereof; and (b) aripiprazole, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, and further comprising one or more pharmaceutically acceptable carriers.

[0014] Furthermore, the present invention provides a kit for preventing, alleviating or treating schizophrenia, which contains in a container: (a) a first composition containing a carbamate compound of formula (1), or a pharmaceutically acceptable salt, solvate or hydrate thereof; and (b) a second composition containing aripiprazole, or a pharmaceutically acceptable salt, solvate or hydrate thereof.

Advantages of the Invention

[0015] The formulations and pharmaceutical compositions of the present invention provide an improved effect in preventing, alleviating or treating schizophrenia without increasing side effects. In one embodiment, the formulations and pharmaceutical compositions of the present invention exhibit a synergistic effect in preventing, alleviating or treating schizophrenia. In particular, the formulations and pharmaceutical compositions of the present invention are effective in treating the negative symptoms of schizophrenia or improving cognitive impairment.

[0016] In addition, as drugs having a mechanism of action different from that of conventional antipsychotics, the formulations and pharmaceutical compositions of the present invention select a carbamate compound of formula (1), and when the carbamate compound is combined with the conventional atypical antipsychotic aripiprazole, even if the dose required for the drug effect is reduced, the side effects of the conventional antipsychotics can be reduced while maintaining or improving the drug effect.

Brief Description of the Drawings

[0017]

Figure 1

[0018] The explanations of the symbols in FIG. 1 are as follows: Social interaction = the total amount of time spent active social interaction s; seconds sc; mg / kg, subcutaneous administration po; mg / kg, oral administration -; non-treatment

Best Mode for Carrying Out the Invention

[0019] The present invention will be described in detail below. The present invention relates to (a) the carbamate compound represented by the following formula (1)

Chemical Formula

[0020] Further, the present invention provides a pharmaceutical composition for preventing, reducing or treating schizophrenia, which contains, as active ingredients, (a) the carbamate compound of formula (1), or a pharmaceutically acceptable salt, solvate or hydrate thereof; and (b) aripiprazole, or a pharmaceutically acceptable salt, solvate or hydrate thereof; and further contains one or more pharmaceutically acceptable carriers.

[0021] Furthermore, the present invention provides a kit for preventing, reducing or treating schizophrenia, which contains, in a container, (a) a first composition containing the carbamate compound of formula (1), or a pharmaceutically acceptable salt, solvate or hydrate thereof; and (b) a second composition containing aripiprazole, or a pharmaceutically acceptable salt, solvate or hydrate thereof.

[0022] Furthermore, the present invention provides a method for preventing, reducing or treating schizophrenia, which comprises administering to a subject in need thereof a therapeutically effective amount of (a) a carbamate compound of formula (1), or a pharmaceutically acceptable salt, solvate or hydrate thereof; and (b) aripiprazole, or a pharmaceutically acceptable salt, solvate or hydrate thereof.

[0023] In addition, the present invention provides the use of a formulation comprising (a) a carbamate compound of formula (1), or a pharmaceutically acceptable salt, solvate or hydrate thereof; and (b) aripiprazole, or a pharmaceutically acceptable salt, solvate or hydrate thereof for preventing, reducing or treating schizophrenia.

[0024] According to one embodiment of the present invention, in the said formulation, components (a) and (b) can be administered simultaneously, separately or sequentially.

[0025] According to one embodiment of the present invention, in the said kit, (a) the first composition and (b) the second composition can be administered simultaneously, separately or sequentially.

[0026] According to one embodiment of the present invention, in the said method for preventing, reducing or treating, components (a) and (b) can be administered to the subject simultaneously, separately or sequentially.

[0027] According to one embodiment of the present invention, in the said use, components (a) and (b) can be administered simultaneously, separately or sequentially.

[0028] According to one embodiment of the present invention, in formula (1), R1 and R2 are each independently selected from the group consisting of hydrogen, halogen and C1-C8 alkyl.

[0029] In one embodiment, the halo C1-C8 alkyl is perfluoroalkyl.

[0030] According to another embodiment of the present invention, the carbamate compound of formula (1) is of the following formula (2) [Chemical formula] (2) It is (R)-1-(2-chlorophenyl)-2-tetrazol-2-yl)ethyl carbamate shown by

[0031] The production of the carbamate compounds of the above formulas (1) and (2) can be carried out by those having ordinary knowledge in the art regarding compound synthesis using known compounds or compounds that can be easily produced therefrom. In particular, the production method of the compound of the formula (1) is described in detail in International Publication Patents WO2006 / 112685A1, WO2010 / 150946A1 and WO2011 / 046380A2, and the said documents are incorporated herein by reference. The compound of the formula (1) can be chemically synthesized according to any of the methods described in the said documents, but these methods are only examples, and the order of unit operations etc. may be selectively changed as necessary. Therefore, it is not intended to limit the scope of the present invention.

[0032] Aripiprazole is a product sold under the trademark Abilify. The chemical name is 7-{4-[4-(2,3-dichlorophenyl)piperazin-1-yl]butoxy}-3,4-dihydroquinolin-2(1H)-one, and its structure is as follows. [Chemical formula]

[0033] In one embodiment of the present invention, in addition to aripiprazole, an atypical antipsychotic agent selected from the group consisting of asenapine, clozapine, iloperidone, olanzapine, lurasidone, paliperidone, quetiapine, risperidone and ziprasidone may also be preferably used.

[0034] In the present invention, as the compound of the formula (1) or (2) and aripiprazole, their free forms, or pharmaceutically acceptable salts, solvates or hydrates thereof can be used.

[0035] According to one embodiment of the present invention, as the compound of the formula (1) or (2) and aripiprazole, their free forms can be used.

[0036] For example, pharmaceutically acceptable salts of the compound of the formula (1) or (2) or aripiprazole include, for example, independently, acetate, benzenesulfonate, benzoate, bitartrate, calcium acetate, camsylate, carbonate, citrate, edetate, edisytrate, estolate, esilate, fumarate, gluceptate, gluconate, glutamate, glycolylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydrogen carbonate, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate, mandelate, mesylate, methylnitrate, methylsulfate, mucate, napsylate, nitrate, pamoate (embonate), pantothenate, phosphate / diphosphate, polygalacturonate, salicylate, stearate, subacetate, succinate or hemi-succinate, sulfate or hemi-sulfate, tannate, tartrate, oxalate or hemi-tartrate, theoclate, triethiodide, benzathine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine, procaine, aluminum, ammonium, tetramethylammonium, calcium, lithium, magnesium, potassium, sodium and zinc, etc.

[0037] In the formulation or pharmaceutical composition according to an embodiment of the present invention, the therapeutically effective amount or dosage of the compound of formula (1) is 12.5 to 500 mg, 12.5 to 400 mg, 25 to 400 mg, 25 to 300 mg, 25 to 200 mg, 50 to 400 mg, 50 to 300 mg, 50 to 200 mg, or 100 to 200 mg based on once-daily administration of the free form upon administration to humans.

[0038] In the formulation or pharmaceutical composition according to an embodiment of the present invention, the therapeutically effective amount or dosage of aripiprazole can include 5 to 90 mg, preferably 5 to 60 mg, more preferably 5 to 30 mg based on once-daily administration of the free form upon administration to humans.

[0039] In one embodiment of the present invention, the dosage of the atypical antipsychotic agent containing aripiprazole may be lower than the dosage required to exhibit a therapeutically effective amount when administered alone without the carbamate compound of formula (1). This is because the combination with the carbamate compound of formula (1) can maintain an effective medicinal effect while reducing the dosage required for the medicinal effect of the atypical antipsychotic agent.

[0040] According to an embodiment of the present invention, the compounding weight ratio of component a) the carbamate compound of formula (1), or a pharmaceutically acceptable salt, solvate or hydrate thereof; to component b) aripiprazole, or a pharmaceutically acceptable salt, solvate or hydrate thereof is 1:1 to 40:1, 1:1 to 20:1, 2:1 to 20:1, or 2:1 to 10:1.

[0041] The formulations and pharmaceutical compositions of the present invention can be manufactured in various forms of oral or parenteral preparations, and can be administered, for example, by intravenous injection, intramuscular injection, intradermal injection, subcutaneous injection, duodenal injection, intraperitoneal or intrathecal injection. Alternatively, they can also be administered by a transdermal route. Furthermore, the composition can be administered by any device through which the active substance can move to the target cells. The administration route varies depending on the general condition and age of the treatment subject, the nature of the treatment condition, and the active ingredient selected.

[0042] The appropriate dosage of the formulation or pharmaceutical composition according to an embodiment of the present invention varies depending on factors such as the formulation method, administration method, age, weight, gender, pathological condition, diet, administration time, administration route, excretion rate, and reaction sensitivity of the patient. A physician with ordinary proficiency can easily determine and prescribe an effective dosage for the desired treatment or prevention. The pharmaceutical composition according to one embodiment can be administered in one or more dosages, for example, 1 to 4 times a day. The pharmaceutical composition according to one embodiment, based on the free form, contains a) the compound of formula (1) in an amount of 12.5 to 500 mg, 12.5 to 400 mg, 25 to 400 mg, 25 to 300 mg, 25 to 200 mg, 50 to 400 mg, 50 to 300 mg, 50 to 200 mg, or 10 to 200 mg; b) aripiprazole in an amount of 5 to 90 mg, preferably 5 to 60 mg, more preferably 5 to 30 mg.

[0043] The pharmaceutical composition according to an embodiment of the present invention can be manufactured in unit dosage form or contained in a multi-dose container by formulating it using pharmaceutically acceptable carriers and / or excipients according to methods that can be easily implemented by those skilled in the art. The formulation may be in the form of a solution, suspension, or emulsion in an oily or aqueous medium, an extract, powder, granule, tablet, or capsule, and may additionally contain a dispersant or stabilizer. Further, the pharmaceutical composition can be administered in the form of a suppository, spray, ointment, cream, gel, inhalant, or skin patch. Further, the pharmaceutical composition can be manufactured for administration to mammals, more preferably for administration to humans.

[0044] The pharmaceutical composition of the present invention further contains one or more pharmaceutically acceptable carriers in addition to the active ingredients (a) and (b) described above.

[0045] The pharmaceutically acceptable carrier may be solid or liquid, and may be one or more selected from excipients, antioxidants, buffers, bacteriostatic agents, dispersants, adsorbents, surfactants, binders, preservatives, disintegrants, sweeteners, flavoring agents, lubricants, release regulators, wetting agents, stabilizers, suspending agents, and lubricants. Further, the pharmaceutically acceptable carrier can be selected from physiological saline, sterile water, Ringer's solution, buffered saline, dextrose solution, maltodextrin solution, glycerol, ethanol, and mixtures thereof.

[0046] In one embodiment, suitable fillers include, but are not limited to, sugars (e.g., dextrose, sucrose, maltose, and lactose), starches (e.g., corn starch), sugar alcohols (e.g., mannitol, sorbitol, maltitol, erythritol, and xylitol), starch hydrolysates (e.g., dextrin and maltodextrin), cellulose loss or cellulose derivatives (e.g., microcrystalline cellulose), or mixtures thereof.

[0047] In one embodiment, suitable antioxidants include, but are not limited to, tocopherol, ascorbic acid, gallate, etc.

[0048] In one embodiment, a suitable buffer may be citric acid monohydrate.

[0049] In one embodiment, suitable surfactants (emulsifiers) include, but are not limited to, anionic, cationic, or nonionic surfactants, such as sodium laurate, sodium lauryl sulfate, sodium dodecylsulfonate, sodium oleyl sulfate, benzalkonium chloride, alkyltrimethylammonium bromide, glyceryl monooleate, polyoxyethylene sorbitan fatty acid ester, polyvinyl alcohol, or sorbitan S, etc.

[0050] In one embodiment, suitable binders include, but are not limited to, povidone, copovidone, methylcellulose, hydroxymethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, gelatin, gums, sucrose, starch, or mixtures thereof.

[0051] In one embodiment, suitable preservatives include, but are not limited to, benzoic acid, sodium benzoate, benzyl alcohol, butylated hydroxyanisole, butylated hydroxytoluene, chlorobutanol, gallate, hydroxybenzoate, EDTA, or mixtures thereof.

[0052] In one embodiment, suitable disintegrants include, but are not limited to, sodium starch glycolate, cross-linked polyvinylpyrrolidone, cross-linked carboxymethylcellulose, starch, microcrystalline cellulose, or mixtures thereof.

[0053] In one embodiment, suitable sweeteners include, but are not limited to, sucralose, saccharin, sodium or potassium or calcium saccharin, acesulfame potassium or sodium cyclamate, mannitol, fructose, sucrose, maltose, or mixtures thereof.

[0054] In one embodiment, suitable lubricants include, but are not limited to, colloidal silicon dioxide.

[0055] In one embodiment, suitable release regulators include, but are not limited to, hydroxypropylmethylcellulose, polyethylene oxide, carbomer, pH-independent polymers such as alginic acid, pH-dependent polymers, or mixtures thereof.

[0056] In one embodiment, suitable wetting agents include, but are not limited to, hypromellose (HPMC), polyoxyethylene derivatives of sorbitan esters such as polysorbate 20 and polysorbate 80, lecithin, polyoxyethylene- and polyoxypropylene ethers, sodium deoxycholate, or mixtures thereof.

[0057] In one embodiment, suitable suspending agents include, but are not limited to, cellulose derivatives such as microcrystalline cellulose, methylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, alginate, chitosan, dextran, gelatin, polyethylene glycol, polyoxyethylene- and polyoxypropylene ethers, or mixtures thereof.

[0058] In one embodiment, suitable lubricants include, but are not limited to, long-chain fatty acids and their salts such as magnesium stearate and stearic acid, talc, glyceride wax, or mixtures thereof.

[0059] The pharmaceutical composition of the present invention may be formulated into injectable preparations such as aqueous solutions, suspensions or emulsions, or may be formulated into pills, capsules, granules or tablets. In the case of powders, the carrier may be a fine solid that can be mixed with the active ingredient in the form of a mixture. In the case of tablets, the active ingredient can be mixed with the carrier to impart binding characteristics that allow tableting in the desired form and size at an appropriate ratio.

[0060] The pharmaceutical composition of the present invention can be manufactured in capsule form.

[0061] For example, based on the free form, the pharmaceutical composition of the present invention contains a) 12.5 to 500 mg, 12.5 to 400 mg, 25 to 400 mg, 25 to 300 mg, 25 to 200 mg, 50 to 400 mg, 50 to 300 mg, 50 to 200 mg, or 100 to 200 mg of the compound of formula (1); b) 5 to 90 mg of aripiprazole, preferably 5 to 60 mg, more preferably 5 to 30 mg; and can be manufactured with capsules containing gelatin and titanium dioxide as the capsule base. The above amounts can be adjusted as needed.

[0062] The formulations and pharmaceutical compositions of the present invention have pharmaceutical uses for the prevention, alleviation or treatment of schizophrenia.

[0063] According to one embodiment of the present invention, the symptoms of schizophrenia may be one or more selected from the group consisting of positive symptoms, negative symptoms, cognitive symptoms and residual symptoms of schizophrenia.

[0064] According to one embodiment of the present invention, the schizophrenia may be one or more selected from the group consisting of paranoid schizophrenia, undifferentiated schizophrenia, latent schizophrenia, post-schizophrenic depression, residual schizophrenia, simple schizophrenia, catatonic schizophrenia, schizophreniform disorder, schizoaffective disorder, delusional disorder, brief psychotic disorder, shared psychotic disorder, psychotic disorder due to other medical diseases, substance / medication-induced psychotic disorder and psychotic disorder of unknown cause.

[0065] The antipsychotic activities of the carbamate compound of formula (1) and aripiprazole against schizophrenia can be tested through animal behavioral tests of social interaction used in the drug development for the negative symptoms of schizophrenia (Neill JC, Grayson B, Kiss B, Gyertyan I, Ferguson P, Adham N, Effects of cariprazine, a novel antipsychotic, on cognitive deficit and negative symptoms in a rodent model of schizophrenia symptomatology., Eur Neuropsychopharmacol. 2016 Jan;26(1):3-14). Since the effects of administration of N-methyl-D-aspartic acid (NMDA) receptor inhibitors are similar to the symptoms caused by schizophrenia, in the social interaction animal behavioral test induced by dizocilpine (MK-801), an N-methyl-D-aspartic acid (NMDA) receptor inhibitor that can be used as a model of schizophrenia by administering an N-methyl-D-aspartic acid (NMDA) receptor inhibitor to animals, administration of dizocilpine can induce schizophrenia-like symptoms (Rung JP, Carlsson A, Ryden Markinhuhta K, Carlsson ML, (+)-MK-801 induced social withdrawal in rats; a model for negative symptoms of schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry. 2005 Jun;29(5):827-32).Aripiprazole, known as an atypical antipsychotic, suppresses schizophrenia-like symptoms in proportion to the dose of dizocilpine (Deiana S, Watanabe A, Yamasaki Y, Amada N, Kikuchi T, Stott C, Riedel G, MK-801-induced deficits in social recognition in rats: reversal by aripiprazole, but not olanzapine, risperidone, or cannabidiol. Behav Pharmacol. 2015 Dec;26(8 Spec No):748-65).

[0066] The dosages of the carbamate compound of formula (1) and aripiprazole for the prevention, alleviation or treatment of the above-mentioned diseases usually vary depending on the severity of the disease, the weight of the treatment target and the metabolic state. The "therapeutically effective amount" for an individual patient means the above-described pharmacological effect, that is, the amount of the active compound sufficient to achieve a therapeutic effect.

[0067] As used herein, the terms "prevent", "preventing" and "prevention" refer to reducing or eliminating the possibility of contracting a disease.

[0068] As used herein, the terms "alleviate", "alleviating" and "alleviation" refer to alleviating all or part of a disease and / or the symptoms associated therewith.

[0069] As used herein, the terms "treat", "treating" and "treatment" refer to removing all or part of a disease and / or the symptoms associated therewith.

[0070] As used herein, the term "subject" means an animal in the context of treatment, observation or experiment, preferably a mammal (e.g., primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, etc.), most preferably a human.

[0071] As used herein, the term "therapeutically effective amount" means an amount of an active compound or pharmaceutical formulation that induces a biological or medical response in a system, animal, or human, including reducing the symptoms of a disease or disorder being treated, where such amount is determined by a researcher, veterinarian, physician, or other clinician.

[0072] As used herein, the term "formulation or combination" or "combination therapy agent" refers to the use of two or more drugs in combination, but does not necessarily mean that the two or more drugs are in a mixed state. This means that two or more drugs may be present together in a single formulation in a mixed state or may be used as separate formulations. That is, the term "formulation" includes both a single formulation and two separate formulations, and thus simultaneous, separate, or sequential administration is possible.

[0073] As used herein, the term "composition" means a single formulation in which two or more drugs are present in a mixed state.

[0074] As used herein, the term "kit" generally means a finished product, and when two or more drugs are used, it means a finished product containing these drugs in the form of a formulation. Two or more drugs may be packaged in a single formulation of the finished product and administered simultaneously, or may be packaged in two separate formulations of the finished product and administered simultaneously, separately, or sequentially.

[0075] The present invention will be described in more detail below by way of examples. The objectives, features, and advantages of the present invention will be easily understood through the following examples. The present invention is not limited to the examples described herein and may be embodied in other forms. The examples described herein are provided to ensure that the disclosed content is thorough and complete and that the technical concept of the present invention is fully conveyed to those skilled in the art to which the present invention pertains. Therefore, the present invention should not be limited by the following examples.

[0076] Examples Production Example: Production of (R)-1-(2-chlorophenyl)-2-(tetrazol-2-yl)ethyl carbamate (R)-1-(2-chlorophenyl)-2-(tetrazol-2-yl)ethyl carbamate (the compound of general formula (2), hereinafter also referred to as 'test compound') was produced according to the method described in Production Example 50 of International Publication Patent WO2010 / 150946.

Examples

[0077] Effect on social interaction animal behavior test in an animal model with schizophrenia-like symptoms induced by dizocilpine treatment

[0078] Experimental animals Male rats (Wistar, 4 weeks old, Orient Bio Co., Ltd.) were purchased, divided into two groups in an animal breeding room, and acclimatized on separate shelves for more than one week. The experimental animals were stored and managed in an environment with a 12-hour light-dark cycle, a temperature of 22 - 25°C, a relative humidity of 40 - 60%, and free access to water and food, in accordance with the laboratory animal management standards of the Institutional Animal Care and Use Committee (IACUC). After being stabilized for more than one week, pairs of rats with a body weight difference not exceeding 20 g were used for the social interaction animal behavior test.

[0079] Social interaction animal behavior test Since the symptoms induced by the administration of N-methyl-D-aspartic acid (NMDA) receptor inhibitors are similar to those of schizophrenia, an animal model in which schizophrenia-like symptoms are induced by dizocilpine treatment, which is an N-methyl-D-aspartic acid (NMDA) receptor inhibitor, was used.

[0080] Dizocilpine (purchased from Sigma) was freshly prepared by dissolving it in physiological saline used as a vehicle, and a dose of 0.1 mg / kg was subcutaneously administered at a volume of 1 mL per 1 kg of rat body weight 4 hours before the experiment.

[0081] Aripiprazole and the test compound were freshly prepared by dissolving them in 30% polyethylene glycol 400 (Sigma) used as a vehicle. One hour before the experiment, aripiprazole at a dose of 0.003 mg / kg was orally administered at a volume of 1 mL per kg of rat body weight.

[0082] Male rats were placed in pairs in the same observation cage. After allowing 1-to-1 interactions and measuring the total time of mutual (under or over the other rat) sniffing, grooming, licking, mounting, and crawling, which can be regarded as 5 minutes of positive social interaction, social interaction was evaluated based on this.

[0083] Statistical analysis of experimental results All data are shown as mean ± SEM. Statistical analysis of the total time of positive social interaction between groups was analyzed by the GraphPad Prism ver.5.04 program, one-way analysis of variance, and Dunnett's multiple comparison test.

[0084] The average total time of positive social interaction in the negative control group treated with dizocilpine alone was observed to be 53.86 ± 2.90 seconds, and the average total time of positive social interaction in the vehicle group, which was the positive control group, was observed to be 69.63 ± 3.13 seconds. In the aripiprazole 0.003 mg / kg administration group, it was 57.52 ± 3.04 seconds, in the test compound 3 mg / kg administration group, it was 56.78 ± 2.19 seconds, and in the group administered both aripiprazole 0.003 mg / kg and the test compound 3 mg / kg, it was 63.76 ± 1.87 seconds.

[0085] Table 1 Effects of aripiprazole and the test compound on the social interaction animal behavior test treated with dizocilpine [Table 1] 1) Social interaction + Total time of positive interactions of sniffing, grooming, licking, mounting, and crawling 2) sc; mg / kg, subcutaneous administration 3) po; mg / kg, oral administration 4) -; untreated

[0086] Table 2 below shows the recovery rate (%) of the total time of positive social interactions of the test compound and / or aripiprazole treatment group and the vehicle group, which is the positive control group, compared with the negative control group treated with dizocilpine only. The recovery rate was calculated as follows.

[0087] Recovery rate (%) = (Social interaction time of the test group - Social interaction time of the negative control group) / (Social interaction time of the positive control group - Social interaction time of the negative control group) × 100 Table 2 Summary of recovery rate and statistical significance compared with the negative control group in the social interaction animal behavior test treated with dizocilpine

Table 2

[0088] The aripiprazole administration group and the test compound administration group showed recovery rates of 23.2% and 18.5% respectively compared with the negative control group, and there was no statistically significant difference from the negative control group treated with dizocilpine only, but there was a statistically significant difference from the positive control group. In the group administered both with 0.003 mg / kg of aripiprazole and 3 mg / kg of the test compound, which showed no significant recovery effect compared with the negative control group, it showed a recovery rate of 62.8% compared with the negative control group, showed a statistically significant difference from the negative control group, and showed no statistically significant difference from the positive control group (Figure 1).

[0089] As described above, it was confirmed that the combined use of aripiprazole and the test compound synergistically increased the effect on social interaction. This indicates that these two drugs are effective in the treatment of schizophrenia, particularly the negative symptoms of schizophrenia.

Claims

1. (a) Formula (1) below 【Chemistry 1】 （１） (In the formula, R １ and R ２ are each independently hydrogen, halogen, or C １ -C ８ Alkyl, haloC １ -C ８ Alkyl, C １ -C ８ Thioalkoxy and C １ -C ８ alkoxy; A １ and A ２ wherein one of the groups is CH and the other is N; or a pharma- ceutically acceptable salt, solvate or hydrate thereof; and (b) aripiprazole, or a pharma- ceutically acceptable salt, solvate, or hydrate thereof; A formulation for the prevention, alleviation or treatment of schizophrenia comprising:

2. R １ and R ２ are each independently hydrogen, halogen, or C １ -C ８ 2. The composition of claim 1, wherein the alkyl group is selected from the group consisting of alkyl.

3. The carbamate compound of formula (1) is represented by the following formula (2): 【Chemistry 2】 （２） 2. The composition according to claim 1, characterized in that the compound is carbamic acid (R)-1-(2-chlorophenyl)-2-tetrazol-2-yl)ethyl ester represented by the formula:

4. 2. Formulation according to claim 1, characterized in that it contains the compound of formula (1) in an amount ranging from 12.5 mg to 500 mg, based on the free form.

5. 2. The formulation according to claim 1, characterized in that it contains aripiprazole in an amount of from 5 mg to 90 mg, based on the free form.

6. Contains 12.5 mg to 500 mg of the compound of formula (1) based on the free form, 2. The formulation according to claim 1, comprising from 5 mg to 90 mg of aripiprazole, based on the free form.

7. 2. The composition of claim 1, wherein the schizophrenia exhibits one or more symptoms selected from the group consisting of positive symptoms, negative symptoms, cognitive symptoms and residual symptoms.

8. The composition of claim 1, characterized in that the schizophrenia is one or more selected from the group consisting of delusional catatonic schizophrenia, undifferentiated schizophrenia, latent schizophrenia, post-schizophrenic depression, residual schizophrenia, simple schizophrenia, unspecified schizophrenia, schizophreniform disorder, schizoaffective disorder, delusional disorder, brief psychotic disorder, shared psychotic disorder, psychotic disorder due to another medical illness, substance- or medication-induced psychotic disorder and psychotic disorder of unknown etiology.

9. 2. The formulation of claim 1, which is for mammalian administration.

10. 2. The combination according to claim 1, characterized in that components (a) and (b) are administered simultaneously or sequentially.

11. 2. The formulation according to claim 1, characterized in that components (a) and (b) are administered separately.

12. The formulation according to any one of claims 1 to 11, characterized in that it is in the form of a kit.

13. (a) a first composition comprising a carbamate compound of formula (1), or a pharma- ceutically acceptable salt, solvate, or hydrate thereof; and (b) a second composition comprising aripiprazole, or a pharma- ceutically acceptable salt, solvate, or hydrate thereof; 13. The formulation of claim 12, comprising in a container:

14. (a) Formula (1) below 【Chemistry 3】 （１） (In the formula, R １ and R ２ are each independently hydrogen, halogen, or C １ -C ８ Alkyl, haloC １ -C ８ Alkyl, C １ -C ８ Thioalkoxy and C １ -C ８ alkoxy; A １ and A ２ wherein one of the groups is CH and the other is N; or a pharma- ceutically acceptable salt, solvate or hydrate thereof; and (b) aripiprazole, or a pharma- ceutically acceptable salt, solvate, or hydrate thereof; A pharmaceutical composition for preventing, alleviating or treating schizophrenia or ataxia, further comprising one or more pharma- ceutically acceptable carriers.

15. R １ and R ２ are each independently hydrogen, halogen, or C １ -C ８ 15. The pharmaceutical composition of claim 14, wherein the alkyl group is selected from the group consisting of alkyl.

16. The carbamate compound of formula (1) is represented by the following formula (2): 【Chemistry 4】 （２） The pharmaceutical composition according to claim 14, characterized in that the carbamic acid (R)-1-(2-chlorophenyl)-2-tetrazol-2-yl)ethyl ester is represented by the formula:

17. The pharmaceutical composition according to claim 14, characterized in that the schizophrenia exhibits one or more symptoms selected from the group consisting of positive symptoms, negative symptoms, cognitive symptoms and residual symptoms.

18. The pharmaceutical composition according to claim 14, characterized in that the schizophrenia is one or more selected from the group consisting of delusional catatonic schizophrenia, undifferentiated schizophrenia, latent schizophrenia, post-schizophrenic depression, residual schizophrenia, simple schizophrenia, unspecified schizophrenia, schizophreniform disorder, schizoaffective disorder, delusional disorder, brief psychotic disorder, shared psychotic disorder, psychotic disorder due to other medical illness, substance- or medication-induced psychotic disorder, and psychotic disorder of unknown etiology.

19. The pharmaceutical composition according to any one of claims 14 to 18, which is prepared for administration to a mammal.

20. 19. The pharmaceutical composition according to any one of claims 14 to 18, comprising the compound of formula (1) in an amount of from 12.5 mg to 500 mg, based on the free form.

21. 19. The pharmaceutical composition according to any one of claims 14 to 18, characterized in that it contains aripiprazole in an amount of 5 mg to 90 mg, based on the free form.

22. Contains 12.5 mg to 500 mg of the compound of formula (1) based on the free form, The pharmaceutical composition according to any one of claims 14 to 18, characterized in that it contains 5 mg to 90 mg of aripiprazole based on the free form.

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