Blends containing carbamate compounds used for the prevention, relief, or treatment of schizophrenia.

Abstract

This invention relates to blends comprising carbamate compounds for the prevention, relief, or treatment of schizophrenia, the blends comprising a carbamate compound of Formula 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, and more specifically, to blends and pharmaceutical compositions comprising a carbamate compound of Formula 1 and aripiprazole, respectively, and their use in the treatment of schizophrenia.

Description

[0001] This application is a divisional application of the invention patent application filed on November 13, 2018, with application number 201880073904.3 and entitled "A blend containing a carbamate compound for the prevention, relief or treatment of schizophrenia". Technical Field

[0002] This invention relates to carbamate compounds comprising formula 1 below, or combinations thereof, which are pharmaceutically acceptable salts, solvates, or hydrates, for the prevention, relief, or treatment of schizophrenia, and more particularly to combinations thereof, comprising carbamate compounds of formula 1 and aripiprazole:

[0003] [Formula 1]

[0004]

[0005] in,

[0006] R1, R2, A1, and A2 are as defined in this document. Background Technology

[0007] Schizophrenia is a typical psychiatric disorder, a syndrome of multiple psychotic symptoms, with the primary pathology being thought disorder. Complex symptoms appear in various areas related to or derived from this thought disorder, such as speech, behavior, emotion, and cognition. It is a range of symptoms that has long been referred to as madness throughout human history.

[0008] Generally, the incidence of schizophrenia is about 1% of the world's population, and this incidence has been observed to be constant regardless of demographic characteristics, regional and cultural differences, such as between the West and the East, and between developed and developing countries. Although the etiology of schizophrenia is not fully understood, its development is believed to be due to genetic predisposition or environmental factors such as problems during pregnancy, parenting environment, and stress.

[0009] Schizophrenia symptoms can be categorized into positive symptoms, negative symptoms, cognitive symptoms, and residual symptoms. Positive symptoms refer to abnormal and bizarre symptoms that appear externally and cannot be detected in healthy individuals. These include sensory abnormalities such as auditory or visual hallucinations; thought abnormalities such as unrealistic and bizarre fantasies; and disturbances in the thought process, where abnormalities occur in the flow of thought. Negative symptoms refer to a state of lethargy characterized by reduced normal emotional responses or behaviors, manifested as poverty of thought content, decreased motivation, and social avoidance. Negative symptoms typically respond less well to medication than positive symptoms. Cognitive symptoms are characterized by difficulty maintaining focus and a decline in the ability to learn new information or organize thoughts. These symptoms prevent patients from doing things they previously did and significantly impair memory and problem-solving abilities, thereby reducing their social and occupational functioning, leading to reintegration into society, unemployment, and frustration. Cognitive symptoms are often overlooked, but they impair the social and occupational functioning of people with schizophrenia, preventing them from reintegrating into society and causing them to experience frustration.

[0010] Schizophrenia can exist in various forms, depending on the symptoms and signs described above. Schizophrenia includes not only paranoid schizophrenia, dissociative schizophrenia, catatonic schizophrenia, and mixed schizophrenia, but also post-schizophrenic depression, residual schizophrenia, simple schizophrenia, and undetermined schizophrenia. In addition, schizophrenia-like disorders, schizophrenic affective disorders, paranoid disorders, transient psychotic disorders, co-occurring psychotic disorders, psychotic disorders arising from other medical conditions, substance / drug-induced psychotic disorders, or psychotic disorders of unknown cause are broadly classified as schizophrenia.

[0011] Typical antipsychotics, such as haloperidol and chlorpromazine, as well as 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 patients begin medication, acute-phase psychomotor agitation, hallucinations, etc., usually improve within a few days, while delusions improve within a few weeks. It is known that in most patients, most acute-phase symptoms improve when the appropriate medication is maintained at an appropriate dose for 6–8 weeks. However, many patients experience drowsiness and dizziness when taking antipsychotics for the first time, and they often experience blurred vision, palpitations, menstrual changes, and rashes.

[0012] Conventional antipsychotic medications alleviate or relieve symptoms to improve quality of life, but this cannot induce a complete cure, and their use is limited due to side effects. Therefore, these medications have limited therapeutic value in the management of schizophrenia, and there is a need to develop new drugs with improved efficacy and reduced side effects. In particular, there are currently no satisfactory medications for treating the negative or cognitive symptoms of schizophrenia, thus necessitating the development of such drugs. Summary of the Invention

[0013] Technical problems to be solved

[0014] The present invention aims to provide combination products and pharmaceutical compositions that exhibit improved effects in the prevention, relief or treatment of schizophrenia without increasing side effects.

[0015] [Technical Solution to the Problem]

[0016] The inventors believe that combining conventional (existing) antipsychotics, such as aripiprazole, with drugs having different mechanisms of action can maintain or increase the efficacy of conventional antipsychotics by reducing the dosage required to achieve the efficacy of the conventional antipsychotics, while reducing side effects, and therefore has been thoroughly studied.

[0017] As a result, the inventors have selected carbamate compounds of Formula 1, or pharmaceutically acceptable salts, solvates, or hydrates thereof, as drugs having a mechanism of action different from conventional antipsychotics:

[0018] [Formula 1]

[0019]

[0020] in,

[0021] R1 and R2 are each independently selected from hydrogen, halogen, C1-C8 alkyl, halo-C1-C8 alkyl, C1-C8 alkylthio, and C1-C8 alkoxy; and

[0022] One of A1 and A2 is CH, and the other is N.

[0023] In addition, as a conventional antipsychotic drug, the inventors have selected an atypical antipsychotic drug chosen from aripiprazole, amoxapine, clozapine, ipraridone, olanzapine, lurasidone, palapirone, quetiapine, risperidone, and ziprasidone. In one embodiment of the invention, the atypical antipsychotic drug is aripiprazole.

[0024] Therefore, as a particular aspect, the present invention provides a combination product for the prevention, relief or treatment of 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.

[0025] In addition, the present invention provides a pharmaceutical composition for the prevention, relief or treatment of 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, one or more pharmaceutically acceptable carriers.

[0026] Additionally, the present invention provides a kit for the prevention, relief or treatment of schizophrenia, comprising in a container (a) a first composition comprising a carbamate compound of formula 1, or a pharmaceutically acceptable salt, solvate or hydrate thereof; and (b) a second composition comprising aripiprazole, or a pharmaceutically acceptable salt, solvate or hydrate thereof.

[0027] [The effects of the invention]

[0028] The combination products and pharmaceutical compositions of the present invention provide improved effects in preventing, alleviating, or treating schizophrenia without increasing side effects. In one embodiment, the combination products and pharmaceutical compositions of the present invention exhibit synergistic effects in preventing, alleviating, or treating schizophrenia. In particular, the combination products and pharmaceutical compositions of the present invention are effective in treating negative symptoms of schizophrenia and improving cognitive impairment.

[0029] Furthermore, by selecting a carbamate compound of Formula 1 as a drug with a mechanism of action different from existing antipsychotics, and combining the carbamate compound with an existing atypical antipsychotic—aripiperazole, the combination products and pharmaceutical compositions of the present invention can reduce the side effects of existing antipsychotics while maintaining or improving drug efficacy, even at a reduced dose required for drug efficacy. Attached Figure Description

[0030] Figure 1 Results of aripiprazole and aripiprazole in animal models of negative symptoms of schizophrenia, demonstrated by a social interaction test of animal behavior, in which schizophrenia-like symptoms were induced by treatment with dezocampine (MK-801). Figure 1 The explanation of each symbol in the code is as follows:

[0031] Social interaction = Total time spent on active social interaction

[0032] s = seconds

[0033] sc = mg / kg, subcutaneous

[0034] po = mg / kg, oral administration

[0035] - = Untreated. Detailed Implementation

[0036] The present invention will be described in detail below.

[0037] This invention provides a combination product for the prevention, relief, or treatment of schizophrenia, comprising (a) a carbamate compound of formula 1 below, or a pharmaceutically acceptable salt, solvate, or hydrate thereof; and (b) aripiprazole or a pharmaceutically acceptable salt, solvate, or hydrate thereof:

[0038] [Formula 1]

[0039]

[0040] in,

[0041] R1 and R2 are each independently selected from hydrogen, halogen, C1-C8 alkyl, halo-C1-C8 alkyl, C1-C8 alkylthio, and C1-C8 alkoxy; and

[0042] One of A1 and A2 is CH, and the other is N.

[0043] In addition, the present invention provides a pharmaceutical composition for the prevention, relief or treatment of 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, one or more pharmaceutically acceptable carriers.

[0044] Additionally, the present invention provides a kit for the prevention, relief or treatment of schizophrenia, comprising in a container (a) a first composition comprising a carbamate compound of formula 1, or a pharmaceutically acceptable salt, solvate or hydrate thereof; and (b) a second composition comprising aripiprazole, or a pharmaceutically acceptable salt, solvate or hydrate thereof.

[0045] Additionally, the present invention provides a method for preventing, alleviating, or treating schizophrenia, comprising administering to a subject requiring such treatment 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.

[0046] Additionally, the present invention provides the use of a combination 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, for the prevention, relief or treatment of schizophrenia.

[0047] According to one embodiment of the present invention, in the above combined product, components (a) and (b) can be administered simultaneously, separately, or sequentially.

[0048] According to one embodiment of the present invention, in the above-described kit, (a) the first composition and (b) the second composition may be administered simultaneously, separately, or sequentially.

[0049] According to one embodiment of the present invention, in the above-described methods of prevention, mitigation or treatment, components (a) and (b) may be administered to the subject simultaneously, separately or sequentially.

[0050] According to one embodiment of the present invention, in the above-described use, components (a) and (b) may be administered simultaneously, separately, or sequentially.

[0051] In one embodiment of the present invention, in Formula 1 above, R1 and R2 are each independently selected from hydrogen, halogens and C1-C8 alkyl groups.

[0052] In one embodiment of the present invention, the halogenated C1-C8 alkyl group is a perfluoroalkyl group.

[0053] According to another embodiment of the present invention, the carbamate compound of formula 1 above is carbamate of formula 2 below: (R)-1-(2-chlorophenyl)-2-tetrazol-2-yl-ethyl ester

[0054] [Equation 2]

[0055]

[0056] Those skilled in the art of compound synthesis can readily prepare the carbamate compounds of formulas 1 and 2 above using known compounds or compounds that can be readily prepared from them. In particular, methods for preparing compounds of formula 1 above are described in detail in PCT publications WO2006 / 112685A1, WO2010 / 150946A1, and WO2011 / 046380A2, the disclosures of which are incorporated herein by reference. Compounds of formula 1 above can be chemically synthesized by any of the methods described in the foregoing documents; however, these methods are merely exemplary, and the order of unit operations, etc., can be selectively changed if desired. Therefore, the above methods are not intended to limit the scope of the invention.

[0057] Aripiprazole is a brand name The product being sold has the chemical name 7-{4-[4-(2,3-dichlorophenyl)piperazin-1-yl]butoxy}-3,4-dihydroquinoline-2(1H)-one, and its structure is as follows:

[0058]

[0059] In one embodiment of the invention, in addition to aripiprazole, atypical antipsychotics selected from amoxapine, clozapine, ipraridone, olanzapine, lurasidone, palapirone, quetiapine, risperidone, and ziprasidone may preferably be used.

[0060] In this invention, aripiprazole, as a compound of formula 1 or 2 above, can be used in its free form or as a pharmaceutically acceptable salt, solvate or hydrate thereof.

[0061] According to one embodiment of the present invention, the compounds of formula 1 or 2 above and aripiprazole can be used in their free forms.

[0062] Examples of pharmaceutically acceptable salts of compounds of formula 1 or 2 above, or pharmaceutically acceptable salts of aripiprazole, independently include acetates, benzenesulfonates, benzoates, bitartrates, calcium acetates, camphorsulfonates, carbonates, citrates, ethylenediaminetetraacetate, ethanesulfonates, estolates, ethanesulfonates, fumarates, glucono-p-aminophenyl arsenate, gluconate, glutamates, ethanolyl-p-aminophenyl arsenate, hexylresorcinate, hydravamine, hydrobromide, hydrochloride, bicarbonate, hydroxynaphthoate, iodides, hydroxyethyl sulfonate, etc. Salts, lactates, lactobionic acid salts, malates, maleates, mandelates, methanesulfonates, methyl nitrates, methyl sulfates, mucates, naphthalenesulfonates, nitrates, pyrates (dihydroxynaphthalate), pantothenates, phosphates / bisphosphates, polygalacturonic acids, salicylates, stearates, basic acetates, succinates or hemisuccinates, sulfates or hemisulfates, tannates, tartrates, oxalates or hemitartrates, teoclates, triethyliodine, benzathine penicillin, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine, procaine, aluminum, ammonium, tetramethylammonium, calcium, lithium, magnesium, potassium, sodium, and zinc.

[0063] In a combination product or pharmaceutical composition according to one embodiment of the invention, a therapeutically effective amount or dose of the compound of formula 1 may comprise 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 in free form, and administered to a person once daily.

[0064] In a combination product or pharmaceutical composition according to one embodiment of the invention, a therapeutically effective amount or dose of aripiprazole may comprise 5 to 90 mg, preferably 5 to 60 mg, more preferably 5 to 30 mg, in free form, and is administered to a person once daily.

[0065] In one embodiment of the invention, the dose of an atypical antipsychotic including aripiprazole can be lower than the dose required to achieve a therapeutically effective amount when administered alone without the carbamate compound of Formula 1. This is because the combination product with the carbamate compound of Formula 1 makes it possible to maintain an effective pharmacological effect while reducing the dose required for the pharmacological effect of the atypical antipsychotic.

[0066] According to one embodiment of the invention, the combined weight ratio of component a) a 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.

[0067] The combination products and pharmaceutical compositions of the present invention can be prepared in various forms as oral or parenteral formulations and can be administered, for example, by intravenous injection, intramuscular injection, intradermal injection, subcutaneous injection, duodenal injection, intraperitoneal injection, or intrathecal injection, or they can also be administered via a transdermal route. Furthermore, the compositions can be administered via any device capable of transferring the active substance to target cells. The route of administration can vary depending on the general condition and age of the subject to be treated, the nature of the treatment condition, and the selected active ingredient.

[0068] The appropriate dosage of a combination product or pharmaceutical composition according to one embodiment of the invention may vary depending on factors such as formulation, administration method, patient's age, weight and sex, pathological condition, diet, frequency of administration, route of administration, excretion rate and responsiveness. A physician with ordinary skills can easily determine and prescribe a dosage effective for the desired treatment or prevention. The pharmaceutical composition according to one embodiment may be administered in one or more doses, for example, 1-4 times daily. The pharmaceutical composition according to one embodiment may comprise a) a compound of formula 1 in amounts 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 100 to 200 mg, based on free form; and b) aripiprazole in amounts of 5 to 90 mg, preferably 5 to 60 mg, more preferably 5 to 30 mg, based on free form.

[0069] The pharmaceutical composition according to one embodiment of the invention can be formulated using pharmaceutically acceptable carriers and / or excipients according to methods readily available to a person skilled in the art, thereby being prepared in unit dose form or contained in multi-dose containers. The formulation can be a solution, suspension, or emulsion (emulsified solution), extract, powder, granules, tablet, or capsule in an oil or aqueous medium, and may further include dispersants or stabilizers. Furthermore, the pharmaceutical composition can be administered in the form of suppositories, sprays, ointments, emulsions, gels, inhalers, or skin patches. The pharmaceutical composition can also be administered to mammals, more preferably to humans.

[0070] The pharmaceutical compositions of the present invention, in addition to the active ingredients (a) and (b) as described above, also include one or more pharmaceutically acceptable carriers.

[0071] Pharmaceutically acceptable carriers can be solid or liquid, and can be one or more selected from fillers, antioxidants, buffers, antibacterial agents, dispersants, adsorbents, surfactants, binders, preservatives, disintegrants, sweeteners, flavoring agents, glidants, release control agents, wetting agents, stabilizers, suspending agents, and lubricants. Furthermore, pharmaceutically acceptable carriers can be selected from saline, sterile water, Ringer's solution, buffered saline, glucose solution, maltodextrin solution, glycerol, ethanol, and mixtures thereof.

[0072] In one embodiment, suitable fillers include, but are not limited to, sugars (e.g., glucose, 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 or cellulose derivatives (e.g., microcrystalline cellulose), or mixtures thereof.

[0073] In one embodiment, suitable antioxidants include, but are not limited to, tocopherol, ascorbic acid, gallate, etc.

[0074] In one implementation, a suitable buffer may be citric acid monohydrate.

[0075] In one embodiment, suitable surfactants (emulsifiers) include, but are not limited to, anionic, cationic, or nonionic surfactants, such as sodium lauryl sulfate, sodium dodecyl sulfate, sodium dodecyl sulfonate, sodium oleyl sulfate, benzalkonium chloride, alkyltrimethylammonium bromide, glyceryl monooleate, polyoxyethylene dried sorbitol fatty acid ester, polyvinyl alcohol, and dried sorbitol S or mixtures thereof.

[0076] In one embodiment, suitable adhesives include, but are not limited to, povidone, copovidone, methylcellulose, hydroxymethylcellulose, hydroxypropyl methylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, gelatin, gum, sucrose, starch, or mixtures thereof.

[0077] 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.

[0078] In one embodiment, suitable disintegrants include, but are not limited to, sodium starch glycolate, cross-linked polyvinylpyrrolidone, cross-linked carboxymethyl cellulose, starch, microcrystalline cellulose, or mixtures thereof.

[0079] In one embodiment, suitable sweeteners include, but are not limited to, sucralose, saccharin, sodium saccharin, potassium saccharin, calcium saccharin, acesulfame potassium or sodium cyclohexane, mannitol, fructose, sucrose, maltose or mixtures thereof.

[0080] In one embodiment, a suitable flow aid includes, but is not limited to, colloidal silica.

[0081] In one embodiment, suitable release control agents (release-improving excipients) include, but are not limited to, hydroxypropyl methylcellulose, polyethylene oxide, carbomer, pH-independent polymers such as alginate, pH-dependent polymers, or mixtures thereof.

[0082] In one embodiment, suitable wetting agents include, but are not limited to, hydroxypropyl methylcellulose (HPMC), polyoxyethylene derivatives of sorbitol esters, such as polysorbate 20 and polysorbate 80, lecithin, polyoxyethylene and polyoxypropylene ethers, sodium deoxycholate, or mixtures thereof.

[0083] In one embodiment, suitable suspending agents include, but are not limited to, cellulose derivatives such as microcrystalline cellulose, methylcellulose, sodium carboxymethyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, alginate, chitosan, dextran, gelatin, polyethylene glycol, polyoxyethylene and polyoxypropylene ether or mixtures thereof.

[0084] 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, glyceryl ester waxes or mixtures thereof.

[0085] The pharmaceutical compositions of the present invention can be formulated into injectable formulations, such as aqueous solutions, suspensions, or emulsions, or into pills, capsules, granules, or tablets. In powders, the carrier can be a fine solid that can be mixed with the active ingredient in a mixture form; in tablets, the active ingredient can be mixed with the carrier to have adhesive properties that allow for tableting in appropriate proportions and desired shapes and sizes.

[0086] The pharmaceutical composition of the present invention can be prepared in capsule form.

[0087] For example, the pharmaceutical composition of the present invention can be prepared in capsule form, said capsule comprising a) a 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 100 to 200 mg, based on free form; and b) aripiprazole in an amount of 5 to 90 mg, preferably 5 to 60 mg, more preferably 5 to 30 mg, based on free form; and gelatin and titanium dioxide as the capsule matrix. The above amounts can be adjusted as needed.

[0088] The combination products and pharmaceutical compositions of the present invention have medical uses for the prevention, relief or treatment of schizophrenia.

[0089] According to one embodiment of the present invention, the symptoms of schizophrenia may be one or more selected from positive symptoms, negative symptoms, cognitive symptoms and residual symptoms of schizophrenia.

[0090] According to one embodiment of the present invention, schizophrenia can be selected from one or more of the following: paranoid schizophrenia, dissociative schizophrenia, catatonic schizophrenia, mixed schizophrenia, residual schizophrenia, post-schizophrenic depression, simple schizophrenia, undetermined schizophrenia, schizophrenia-like disorder, schizophrenic affective disorder, paranoid disorder, transient psychotic disorder, co-occurring psychotic disorder, psychotic disorder caused by another medical condition, substance / drug-induced psychotic disorder, and psychotic disorder of unknown cause.

[0091] The antipsychotic activity of carbamate compounds of Formula 1 and aripiprazole against schizophrenia can be tested using social interaction animal behavior tests, which are used in drug development for negative symptoms of schizophrenia (Neill JC, Grayson B, Kiss B, Gyertyán 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 N-methyl-D-aspartate (NMDA) receptor inhibitors are similar to the symptoms of schizophrenia, animals given NMDA receptor inhibitors can be used as models of schizophrenia. Dezocampine (MK-801) is an NMDA receptor inhibitor. In a dezocephalin-induced (MK-801-induced) social interaction animal behavior test, schizophrenia-like symptoms could be induced by administration of dezocephalin (Rung JP, Carlsson A, Rydén 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 a dose-proportionate manner with dezocine (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 notolanzapine, risperidone, or cannabidiol. Behav Pharmacol. 2015 Dec; 26(8Spec No):748-65).

[0092] The dosage of the carbamate compound of Formula 1 and aripiprazole for the prevention, relief, or treatment of the aforementioned diseases can generally vary depending on the severity of the disease, weight, and metabolic status of the individual. For an individual patient, the "therapeutic effective amount" refers to the amount of active compound sufficient to achieve the aforementioned pharmacological effects (i.e., the therapeutic effects described above).

[0093] As used in this article, the terms "prevent," "preventing," and "prevention" refer to reducing or eliminating the possibility of disease.

[0094] As used herein, the terms "alleviate," "alleviating," and "alleviation" refer to the complete or partial improvement of a disease and / or its accompanying symptoms.

[0095] As used herein, the terms "treat," "treating," and "treatment" refer to the complete or partial elimination of a disease and / or its accompanying symptoms.

[0096] As used herein, the term "object" refers to an animal, preferably a mammal (e.g., primates (e.g., humans), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, mice, etc.), and most preferably humans.

[0097] As used herein, the term "therapeutic effective amount" refers to the amount of an active compound or pharmaceutical preparation that elicits a biological or medical response in a system, animal, or human, including the relief of symptoms of a disease or disorder to be treated, wherein said amount is sought by a researcher, veterinarian, physician (physician), or other clinician.

[0098] As used herein, the terms "blend or mixture or combination" or "combination therapy" refer to the use of two or more drugs together, but do 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 as a mixture, or may be used as separate formulations. In other words, the term "combination" includes both single formulations and two separate formulations, so simultaneous, separate or sequential administration is possible.

[0099] As used herein, the term "composition" refers to a single formulation in which two or more drugs are present in a mixed state.

[0100] As used herein, the term "kit" generally refers to a finished product, and when two or more drugs are used, it refers to a finished product containing a combination of those drugs. Two or more drugs may be packaged as a single formulation in a finished product and administered simultaneously, or may be packaged as two separate formulations in a finished product and administered simultaneously, separately, or sequentially.

[0101] The invention will be explained in more detail below by way of working examples. The objects, features, and advantages of the invention will be readily understood through the following working examples. The invention is not limited to the working examples described herein, but may be practiced in other forms. The working examples described herein are provided to ensure that the disclosure is thorough and complete, and to fully convey the technical concepts of the invention to those skilled in the art. Therefore, the invention should not be limited to the following working examples.

[0102] Preparation Example: Synthesis of (R)-1-(2-chlorophenyl)-2-tetrazol-2-yl-ethyl ester of carbamate (the compound of Formula 2, hereinafter referred to as "test compound") was prepared according to the method described in Preparation Example 50 of PCT Publication No. WO2010 / 150946.

[0103] Example: The effect of social interaction animal behavior testing in an animal model exhibiting schizophrenia-like symptoms induced by dezocine treatment.

[0104] laboratory animals

[0105] Male Wistar rats (4 weeks old, Orient Bio Co., Ltd.) were purchased and divided into two groups in the animal breeding room, acclimatizing to their new environment on separate racks for at least one week. Following the Institutional Animal Care and Use Committee (IACUC) standards for laboratory animal care, the animals were housed and fed under 12-hour light-dark cycles, at a temperature of 22-25°C, relative humidity of 40-60%, and with free access to food and water. After stabilization for more than one week, the rats were used for social interaction behavior testing in pairs, with a weight difference not exceeding 20 grams.

[0106] Social Interaction Animal Behavior Test

[0107] The symptoms induced by administration of N-methyl-D-aspartate (NMDA) receptor inhibitors are similar to those arising from schizophrenia. Therefore, an animal model was used in which schizophrenia-like symptoms could be induced by treatment with dezocampine (an N-methyl-D-aspartate (NMDA) receptor inhibitor).

[0108] Dezocampine (purchased from Sigma) was dissolved in physiological saline as a medium to prepare fresh dezocampine, and administered subcutaneously at a dose of 0.1 mg / kg at a dose of 1 ml per kg of rat body weight 4 hours before the experiment.

[0109] Aripiprazole and the test compound were freshly prepared by dissolving them in 30% polyethylene glycol 400 (Sigma) as the medium. One hour prior to the experiment, aripiprazole at a dose of 0.003 mg / kg and the test compound at a dose of 3 mg / kg were administered orally at a dose of 1 mL per 1 kg of rat body weight.

[0110] Male rats were placed in pairs in the same observation box, allowing for 1:1 interaction. The total time spent sniffing, wiping, licking, riding, and climbing on or under the other rat, which could be considered positive social interaction, was measured up to 5 minutes, and social interaction was assessed accordingly.

[0111] Statistical analysis of experimental results

[0112] All data are presented as mean ± SEM. Statistical analysis of the total time of positive social interaction between groups was performed using GraphPad Prism ver. 5.04, and the analysis was conducted using one-way ANOVA and Dunnett's multiple comparison test.

[0113] The mean total time of positive social interaction was observed to be 53.86 ± 2.90 seconds in the negative control group treated with dezocampine alone, compared to 69.63 ± 3.13 seconds in the positive control group. The mean total time of positive social interaction was 57.52 ± 3.04 seconds in the aripiprazole 0.003 mg / kg group, 56.78 ± 2.19 seconds in the test compound 3 mg / kg group, and 63.76 ± 1.87 seconds in the group treated with both aripiprazole 0.003 mg / kg and the test compound 3 mg / kg.

[0114] Table 1: Effects of aripiprazole and test compounds on behavioral tests in socially interactive animals treated with dezocampine

[0115] 1) Social interaction = Total time of positive social interactions such as smelling, wiping, licking, riding, and crawling (in seconds)

[0116] 2) sc = mg / kg, subcutaneous

[0117] 3) po = mg / kg, oral administration

[0118] 4) - = Unprocessed.

[0119] Table 2 shows the recovery rate (%), which represents the total time of positive social interaction in the test compound and / or aripiprazole treatment group and the positive control mediator group compared to the negative control group treated with dezocampine alone. The recovery rate was calculated as follows.

[0120] Recovery rate (%) = (Time of positive social interaction in the test group - Time of positive social interaction in the negative control group) / (Time of positive social interaction in the positive control group - Time of positive social interaction in the negative control group) × 100 Table 2 Summary and statistical significance of recovery rates compared to the negative control group in social interaction behavior tests of animals treated with dezocyclopine

[0121]

[0122] Compared to the negative control group, the aripiprazole and test compound treatment groups showed recovery rates of 23.2% and 18.5%, respectively, with no statistically significant difference compared to the negative control group treated with dezocine alone, but a statistically significant difference compared to the positive control group. Although administration of aripiprazole 0.003 mg / kg or test compound 3 mg / kg alone did not show a significant recovery effect compared to the negative control group, the group receiving these doses together showed a recovery rate of 62.8%, demonstrating a statistically significant difference compared to the negative control group but no statistically significant difference compared to the positive control group. Figure 1 ).

[0123] The above confirms that the combination of aripiprazole and the test compound showed a synergistic increase in the effect on social interaction. This suggests that the two drugs are effective in treating schizophrenia, especially the negative symptoms of schizophrenia.

Claims

1. Use of the combination product in the preparation of a medicament for the prevention, reduction, or treatment of positive symptoms, cognitive symptoms, or residual symptoms of schizophrenia, wherein the combination product comprises (a) a carbamate compound or a pharmaceutically acceptable salt thereof, wherein the carbamate compound is carbamic acid (R)-1-(2-chlorophenyl)-2-tetrazol-2-yl-ethyl ester of formula 2; and (b) aripiprazole or a pharmaceutically acceptable salt thereof: [Equation 2] ， The combined product comprises 12.5 mg to 500 mg of the compound of formula 2 in free form and 5 mg to 90 mg of the aripiprazole in free form.

2. The use according to claim 1, wherein the schizophrenia is selected from one or more of the following: paranoid schizophrenia, dissociative schizophrenia, catatonic schizophrenia, mixed schizophrenia, residual schizophrenia, post-schizophrenic depression, simple schizophrenia, undetermined schizophrenia, schizophrenia-like disorder, schizophrenic affective disorder, paranoid disorder, transient psychotic disorder, co-occurring psychotic disorder, substance / drug-induced psychotic disorder, and psychotic disorder of unknown cause.

3. The use according to claim 1, wherein the combined product is to be used for administration to mammals.

4. The use according to claim 1, wherein the components (a) and (b) of the combined product are administered simultaneously or sequentially.

5. The use according to claim 1, wherein components (a) and (b) of the combined product are administered separately.

6. The use according to any one of claims 1-5, wherein the combined product is in the form of a kit.

7. The use according to claim 6, wherein the kit comprises, in a container, (a) a first composition comprising a carbamate compound of formula 2 or a pharmaceutically acceptable salt thereof; and (b) a second composition comprising aripiprazole or a pharmaceutically acceptable salt thereof.

8. Use of a pharmaceutical composition in the preparation of a medicament for the prevention, relief, or treatment of positive symptoms, cognitive symptoms, or residual symptoms of schizophrenia, wherein the pharmaceutical composition comprises (a) a carbamate compound or a pharmaceutically acceptable salt thereof, wherein the carbamate compound is carbamic acid (R)-1-(2-chlorophenyl)-2-tetrazol-2-yl-ethyl ester of formula 2; and (b) aripiprazole or a pharmaceutically acceptable salt thereof, and further comprising one or more pharmaceutically acceptable carriers: [Equation 2] ， wherein The pharmaceutical composition comprises 12.5 mg to 500 mg of the compound of formula 2 in free form and 5 mg to 90 mg of the aripiprazole in free form.

9. The use according to claim 8, wherein the schizophrenia is selected from one or more of the following: paranoid schizophrenia, dissociative schizophrenia, catatonic schizophrenia, mixed schizophrenia, residual schizophrenia, post-schizophrenic depression, simple schizophrenia, undetermined schizophrenia, schizophrenia-like disorder, schizophrenic affective disorder, paranoid disorder, transient psychotic disorder, co-occurring psychotic disorder, substance / drug-induced psychotic disorder, and psychotic disorder of unknown cause.

10. The use according to claim 8 or 9, wherein the pharmaceutical composition is prepared for administration to mammals.

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