Pharmaceutical combination or composition for the prevention, relief, or treatment of schizophrenia and its uses.

Abstract

The present invention relates to a combination for the prevention, reduction or treatment of schizophrenia, the combination containing a carbamate compound of chemical formula 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof and, more specifically, to a combination and a pharmaceutical composition, each containing a carbamate compound of chemical formula 1 and aripiprazole, and to the use thereof for treating schizophrenia.

Description

1 / 22 Pharmaceutical combination or composition for the prevention, relief, or treatment of schizophrenia, and its uses. Field of invention

[001] The present invention relates to a combination comprising a carbamate compound of Formula 1 below, or a pharmaceutically acceptable salt, solvate or hydrate thereof, for preventing, relieving or treating schizophrenia, more specifically to a combination comprising the carbamate compounds of Formula 1 and aripiprazole: [Formula 1] in which Ri, R2, Ai and A2 are as defined herein. Fundamentals of the technique

[002] Schizophrenia, a representative psychiatric disorder, is a syndrome of multiple psychotic symptoms in which the main pathology is a thought disorder, and complex symptoms appear in various areas, such as speech, behavior, emotion, and cognition, which are associated with or derived from such a thought disorder. It is a series of symptoms that have been called madness throughout human history.

[003] Overall, the prevalence of schizophrenia is approximately 1% of the world's population and has been observed to be constant regardless of population characteristics, and regional and cultural differences, such as between the West and the East, and between developed and developing countries. Although the cause of schizophrenia is unclear, it is said that its likelihood of development increases due to predispositions. Petition 870210087477, dated 09 / 22 / 2021, page 6 / 34 / 22 genetic or environmental factors, such as problems during pregnancy, parental environment and stress.

[004] The symptoms of schizophrenia can be classified into positive symptoms, negative symptoms, cognitive symptoms, and residual symptoms. Positive symptoms refer to abnormal and strange symptoms that appear externally, psychotic symptoms that cannot be found in healthy people, including sensory abnormalities such as auditory or visual hallucinations, thought abnormalities such as unrealistic and strange delusions, and disturbances in the thought process where an abnormality occurs in the flow of thought. Negative symptoms refer to a phenomenon in which a normal emotional reaction or behavior diminishes to become a monotonous state that shows poverty of thought content, decreased motivation, social isolation, etc. Negative symptoms, in general, do not respond better to medication than positive symptoms.Cognitive symptoms refer to symptoms that show difficulty maintaining concentration and a decrease in the ability to learn new information or organize thoughts. These symptoms leave the patient unable to perform what they used to do well in the past, and significantly reduce memory and problem-solving abilities, thus degrading the patient's social and occupational functions, causing patients to suffer failure upon returning to society, becoming unemployed, and experiencing frustration. Cognitive symptoms refer to symptoms that show difficulty maintaining concentration and a decrease in the ability to learn new information or organize thoughts. Patients are unable to perform what they used to do well in the past, and exhibit a significant reduction in memory and problem-solving abilities.Cognitive symptoms are less noticeable, but they impair patients' social and occupational functioning. Petition 870210087477, dated 09 / 22 / 2021, page 7 / 34 / 22 with schizophrenia, causing them to fail upon returning to society and experience frustration.

[005] Schizophrenia can present in various forms, depending on the symptoms and signs, as described previously. Schizophrenia includes not only paranoid schizophrenia, disorganized schizophrenia, catatonic schizophrenia, and undifferentiated schizophrenia, but also post-schizophrenia depression, residual schizophrenia, simple schizophrenia, and schizophrenia not otherwise specified. Furthermore, schizophreniform disorder, schizoaffective disorder, delusional disorder, brief psychotic disorder, shared psychotic disorder, psychotic disorder due to another medical condition, substance / medication-induced psychotic disorder, or psychotic disorder of unknown cause are included in schizophrenia in a broad sense.

[006] Typical antipsychotic drugs, such as haloperidol and chlorpromazine, and atypical antipsychotic drugs, such as aripiprazole, risperidone, and clozapine, have been developed, and these drugs are known to be effective especially for the positive symptoms of schizophrenia. When patients start medication, the psychomotor agitation, hallucinations, etc., of the acute phase generally improve within a few days, and the delusions also improve within a few weeks. It is known that in most patients, a significant portion of the symptoms of the acute phase improves when appropriate medication is maintained at the appropriate dose for 6 to 8 weeks. However, when patients first take antipsychotic drugs, many of them experience drowsiness and dizziness, and they frequently experience blurred vision, palpitations, menstrual changes, and skin rashes.

[007] Conventional antipsychotic drugs attenuate or alleviate patients' symptoms to improve their quality of life, but this does not induce a complete cure and their use is limited due to side effects. Petition 870210087477, dated 09 / 22 / 2021, page 8 / 34 4 / 22 Thus, these drugs have limited therapeutic value in controlling schizophrenia, and there is a need to develop new drugs with improved efficacy and side effects. In particular, no drug is currently satisfactory for treating the negative or cognitive symptoms of schizophrenia, and therefore, the development of such a drug is necessary. Dissemination of the invention. Problem to be solved.

[008] The present invention is intended to provide a pharmaceutical combination and composition that has an improved effect in the prevention, relief or treatment of schizophrenia without increasing side effects. Technical solution to the problem

[009] The present inventors considered that combining conventional (existing) antipsychotic agents, such as aripiprazole, with drugs with different mechanisms of action could maintain or increase their effectiveness, while reducing side effects by lowering the dose required for the effectiveness of conventional antipsychotic agents, and thus conducted an in-depth study.

[0010] As a result, the present inventors have selected a carbamate compound of the following Formula 1, or a pharmaceutically acceptable salt, solvate or hydrate thereof, as a drug with a mechanism of action different from conventional antipsychotic agents: [Formula 1] wherein Petition 870210087477, dated 09 / 22 / 2021, page 9 / 34 / 22 Ri and R2 are each independently selected from the group consisting of hydrogen, halogen, Q-C8 alkyl, C1-C8 haloalkyl, C1-C8 thioalkoxy and CrC^ alkoxy, and one of A1 and A2 is CH, and the other is N.

[0011] Furthermore, as with the conventional antipsychotic agent, the present inventors have selected an atypical antipsychotic agent 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 agent is aripiprazole.

[0012] Thus, as a specific aspect, the present invention provides a combination 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.

[0013] Furthermore, the present invention provides a pharmaceutical composition for the prevention, relief or treatment of schizophrenia, comprising as active ingredients (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 additionally one or more of a pharmaceutically acceptable carrier.

[0014] Furthermore, the present invention provides a kit for the prevention, relief or treatment of schizophrenia, comprising (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, in a container. Effect of the invention

[0015] The pharmaceutical combination and composition of the present Petition 870210087477, dated 09 / 22 / 2021, page 10 / 34 / 22 The invention provides an improved effect in the prevention, relief, or treatment of schizophrenia without increasing side effects. In one embodiment, the combination and pharmaceutical composition of the present invention exhibits a synergistic effect in the prevention, relief, or treatment of schizophrenia. In particular, the combination and pharmaceutical compositions of the present invention are effective in treating negative symptoms of schizophrenia or improving cognitive impairment.

[0016] Furthermore, by selecting the carbamate compounds of Formula 1 as a drug with a mechanism of action different from existing antipsychotic agents, and by combining the carbamate compounds with the existing atypical antipsychotic drug, aripiprazole, the combination and pharmaceutical composition of the present invention can reduce the side effects of existing antipsychotic drugs, while maintaining or increasing the drug's effectiveness even if the dose required for the drug's effectiveness is reduced. Brief description of the drawings

[0017] Figure 1 shows the results of a test compound and aripiprazole from the animal behavior test of social interaction related to negative symptoms of schizophrenia in an animal model in which schizophrenia-like symptoms were induced by treatment with dizocilpine (MK-801). The description of each symbol in Figure 1 is as follows: Social interaction = the total amount of time spent in active social interaction s = seconds sc = mg / kg, subcutaneously po = mg / kg, per os - = Not treated Specific methods for carrying out the invention Petition 870210087477, dated 09 / 22 / 2021, page 11 / 34 7 / 22

[0018] Hereafter, the present invention will be described in detail.

[0019] The present invention provides a combination for the prevention, relief or treatment of schizophrenia, comprising (a) a carbamate compound of the following Formula 1, or a pharmaceutically acceptable salt, solvate or hydrate thereof, and (b) aripiprazole, or a pharmaceutically acceptable salt, solvate or hydrate thereof: [Formula 1] in which Ri and R2 are each independently selected from the group consisting of hydrogen, halogen, C1-C8 alkyl, C1-C8 haloalkyl, C1-C8 thioalkoxy and C1-C8 alkoxy; and one of A1 and A2 is CH, and the other is N.

[0020] Furthermore, the present invention provides a pharmaceutical composition for the prevention, relief or treatment of schizophrenia, comprising as active ingredients (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 additionally one or more of a pharmaceutically acceptable carrier.

[0021] Furthermore, the present invention provides a kit for the prevention, relief or treatment of schizophrenia, comprising (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 salt, solvate or Petition 870210087477, dated 09 / 22 / 2021, page 12 / 34 / 22 pharmaceutically acceptable hydrate thereof, in a container.

[0022] Furthermore, the present invention provides a method for preventing, alleviating or treating schizophrenia, comprising administering to an individual in need of 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.

[0023] Furthermore, the present invention provides the use of a combination 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, and additionally one or more of a pharmaceutically acceptable carrier for the prevention, relief or treatment of schizophrenia.

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

[0025] According to one embodiment of the present invention, in the previous 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 previous prevention, relief or treatment method, components (a) and (b) can be administered simultaneously, separately or sequentially.

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

[0028] In one embodiment of the present invention, in the preceding Formula 1, R1 and R2 are each independently selected from the group consisting of hydrogen, halogen and C1-C8 alkyl.

[0029] In one embodiment of the present invention, the C1-C8 haloalkyl Petition 870210087477, dated 09 / 22 / 2021, p. 13 / 34 9 / 22 is perfluoroalkyl.

[0030] According to another embodiment of the present invention, the carbamate compound of the preceding Formula 1 is the (R)-l-(2-chlorophenyl)-2-tetrazol-2-yl-ethyl ester of carbamic acid of the following Formula 2. [Formula 2]

[0031] A person skilled in the art of compound synthesis could easily have prepared the carbamate compounds of the preceding Formulas 1 and 2 using known compounds or compounds that can be easily prepared from them. In particular, the methods for preparing the compounds of the preceding Formula 1 are described in detail in PCT Applications No. WO 2006 / 112685 A1, WO 2010 / 150946 A1 and WO 2011 / 046380 A2, disclosures of which are incorporated herein by reference. The compounds of the preceding Formula 1 can be chemically synthesized by any of the methods described in the preceding documents, but the methods are merely exemplary, and the order of operation of the unit and the like may be selectively altered if necessary. Thus, the preceding methods should not limit the scope of the invention.

[0032] Aripiprazole is a product marketed under the trade name Abilify®. The chemical name is 7-{4-[4-(2,3-dichlorophenyl)piperazin-lyl]butoxy}-3,4-dihydroquinolin-2(1H)-one, and the structure is as follows: Cl ci^^L HERE H

[0033] In one embodiment of the present invention, in addition to Petition 870210087477, dated 22 / 09 / 2021, page 14 / 34 / 22 aripiprazole, an atypical antipsychotic agent selected from the group consisting of asenapine, clozapine, iloperidone, olanzapine, lurasidone, paliperidone, quetiapine, risperidone and ziprasidone may also preferably be used.

[0034] In the present invention, as the compounds of Formula 1 or 2 above and aripiprazole, their free forms, or a pharmaceutically acceptable salt, solvate or hydrate thereof, may be used.

[0035] According to one embodiment of the present invention, such as the compounds of Formula 1 or 2 above and aripiprazole, their free forms may be used.

[0036] For example, examples of pharmaceutically acceptable salts of the compounds of Formula 1 or 2 above or pharmaceutically acceptable salts of aripiprazole include, independently, acetate, benzenesulfonate, benzoate, bitartrate, calcium acetate, camsylate, carbonate, citrate, edetate, edisylate, estolate, esilate, fumarate, gluceptate, gluconate, glutamate, glycoloyl arsanilate, hexylresorcinate, hydravamine, 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 hemisuccinate, sulfate or hemisulfate, tannate, tartrate, oxalate or hemitartrate, theoaclate, triethiodide, benzathine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine, procaine, aluminum, ammonium, tetramethylammonium, calcium, lithium,magnesium, potassium, sodium, and zinc.

[0037] In the pharmaceutical combination or composition according to an embodiment of the present invention, a therapeutically effective amount or dose of the compounds of Formula 1 may include 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 the free form and once-daily administration to humans. Petition 870210087477, dated 09 / 22 / 2021, p. 15 / 34 / 22

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

[0039] In one embodiment of the present invention, the dose of the atypical antipsychotic agent including aripiprazole may be lower than the dose required to produce a therapeutically effective amount when administered alone without the carbamate compounds of Formula 1. This is due to the combination with the carbamate compounds of Formula 1, which makes it possible to maintain an effective pharmacological effect while decreasing the dose required for the pharmacological effect of the atypical antipsychotic agent.

[0040] According to one embodiment of the present invention, the weight ratio of the combination 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.

[0041] The combination and pharmaceutical composition of the present invention can be prepared in various forms of oral or parenteral formulations, and can be administered, for example, by intravenous injection, intramuscular injection, intradermal injection, subcutaneous injection, intraduodenal injection, intraperitoneal injection or intrathecal injection, or they can be administered via a transdermal route. Furthermore, the composition can be administered by any device capable of transferring the active substance to a target cell. The route of administration may vary depending on the general condition and age of the individual to be treated, the nature of the treatment condition and the active ingredient selected. Petition 870210087477, dated 09 / 22 / 2021, page 16 / 34 / 22

[0042] The appropriate dosage of the pharmaceutical combination and composition according to an embodiment of the present invention may vary depending on factors such as the formulation method, method of administration, age, body weight and sex of the patients, pathological condition, diet, administration time, route of administration, excretion rate and sensitivity of the reaction, and skilled physicians can easily determine and prescribe dosages that are effective for the desired treatment or prophylaxis. The pharmaceutical composition according to an embodiment may be administered in one or more doses, for example, one to four times a day.The pharmaceutical composition according to one embodiment may contain a) the compounds 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 the 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 the free form.

[0043] The pharmaceutical composition according to one embodiment of the present invention may be formulated using a pharmaceutically acceptable carrier and / or excipient according to a method that one skilled in the art could easily perform, so as to be prepared in a unit dose form or contained in a multi-dose container. The aforementioned formulation may be an oil solution or an aqueous solution, a suspension or an emulsion (emulsified solution), an extract, a powder, granules, a tablet, or a capsule, and may additionally include a dispersing or stabilizing agent. Furthermore, the pharmaceutical composition may be administered in the form of suppositories, sprays, ointments, creams, gels, inhalants, or patches. The pharmaceutical composition may also be prepared for administration to mammals, more preferably for administration to humans.

[0044] The pharmaceutical composition of the present invention comprises Petition 870210087477, dated 09 / 22 / 2021, page 17 / 34 / 22 additionally one or more pharmaceutically acceptable carriers in addition to the active ingredients (a) and (b), as described above.

[0045] Pharmaceutically acceptable carriers may be solid or liquid, and may be one or more selected from fillers, antioxidants, buffers, bacteriostats, dispersants, adsorbents, surfactants, binders, preservatives, disintegrants, sweeteners, flavorings, glidants, release control agents, wetting agents, stabilizers, suspending agents and lubricants. Furthermore, pharmaceutically acceptable carriers may be selected from saline, sterile water, Ringer's solution, buffered saline, dextrose solution, maltodextrin, glycerol, ethanol and mixtures thereof.

[0046] In one embodiment, suitable fillers include, but are not limited to, sugar (e.g., dextrose, sucrose, maltose, and lactose), starch (e.g., corn starch), sugar alcohols (e.g., mannitol, sorbitol, maltitol, erythritol, and xylitol), hydrolyzed starch (e.g., dextrin and maltodextrin), cellulose 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, and the like.

[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 non-ionic surfactants, such as sodium laurate, sodium lauryl sulfate, sodium dodecanesulfonate, sodium oleyl sulfate, benzalkonium chloride, alkyltrimethylammonium bromide, glyceryl monooleate, dry polyoxyethylene sorbitan fatty acid ester, polyvinyl alcohol and dry sorbitan S or a mixture thereof.

[0050] In one embodiment, the appropriate agglutinants include, but Petition 870210087477, dated 09 / 22 / 2021, page 18 / 34 / 22 are not limited to, povidone, copovidone, methylcellulose, hydroxymethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, gelatin, gum, sucrose, starch and mixtures thereof.

[0051] In one embodiment, suitable preservatives include, but are not limited to, benzoic acid, sodium benzoate, benzyl alcohol, butylated hydroxyanisole, butylated hydroxytoluene, chlorbutol, 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, sweeteners include, but are not limited to, sucralose, saccharin, sodium saccharin, potassium saccharin, calcium saccharin, acesulfame potassium or sodium cyclamate, mannitol fructose, sucrose, maltose or mixtures thereof.

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

[0055] In one embodiment, the release control agents (release-modifying excipients) include, but are not limited to, hydroxypropyl methylcellulose, poly(ethylene 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), a polyoxyethylene derivative of sorbitan esters such as polysorbate 20 and polysorbate 80, lecithin, polyoxyethylene and polyoxypropylene ether, sodium deoxycholate or mixtures thereof.

[0057] In one embodiment, suitable suspending agents include, but are not limited to, cellulose derivatives, such as cellulose Petition 870210087477, dated 09 / 22 / 2021, page 19 / 34 / 22 microcrystalline, methyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl methyl cellulose, polyvinylpyrrolidone, alginate, chitosan, dextran, gelatin, polyethylene glycol, polyethylene ether and polyoxypropylene or mixtures thereof.

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

[0059] The pharmaceutical composition of the present invention can be formulated in an injectable formulation, such as an aqueous solution, a suspension or an emulsion, or it can be formulated in pills, capsules, granules or tablets. In powders, the carrier can be a fine solid that can be mixed with the active ingredient in the form of a mixture, and in tablets, the active ingredient can be mixed with the carrier to have agglutinating properties that can be compacted into an appropriate ratio and desired shape and size.

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

[0061] For example, the pharmaceutical composition of the present invention may be prepared in capsules containing a) the compounds 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 the 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 the free form; and gelatin and titanium dioxide as a capsule base. The foregoing amounts may be adjusted as required.

[0062] The pharmaceutical combinations and compositions of the present invention have medicinal uses for the prevention, relief or treatment of schizophrenia. Petition 870210087477, dated 09 / 22 / 2021, page 20 / 34 / 22

[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, schizophrenia may be one or more of the group consisting of paranoid schizophrenia, disorganized schizophrenia, catatonic schizophrenia, undifferentiated schizophrenia, residual schizophrenia, post-schizophrenic depression, simple schizophrenia, unspecified schizophrenia, schizophreniform disorder, schizoaffective disorder, delusional disorder, brief psychotic disorder, shared psychotic disorder, psychotic disorder due to another medical condition, substance / medication-induced psychotic disorder, and psychotic disorder of unknown cause.

[0065] The antipsychotic activity of the carbamate compounds of Formula 1 and aripiprazole against schizophrenia can be tested using animal behavior tests with social interaction used in the development of drugs for the 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 effect of administering the N-methyl-S-aspartate (NMDA) receptor inhibitor and symptoms due to schizophrenia are similar, animals administered with the N-methyl-S-aspartate (NMDA) receptor inhibitor can be used as a model of schizophrenia. Dizocilpine (MK-801) is an N-methyl-S-aspartate (NMDA) receptor agonist.In the dizocilpine-induced animal behavior test with social interaction (MK-801-induced), schizophrenia-like symptoms may be induced by dizocilpine administration (Rung JP, Carlsson A, Rydén Markinhuhta K, Carlsson ML, (+) Petition 870210087477, 22 / 09 / 2021, p. 21 / 34 / 22. 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 drug, inhibits 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.

[0066] The dosage of the carbamate compounds of Formula 1 and aripiprazole for the prevention, relief, or treatment of the aforementioned diseases may normally vary depending on the severity of the disease, body weight, and metabolic state of the individual. A “therapeutically effective amount” for an individual patient refers to an amount of the active compound sufficient to achieve the aforementioned pharmacological effect, that is, the therapeutic effect as described above.

[0067] As used here, the terms “prevent”, “preventing” and “prevention” refer to reducing or eliminating the probability of a disease.

[0068] As used here, the terms “alleviate”, “alleviating” and “relief” refer to the improvement of a disease and / or its corresponding symptoms, all together or in part.

[0069] As used herein, the terms “treat”, “treating” and “treatment” refer to the improvement of a disease and / or its corresponding symptoms, all together or in part.

[0070] As used herein, the term “individual” refers to an animal that is the object of therapy, observation or experiment, preferably a mammal (such as primates (e.g., a human), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, mice, etc.), more preferably a human. Petition 870210087477, dated 09 / 22 / 2021, page 22 / 34 / 22

[0071] As used herein, the term “therapeutically effective amount” refers to the amount of active compound or pharmaceutical formulation that elicits a biological or medical response in the animal or human system, including relief of the symptoms of the disease or disorder being treated, where said amount is sought by a researcher, veterinarian, doctor (physician), or other clinician.

[0072] As used herein, the term “union or mixture or combination” or “combination therapy” means that two or more drugs are used together, but does not necessarily mean a state in which two or more drugs are mixed. It means that two or more drugs may be present together in a single preparation in a mixed state, or may be used as separate preparations. In other words, the term “combination” includes a single preparation as well as two separate preparations, so simultaneous, separate or sequential administration is possible.

[0073] As used here, the term “composition” refers to a single preparation in which two or more drugs are present in a mixed state.

[0074] As used herein, the term “kit” normally 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 combination. Two or more drugs may be packaged in a single formulation in the finished product and administered simultaneously, or they may be packaged in two separate formulations in the finished product and administered simultaneously, separately or sequentially.

[0075] Hereafter, the present invention will be explained in more detail by means of working examples. The objectives, features and advantages of the present invention will be quickly understood by means of the following working examples. The present invention is not limited to Petition 870210087477, dated 09 / 22 / 2021, p. 23 / 34 / 22 examples of work described herein, but may be incorporated into other forms. The examples of work described herein are provided to ensure that the contents of the disclosure are thorough and complete, and that the technical concept of the present invention is sufficiently conveyed to one skilled in the art to which the present invention pertains. Therefore, the present invention should not be limited by the following examples of work. Example of preparation: Synthesis of (R)-1-(2-chlorophenyl)-2-tetrazol-2-yl-ethyl carbamic acid ester

[0076] The (R)-1-(2-chlorophenyl)-2-tetrazol-2-yl-ethyl carbamic acid ester (the compound of Formula 2, hereinafter referred to as the “test compound”) was prepared in accordance with the method described in Preparation Example 50 of PCT Application No. WO 2010 / 150946. Example: Effects on animal behavior tests with social interaction in animal models with schizophrenia-like symptoms induced by dizocilpine treatment. Experimental animals

[0077] Male Wistar rats (4 weeks old, Orient Bio Co., Ltd.) were purchased, divided into 2 groups in an animal bloodletting environment, and acclimatized for more than 1 week on separate shelves. The experimental animals were housed and maintained according to the Institutional Animal Care and Use Committee (IACUC) Laboratory Animal Care Standards under conditions of a 12-hour light-dark cycle, a temperature of 22 to 25 °C, a relative humidity of 40 to 60%, and free access to food and water. After stabilization for more than one week, the rats were used in an animal behavior test with social interaction in pairs of rats whose weight difference did not exceed 20 g. Animal behavior tests with social interaction

[0078] Symptoms resulting from the administration of the N-methyl-D-aspartate (NMDA) receptor inhibitor and symptoms due to Petition 870210087477, dated 09 / 22 / 2021, page 24 / 34 / 22 schizophrenia are similar. Thus, an animal model is used in which schizophrenia-like symptoms can be induced by treatment with dizocilpine, an N-methyl-D-aspartate (NMDA) receptor inhibitor.

[0079] Dizocilpine (purchased from Sigma) was freshly prepared by dissolving it in physiological saline used as a vehicle, and 4 hours before the experiment, a dose of 0.1 mg / kg was administered subcutaneously in a volume of 1 ml per 1 kg of rat body weight.

[0080] 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, a dose of 0.003 mg / kg of aripiprazole and a dose of 3 mg / kg of the test compound were administered orally in a volume of 1 ml per 1 kg of rat body weight.

[0081] Male rats were placed in the same observation box in pairs, allowing 1:1 interaction, and then the total time spent sniffing, self-grooming, licking, mounting, and crawling under and over another rat, which can be considered as active social interactions, was measured for 5 minutes, and social interaction was assessed based on this. Statistical analysis of experimental results

[0082] All data are expressed as mean ± SEM. Statistical analysis of the total time of active social interactions between groups was performed using GraphPad Prism ver. 5.04, and analyzed by one-way ANOVA (one-way analysis of variance) and Dunnett's multiple comparisons test.

[0083] The mean total time of active social interactions in the negative control group treated with dizocilpine alone was observed to be 53.86 ± 2.90 seconds, and the mean total time of active social interactions in the positive control vehicle group was observed to be 69.63 ± 3.13 seconds. The mean total time of active social interactions was observed to be 57.52 ± 3.04 seconds in the aripiprazole administration group. Petition 870210087477, dated 09 / 22 / 2021, page 25 / 34 21 / 22 0.003 mg / kg, 56.78 ± 2.19 seconds in the group administered with the 3 mg / kg test compound, and 63.76 ± 1.87 seconds in the group administered with both aripiprazole 0.003 mg / kg and the 3 mg / kg test compound. Table 1. Effects of aripiprazole and the test compound on behavioral tests of animals with social interaction treated with dizocilpine. Drugs administered Dosage Number of animals Social interaction b (Average + SEM) Dizocilpine (mg / kg, s 2)) Aripiprazole (mg / kg, po 3)) Test compound (mg / kg, po) Vehicle _ 4) - 20 pairs 69.63 + 3.13 Dizocilpine 0.1 - 20 pairs 53.86 + 2.90 Aripiprazole 0.1 0.003 20 pairs 57.52 + 3.04 Test compound 0.1 - 3 20 pairs 56.78 + 2.19 Aripiprazole and test compound 0.1 0.003 3 20 pairs 63.76 + 1.87 Social interaction = Total time of active social interactions including sniffing, self-grooming, licking, mounting, and crawling (unit: second)2|sc = mg / kg, subcutaneously3|po = mg / kg, per os11- = Untreated

[0084] Table 2 shows the recovery rate (%) representing the total time of active social interactions in the group treated with the test compound and / or aripiprazole and the positive control vehicle group, compared to the negative control group treated with dizocilpine alone. The recovery rate was calculated as follows.

[0085] Recovery rate (%) = (Time of active social interactions in the test group - Time of active social interactions in the negative control group) / (Time of active social interactions in the positive control group - Time of active social interactions in the negative control group) x 100 Table 2. Summary of recovery rate compared to a negative control group in animal behavior tests with social interaction treated with dizocilpine and statistical significance. Drugs administered Number of animals Recovery rate compared to negative control Statistical significance compared to negative control (P<0.05?) Statistical significance compared to positive control (P<0.05?) Vehicle 20 pairs 100.00% Significant Dizocilpine 20 pairs 0.0% Significant Aripiprazole 20 pairs 23.2% Not significant Significant Test composite 20 pairs 18.5% Not significant Significant Petition 870210087477, dated 09 / 22 / 2021, page 26 / 34 / 22 Aripiprazole and test compound 20 pairs 62.8% Significant Not significant

[0086] The aripiprazole administration group and the test compound administration group showed recovery rates of 23.2% and 18.5%, respectively, compared to the negative control group, and showed no statistically significant difference from the negative control group treated with dizocilpine alone, and showed a statistically significant difference from the positive control group. Although the respective administration of aripiprazole 0.003 mg / kg or the test compound 3 mg / kg did not show a significant recovery effect compared to the negative control group, the group administered with these dosages together showed a recovery rate of 62.8% compared to the negative control group, showing a statistically significant difference from the negative control group and no statistically significant difference from the positive control group (Figure 1).

[0087] Based on the foregoing, it has been confirmed that a combination of aripiprazole and the test compound shows a synergistic increase in the effect on social interaction. This indicates that these two drugs are effective in the treatment of schizophrenia, especially the negative symptoms of schizophrenia. Petition 870210087477, dated 09 / 22 / 2021, page 27 / 34

Claims

1 / 4 CLAIMS 1. Combination for the prevention, relief or treatment of schizophrenia, characterized in that it comprises (a) a carbamate compound which is an (R)-1-(2-chlorophenyl)-2-tetrazol-2-yl-ethyl ester of carbamic acid of the following Formula 2, or a pharmaceutically acceptable salt thereof, and (b) aripiprazole, or a pharmaceutically acceptable salt thereof: [Formula 2] 2. Combination according to claim 1, characterized in that it comprises the compound of Formula 2 in an amount of 12.5 mg to 500 mg, based on the free form.

3. Combination according to claim 1, characterized in that it comprises said aripiprazole in an amount of 5 mg to 90 mg, based on the free form.

4. Combination according to claim 1, characterized in that it comprises 12.5 mg to 500 mg of the compound of Formula 2, based on the free form, and 5 mg to 90 mg of said aripiprazole, based on the free form.

5. Combination according to claim 1, characterized in that said schizophrenia presents one or more symptoms selected from the group consisting of positive symptoms, negative symptoms, cognitive symptoms and residual symptoms.

6. Combination according to claim 1, characterized in that said schizophrenia is one or more of the group consisting of paranoid schizophrenia, disorganized schizophrenia, catatonic schizophrenia, undifferentiated schizophrenia, residual schizophrenia, post-schizophrenic depression, simple schizophrenia, unspecified schizophrenia, schizophrenia-like disorder, schizoaffective disorder, delusional disorder, brief psychotic disorder, shared psychotic disorder, psychotic disorder due to another medical condition, substance / medication-induced psychotic disorder, and psychotic disorder of unknown cause.

7. Combination according to claim 1, characterized in that it is for use in administration to mammals.

8. Combination according to any one of claims 1 to 7, characterized in that it is in the form of a kit.

9. Combination according to claim 8, characterized in that it contains (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, in a container.

10. Pharmaceutical composition for the prevention, relief or treatment of schizophrenia, characterized in that it comprises (a) a carbamate compound that is an (R)-1-(2-chlorophenyl)-2-tetrazol-2-ylethyl ester of carbamic acid of Formula 2, or a pharmaceutically acceptable salt thereof, and (b) aripiprazole, or a pharmaceutically acceptable salt thereof, and additionally one or more pharmaceutically acceptable carriers: [Formula 2] 11. Pharmaceutical composition according to claim Petition 870260081854, dated 08 / 13 / 2026, page 11 / 20 3 / 4 10, characterized by the fact that said schizophrenia presents one or more symptoms selected from the group consisting of positive symptoms, negative symptoms, cognitive symptoms and residual symptoms.

12. Pharmaceutical composition according to claim 10, characterized in that said schizophrenia is one or more of the group consisting of paranoid schizophrenia, disorganized schizophrenia, catatonic schizophrenia, undifferentiated schizophrenia, residual schizophrenia, post-schizophrenic depression, simple schizophrenia, unspecified schizophrenia, schizophreniform disorder, schizoaffective disorder, delusional disorder, brief psychotic disorder, shared psychotic disorder, psychotic disorder due to another medical condition, substance / medication-induced psychotic disorder, and psychotic disorder of unknown cause.

13. Pharmaceutical composition according to any one of claims 10 to 12, characterized in that it is prepared for administration to a mammal.

14. Pharmaceutical composition according to any one of claims 10 to 12, characterized in that it comprises the compound of Formula 2 in an amount of 12.5 mg to 500 mg, based on the free form.

15. Pharmaceutical composition according to any one of claims 10 to 12, characterized in that it comprises said aripiprazole in an amount of 5 mg to 90 mg, based on the free form.

16. Pharmaceutical composition according to any one of claims 10 to 12, characterized in that it comprises 12.5 mg to 500 mg of the compound of Formula 2, based on the free form, and 5 mg to 90 mg of said aripiprazole, based on the free form.

17. Use of a combination comprising (a) a carbamate compound that is an (R)-1-(2-chlorophenyl)-2-tetrazol-2-yl-ethyl ester of carbamic acid of Formula 2, or a pharmaceutically acceptable salt thereof; and (b) aripiprazole or a pharmaceutically acceptable salt thereof, characterized in that it is for the manufacture of a medicament for the prevention, relief or treatment of schizophrenia: [Formula 2] 18. Use of a pharmaceutical composition comprising (a) a carbamate compound that is an (R)-1-(2-chlorophenyl)-2-tetrazol-2-ylethyl ester of carbamic acid of Formula 2, or a pharmaceutically acceptable salt thereof; and (b) aripiprazole or a pharmaceutically acceptable salt thereof, and also one or more pharmaceutically acceptable carriers, characterized in that it is for the manufacture of a medicament for the prevention, relief or treatment of schizophrenia: [Formula 2] Petition 870260081854, dated 13 / 08 / 2026, page 13 / 20

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