KR20180068493A - Use of carbamate compound for prevention, alleviation or treatment of psychiatric disorder selected from schizophrenia, obsessive-compulsive disorder and tourette syndrome - Google Patents

Abstract

The present invention relates to a use of a carbamate compound for preventing, alleviating and/or treating psychotic disorders selected from the group consisting of schizophrenia, obsessive-compulsive disorder, and tourette syndrome by administering a pharmaceutical composition comprising a carbamate compound represented by chemical formula 1. In the chemical formula 1, R_1, R_2, A_1, and A_2 are the same as defined in the specification.

Description

Use of carbamate compounds in the prevention, alleviation or treatment of psychotic disorders selected from asthma, obsessive compulsive disorder and Tourette's syndrome. USE OF CARBAMATE COMPOUND FOR PREVENTION, ALLEVIATION OR TREATMENT OF PSYCHIATRIC DISORDER SELECTED FROM SCHIZOPHRENIA, OBSESSIVE-COMPULSIVE DISORDER AND TOURETTE SYNDROME}

The present invention relates to the use of a pharmaceutical composition comprising a carbamate compound of the following formula 1 for the purpose of preventing, alleviating or treating a psychotic disorder selected from the group consisting of asthma, obsessive compulsive disorder and Tourette's syndrome will be:

[Chemical Formula 1]

In Formula 1, R ₁ , R ₂ , A ₁ and A ₂ are as defined herein.

Schizophrenia is a representative psychiatric disorder, which is defined as the main pathology of thinking disorders, and is a collection of psychosomatic symptoms that manifest complex symptoms in various areas such as related, derived words, behavior, emotion, (syndrome), a series of symptoms that have long been known in human history as madness (madness).

In general, prevalence of prevalence is approximately 1% of the world's population and is constant regardless of population characteristics, regional and cultural differences, such as western and eastern, developed and developing countries. The cause of the disease is not clear, but it is said that the possibility of the disease is increased due to environmental factors such as genetic predisposition or problems during pregnancy, parenting environment and stress.

Symptoms can be categorized as benign, negative, cognitive, and residual symptoms. Positive symptoms are abnormal and bizarre symptoms that appear on the surface, psychotic symptoms that can not be found in healthy people, abnormalities of sensation such as hallucination or hallucination, abnormalities of imagination such as unrealistic and bizarre delusions, There may be obstacles in the process. Negative symptoms are a dull state due to a decrease in normal emotional responses or behaviors. Predicted incidents, loss of motivation, social atrophy, etc., and generally the drug response is less favorable than positive symptoms. Cognitive symptoms are symptoms that are difficult to maintain concentration, and which impair their ability to learn new information or organize their thoughts. In the past, they did not do what they were proficient in doing well and drastically reduced their memory and problem solving abilities, It causes the patients' social and occupational function to decline, causing patients to fail to return to society and lose their job and become frustrated.

It can be presented in various forms according to the above symptoms and signals. Schizophrenia includes schizophrenia, paranoid schizophrenia, tension schizophrenia, and non-classified schizophrenia as well as depression after schizophrenia, current schizophrenia, simple schizophrenia, and unspecified schizophrenia, and schizophrenia, schizophrenia, Symptomatic disorders in a broad sense include affective disorders, delusional disorders, short term manifestations, shared psychotic disorders, psychotic disorders due to general medical disorders, psychotic disorders due to substance or psychotic disorders of unknown origin.

Haloperidol, chlorpromazine, and other antipsychotic drugs have been developed and are known to be effective for the benign symptoms of asthma. When drug therapy is started, psychomotor retardation and hallucination in acute phase are improved within a few days and reticence is also improved within several weeks. In most patients, when appropriate drugs are maintained in appropriate doses for 6-8 weeks, The part is known to improve. However, the first dose of antipsychotic medication may cause sleepiness or dizziness, and blurred vision, palpitations, menstrual changes, and skin rash may occur. Clozapine, an atypical antipsychotic drug, is used for psychotic symptoms, especially negative symptoms, that cause serious side effects but do not respond to other medications. These medicines improve the quality of life by alleviating or relieving the symptoms of the patients, but this does not induce complete healing. [Stephen H. Schultz, Sstephen W. North, Cleveland G. Shields, Schizophrenia: A Review, 2007, Am. Fam. Physician, 75, 1821-1829].

Obsessive-Compulsive Disorder (OCD) refers to a state of repetition without any attempt, regardless of whether or not it is desired to throw away any particular thought or behavior, including obsessive behavior and obsessive thoughts DSM-IV). Obsessive thoughts are repetitive and constantly experiencing accidents, impulses, and images, which cause significant anxiety and distress, feeling themselves intrusive and inappropriate. Obsessive behaviors include, for example, repetitive behaviors such as washing hands, organizing and confirming, praying, number counting, repetition of words, and so on. In response to this, strict rules are followed. These obsessive thoughts and compulsive behaviors are clearly uncomfortable and cause considerable disruption to the individual's daily life, work, academic performance, social behavior, and social relationships. The lifetime prevalence of obsessive - compulsive disorder is estimated to be about 2 ~ 3%, and it is the fourth most common psychiatric disorder. Obsessive - compulsive disorder is known to occur due to insufficient supply of serotonin among neurotransmitters in the brain. It is caused by abnormal function of the neural network between the frontal lobe and basal ganglia of the brain. Drug therapy, which is one of the measures to treat OCD, is mainly used for drugs that are designed to control serotonin in the brain, which medicines the treatment of obsessive-compulsive disorder by normalizing serotonin function in the brain [Jennifer Schoelles Williams, Thea Moore, Candace L. Collins, Kerry-Ann E. Thomas, Selective Serotonin Reuptake Inhibitors for the Treatment of Obsessive-Compulsive Disorders in Children and Adolescents, 2003, J. Pediatr. Pharmacol. Ther., 8, 77-86].

Tourette's syndrome (Tourette's syndrome or Tourette's Disorder) is a neurological disease that repeatedly shows involuntary movements and sounds. It is a blinking eye, a coughing sound, ) And a voice tick (tic) appear for more than one year. The motion tick and the voice tick may appear at the same time or separately.

Ticks are very common in school-aged children, with temporary tic symptoms in 10 to 20% of all children, transient tic disorders in which tic symptoms last longer than 1 month, 5-15% This persistent chronic tic disorder occurs in 1% of children. If you experience both exercise tics and vocal tics, it is called Tourette's syndrome and appears in about 4-5 out of 10,000 people. Ticks are unregulated, have repetitive features and appear in a wide variety of forms, which may be exacerbated by emotional changes such as anxiety, excitement, anger, fatigue,

The causes of Tourette's syndrome include genetic factors, environmental factors such as stress and infection, structural and functional abnormalities of the brain, biochemical abnormalities of the brain, hormones, brain damage during the birth process, Are associated with the development of ticks, but the exact cause has not been elucidated. It is also often accompanied by behavioral and emotional disturbances, such as attention deficit hyperactivity disorder (ADHD), obsessive compulsive disorder, learning disabilities, sleep disorders, depression and anxiety [James E. Swain, Lawrence Scahill, Paul J. Lombroso, Robert A. King, James F. Leckman, Tourette syndrome and Tic disorder: A decade of progress, Journal of the American Academy of Child and Adolescent Psychiatry, 2007, 46, 947-968].

In the case of such a psychotic disorder, a satisfactory level of therapeutic effect is not obtained through the use of a drug, or its use is restricted due to side effects, and development of a new drug having improved pharmacological efficacy and side effects is required.

The present invention is intended to provide a method for preventing, alleviating or treating a psychotic disorder selected from the group consisting of asthma, obsessive compulsive disorder and Tourette's syndrome.

The present invention also relates to the use of a carbamate compound of formula 1, or a pharmaceutically acceptable salt, solvate or hydrate thereof, in the prevention, alleviation or treatment of psychotic disorders selected from the group consisting of asthma, obsessive compulsive disorder and Tourette's syndrome It is intended to provide use for:

[Chemical Formula 1]

In Formula 1, R ₁ , R ₂ , A ₁ and A ₂ are as defined herein.

The present invention provides a method for the prevention of a psychotic disorder selected from the group consisting of asthma, obsessive compulsive disorder and Tourette's syndrome, comprising a therapeutically effective amount of a carbamate compound of formula 1, or a pharmaceutically acceptable salt, solvate or hydrate thereof: , ≪ / RTI > a medicament for alleviating or treating:

[Chemical Formula 1]

In Formula 1,

R ₁ and R ₂ are each independently selected from the group consisting of hydrogen, halogen, C ₁ -C ₈ alkyl, C ₁ -C ₈ haloalkyl, C ₁ -C ₈ thioalkoxy and C ₁ -C ₈ alkoxy,

One of A ₁ and A ₂ is CH and the other is N.

The present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of a carbamate compound of Formula 1, or a pharmaceutically acceptable salt, solvate or hydrate thereof, and further comprising one or more pharmaceutically acceptable carriers, A medicament for preventing, alleviating or treating a psychotic disorder selected from the group consisting of a disease, obsessive compulsive disorder and Tourette's syndrome.

The present invention also relates to the use of a carbamate compound of formula 1, or a pharmaceutically acceptable salt, solvate or hydrate thereof, in a therapeutically effective amount, A method for preventing, alleviating or treating a psychotic disorder selected from the group.

The present invention also relates to the use of a carbamate compound of formula 1, or a pharmaceutically acceptable salt, solvate or hydrate thereof, in a therapeutically effective amount, Lt; RTI ID = 0.0 > psychiatric < / RTI > disorder selected from the group.

The present invention also relates to the use of a carbamate compound of formula 1, or a pharmaceutically acceptable salt, solvate or hydrate thereof for the prevention, alleviation or treatment of a psychotic disorder selected from the group consisting of asthma, obsessive compulsive disorder and Tourette's syndrome Or to improve the indications associated therewith.

According to one embodiment of the present invention, R ₁ and R ₂ in the general formula (1) are each independently selected from the group consisting of hydrogen, halogen and C ₁ -C ₈ alkyl.

In one embodiment, the C ₁ -C ₈ haloalkyl is perfluoroalkyl.

According to another embodiment of the present invention, the carbamate compound of Formula 1 is carbamic acid (R) -1- (2-chlorophenyl) -2-tetrazol-2-yl) ethyl ester of Formula 2:

(2)

The carbamate compounds of Formulas (1) and (2) above can be prepared by using known compounds or compounds which can be easily prepared therefrom, as long as those skilled in the art are familiar with the synthesis of the compounds. In particular, the process for preparing the compound of formula 1 is described in detail in WO 2006/112685 A1, WO 2010/150946 A1 and WO 2011/046380 A2, which are incorporated herein by reference. The compound of the formula (1) can be synthesized chemically by the method described in the above document, but it is merely a suggestion of one exemplary method, and the order of the unit operation and the like can be selectively changed as necessary, Is not intended to limit.

The carbamate compound of Formula 1 may be used for the prevention, alleviation or treatment of psychotic disorders selected from the group consisting of asthma, obsessive compulsive disorder and Tourette's syndrome.

According to one embodiment of the present invention, the symptom of the asthmatic disease may be at least one selected from the group consisting of positive symptoms, negative symptoms, cognitive symptoms and residual symptoms of asthma.

According to one embodiment of the present invention, the outbreak disease is selected from the group consisting of paranoid schizophrenia, disorganized schizophrenia, catatonic schizophrenia, undifferentiated schizophrenia, Schizophrenia, schizophreniform disorder, schizophreniform disorder, delusional disorder, short-term schizophrenia, shared psychosis disorder, generalized schizophrenia, schizophrenia, schizophrenia, schizophrenia, schizophrenia, schizophrenia, schizophrenia A psychotic disorder caused by a medical condition, a psychotic disorder caused by a substance, and an unexplained psychotic disorder.

According to one embodiment of the invention, the obsessive-compulsive disorder can be an obsessive behavior, an obsessive mind, or both.

According to one embodiment of the present invention, the obsessive-compulsive disorder is an obsessive thoughts to repetitive infiltrative thinking, conscious behavior, repetitive behavior, attachment, pollution / storage / storage / collection / Physical or obsessive thoughts on accidents, illnesses, aggression-related obsessive thoughts that may be harmful to oneself or opponents, obsessive thoughts related to sex, and repeated verbal or physical repetitions to neutralize obsessive thoughts And anxiety psychology caused by the obsessive behavior and the anxiety psychology resulting therefrom.

According to one embodiment of the present invention, the Tourette's syndrome may be a movement tic disorder, a vocal tic disorder or both.

According to one embodiment of the present invention, the Tourette's syndrome includes eye blinking, pupil rolling, facial and nasal obstruction, shoulder disturbance, sudden bowing of the head, abrupt force on the abdominal muscles, leg kick, coughing, sniffing The distance may be one or more selected from the group consisting of sounds, animal cries and false speech (bath, obscene).

Using a DOI-induced head-and-spasm animal model known as an animal model used in the development of drugs for the treatment of obsessive-compulsive disorder and Tourette syndrome, Obsessive-Compulsive Disorder, and Tourette's syndrome. [Effect of co-treatment with mirtazapine and risperidone in animal models of the positive symptoms of schizophrenia in mice, Pharmacological Reports, 2012, 64, 1567 -1572; Shlomit Flaisher-Grinberg, Oded Klavir, Daphna Joel, The role of 5-HT2A and 5-HT2C receptors in the signal attenuation rat model of obsessive-compulsive disorder, 2008, International Journal of Neuropsychopharmacology, 11, 811-825; Renee L. Hayslett, Yousef Tizabi, Effects of donepezil on DOI-induced head twitch response in mice: implications for Tourette syndrome, Pharmacology, Biochemistry and Behavior, 2003, 76, 409-415]. DOI (1- (2,5-dimethoxy-4-iodophenyl) -2-aminopropane hydrochloride) is an efficacious agent for 5-HT2A / 2C serotonin receptors and has a high affinity and selectivity for hallucinogen )to be. Since the effects of halushinogen administration are similar to those caused by asthma, it can be used as a model of asthma by administering hallucinogenic drugs to animals. In DOI-induced head-twitch or head-shaking animal models, dosing with DOI induces head spasm, whereas atypical antipsychotics such as risperidone, haloperidol, clozapine, and olanzapine, Inhibition of tof spasm behavior is proportional to dose of DOI.

DOI-induced HTR is used as an effective model of OCD and Tourette's syndrome because DOI-induced HTRs exhibit this similar behavior, one of the symptoms of OCD and Tourette's syndrome being ticks. In particular, Tourette's syndrome is a very complex syndrome, accompanied by abnormal levels of chemicals (neurotransmitters) that transmit nerve impulses, including dopamine and serotonin. Olanzapine, a 5-HT2A serotonin receptor antagonist capable of controlling serotonin and dopamine , Quetiapine, risperidone, and aripiprazole have demonstrated clinical efficacy in patients with Tourette's syndrome [Michael Behen, Harry T. Chugani, Csaba Juhasz, Emily Helder, Albert Ho, Mohsin Maqbool, Robert D. Rothermel, Jacquie Perry, Otto Music, Abnormal Brain Tryptophan Metabolism and Clinical Correlates in Tourette Syndrome, Movement Disorders, 2007, 22, 2256-2262; Myung Ho Lim, Soo Churl Cho, Psychotrophic Drug Therapy of the Tourette's Disorder, Clinical Psychopharmacology and Neuroscience, 2013, 24, 147-159]

The dosage of the carbamate compound of formula (I) for the prevention, amelioration or treatment of the disease will usually vary depending on the severity of the disease, the body weight of the subject being treated and the metabolic status. A "therapeutically effective amount" for an individual patient means an amount sufficient to achieve the pharmacological effect, i. The therapeutically effective amount of the compound of the formula (1) is 50 to 500 mg, preferably 50 to 400 mg, more preferably 50 to 300 mg, and more preferably 50 to 200 mg on a daily basis upon administration to a human.

The compounds of the present invention may be administered by any conventional method used for administration of therapeutic agents, such as oral, parenteral, intravenous, intramuscular, subcutaneous or rectal administration.

A pharmaceutical or pharmaceutical composition according to one embodiment of the present invention comprises a therapeutically effective amount of a compound selected from the group consisting of a carbamate compound of the invention, a pharmaceutically acceptable salt, solvate, hydrate thereof and combinations thereof can do.

The pharmaceutically acceptable salts of the carbamate compounds of Formula 1 include, for example, acetate, benzenesulfonate, benzoate, bitartrate, calcium acetate, camsylate, carbonate, citrate, ede But are not limited to, tartrate, eddylate, esterylate, esterylate, esterylate, ethylate, fumarate, glucosate, gluconate, glutamate, glycoloylarsanylate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, But are not limited to, sodium carbonate, sodium carbonate, sodium carbonate, sodium carbonate, sodium carbonate, sodium carbonate, sodium carbonate, sodium carbonate, sodium carbonate, sodium carbonate, Pateoate (embonate), pantothenate, phosphate / diphosphate, polygalactous europaea It. Salicylates, stearates, subacetates, succinates or hemi-succinates, sulphates or hemi-sulphates, tannates, tartrates, oxalates or hemi-tartrates, theoclates, triethiodides , Benzenetine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine, procaine, aluminum, ammonium, tetramethylammonium, calcium, lithium, magnesium, potassium, sodium and zinc.

The pharmaceutical or pharmaceutical composition according to one embodiment of the present invention may be administered orally or parenterally. In the case of parenteral administration, intravenous injection, subcutaneous injection, muscle injection, intraperitoneal injection, endothelial administration, topical administration, intranasal administration , Intravaginal administration, intrapulmonary administration, rectal administration, and the like. Upon oral administration, the pharmaceutical composition according to one embodiment may be formulated to be nasal, or to be coated against, or protected from degradation from, the active agent. In addition, the composition may be administered by any device capable of transferring the active agent to the target cell. The route of administration may vary depending upon the general conditions and age of the subject to be treated, the nature of the treatment conditions, and the active ingredient selected

The appropriate dosage of the pharmaceutical or pharmaceutical composition according to one embodiment of the present invention may be appropriately determined depending on the formulation method, administration method, age, body weight, sex, pathological condition, food, administration time, administration route, Factors, and the ordinarily skilled physician can readily determine and prescribe dosages effective for the desired treatment or prophylaxis. The pharmaceutical composition according to one embodiment may be administered in one or more doses, for example, one to four times per day. The pharmaceutical composition according to one embodiment may contain 50 to 500 mg, preferably 50 to 400 mg, more preferably 50 to 300 mg, more preferably 50 to 200 mg of the compound of formula (1).

The pharmaceutical composition or the pharmaceutical composition according to one embodiment of the present invention may be prepared by using a pharmaceutically acceptable carrier and / or excipient according to a method which can be easily carried out by a person skilled in the art Or may be prepared in unit dosage form by injection or by intrusion into a multi-dose container. Here, the formulations may be in the form of solutions, suspensions or emulsions in oils or aqueous media, or in the form of excipients, powders, granules, tablets or capsules, and may additionally contain dispersing or stabilizing agents. In addition, the pharmaceutical composition may be administered in the form of suppositories, sprays, ointments, creams, gels, inhalants or skin patches. The pharmaceutical composition may also be prepared for mammalian administration, more preferably for human administration.

Pharmaceutically acceptable carriers may be solid or liquid and may be in the form of pharmaceutical preparations such as excipients, antioxidants, buffers, bacteriostats, dispersants, adsorbents, surfactants, binders, preservatives, disintegrants, sweeteners, flavors, lubricants, release modifiers, Stabilizers, suspending agents, and lubricants. In addition, pharmaceutically acceptable carriers may be selected from saline, sterile water, Ringer's solution, buffered saline, dextrose solution, maltodextrin solution, glycerol, ethanol and mixtures thereof.

In one embodiment, suitable fillers include sugars (such as dextrose, sucrose, maltose and lactose), starches (such as corn starch), sugar alcohols (e.g., mannitol, sorbitol, maltitol, erythritol, Starch hydrolyzates (e.g., dextrin and maltodextrin), celluloses or cellulose derivatives (such as microcrystalline cellulose), or mixtures thereof, but are not limited thereto.

In one embodiment, suitable binders include povidone, copovidone, methylcellulose, hydroxymethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, gelatin, gum, sucrose, starch or Mixtures of these may be used, but are not limited thereto.

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, But is not limited thereto.

In one embodiment, suitable disintegrants include starch glycolate, cross-linked polyvinylpyrrolidone, cross-linked carboxymethylcellulose, starch, microcrystalline cellulose, or mixtures thereof But is not limited thereto.

In one embodiment, suitable sweeteners may be sucralose, saccharin, sodium or potassium or calcium saccharin, acesulfame potassium or sodium cyclamate, mannitol, fructose, sucrose, maltose or mixtures thereof It is not limited.

In one embodiment, a suitable glidant may be, but is not limited to, colloidal silicon dioxide.

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.

As used herein, the terms "preventing "," preventing ", and "prevention" are intended to reduce the likelihood of or susceptibility to disease.

The terms " alleviate, "" alleviating," and "alleviation ", as used herein, refer to alleviating all or part of the disease and /

The terms "treat", "treating" and "treatment" as used herein refer to the elimination of all or part of the disease and / or its attendant symptoms.

The term "subject" as used herein refers to an animal, preferably a mammal (e.g., primates (e.g., a person), cow, sheep, goat, horse, dog , A cat, a rabbit, a mouse, a mouse, etc.), and most preferably a human.

The term "therapeutically effective amount ", as used herein, is intended to be sought by a researcher, veterinarian, physician or other clinician, and refers to any biological or medicinal agent in the system, animal or human, including alleviating the symptoms of the disease or disorder Quot; means the amount of active compound or pharmaceutical agent that elicits the response.

The term "composition" as used herein encompasses any product that results, directly or indirectly, from a product comprising a specified amount of a particular ingredient and a specified amount of a particular ingredient combination.

The medicines and pharmaceutical compositions according to the present invention can effectively treat psychotic disorders such as asthma, obsessive compulsive disorder, and Tourette's syndrome.

Hereinafter, the present invention will be described in more detail with reference to examples. However, these embodiments are intended to illustrate one or more embodiments only and are not intended to limit the scope of the invention.

Manufacturing example : Carbamic acid (R) -1- (2- Chlorophenyl )-2- Tetrazole -2-yl) ethyl ester

2-tetrazol-2-yl) ethyl ester (compound of formula (2), hereinafter also referred to as "test compound") was prepared according to the method described in WO 2010/150946 Prepared according to the method described in Production Example 50. [

Example  One: In DOI processing  Induced tofu Spasm  Effects on models

DOI  Induced tofu Spasm  Model

As a model for assessing the potential efficacy of psychotic disorder treatments, a head-shaking model according to DOI's rodent administration was used.

Male ICR mice (Crlj: CD1) were purchased from Bio Genomics, Inc. of Korea and cultured for 20 days at an ambient temperature of 20 to 24 ° C, 55 to 75% relative humidity and 12- (Purchased from Korea, Inc.) and placed in a wire mesh cage under an environment in which water can be freely taken, maintained and maintained in accordance with the Laboratory Animal Care Standards of the Institutional Animal Care and Use Committee (IACUC) . After approximately one week of stabilization, mice weighing 20-23 g were used in the experiment.

The test compound and a positive control drug, ketanserin (purchased from Sigma, St. Louis, Mo., USA) were mixed with 30% polyethylene glycol 400, a vehicle used as a vehicle 30-45 minutes before each experiment, Sigma Corp.). Test compounds were administered at a dose of 3, 10, 30 mg / kg and Ketanserin at a dose of 10 mg / kg body weight per mouse, respectively. After 30 minutes, (±) -2,5-Dimethoxy-4-iodoamphetamine (DOI) hydrochloride (purchased from Sigma) dissolved in saline and prepared at a dose of 3 mg / kg was subcutaneously injected into the back of mouse neck. The mice dosed with DOI were immediately placed in an observation cylinder (diameter 25 cm, width 20 cm, height 13 cm) made of clear polycarbonate, and the number of tofu spasticity behavior for 6 minutes after 1 minute was measured using a mechanical counter Respectively. All these experiments were performed between 10:00 am and 4:00 pm [Darmani NA, Martin BR, Pandey U and Glennon RA, Do functional relationships exist between 5-HT1A and 5-HT2 receptors, Pharmacol. Biochem. Behav., 1990, 36, 901-906].

Results of statistical analysis

All data are expressed as mean ± SEM. The number of DOI-induced head flushing behavior in the test compound and the group treated with the positive control, ketanserin, is expressed as percent inhibition compared to the negative control vehicle group. Statistical analysis of the number of head-to-head spasticity behaviors was performed using one-way analysis of variance (ANOVA) and Dunnett's multiple comparison test using the GraphPad Prism ver. 4.0 program. Respectively. The mean number of head injuries in the vehicle group, a negative control group, was 26.5 ± 1.2, and the frequency of DOI - induced head injury was 100% inhibited in the positive control group, ketanserin. In the test compound administration group, the half-effective dose (ED ₅₀ ) was inhibited by 25.8% at 3 mg / kg, 46.5% at 10 mg / kg and 67.9% at 30 mg / The value was calculated as 11.6 mg / kg. In other words, the test compound showed a significant effect in the DOI-induced head spasticity model, which is a representative animal model of amyotrophic lateral sclerosis, obsessive-compulsive disorder, and Tourette's syndrome.

Table 1 summarizes the experimental data (inhibition rate).

Claims (22)

The prevention, alleviation or prevention of a psychotic disorder selected from the group consisting of asthma, obsessive compulsive disorder and Tourette's syndrome, comprising a therapeutically effective amount of a carbamate compound of formula 1: EMI2.1 or a pharmaceutically acceptable salt, solvate or hydrate thereof. Therapeutic Agents:
[Chemical Formula 1]

In Formula 1,
R ₁ and R ₂ are each independently selected from the group consisting of hydrogen, halogen, C ₁ -C ₈ alkyl, C ₁ -C ₈ haloalkyl, C ₁ -C ₈ thioalkoxy and C ₁ -C ₈ alkoxy,
One of A ₁ and A ₂ is CH and the other is N. 2. The medicament according to claim 1, wherein R ₁ and R ₂ are each independently selected from the group consisting of hydrogen, halogen and C ₁ -C ₈ alkyl. The pharmaceutical composition according to claim 1, wherein the carbamate compound of formula (1) is carbamic acid (R) -1- (2-chlorophenyl) -2-tetrazol-
(2)

The medicament according to claim 1, wherein the symptom of asthma is at least one selected from the group consisting of positive symptoms, negative symptoms, cognitive symptoms and residual symptoms of asthma. The method of claim 1, wherein the disease is selected from the group consisting of paranoia-type schizophrenia, disorganized type schizophrenia, crack type schizophrenia, unspecified schizophrenia, latent schizophrenia, schizophrenia-related depression, current schizophrenia, A disorder selected from the group consisting of schizophrenia, schizophreniform disorder, schizophreniform affective disorder, delusional disorder, short term asthma, shared psychosis disorder, psychotic disorder due to general medical disorder, psychotic disorder due to substance and psychotic disorder of unknown origin Or more. 12. The medicament according to claim 1, wherein the obsessive-compulsive disorder is an obsessive-compulsive behavior, an obsessive-thinking or both. The method of claim 1, wherein the obsessive-compulsive disorder is selected from the group consisting of repetitive intrusive thoughts, conscious actions, repetitive behaviors, obsessions, obsessive thoughts of pollution / storage / storage / collection / or ordering, obsessive thoughts of being conscientious and moral, Physical obsessive thoughts, aggressive obsessive thoughts that may harm themselves or opponents, obsessive thoughts about sex, obsessive behavior as a repetitive verbal or physical repetitive act to neutralize obsessive thoughts, Wherein the medicament is one or more selected from the group consisting of anxiety psychoses caused thereby. 2. The medicament according to claim 1, wherein the Tourette's syndrome is a tic disorder, a vocal tic disorder or both. The method of claim 1, wherein the Tourette's syndrome is selected from the group consisting of eye blinking, pupil rolling, face and nose hairs, shoulder dentition, sudden bowing of the head, sudden force on the abdominal muscles, leg kick, coughing, Of crying and excessive speech (bathing, obscenity). 10. The medicament according to any one of claims 1 to 9, which is prepared for mammalian administration. 10. A medicament according to any one of claims 1 to 9, comprising 50 to 500 mg of a carbamate compound of formula (I). Or a pharmaceutically acceptable salt, solvate or hydrate thereof, which further comprises one or more pharmaceutically acceptable carriers, and a pharmaceutically acceptable salt, solvate or hydrate of the compound of formula (I), or a pharmaceutically acceptable salt, solvate or hydrate thereof, A pharmaceutical composition for preventing, alleviating or treating a psychotic disorder selected from the group consisting of Tourette's syndrome:
[Chemical Formula 1]

In Formula 1,
R ₁ and R ₂ are each independently selected from the group consisting of hydrogen, halogen, C ₁ -C ₈ alkyl, C ₁ -C ₈ haloalkyl, C ₁ -C ₈ thioalkoxy and C ₁ -C ₈ alkoxy,
One of A ₁ and A ₂ is CH and the other is N. 13. The pharmaceutical composition according to claim 12, wherein R ₁ and R ₂ are each independently selected from the group consisting of hydrogen, halogen and C ₁ -C ₈ alkyl. The pharmaceutical composition according to claim 12, wherein the carbamate compound of formula (1) is carbamic acid (R) -1- (2-chlorophenyl) -2-tetrazol-
(2)

13. The pharmaceutical composition according to claim 12, wherein the symptom of asthma is at least one selected from the group consisting of positive symptoms, negative symptoms, cognitive symptoms and residual symptoms of asthma. 13. The method of claim 12, wherein the disorder is selected from the group consisting of paranoia-type schizophrenia, disorganized type schizophrenia, crack type schizophrenia, unspecified schizophrenia, latent schizophrenia, schizophrenia-related depression, current schizophrenia, A disorder selected from the group consisting of schizophrenia, schizophreniform disorder, schizophreniform affective disorder, delusional disorder, short term asthma, shared psychosis disorder, psychotic disorder due to general medical disorder, psychotic disorder due to substance and psychotic disorder of unknown origin Lt; / RTI > 13. The pharmaceutical composition of claim 12, wherein the obsessive compulsive disorder is an obsessive behavior, an obsessive mind, or both. 13. The method of claim 12, wherein the obsessive-compulsive disorder is selected from the group consisting of repetitive intrusive thoughts, conscious behavior, repetitive behavior, obsession, obsessive thinking about pollution / storage / storage / collection / or ordering, obsessive thoughts that should be conscientious and moral, Physical obsessive thoughts, aggressive obsessive thoughts that may harm themselves or opponents, obsessive thoughts about sex, obsessive behavior as a repetitive verbal or physical repetitive act to neutralize obsessive thoughts, And anxiety psychology resulting therefrom. 13. The pharmaceutical composition according to claim 12, wherein the Tourette's syndrome is a tic disorder, a vocal tic disorder or both. 13. The method of claim 12, wherein the Tourette's syndrome is selected from the group consisting of eye blinking, pupil rolling, face / nose dullness, shoulder dentition, sudden bowing of the head, sudden force on the abdominal muscles, leg kick, coughing, And crying (bath, obscenity). ≪ Desc / Clms Page number 13 > 21. The pharmaceutical composition according to any one of claims 12 to 20, which is prepared for mammalian administration. 21. The pharmaceutical composition according to any one of claims 12 to 20, comprising 50 to 500 mg of a carbamate compound of formula (I).