Composition for preventing or treating neurodevelopmental disorders or neuropsychiatric disorders comprising carbapenem-based compound

Abstract

The present invention relates to a composition for preventing, alleviating, or treating autism spectrum disorders or related developmental disorders, the composition comprising Tebipenem pivoxil or a pharmaceutically acceptable salt thereof.

Description

Composition for the prevention or treatment of neurodevelopmental or neuropsychiatric disorders comprising carbapenem-based compounds

[0001] The present invention relates to a composition for the prevention, improvement, or treatment of neurodevelopmental disorders or neuropsychiatric disorders comprising a carbapenem-based compound.

[0002] Autism Spectrum Disorder (ASD) is caused by a complex interplay of genetic, environmental, and social factors and is characterized by deficits in social communication resulting from nonsocial behaviors associated with various symptoms, such as social deficits, repetitive behaviors, and aggression. It refers to a neurodevelopmental disorder characterized by primary symptoms including repetitive behaviors, restricted interest ranges, impairments in verbal and nonverbal communication, or reduced ability to understand social interactions. Previously named "autism," the diagnostic name was recently revised to Autism Spectrum Disorder to emphasize the significant variability in the severity and prognosis of autism. Autism Spectrum Disorder (ASD) encompasses pervasive developmental disorder (PDD), which includes autism, Asperger's syndrome, Rett's Disorder, childhood disintegrative disorder, and pervasive developmental disorder not otherwise classified (PDD NOS). Autism Spectrum Disorder is characterized by developmental delay or abnormal functioning in at least one of the following areas—qualitative deficits in social interaction, qualitative deficits in communication, hyperactivity, and restricted and repetitive behaviors—before the age of 3, and in addition to the main symptoms, it is accompanied by concomitant symptoms of intellectual disability, sleep disorders, gastrointestinal problems, epilepsy, or impulsive behavior.

[0003] Globally, the incidence of autism is showing a rapid increasing trend. In the case of Korea, the number of people with autism exceeded 28,000 in 2019, and in 2020, with 263 children per 10,000, it showed the second highest incidence rate in the world.

[0004] However, the physiological causes and mechanisms of the pathogenesis of autism are not yet known; consequently, diagnostic methods for autism spectrum disorder based on molecular biological or pathological indicators have not yet been established, and there are no treatments available for the underlying causes. Currently, only symptomatic drug treatments are administered for comorbid symptoms such as epilepsy, self-harm, aggressive behavior, anxiety, or emotional disorders, and there are no treatments available to address the core symptoms of social deficits and repetitive behaviors.

[0005] Currently, the only drugs used to treat autism are atypical antipsychotics such as risperidone and aripiprazole, and there are no FDA-approved standard drugs for core autism symptoms such as social interaction disorders, communication problems, and repetitive behaviors.

[0006] To date, the clear etiology of autism remains unknown, and it is believed to be caused by a complex interplay of various factors, including genetic, epigenetic, neuropathological, biochemical, immunological, and environmental factors. Due to these diverse causes and symptoms, the lack of appropriate new drug targets and biomarkers is considered a limitation in the development of autism treatments. Consequently, the verification of pharmacological effects largely relies on behavioral experiments using animal models of autism. Furthermore, due to the absence of suitable targets, drug repurposing strategies utilizing existing medications are predominantly employed.

[0007] While striving to develop a therapeutic agent capable of achieving a direct therapeutic effect on various symptoms of neurodevelopmental disorders or neuropsychiatric disorders, the inventors completed the present invention by confirming that the carbapenem-based compound of the present invention, specifically tebipenem pivoxil, has the effect of alleviating and treating symptoms of neurodevelopmental disorders or neuropsychiatric disorders.

[0008] Accordingly, the present invention provides a composition for the prevention or treatment of neurodevelopmental disorders or neuropsychiatric disorders comprising a carbapenem-based compound.

[0009] However, the technical problems that the present invention aims to solve are not limited to those mentioned above, and other unmentioned problems will be clearly understood by those skilled in the art from the description below.

[0010] Various embodiments of the present invention are described with reference to the drawings. In the following description, for a complete understanding of the present invention, various specific details, such as specific forms, compositions, and processes, are described. However, specific embodiments may be practiced without one or more of these specific details, or in combination with other known methods and forms. In other examples, known processes and manufacturing techniques are not described as specific details so as not to make the present invention unnecessary or obscure. Reference throughout this specification to one embodiment implies that the particular features, forms, compositions, or characteristics described in association with the embodiment are included in one or more embodiments of the present invention. Accordingly, the circumstances of the embodiments expressed at various locations throughout this specification do not necessarily represent the same embodiment of the present invention. Additionally, particular features, forms, compositions, or characteristics may be combined in any suitable way in one or more embodiments. Unless otherwise defined in the specification, all scientific and technical terms used in this specification have the same meaning as commonly understood by those skilled in the art to which the present invention pertains.

[0011] To achieve the above objective, the present invention provides a composition for the prevention, improvement, or treatment of neurodevelopmental disorders or neuropsychiatric disorders, comprising a carbapenem-based compound or a pharmaceutically acceptable salt thereof as an active ingredient. The carbapenem-based compound is not limited thereto but is one or more selected from the group consisting of imipenem, meropenem, ertapenem, doripenem, panipenem, viapenem, tebipenem, and tebipenem pivoxil.

[0012] The above composition may be a pharmaceutical composition or a food composition.

[0013] The above carbapenem series of compounds refers to a group of compounds that have a bicyclic structure containing a β-lactam ring as their basic framework and in which the C-1 position of the penem structure is substituted with a carbon. Such structural characteristics provide high stability against various β-lactamases and serve as the basis for exhibiting broad-spectrum antibacterial activity.

[0014] Carbapenem compounds exhibit excellent antibacterial effects against a wide range of pathogens, including Gram-positive, Gram-negative, and anaerobic bacteria, and due to these characteristics, carbapenems are considered a clinically important class of antibiotics.

[0015] In one embodiment, the carbapenem series compound may be represented by the following chemical formula 1:

[0016] [Chemical Formula 1]

[0017]

[0018] In the above chemical formula 1,

[0019] R1 and R2 are each independently straight-chain or branched C1-C5 alkyls.

[0020] More specifically, one embodiment of the present invention provides a composition for the prevention, improvement, or treatment of neurodevelopmental disorders or neuropsychiatric disorders, comprising tebipenem pivoxil or a pharmaceutically acceptable salt thereof as an active ingredient. The tebipenem pivoxil may be a compound represented by the following chemical formula 2:

[0021] [Chemical Formula 2]

[0022]

[0023] Neurodevelopmental disorders or neuropsychiatric disorders may be autism spectrum disorders.

[0024] The above autism spectrum disorder may involve one or more symptoms selected from repetitive behaviors, hyperactivity, or social deficits.

[0025] The above-mentioned developmental disorder related to autism spectrum disorder may involve one or more symptoms selected from the group consisting of repetitive behaviors, hyperactivity, learning impairment, social deficits, obsessions, impulsivity, and anxiety symptoms.

[0026] The above-mentioned developmental disorders related to autism spectrum disorder may include one or more selected from the group consisting of fragile X syndrome, attention deficit hyperactivity disorder (ADHD), intellectual disability, cognitive impairment, impulse control disorders, and anxiety disorder.

[0027] In one embodiment of the present invention, the first aspect provides a pharmaceutical composition for the prevention or treatment of neurodevelopmental disorders or neuropsychiatric disorders, comprising as an active ingredient a compound of Formula 1 below or a pharmaceutically acceptable salt thereof among carbapenem series compounds.

[0028] [Chemical Formula 1]

[0029]

[0030] In the above chemical formula 1, R1 and R2 are each independently straight-chain or branched C1-C5 alkyls.

[0031] In the first embodiment above, the second embodiment provides a pharmaceutical composition comprising one or more symptoms selected from the group consisting of repetitive behavior, hyperactivity, reduced learning ability, lack of social skills, compulsion, impulsivity, and anxiety symptoms of a neurodevelopmental disorder or neuropsychiatric disorder.

[0032] In the first or second embodiment above, the third embodiment provides a pharmaceutical composition for a neurodevelopmental disorder or neuropsychiatric disorder or autism spectrum disorder.

[0033] In any one of the first to third embodiments above, the fourth embodiment provides a pharmaceutical composition in which R1 represents (CH2)n as a straight-chain residue, where n is an integer from 1 to 3, and R2 represents C-(CH2)m as a branched residue, where m is an integer from 1 to 3.

[0034] In any one of the first to fourth embodiments above, the fifth embodiment provides a pharmaceutical composition in which R1 is a methyl group (-CH3) and R2 is a tert-butyl group (tert-butyl, -C(CH3)3).

[0035] In any one of the first to fifth embodiments above, the sixth embodiment provides a pharmaceutical composition characterized in that the developmental disorder related to autism spectrum disorder comprises one or more selected from the group consisting of Fragile X Syndrome (FXS), attention deficit hyperactivity disorder (ADHD), intellectual disability, cognitive impairment, impulse control disorders, and anxiety disorder.

[0036] In one embodiment of the present invention, the seventh aspect provides a food composition for the prevention or improvement of neurodevelopmental disorders or neuropsychiatric disorders, comprising a compound of the following formula 1 or a food-grade acceptable salt thereof as an active ingredient.

[0037] [Chemical Formula 1]

[0038]

[0039] In the above Chemical Formula 1, R1 and R2 are each independently a straight-chain or branched C1-C5 alkyl.

[0040] In the seventh embodiment above, the eighth embodiment provides a food composition comprising one or more symptoms selected from the group consisting of repetitive behavior, hyperactivity, reduced learning ability, lack of social skills, compulsion, impulsivity, and anxiety symptoms of a neurodevelopmental disorder or neuropsychiatric disorder.

[0041] In the above seventh or eighth embodiment, the ninth embodiment provides a food composition for a neurodevelopmental disorder or neuropsychiatric disorder, or an autism spectrum disorder.

[0042] In any one of the above 7th to 9th embodiments, the 10th embodiment provides a food composition in which R1 represents (CH2)n as a straight-chain residue, where n is an integer from 1 to 3, and R2 represents C-(CH2)m as a branched residue, where m is an integer from 1 to 3.

[0043] In any one of the above 7th to 10th embodiments, the 11th embodiment provides a food composition in which R1 is a methyl group (-CH3) and R2 is a tert-butyl group (tert-butyl, -C(CH3)3).

[0044] In any one of the above 7th to 11th embodiments, the 12th embodiment provides a food composition characterized in that the autism spectrum disorder-related developmental disorder comprises one or more selected from the group consisting of Fragile X Syndrome (FXS), attention deficit hyperactivity disorder (ADHD), intellectual disability, cognitive impairment, impulse control disorders, and anxiety disorder.

[0045] In one embodiment of the present invention, the 13th aspect provides a method for preventing or treating a neurodevelopmental disorder or a neuropsychiatric disorder by administering a compound of Formula 1 or a pharmaceutically acceptable salt thereof to a subject having a neurodevelopmental disorder or a neuropsychiatric disorder.

[0046] [Chemical Formula 1]

[0047]

[0048] In the above chemical formula 1, R1 and R2 are each independently straight-chain or branched C1-C5 alkyls.

[0049] In the above 13th embodiment, the 14th embodiment provides a method for prevention or treatment of a neurodevelopmental disorder or neuropsychiatric disorder that involves one or more symptoms selected from the group consisting of repetitive behaviors, hyperactivity, reduced learning ability, lack of social skills, compulsions, impulsivity, and anxiety symptoms.

[0050] In the above 13th or 14th embodiment, the 15th embodiment provides a method for preventing or treating neurodevelopmental disorders or neuropsychiatric disorders, or autism spectrum disorder.

[0051] In any one of the above 13th to 15th embodiments, the 16th embodiment provides a method for prevention or treatment in which R1 represents (CH2)n as a linear residue, where n is an integer from 1 to 3, and R2 represents C-(CH2)m as a branched residue, where m is an integer from 1 to 3.

[0052] In any one of the above 13th to 16th embodiments, the 17th embodiment provides a method for prevention or treatment in which R1 is a methyl group (-CH3) and R2 is a tert-butyl group (tert-butyl, -C(CH3)3).

[0053] In any one of the above 13th to 17th embodiments, the 18th embodiment provides a method for prevention or treatment characterized in that the developmental disorder related to autism spectrum disorder comprises one or more selected from the group consisting of Fragile X Syndrome (FXS), attention deficit hyperactivity disorder (ADHD), intellectual disability, cognitive impairment, impulse control disorders, and anxiety disorder.

[0054] In one embodiment of the present invention, the 19th aspect provides a use for manufacturing a drug for the prevention or treatment of a neurodevelopmental disorder or neuropsychiatric disorder, comprising a compound of the following formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

[0055] [Chemical Formula 1]

[0056]

[0057] In the above chemical formula 1, R1 and R2 are each independently straight-chain or branched C1-C5 alkyls.

[0058] In the above 19th embodiment, the 20th embodiment provides a use in which a neurodevelopmental disorder or neuropsychiatric disorder involves one or more symptoms selected from the group consisting of repetitive behaviors, hyperactivity, reduced learning ability, lack of social skills, compulsions, impulsivity, and anxiety symptoms.

[0059] In any one of the above 19th to 20th embodiments, the 21st embodiment provides use for neurodevelopmental disorders or neuropsychiatric disorders and autism spectrum disorder.

[0060] In any one of the above 19th to 21st embodiments, the 22nd embodiment provides a use in which R1 represents (CH2)n as a straight-chain residue, where n is an integer from 1 to 3, and R2 represents C-(CH2)m as a branched residue, where m is an integer from 1 to 3.

[0061] In any one of the above 19th to 22nd embodiments, the 23rd embodiment provides a use in which R1 is a methyl group (-CH3) and R2 is a tert-butyl group (tert-butyl, -C(CH3)3).

[0062] In any one of the above 19th to 23rd embodiments, the 24th embodiment provides a use characterized in that the autism spectrum disorder-related developmental disorder comprises one or more selected from the group consisting of Fragile X Syndrome (FXS), attention deficit hyperactivity disorder (ADHD), intellectual disability, cognitive impairment, impulse control disorders, and anxiety disorder.

[0063] The carbapenem-based compound of the present invention, specifically tebipenem pivoxil or a pharmaceutically acceptable salt thereof, has the effect of alleviating, improving, and treating neurodevelopmental disorders or neuropsychiatric disorders, including symptoms of autism and developmental disorders, and can therefore be usefully used as a preventive or therapeutic agent for neurodevelopmental disorders or neuropsychiatric disorders.

[0064] Furthermore, the present invention can produce useful effects without administering various drugs by alleviating multiple symptoms at once with a single drug, thereby mitigating side effects associated with administering many drugs and reducing the economic burden. Moreover, the composition according to the present invention can be utilized in the treatment of various brain and mental developmental disorders, as well as autism spectrum disorder or related developmental disorders.

[0065] Figure 1 is a schematic diagram of the measurement of sociability during a 3-chamber assay for the analysis of social behavior (a) and the results of the measurement of sociability for an autistic animal model induced by maternal immune activation (MIA) (b) (S1: subject animal, O: object; **, P<0.01).

[0066] Figure 2 is a schematic diagram (a) of the measurement of social novelty during a 3-chamber assay for social behavior analysis and (b) the results of the measurement of social novelty for an autistic animal model induced by maternal immune activation (MIA) (S1: familiar animal, S2: new animal; *, P<0.05).

[0067] Figure 3 shows the results of confirming and quantifying the social recovery effect of tebipenem pivoxil (TP) in a Shank3 tg autism gene mouse model through a 3-chamber experiment (a) and a diagram showing the accumulated mouse mobility in the 3-chamber experiment (S1: subject animal, O: object; **: P<0.01, ****: P<0.0001).

[0068] Figure 4 is a diagram showing the results of confirming the effect of tebipenem pivoxil (TP) on improving repetitive behavior patterns through a grooming behavior observation experiment (**, P<0.01).

[0069] Figure 5 shows a movement map obtained by observing the movement patterns of experimental mice (Shank3 Tg and wild type) administered tebipenem pivoxil (TP).

[0070] The present invention will be described in more detail below.

[0071] As described above, neurodevelopmental disorders or neuropsychiatric disorders refer to a group of clinical disorders resulting from abnormalities in the developmental process or functional regulation of the central nervous system, and may include autism spectrum disorder.

[0072] Furthermore, the aforementioned Autism Spectrum Disorder (ASD) is characterized by deficits in social communication resulting from antisocial behaviors associated with various symptoms such as social deficits, repetitive behaviors, and aggression, and it is accompanied by co-occurring symptoms of developmental disorders such as autism and Attention Deficit Hyperactivity Disorder. Although ASD involves symptoms such as hyperactivity or social deficits, no drug has yet been reported that can effectively treat one or more symptoms of ASD and related developmental disorders simultaneously.

[0073] Since the carbapenem-based compound according to the present invention exhibits excellent therapeutic effects on neurodevelopmental disorders or neuropsychiatric disorders, the carbapenem-based compound of the present invention can be usefully used as an active ingredient for neurodevelopmental disorders or neuropsychiatric disorders.

[0074] The above carbapenem series compound can be represented by the following chemical formula 1.

[0075] [Chemical Formula 1]

[0076]

[0077] In the above chemical formula 1, R1 and R2 are each independently straight-chain or branched C1-C5 alkyls.

[0078] In addition, since tebipenem pivoxil (CAS Registry Number: 161715-21-5) or a pharmaceutically acceptable salt thereof according to one embodiment of the present invention exhibits excellent therapeutic effects for autism spectrum disorder or related developmental disorders, tebipenem pivoxil or a pharmaceutically acceptable salt thereof can be usefully used as an active ingredient in pharmaceutical compositions for the prevention and treatment of autism spectrum disorder and / or related developmental disorders.

[0079] Accordingly, the present invention provides a pharmaceutical composition for the prevention or treatment of autism spectrum disorder or related developmental disorders, comprising tebipenem pivoxil or a pharmaceutically acceptable salt thereof as an active ingredient. The tebipenem pivoxil may be represented by the following chemical formula 1.

[0080] [Chemical Formula 1]

[0081]

[0082] In the above chemical formula 1, R1 may be a methyl group (-CH3) and R2 may be a tert-butyl group (-C(CH3)3). Additionally, the above tebipenem pivoxil may be represented by the following chemical formula 2.

[0083] [Chemical Formula 2]

[0084]

[0085] In the present invention, "pharmaceuticalally acceptable salt," "food-acceptable salt," or "salt thereof" may be an acid addition salt formed by a free acid. The acid addition salt may be prepared by a conventional method, for example, by dissolving a compound in an excess amount of an aqueous acid solution and precipitating the salt using a water-miscible organic solvent, for example, methanol, ethanol, acetone, or acetonitrile. Alternatively, an equal molar amount of the compound and an acid or alcohol (e.g., glycol monomethyl ether) in water may be heated, and then the mixture may be dried by evaporation or the precipitated salt may be filtered by suction. The free acid may be an inorganic acid or an organic acid. Non-limiting examples of the inorganic acid may include hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, tartaric acid, etc., which may be used alone or in a mixture of two or more.

[0086] The salt of the tebipenem pivoxyl may include all salts of acidic or basic groups that may be present in the tebipenem pivoxyl compound, unless otherwise indicated. For example, the salt of the tebipenem pivoxyl may include sodium, calcium, and potassium salts of the hydroxyl group, and other cosmetically acceptable salts of the amino group may include hydrobromide, sulfuric acid, hydrogen sulfate, phosphate, hydrogen phosphate, dihydrogen phosphate, acetate, succinate, citrate, tartrate, lactate, mandelate, methanesulfonate (mesylate), and p-toluenesulfonate (tosylate) salts, and may be prepared through methods for preparing salts known in the art.

[0087] In the present invention, "prevention" refers to any act of suppressing or delaying the onset of the disease through the administration of a composition. In the present invention, "improvement" or "treatment" refers to any act of improving or beneficially altering the symptoms of the said disease through the administration of a composition.

[0088] In the present invention, “subject” refers to an individual subject to administration of a compound according to one embodiment of the present invention or a pharmaceutically acceptable salt thereof, and typically includes humans or animals having or at risk of having a neurodevelopmental disorder, a neuropsychiatric disorder, or an autism spectrum disorder. Additionally, “subject” refers to the entire biological individual to whom the pharmaceutical composition is administered for the prevention, improvement, or treatment of a disease, and is not limited to a specific age, gender, or clinical condition.

[0089] In the present invention, "neurodevelopmental disorder or neuropsychiatric disorder" refers to a group of disorders characterized by persistent functional decline or abnormal patterns in various domains, such as cognition, behavior, emotion, and social interaction, due to abnormalities in the developmental process or functional regulation of the brain and central nervous system. Generally, symptoms often begin in infancy or childhood, and these disorders may be associated not only with developmental disorders such as autism spectrum disorder, intellectual disability, ADHD, and learning disabilities, but also with problems in the regulation of mental functions, such as anxiety disorders and mood disorders. While it is known that these disorders result from the complex interplay of genetic factors, abnormal progression of neurodevelopment, and environmental factors, the specific etiology is often unclear. Furthermore, the aforementioned neurodevelopmental disorder or neuropsychiatric disorder may include autism spectrum disorder.

[0090] In the present invention, "autism spectrum disorder" may involve one or more symptoms selected from the group consisting of repetitive behaviors, hyperactivity symptoms, and social deficit symptoms, but is not limited thereto, and may include any symptom reported as a symptom of autism spectrum disorder.

[0091] In the present invention, "developmental disorder related to autism spectrum disorder" preferably includes one or more developmental disorders selected from the group consisting of Attention deficit hyperactivity disorder (ADHD), Intellectual disability, Cognitive impairment, Impulse control disorder, Fragile X syndrome, and Anxiety disorder, but is not limited thereto, and may include any of which have been reported as comorbid disorders or diseases of autism spectrum disorder.

[0092] The above autism spectrum disorders may include autistic disorder, Rett's disorder, Asperger's syndrome, and pervasive developmental disorder not otherwise specified (PDD-NOS).

[0093] In the present invention, the "developmental disorder related to autism spectrum disorder" may involve one or more symptoms selected from the group consisting of repetitive behaviors, hyperactivity, reduced learning ability, lack of social skills, obsessive-compulsiveness, impulsivity, and anxiety symptoms, but is not limited thereto, and may include any symptom reported as a symptom of "autism spectrum disorder."

[0094] In one embodiment of the present invention, the inventors confirmed that the pattern of social deficits and increased repetitive behaviors is improved by the administration of tebipenem pivoxil, which is one of the carbapenem-class compounds, and thus the compound of the present invention can be usefully used as a preventive or therapeutic agent for autism spectrum disorder or related developmental disorders (Figs. 1 to 4).

[0095] When the composition of the present invention is used as a pharmaceutical product, the pharmaceutical composition containing a carbapenem-class compound, tebipenem pivoxil, or a pharmaceutically acceptable salt thereof as an active ingredient may be formulated and administered in various oral or parenteral forms as described below for clinical administration, but is not limited thereto.

[0096] Formulations for oral administration include, for example, tablets, pills, hard / soft capsules, liquids, suspensions, emulsifiers, syrups, granules, elixirs, etc., and these formulations contain, in addition to the active ingredient, diluents (e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine) and lubricants (e.g., silica, talc, stearic acid and its magnesium or calcium salts and / or polyethylene glycol). Tablets may also contain binders such as magnesium aluminum silicate, starch paste, gelatin, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidine, and, in some cases, disintegrants or boiling mixtures such as starch, agar, alginic acid or its sodium salt and / or absorbents, coloring agents, flavoring agents, and sweeteners.

[0097] A pharmaceutical composition containing a carbapenem-based compound, tebipenem pivoxil, or a pharmaceutically acceptable salt thereof as an active ingredient according to the present invention may be administered parenterally, and parenteral administration may be carried out by subcutaneous injection, intravenous injection, intramuscular injection, or intrathoracic injection. In this case, to formulate a formulation for parenteral administration, a pharmaceutical composition containing tebipenem pivoxil or a pharmaceutically acceptable salt thereof as an active ingredient may be mixed with water together with a stabilizer or a buffer to prepare a solution or suspension, and may be prepared in an ampoule or vial unit dosage form. The composition may be sterile and / or contain adjuvants such as preservatives, stabilizers, hydrating agents or emulsification promoters, salts and / or buffers for osmotic pressure regulation, and other therapeutically useful substances, and may be formulated according to conventional mixing, granulation, or coating methods.

[0098] In addition, in the pharmaceutical composition of the present invention, the dosage of the active ingredient, a carbapenem-based compound, tebipenem pivoxil, or a salt thereof, to the human body may vary depending on the patient's age, body weight, gender, form of administration, health condition, and degree of disease. Based on an adult patient weighing 60 kg, the dosage is generally 0.001 to 1,000 mg / day, preferably 0.01 to 500 mg / day, and may be divided into one or several doses per day at regular intervals according to the judgment of a doctor or pharmacist.

[0099] The pharmaceutical composition of the present invention may contain the active ingredient in an amount of 0.1 to 90 weight% based on the total weight of the composition. However, the content is not necessarily limited thereto and may vary depending on the patient's condition and the type and degree of progression of the disease.

[0100] In another aspect, one embodiment of the present invention provides a food composition or a health functional food composition for preventing or improving symptoms of autism spectrum disorder or related disorders, comprising a carbapenem-based compound, tebipenem pivoxil, or a salt thereof as an active ingredient.

[0101] In the present invention, the term "health functional food" refers to a food manufactured and processed in the form of tablets, capsules, powders, granules, liquids, pills, etc., using raw materials or ingredients that possess functional properties useful to the human body. Here, "functionality" means obtaining effects useful for health purposes, such as regulating nutrients or physiological actions regarding the structure and function of the human body. The health functional food of the present invention can be manufactured by methods commonly used in the industry, and during such manufacturing, raw materials and ingredients commonly added in the industry may be added. Furthermore, the formulation of the health functional food may be manufactured without restriction as long as it is a formulation recognized as a health functional food. Unlike general pharmaceuticals, the health functional food composition of the present invention uses food as a raw material, which has the advantage of not causing side effects that may occur with long-term consumption, and is highly portable, making it suitable for consumption as an adjuvant to enhance the effect of alleviating symptoms of autism spectrum disorder or related developmental disorders.

[0102] In a health functional food for the prevention or improvement of autism spectrum disorder or related developmental disorders according to the present invention, when the tebipenem pivoxil is used as an additive to the health functional food, it may be added as is or used together with other foods or food ingredients, and may be used appropriately according to conventional methods. The amount of the active ingredient can be appropriately determined according to each purpose of use, such as prevention, health, or treatment.

[0103] The formulation of health functional foods can be in the form of powders, granules, pills, tablets, or capsules, as well as in the form of general foods or beverages.

[0104] There are no specific restrictions on the types of food mentioned above, and examples of food to which the substance may be added include meat, sausage, bread, chocolate, candy, snacks, confectionery, pizza, ramen, other noodles, chewing gum, dairy products including ice cream, various soups, beverages, tea, drinks, alcoholic beverages, and vitamin complexes, and may include all food in the conventional sense.

[0105] The amount of the active ingredient can be appropriately determined according to its purpose of use (for prevention or improvement). Generally, the amount of the above compound (active ingredient) in the health food can be added in an amount of 0.1 to 90 weight percent relative to the total weight of the food. However, in the case of long-term consumption for the purpose of health and hygiene or for health control, the above amount may be less than the above range, and since there is no problem in terms of safety, the active ingredient may also be used in an amount greater than the above range.

[0106] Among the functional foods according to the present invention, the beverage may contain various flavoring agents or natural carbohydrates as additional ingredients, as in conventional beverages. The natural carbohydrates mentioned above may be monosaccharides such as glucose and fructose, disaccharides such as maltose and sucrose, polysaccharides such as dextrin and cyclodextrin, and sugar alcohols such as xylitol, sorbitol, and erythritol. As sweeteners, natural sweeteners such as taumatin and stevia extract, or synthetic sweeteners such as saccharin and aspartame may be used. The proportion of the natural carbohydrates may be about 0.01 to 0.04 g, preferably about 0.02 to 0.03 g, per 100 mL of the beverage according to the present invention.

[0107] In addition to the above, the health functional food according to the present invention for the prevention or improvement of neurodevelopmental disorders, neuropsychiatric disorders, autism spectrum disorders, or related developmental disorders may contain various nutritional supplements, vitamins, electrolytes, flavoring agents, coloring agents, pectic acid and its salts, alginic acid and its salts, organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohol, and carbonating agents used in carbonated beverages. Furthermore, the composition of the health functional food for the prevention or improvement of autism spectrum disorders or related developmental disorders according to the present invention may contain fruit pulp for the production of natural fruit juices, fruit juice beverages, and vegetable beverages. These ingredients may be used independently or in combination. The proportion of these additives is not limited, but is generally selected in the range of 0.01 to 0.1 parts by weight per 100 parts by weight of the functional food of the present invention.

[0108]

[0109] The present invention will be described in more detail below through examples. These examples are intended solely to illustrate the present invention, and it will be obvious to those skilled in the art that the scope of the present invention is not to be interpreted as being limited by these examples.

[0110] <Example>

[0111]

[0112] Example 1. Analysis of social behavior using an autism mouse model induced by Maternal Immune Activation (MIA).

[0113] 1-1. Induction Process of the Autism Mouse Model

[0114] Poly(I:C), which induces an immune response, was injected at 10 mg / kg intraperitoneally into gestation day 17 B6 / J mice received from Daehan Biolink (DBL). The offspring were raised with their mothers until 4 weeks after birth, and then separated according to sex.

[0115] 1-2. Behavioral Experiment Procedure

[0116] When the male offspring reached week 7, a three-chamber assay was conducted as a preliminary experiment to test sociality and novelty. The experimental environment was set to a temperature of 24–26°C, a brightness of 35–50 LUX, and a humidity of 60% or less. Among the three chambers of the frame to be used for the experiment, the subjects were placed in the middle chamber for 5–10 minutes to acclimatize; afterward, the mice were removed and placed in a different cage, and the frame was cleaned with 70% ethanol. Subsequently, familiar subjects who had previously interacted with the subjects were placed in the cages of each side chamber, while subjects who were encountering them for the first time were placed in the cages of the opposite side. The mice in the cages were of the same age, sex, and species as the subjects. The subjects were carefully moved to the middle chamber, and their behavior was recorded for 20 minutes. Afterward, the Noldus program was used to calculate the interaction time between the subjects and the mice in the cages, measured between minutes 1 and 11 of the total recording time. The experiment was conducted to be completed between 10:00 AM and 4:00 PM, which is the active time for mice.

[0117] One week after the preliminary experiment, at week 8, mice were orally administered 30 mg / kg of the drug (Tebipenem pivoxil) (composition: 2% DMSO in distilled water) daily for 3 days. Three hours after the last injection, a novelty test was conducted in the same manner as the preliminary experiment.

[0118] 1-3. Experimental Results

[0119] The results of analyzing social interactions by injecting a drug (Tebipenem Pivoxil) into an autism mouse model induced by maternal immune activation (MIA) are shown in Figures 1 and 2 (3-chamber assay).

[0120] Figure 1a is a schematic diagram of the measurement of sociability for evaluating the interaction between the subject animal and the object, and Figure 1b shows the results of the measurement of sociability according to drug administration in a normal mouse model and an MIA model.

[0121] It was confirmed that while the control group (normal mouse model) showed a high tendency to prefer the subject animal (S1), the MIA-induced autistic animal model showed a lower tendency to prefer the subject animal compared to the control group. Subsequently, after administering the drug to the MIA-induced autistic animal model for 3 days, the same behavioral experiment was conducted, and the preference for the subject animal (S1) increased, confirming a behavioral pattern in which the deficient social skills were restored.

[0122] Figure 2a is a schematic diagram of the measurement of social novelty for evaluating the interaction between familiar and new animals, and figure 2b shows the results of measuring social novelty according to drug administration in a normal mouse model and an MIA model.

[0123] In the control group (normal mouse model), the tendency to prefer novel animals (S2) in the social cognitive ability measurement experiment was high, whereas in the MIA-induced autistic animal model, the tendency to prefer novel animals (S2) was lower compared to the control group. Subsequently, after administering the drug to the MIA-induced autistic animal model for 3 days, the same behavioral experiment was conducted, and a behavioral pattern was observed in which the preference for novel animals (S2) increased, and the deficient social cognitive ability was restored.

[0124]

[0125] Example 2. Confirmation of the effect of Tebipenem pivoxil on alleviating autism symptoms using Shank3 Tg mice, an animal model of autism

[0126] To confirm the effects of tebipenem pivoxil on social recovery and inhibition of repetitive behavior, tebipenem pivoxil and DMSO were administered to mice.

[0127] 5-week-old male B6-derived Shank3 Tg mice (autistic animal model mice) and wt mice (normal mice) were obtained from the rearing room within the animal laboratory of the Korea Institute of Science and Technology (KIST) and underwent a 2-day acclimatization period. Sociality experiments were conducted at the end of 5 weeks of age, while grooming and movement observation experiments were performed at the beginning of 6 weeks of age. Starting 6 days prior to the experiment, DMSO or tebipenem pivoxil (25 mg / kg) was administered orally (po) once a day, and on the day of the experiment, it was administered orally two hours prior. (Composition of the administration solution: 2% DMSO, 30% PEG / total within 300 ul). Experimental animals that had completed drug administration the day before the sociality experiment were transferred to individual cages. Subsequently, three experiments were conducted as follows.

[0128] Example 2-1: 3-Chamber Test (TCA)

[0129] The 3-chamber test is a representative behavioral experiment generally used to measure sociality and social intelligence. Since rats typically prefer interacting with other animals rather than being isolated, this method allows for the experimental verification of whether laboratory animals have issues with social skills. This experiment is conducted by placing a rat in one of three interconnected rooms and placing unfamiliar rats with whom the rat had no prior interaction and new objects in the other two rooms. The sociality index is determined by quantifying which direction the rat moves to and shows greater interest in interacting with. The prepared rats were placed in the center of an empty test box and allowed to acclimate to the space for 10 minutes. Afterward, the rats were confined in the center with the entrance blocked by a transparent door. The left and right spaces were randomly designated as 'S' (where the new rat is placed) and 'O' (where the new object is placed), respectively; the rats and objects were placed in cages in these areas, and time was given for spatial adaptation. After a 5-minute adaptation period, the transparent door was opened, and the rats' behavior was observed for 10 minutes. The results of the experiment were evaluated by measuring the time spent in the S, O, and remaining spaces; the animal's interaction with other animals was considered sociality, and this behavior was assessed accordingly.

[0130] As a result of the experiment, compared to wt mice, which spent nearly 400 seconds in zone S where a strange mouse was located, Shank3 tg mice spent nearly half as much time there, while it was observed that they spent more time in other areas and in the areas where objects were placed. However, when the drug (tevipenem pivoxil) was administered to Shank3 tg mice, it was observed that sociality was restored through increased interaction with new mice and an increase in the time spent in those areas (Fig. 3).

[0131] Example 2-2: Observation of grooming behavior (Self-Grooming test)

[0132] Grooming behavior observation is an experiment that measures the repetitiveness of animal behavior by videotaping the animal's movements over a set period. Normal rats exhibit behaviors such as sniffing, exploring various areas, and wandering around due to their high curiosity about new environments. However, rats with autistic symptoms show repetitive behaviors and consequent reduced movement, and since they repeatedly engage in grooming behaviors, repetitive behavior can be assessed by observing an increase in grooming behavior. This experiment was conducted by placing experimental rats in a box with four opaque sides and a 1 cm layer of bedding, then observing them for 20 minutes. The rats were allowed to adapt to the space for 5 minutes, and their behavior was observed and quantified for the following 15 minutes. Grooming behavior in the experimental rats was evaluated by determining that they groomed their fur by stroking or licking their face, head, or body with their two front paws. The results of this experiment were measured as the average value based on observations by three observers, and the results for each experimental group were plotted as a single result on a graph, as shown in Figure 4. As shown in Figure 4, Shank3 tg mice showed a significantly increased repetitive behavior time compared to Wt mice, but the repetitive behavior pattern was observed to improve with the administration of the drug (tevipenem pivoxil), reducing it by more than half (Figure 4).

[0133] Example 2-3: Observation of Movement and Mobility

[0134] Using video from the grooming experiment, the animals' movements and distances traveled were measured and quantified through an analysis program. Movement was observed and analyzed by adjusting the movement limits of the 'Mobility State' measurement parameter within the Noldus EthoVision XT program. Mobility was observed and quantified by measuring the distance the experimental rats traveled within a designated area using 'Distance moved,' another measurement parameter within the same program.

[0135] As a result of analyzing movement maps obtained by observing the movement patterns of the experimental mice through a program, the wt experimental group showed a lot of movement, with lines drawn that filled most of the space, whereas the Shank3 tg experimental mice showed less movement, with many empty spaces where lines were not drawn and were observed staying only in specific areas. However, upon administration of the drug (tevipenem pivoxil), the movement lines increased, and the large areas marked while staying in one place also appeared dispersed into smaller areas. Through these results, it was observed that repetitive behaviors and movement patterns improved (Fig. 5).

[0136]

[0137] Hereinafter, examples of the preparation of a pharmaceutical or food containing the above-mentioned tebipenem pivoxil as an active ingredient according to the present invention are described; however, the present invention is not intended to be limited but merely to be described in detail. Using the above-mentioned active ingredient, the pharmaceutical or food composition of Preparation Example 1 or 2 was prepared according to a conventional method according to the following compositional ingredients and compositional ratios.

[0138]

[0139] [Preparation Example 1] Preparation of a pharmaceutical composition

[0140] <1-1> Preparation of Powders

[0141] Tevipenem pivoxil 20 mg

[0142] Lactose monohydrate 100 mg

[0143] Talc 10 mg

[0144] The above ingredients were mixed and filled into an airtight bag to produce a powder.

[0145] <1-2> Preparation of Tablets

[0146] Tevipenem pivoxil 10 mg

[0147] 100 mg corn starch

[0148] Lactose monohydrate 100 mg

[0149] Magnesium stearate 2 mg

[0150] After mixing the above ingredients, tablets were manufactured by compressing them according to the conventional method of manufacturing tablets.

[0151] <1-3> Manufacture of Capsules

[0152] Tevipenem pivoxil 10 mg

[0153] Microcrystalline cellulose 3 mg

[0154] Lactose monohydrate 14.8 mg

[0155] Magnesium stearate 0.2 mg

[0156] After mixing the above ingredients, a capsule was manufactured by filling it into a gelatin capsule according to a conventional method for manufacturing capsules.

[0157] <1-4> Preparation of Injectables

[0158] Tevipenem pivoxil 10 mg

[0159] Mannitol 180 mg

[0160] 2974 mg sterile distilled water for injection

[0161] Sodium monohydrogen phosphate 26 mg

[0162] After mixing the above ingredients, the above ingredients were prepared in an amount of 2 mL per ampoule according to the conventional method of preparing injectables.

[0163] <1-5> Preparation of Liquid Formulations

[0164] Tevipenem pivoxil 10 mg

[0165] 10 mg isomerized sugar

[0166] Mannitol 5 mg

[0167] Appropriate amount of purified water

[0168] Appropriate amount of lemon flavor

[0169] The above ingredients are dissolved in purified water according to a conventional manufacturing method, an appropriate amount of lemon scent is added, then purified water is added to adjust the total volume to 100 mL, sterilized, and filled into a brown bottle to prepare a liquid preparation.

[0170]

[0171] [Preparation Example 2] Preparation of a health functional food

[0172] <2-1> Manufacturing of Health Supplements

[0173] Tevipenem pivoxil 10 mg

[0174] Appropriate amount of vitamin mixture

[0175] Vitamin A acetate 70 µg

[0176] Vitamin E 1.0 mg

[0177] Vitamin B1 0.13 mg

[0178] Vitamin B2 0.15 mg

[0179] Vitamin B6 0.5 mg

[0180] Vitamin B 12 0.2 µg

[0181] Vitamin C 10 mg

[0182] Biotin 10 µg

[0183] Nicotinamide 1.7 mg

[0184] Folic acid 50 µg

[0185] Calcium pantothenate 0.5 mg

[0186] Appropriate amount of mineral mixture

[0187] Ferrous sulfate 1.75 mg

[0188] Zinc oxide 0.82 mg

[0189] Magnesium carbonate 25.3 mg

[0190] Potassium dihydrogen phosphate 15 mg

[0191] 55 mg dicalcium phosphate

[0192] Potassium citrate 30 mg

[0193] Calcium carbonate 100 mg

[0194] Magnesium chloride 24.8 mg

[0195] The composition ratio of the above vitamin and mineral mixture is composed of ingredients that are relatively suitable for health food as a preferred example, but the mixing ratio may be modified at will. The above ingredients may be mixed according to a conventional method for manufacturing health food, then granules may be prepared and used to manufacture a health food composition according to a conventional method.

[0196] <2-2> Preparation of Health Drinks

[0197] Tevipenem pivoxil 10 mg

[0198] 15 g of Vitamin C

[0199] Vitamin E (powder) 100 g

[0200] Iron lactate 19.75 g

[0201] 3.5 g zinc oxide

[0202] Nicotinamide 3.5 g

[0203] Vitamin A 0.2 g

[0204] Vitamin B1 0.25 g

[0205] Vitamin B2 0.3 g

[0206] Quantification of purified water

[0207] The above ingredients are mixed according to a conventional method for manufacturing health drinks, then stirred and heated at 85°C for about 1 hour, the resulting solution is filtered, obtained in a sterilized 2-liter container, sealed and sterilized, and then refrigerated and used to manufacture the health drink composition of the present invention.

[0208] Although the above composition ratio was formulated by mixing ingredients relatively suitable for beverages as a preferred embodiment, the mixing ratio may be arbitrarily modified according to regional and ethnic preferences, such as consumer groups, countries of demand, and intended uses.

[0209] The foregoing description of the present invention is for illustrative purposes only, and those skilled in the art will understand that other specific forms can be easily modified without altering the technical spirit or essential features of the present invention. Therefore, the embodiments described above should be understood as illustrative in all respects and not restrictive.

[0210] Foregoing, specific parts of the present invention have been described in detail. It is evident to those skilled in the art that such specific descriptions are merely preferred embodiments and do not limit the scope of the invention. Accordingly, the actual scope of the invention is defined by the appended claims and their equivalents.

Claims

1. A pharmaceutical composition for the prevention or treatment of neurodevelopmental disorders or neuropsychiatric disorders, comprising as an active ingredient a compound of the following chemical formula 1 or a pharmaceutically acceptable salt thereof among carbapenem series compounds. [Chemical Formula 1] In the above formula, R1 and R2 are each independently straight-chain or branched C1-C5 alkyls.

2. In Paragraph 1, A pharmaceutical composition comprising one or more symptoms selected from the group consisting of repetitive behaviors, hyperactivity, learning impairment, lack of social skills, compulsions, impulsivity, and anxiety symptoms, which are neurodevelopmental disorders or neuropsychiatric disorders.

3. In Paragraph 2, A pharmaceutical composition for neurodevelopmental disorders or neuropsychiatric disorders and autism spectrum disorder.

4. In Paragraph 2, R1 represents (CH2)n as a linear residue, where n is an integer from 1 to 3, and A pharmaceutical composition in which R2 represents C-(CH2)m as a branched residue, where m is an integer from 1 to 3.

5. In Paragraph 4, A pharmaceutical composition in which R1 is a methyl group (-CH3) and R2 is a tert-butyl group (tert-butyl, -C(CH3)3).

6. In Paragraph 3, A pharmaceutical composition characterized by comprising one or more selected from the group consisting of Fragile X Syndrome (FXS), attention deficit hyperactivity disorder (ADHD), intellectual disability, cognitive impairment, impulse control disorders, and anxiety disorder.

7. A food composition for the prevention or improvement of neurodevelopmental disorders or neuropsychiatric disorders, comprising a compound of the following chemical formula 1 or a food-grade acceptable salt thereof as an active ingredient. [Chemical Formula 1] In the above formula, R1 and R2 are each independently straight-chain or branched C1-C5 alkyls.

8. In Paragraph 7, A food composition comprising one or more symptoms selected from the group consisting of repetitive behaviors, hyperactivity, learning impairment, lack of social skills, compulsions, impulsivity, and anxiety symptoms, which are neurodevelopmental disorders or neuropsychiatric disorders.

9. In Paragraph 8, Neurodevelopmental disorder or neuropsychiatric disorder is a food composition for autism spectrum disorder.

10. In Paragraph 8, R1 represents (CH2)n as a linear residue, where n is an integer from 1 to 3, and R2 represents C-(CH2)m as a branched residue, where m is an integer from 1 to 3, in a food composition.

11. In Paragraph 10, A food composition in which R1 is a methyl group (-CH3) and R2 is a tert-butyl group (tert-butyl, -C(CH3)3).

12. In Paragraph 9, A food composition characterized by comprising one or more selected from the group consisting of Fragile X Syndrome (FXS), attention deficit hyperactivity disorder (ADHD), intellectual disability, cognitive impairment, impulse control disorders, and anxiety disorder.

13. A method for the prevention or treatment of a neurodevelopmental disorder or neuropsychiatric disorder by administering a compound of Formula 1 below or a pharmaceutically acceptable salt thereof to a subject having a neurodevelopmental disorder or neuropsychiatric disorder. [Chemical Formula 1] In the above formula, R1 and R2 are each independently straight-chain or branched C1-C5 alkyls.

14. In Paragraph 13, A method of prevention or treatment for neurodevelopmental disorders or neuropsychiatric disorders involving one or more symptoms selected from the group consisting of repetitive behaviors, hyperactivity, learning impairment, lack of social skills, compulsions, impulsivity, and anxiety symptoms.

15. In Paragraph 14, Neurodevelopmental disorders or neuropsychiatric disorders are methods for the prevention or treatment of autism spectrum disorder.

16. In Paragraph 14, R1 represents (CH2)n as a linear residue, where n is an integer from 1 to 3, and R2 represents C-(CH2)m as a branched residue, where m is an integer from 1 to 3, a preventive or therapeutic method.

17. In Paragraph 16, A preventive or therapeutic method in which R1 is a methyl group (-CH3) and R2 is a tert-butyl group (tert-butyl, -C(CH3)3).

18. In Paragraph 15, A method for prevention or treatment characterized in that the above-mentioned developmental disorder related to autism spectrum disorder includes one or more selected from the group consisting of Fragile X Syndrome (FXS), attention deficit hyperactivity disorder (ADHD), intellectual disability, cognitive impairment, impulse control disorders, and anxiety disorder.

19. Use in the manufacture of a drug for the prevention or treatment of neurodevelopmental disorders or neuropsychiatric disorders, comprising a compound of Chemical Formula 1 below or a pharmaceutically acceptable salt thereof as an active ingredient. [Chemical Formula 1] In the above formula, R1 and R2 are each independently straight-chain or branched C1-C5 alkyls.

20. In Paragraph 19, Neurodevelopmental disorders or neuropsychiatric disorders are used for purposes involving one or more symptoms selected from the group consisting of repetitive behaviors, hyperactivity, learning impairment, lack of social skills, compulsions, impulsivity, and anxiety symptoms.

21. In Paragraph 20, Neurodevelopmental disorders or neuropsychiatric disorders are for use by individuals with autism spectrum disorder.

22. In Paragraph 20, R1 represents (CH2)n as a linear residue, where n is an integer from 1 to 3, and R2 represents C-(CH2)m as a branched residue, where m is an integer from 1 to 3.

23. In Paragraph 22, Uses where R1 is a methyl group (-CH3) and R2 is a tert-butyl group (-C(CH3)3).

24. In Paragraph 21, The above-mentioned autism spectrum disorder-related developmental disorder is characterized by comprising one or more selected from the group consisting of Fragile X Syndrome (FXS), attention deficit hyperactivity disorder (ADHD), intellectual disability, cognitive impairment, impulse control disorders, and anxiety disorder.

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