KR102531118B1 - A composition for preventing, alleviating or treating sepsis - Google Patents

Abstract

When administering a compound provided by the present invention, sepsis and various clinical symptoms accompanying sepsis can be prevented, alleviated, or treated just by oral administration. The present invention is a pharmaceutical composition for preventing or treating sepsis comprising a compound selected from a compound represented by chemical formula 3, a pharmaceutically acceptable salt thereof, optical isomers, hydrates, and solvates thereof as an active component.

Description

Composition for preventing, alleviating or treating sepsis {A composition for preventing, alleviating or treating sepsis}

The present invention relates to compositions for various uses that can prevent, ameliorate or treat sepsis.

Sepsis refers to a condition in which a severe inflammatory response occurs throughout the body due to infection with microorganisms. Currently, there are various types of pathogens reported to cause sepsis, but representative examples include streptococci, staphylococci, Escherichia coli, pneumococci, Pseudomonas aeruginosa, fungi, Klebsiella strain Pseudomonas aeruginosa, and the like.

The causative site of infection can be any organ of the body, and sepsis can be caused by pneumonia, pyelonephritis, meningitis, cellulitis, infective endocarditis, peritonitis, bedsores, cholecystitis, and cholangitis. When such an infection occurs, the causative microorganism invades the blood and may cause sepsis. However, even if microorganisms do not penetrate into the blood, systemic sepsis may occur due to inflammatory reactions in parts of the body and production of inflammatory substances.

Early symptoms of sepsis may include rapid breathing, loss of orientation (awareness of time, place, and person) or neurological disorders such as confusion. Due to the decrease in blood pressure and the decrease in the amount of blood supplied to the extremities of the body, the skin may appear blue. Bacteremia (a condition in which germs circulate in the blood) allows germs to travel through the bloodstream and settle in a specific area of the body, causing pathological changes in that area. Symptoms of the digestive system include nausea, vomiting, diarrhea, and intestinal paralysis, and in severe stress situations, bleeding symptoms of the digestive system may also appear.

Sepsis usually has a mortality risk of 20 to 35%, but it is a very fatal disease in which 40 to 60% die when septic shock develops rapidly. Therefore, after quickly finding the infected part of the body that causes sepsis through physical examination, blood test, and imaging test, the infection is treated using appropriate antibiotics.

However, sepsis is still a disease for which fundamental treatment has not been developed, and the global market for sepsis treatment is estimated to be worth 7.4 billion dollars (approximately 8.3 trillion won, as of 2017).
(Prior Patent Document 1) Republic of Korea Patent Publication No. 10-2021-0065684 (2021.06.04)
(Preceding paper 1) Am. J, Respir. Crit. Care Med., 196(6), 787-790 (2017. 09. 15)
(Preceding paper 2)CHEST Journal, poster presentation, 128(4), Suppl. 378S (2005.)

One object of the present invention is to provide a composition for preventing, improving or treating sepsis comprising the compound according to the present invention as an active ingredient.

However, the technical problem to be achieved by the present invention is not limited to the above-mentioned problems, and other problems not mentioned will be clearly understood by those skilled in the art from the following description.

Hereinafter, various embodiments described herein are described with reference to the drawings. In the following description, numerous specific details are set forth, such as specific forms, compositions and processes, etc., in order to provide a thorough understanding of the present invention. However, certain embodiments may be practiced without one or more of these specific details, or with other known methods and forms. In other instances, well known processes and manufacturing techniques have not been described in specific detail in order not to unnecessarily obscure the present invention. Reference throughout this specification to “one embodiment” or “an embodiment” means that a particular feature, form, composition or characteristic described in connection with the embodiment is included in one or more embodiments of the invention. Thus, the appearances of "in one embodiment" or "an embodiment" in various places throughout this specification do not necessarily refer to the same embodiment of the invention. Additionally, particular features, forms, compositions, or properties may be combined in one or more embodiments in any suitable way.

Unless there is a specific definition within the present invention, all scientific and technical terms used herein have the same meaning as commonly understood by a person skilled in the art to which the present invention belongs.

According to one embodiment of the present invention, for the prevention, improvement or treatment of sepsis comprising a compound represented by Formula 1 below, a compound selected from pharmaceutically acceptable salts, optical isomers, hydrates and solvates thereof as an active ingredient It relates to the composition:

[Formula 1]

In Formula 1,

At least one of R ₁ and R ₂ is -C(=O)R ₉ , and the others are H or a C ₁ to C ₆ alkyl group;

R ₃ to R ₆ are each independently H or a C ₁ to C ₆ alkyl group;

At least one of R ₇ and R ₈ is -C(=O)R ₁₀ , and the others are H or C ₁ -C ₆ alkyl groups;

R ₉ and R ₁₀ are each independently a C ₁ to C ₆ alkyl group.

In the present invention, the term 'C ₁ ~ C ₆ alkyl' refers to a straight-chain or branched hydrocarbon residue having 1 to 6 carbon atoms, unless otherwise specified. Examples thereof include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, t-butyl, n-pentyl, n-hexyl, and the like.

In one example of the present invention, the compound may be a compound represented by Formula 2 below, but is not limited thereto:

[Formula 2]

In Formula 2,

Each of R ₁ , R ₂ , R ₇ and R ₈ is defined as defined in Formula 1 above.

In one example of the present invention, the compound may be a compound represented by Formula 3 below, but is not limited thereto:

[Formula 3]

In the present invention, the pharmaceutically acceptable salt is a salt generally regarded by those skilled in the art as being suitable for medical applications (eg, because such a salt is not harmful to a subject that can be treated with the salt), or each salts that cause acceptable side effects within the treatment of Generally, the pharmaceutically acceptable salt is a salt that is considered acceptable by regulatory authorities such as the US Food and Drug Administration (FDA), the European Medicines Agency (EMA), or the Pharmaceuticals and Medical Devices Agency (PMDA) of the Japanese Ministry of Health, Labor and Welfare. . However, the present invention in principle relates to, for example, an intermediate in the preparation of a compound according to the invention or a physiologically functional derivative thereof, or a pharmaceutically acceptable salt of a compound according to the invention or a physiologically functional derivative thereof. As intermediates in the preparation of derivatives, salts of the compounds according to the invention which are not pharmaceutically acceptable per se are also included. The salts include water-insoluble salts and, in particular, water-soluble salts.

In each case, the person skilled in the art can determine whether a particular compound according to the present invention or a physiologically functional derivative thereof can form a salt, i.e., whether said compound according to the present invention or a physiologically functional derivative thereof For example, it can be easily determined whether or not it has a group capable of carrying an electric charge, such as an amino group, a carboxylic acid group, and the like.

Exemplary salts of the compounds of the present invention are acid addition salts or salts with bases, particularly pharmaceutically acceptable inorganic and organic acid addition salts and salts with bases commonly used in pharmaceutics, which are water insoluble or particularly water soluble acid addition salts. It is salt. Depending on the substituents of the compounds of this invention, salts with bases may also be suitable. Acid addition salts are formed, for example, by combining a solution of a compound of the present invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonic acid, or phosphoric acid. It can be formed by mixing. Likewise, pharmaceutically acceptable base addition salts include alkali metal salts (eg sodium or potassium salts); alkaline earth metal salts (eg, calcium or magnesium salts); and salts formed with suitable organic ligands (e.g., ammonium, quaternary ammonium and amines formed using counter anions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, alkyl sulfonates and aryl sulfonates). cations) may be included. Illustrative examples of pharmaceutically acceptable salts include acetates, adipates, alginates, arginates, ascorbates, aspartates, benzenesulfonates, benzoates, bicarbonates, bisulfates, bitartrates, borates, bromide, butyrate, calcium edetate, camphorate, camphorsulfonate, camsylate, carbonate, chloride, citrate, digluconate, dihydrochloride, dodecylsulfate, edetate, edisylate, ethanesulfonate, Formate, fumarate, galactate, galacturonate, gluconate, glutamate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hexylresorcinate, hydrobromide, hydrochloride, hydroiodide , 2-hydroxy-ethanesulfonate, hydroxynaphthoate, iodide, isobutyrate, isothionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, mandelate, methane Sulfonate (mesylate), methyl sulfate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pantothenate, pectinate, persulfate, 3-phenylpropionate, phosphate /diphosphate, phthalate, picrate, pivalate, polygalacturonate, propionate, salicylate, stearate, sulfate, suberate, succinate, tannate, tartrate, tosylate, undecanoate, valerate and the like, but are not limited thereto.

Salts which are not pharmaceutically acceptable in the present invention and which can be obtained, for example, as process products during the preparation of the compounds according to the present invention on an industrial scale, are also included in the present invention and, if desired, are known to the person skilled in the art. It can be converted into a pharmaceutically acceptable salt by the method.

Meanwhile, since the compounds according to the present invention may have an asymmetric carbon center, they may exist as R or S isomers or racemic compounds, and all optical isomers and mixtures thereof may be included in the scope of the present invention.

Specifically, in one example of the present invention, the compound may be an optical isomer compound represented by Formula 4 or 5 or a racemic mixture thereof, but is not limited thereto:

[Formula 4]

[Formula 5]

In addition, the compounds of the present invention, as well as their salts, when isolated, for example in crystalline form, may contain varying amounts of solvent. Thus, solvates, especially hydrates, of the compounds of the present invention as well as solvates, particularly hydrates, of salts of the compounds of the present invention may be included within the scope of the present invention. More particularly, the present invention may include hydrates of the compounds, salts and/or physiologically functional derivatives according to the present invention comprising 1, 2 or 1/2 water molecules relative to the stoichiometry. .

In the present invention, "sepsis" refers to a disease in which a severe inflammatory response occurs throughout the body, and may cause serious organ damage to an individual due to an abnormality in the immune system of the individual due to microbial infection. According to studies on the pathophysiology of sepsis, after infection by microorganisms, immune cells such as neutrophils, macrophages, and monocytes are activated in sepsis. Activation of these immune cells increases the secretion of cytokines such as IL-1, IL-6, IL-8, and TNF-α, and activates the transcription factor NF-κB present in cells, resulting in an inflammatory response throughout the body. It happens. In addition, septic shock is a condition in which sepsis symptoms worsen and circulatory, cellular, and metabolic abnormalities occur, resulting in higher mortality. If not treated in time, it can lead to shock or death.

Specifically, sepsis refers to cases in which the diagnosis criteria for systemic inflammatory response syndrome are satisfied in patients with suspected or proven infection. Systemic inflammatory response syndrome is characterized by body temperature >38°C or <36°C, heart rate >90 beats/min, respiratory rate >20 beats/min or PaCO ₂ <32 mmHg, and white blood cell count >12,000 cells/mm3 or <4,000 cells/min. It is defined as a case where two or more of mm3 or undifferentiated form >10% are satisfied. Severe sepsis is defined as sepsis accompanied by hypotension, organ failure, and decreased tissue perfusion. Septic shock refers to cases accompanied by hypotension (systolic blood pressure less than 90 mmHg or mean arterial pressure less than 65 mmHg) despite appropriate fluid therapy.

In the present invention, the sepsis may be caused by microbial infection as described above, and the causative microorganism may be bacteria, fungi, or viruses. In detail, when infection by microorganisms occurs in a living body, lipopolysaccharide (LPS), a component of the cell wall of bacteria, acts as a toxin and activates the body's immune system excessively, resulting in an inflammatory response and infection throughout the body. It can cause shock or, if the symptoms are severe, can be accompanied by shock. The sepsis causative bacteria may be Staphylococcus aureus, streptococcus, Escherichia coli, Pseudomonas aeruginosa, Mycobacterium tuberculosis, Klebsiella pneumoniae, fungi, anaerobic bacteria, and the like, and more specific examples include Acinetobacter baumannii, Escherichia coli (Escherichia coli), Klebsiella pneumoniae, Pseudomonas aeruginosa, Shigella sonnei, Staphylococcus aureus, Streptococcus pyogenes (Streptococcus pyogenes), Bacillus cereus, Clostridium perfringens, Enterococcus faecalis, Salmonella enteritidis and Campylobacter jejuni ), etc., but is not limited thereto. In addition, viruses include influenza virus, adenovirus, herpes simplex virus, measles virus, lentivirus, retrovirus, cytomegalovirus (Cytomegalovirus), baculovirus, Reovirus, Adeno-associated virus, Myxoma virus, Vesicular stomatitis virus, Poliovirus, It may be any one of Newcastle disease virus, Parvovirus, Coxsackie virus, Senecavirus, Vaccinia virus, or Poxvirus. At this time, the virus may be a wild type or a mutated form.

In the present invention, the term "prevention, improvement or treatment of sepsis" refers to clinical symptoms associated with sepsis and conditions associated with multi-organ dysfunction syndrome (eg, various degrees of fever, hypoxemia, death, tachycardia, endothelitis, myocardial infarction) reduction, amelioration or elimination of all or part of the symptoms of hyperconfusion, altered mental state, vascular collapse and organ damage, acute respiratory distress syndrome, coagulopathy, congestive heart failure, renal failure, shock and/or coma, etc.) do.

In the present invention, the compound can prevent, ameliorate, or treat both sepsis caused by invasion of a causative microorganism into the blood and systemic sepsis caused by an inflammatory reaction in a part of the body and the production of inflammatory substances even if the microorganism does not penetrate into the blood.

The above composition of the present invention can be used as a pharmaceutical composition or food composition.

As used herein, the term "prevention" may include without limitation any action capable of blocking, suppressing or delaying symptoms caused by sepsis by using the composition of the present invention.

In the present invention, the term "treatment" can include without limitation any action that can improve symptoms caused by sepsis by using the composition of the present invention, or can be beneficial.

In the present invention, the term "improvement" may include without limitation any action in which symptoms caused by sepsis are improved or advantageously changed by using the composition of the present invention.

The pharmaceutical compositions of the present invention are not limited thereto, but are formulated in the form of oral formulations such as powders, granules, capsules, tablets, aqueous suspensions, external preparations, suppositories and sterile injection solutions, respectively, according to conventional methods. can be used Preferably, the pharmaceutical composition is for intratracheal administration or inhalation administration; Alternatively, it may be formulated to be used as an injection, but is not limited thereto.

The pharmaceutical composition of the present invention may include a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier may be a binder, a lubricant, a disintegrant, an excipient, a solubilizer, a dispersant, a stabilizer, a suspending agent, a colorant, a flavoring agent, etc. for oral administration, and in the case of an injection, a buffer, a preservative, Pain relievers, solubilizers, isotonic agents, stabilizers, etc. may be mixed and used, and in the case of topical administration, bases, excipients, lubricants, preservatives, etc. may be used. Formulations of the pharmaceutical composition of the present invention may be variously prepared by mixing with the pharmaceutically acceptable carrier as described above. For example, for oral administration, it can be prepared in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, etc., and in the case of injections, it can be prepared in unit dosage ampoules or multiple dosage forms. there is. In addition, it may be formulated into solutions, suspensions, tablets, capsules, sustained-release preparations, and the like.

Examples of carriers, excipients and diluents suitable for the formulation of the present invention include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate , cellulose, methyl cellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, or mineral oil may be used. In addition, fillers, anti-agglomerating agents, lubricants, wetting agents, flavoring agents, emulsifiers, preservatives, and the like may be further included.

The route of administration of the pharmaceutical composition of the present invention is not limited to oral, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, intracardiac, transdermal, subcutaneous, intraperitoneal, intranasal, intestinal, topical , sublingual or rectal. It may be administered orally or parenterally, preferably orally, but is not limited thereto.

The parenteral methods of the present invention include subcutaneous, intradermal, intravenous, intramuscular, intraarticular, intracapsular, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques. The pharmaceutical composition of the present invention may also be administered in the form of a suppository for rectal administration.

The pharmaceutical composition of the present invention depends on various factors, including the activity of the specific compound used, age, body weight, general health, sex, diet, administration time, route of administration, excretion rate, drug combination and severity of the specific disease to be prevented or treated. The dosage of the pharmaceutical composition varies depending on the patient's condition, weight, disease severity, drug type, administration route and period, but can be appropriately selected by those skilled in the art, and is 0.0001 to 50 per day. It can be administered at mg/kg or 0.001 to 50 mg/kg. Administration may be administered once a day, or may be administered in several divided doses. The dosage is not intended to limit the scope of the present invention in any way. The pharmaceutical composition according to the present invention may be formulated into a pill, dragee, capsule, liquid, gel, syrup, slurry, or suspension.

When the food composition of the present invention is prepared in the form of a beverage, there is no particular limitation except that the food composition is included in the indicated ratio, and as in conventional beverages, various flavoring agents or natural carbohydrates may be included as additional ingredients. . Specifically, as natural carbohydrates, common sugars such as monosaccharides such as glucose, disaccharides such as fructose, polysaccharides such as sucrose, dextrin, and cyclodextrins, and sugar alcohols such as xylitol, sorbitol, and erythritol, etc. can include Examples of the flavoring agent may include natural flavoring agents (thaumatin, stevia extract (eg, rebaudioside A, glycyrrhizin, etc.) and synthetic flavoring agents (saccharin, aspartame, etc.).

The food composition of the present invention includes various nutrients, vitamins, minerals (electrolytes), flavors such as synthetic flavors and natural flavors, colorants, pectic acid and salts thereof, alginic acid and salts thereof, organic acids, protective colloidal thickeners, A pH adjusting agent, a stabilizer, a preservative, glycerin, alcohol, a carbonating agent used in carbonated beverages, and the like may be further included.

Components included in the food composition of the present invention may be used independently or in combination. The ratio of the additives does not correspond to the core elements of the present invention, but may be selected in the range of 0.1 to about 50 parts by weight per 100 parts by weight of the food composition of the present invention, but is not limited thereto.

When the composition according to the present invention is administered, sepsis caused by various causes can be prevented, improved, or treated, and more specifically, various clinical symptoms accompanying the sepsis, such as fever, hypotoxemia, Can reduce, ameliorate or treat symptoms such as death, tachycardia, endothelitis, myocardial infarction, hyperconfusion, altered mental state, vascular collapse and organ damage, acute respiratory distress syndrome, coagulopathy, heart failure, renal failure, shock or coma there is.

1 is a graph showing the results of confirming the change in survival rate after oral administration of the compound (α,δ-NAG) according to the present invention according to concentration to the LPS-induced mouse model in Experimental Example 1.
Figure 2 is a graph showing the results of measuring the change in blood TNF-α level after oral administration of the compound (α,δ-NAG) according to the present invention according to concentration to the LPS-induced mouse model in Experimental Example 2.
Figure 3 shows a photograph confirming the degree of pulmonary vascular permeability by staining the lung tissue obtained after administering the compound (α,δ-NAG) according to the present invention to the LPS-induced mouse model in Experimental Example 2 with Evan's blue.

Hereinafter, the present invention will be described in more detail through examples. These examples are only for explaining the present invention in more detail, and it will be apparent to those skilled in the art that the scope of the present invention is not limited by these examples according to the gist of the present invention. .

Example

[Preparation Example 1] Synthesis of 2,5-diacetamido-5-oxopentanoic acid (referred to as 'α,δ-NAG')

According to Scheme 1 below, α,δ-N-acetyl glucosamine, 2,5-diacetamido-5-oxopentanoic acid (2,5-diacetamido-5-oxopentanoic acid) A compound was synthesized and referred to herein as "α,δ-NAG".

[Scheme 1]

1. Synthesis of Benzyl 2-acetamido-5-amino-5-oxopentanoate (a)

2-acetamido-5-amino-5-oxopentanoic acid (26.6 mmol) and benzyl bromide in 100 ml of dimethylformamide (DMF) (1.5 eq) was added and stirred at room temperature. After adding 1,8-diazabicyclo[5,4,0]undec-7-ene (1,8-Diazabicyclo[5.4.0]undec-7-ene; DBU (1.2 eq)), after completion of dropwise addition It was stirred for 24 hours at room temperature. When the reaction was completed, the reaction was terminated using water, and an organic layer was extracted by further adding dichloromethane. After washing the organic layer with brine, water was removed with sodium sulfite, and the residue obtained by distillation of the solvent under reduced pressure was recrystallized using hexane and ethyl acetate to obtain benzyl 2-acetamido-5-amino-5-oxopentanoate. Phosphorus intermediate 1(1) was obtained.

¹ H NMR (400 MHz, MeOD) δ 7.43 - 7.27 (m, 5H), 5.19 (s, 2H), 4.46 (dd, J = 9.1, 5.1 Hz, 1H), 2.36 - 2.24 (m, 2H), 2.26 - 2.12 (m, 1H), 2.00 (s, 3H), 1.99 - 1.85 (m, 1H)

2. Synthesis of benzyl 2,5-diacetamido-5-oxopentanoat (b)

Intermediate 1 (23.0 mmol), acetaldehyde (3.0 eq) and hydrochloric acid (0.001 eq) were put in a microwave tube, and stirred for 30 minutes at 50 W and 120 °C. Then, after extracting the organic layer using ethyl acetate and water, the organic layer was washed with brine and water was removed using sodium sulfite. Thereafter, the remaining solvent was distilled under reduced pressure, and the finally obtained residue was separated and purified using MPLC to obtain intermediate 2(2), which is benzyl 2,5-diacetamido-5-oxopentanoet.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.63 (s, 1H), 8.30 (d, J = 7.5 Hz, 1H), 7.47 - 7.23 (m, 5H), 5.17 - 5.06 (m, 2H), 4.27 (ddd, J = 9.3, 7.5, 5.4 Hz, 1H), 2.70 - 2.38 (m, 2H), 2.12 (s, 3H), 2.07 - 1.91 (m, 1H), 1.85 (s, 3H), 1.83 - 1.73 (m, 1H)

3. Synthesis of 2,5-diacetamido-5-oxopentanoic acid (c) (DN204360)

After dissolving the intermediate 2 (4.06 mmol) in 5 ml of methanol, 0.2 g of Pd/C (palladium adsorbed on activated carbon) was additionally added, and the mixture was stirred under hydrogen for 24 hours. After the reaction is completed, the reaction solution is filtered through Celite and then subjected to cold distillation to obtain the target compound, (S)-2,5-diacetamido-5-oxopentanoic acid (DN204360) was obtained.

^1H NMR (400 MHz, DMSO- d ₆ ) δ 10.64 (s, 1H), 8.13 (d, J = 7.8 Hz, 1H), 4.15 (td, J = 8.9, 5.1 Hz, 1H), 2.56 - 2.46 ( m, 2H), 2.13 (s, 3H), 2.06 - 1.89 (m, 1H), 1.84 (s, 3H), 1.80 - 1.64 (m, 1H)

[Preparation Example 2] Preparation of sepsis experimental animals

8-week-old female C56BL/6 mice free of specific pathogens were purchased from Orient Bio Korea Inc. (Gapyeong, Gyeonggi-do, Republic of Korea), housed in an air flow type sterile laboratory, and fed standard solid feed as desired (ad libitum). Mice were 7-8 weeks old at the start of the examples. All experimental animals used in this example were managed according to protocols approved by the Institutional Animal Care and Use Committee of the Chonbuk National University Medical School. Then, sepsis was induced in the mice using lipopolysaccharide (LPS). More specifically, LPS (Escherichia coli serotype O55:B5,) purchased from Sigma Aldrich was intravenously injected into mice at a dose of 112.5 μg per mouse.

[Experimental Example 1] Evaluation of survival rate change in mice with LPS-induced sepsis

30 minutes before injecting LPS into mice in Preparation Example 2, 2,5-diacetamido-5-oxopentanoic acid (α, δ-NAG) synthesized in Preparation Example 1 was orally administered at various concentrations After 24 hours and 48 hours had elapsed, oral administration was administered three times each, and the survival rate of the mice was observed for 3 days, and the results are shown in FIG. 1.

As shown in FIG. 1, the positive control group injected with only LPS showed a mortality rate of 70% (3 survival/10 animals) 3 days after LPS injection, but 2,5-diacetamido-5-oxo according to the present invention In the groups administered with pentanoic acid (α,δ-NAG) at doses of 10, 25, and 50 μg, the mortality rate was 40% (6 survivors/10 animals), 20% (8 survivors/10 animals), and 0, respectively. It was confirmed that death by LPS was inhibited in a dose-dependent manner by % (10 survival/10), and the survival rate was greatly increased compared to the positive control group.

[Experimental Example 2] Evaluation of change in blood TNF-α level

2,5-diacetamido-5-oxopentanoic acid (α,δ-NAG) synthesized in Preparation Example 1 was orally administered at various concentrations 30 minutes before LPS injection into mice in Preparation Example 2. . After 90 minutes of LPS administration, mouse serum was obtained and changes in blood TNF-α levels were measured using an ELISA kit (R&D Systems, Minneapolis, Minn, USA), and the results are shown in FIG. 2 .

As shown in Figure 2, compared to the case of administering LPS alone to mice, 2,5-diacetamido-5-oxopentanoic acid (α, δ-NAG) according to the present invention was administered together In this case, it was confirmed that the level of TNF-α in serum significantly decreased in a concentration-dependent manner.

[Experimental Example 3] Evaluation of changes in pulmonary vascular permeability

In Preparation Example 2, 30 minutes before LPS injection into mice, 2,5-diacetamido-5-oxopentanoic acid (α, δ-NAG) synthesized in Preparation Example 1 was orally administered in an amount of 30 μg. administered. Then, after euthanasia of the mouse, lung tissue was obtained and stained with Evan's blue, and the degree of pulmonary vascular permeability was measured. A photograph of lung tissue taken after the staining is shown in FIG. 3 .

As shown in Figure 3, compared to the case of administering LPS alone to mice, the administration of 2,5-diacetamido-5-oxopentanoic acid (α, δ-NAG) according to the present invention together In this case, it was confirmed that the amount of Evan's blue inflow into the lung tissue was significantly reduced.

Considering the above results, 2,5-diacetamido-5-oxopentanoic acid (α,δ-NAG) according to the present invention is a cytokine storm caused by hyperinflammation during sepsis only by oral administration ( cytokine storm), hypotension and acute respiratory distress syndrome (ARDS) caused by increased vascular permeability, prevent, improve, and treat, and eventually increase survival rate. From this, it was found that 2,5-diacetamido-5-oxopentanoic acid (α,δ-NAG) according to the present invention can be usefully used as a preventive, ameliorative, or therapeutic agent for sepsis.

Having described specific parts of the present invention in detail above, it is clear that these specific descriptions are merely preferred embodiments for those skilled in the art, and the scope of the present invention is not limited thereto. Accordingly, the substantial scope of the present invention will be defined by the appended claims and equivalents thereof.

Claims (8)

A pharmaceutical composition for preventing or treating sepsis comprising a compound represented by Formula 3 below, a compound selected from pharmaceutically acceptable salts, optical isomers, hydrates and solvates thereof as an active ingredient:
[Formula 3]

delete delete According to claim 1,
The pharmaceutical composition is suitable for sepsis-induced fever, hypoxemia, death syndrome, tachycardia, endothelitis, myocardial infarction, hyperconfusion, altered mental state, vascular collapse and organ damage, acute respiratory distress syndrome, coagulopathy, heart failure, renal failure, A pharmaceutical composition for reducing, ameliorating or eliminating symptoms of shock or coma. A food composition for preventing or improving sepsis comprising as an active ingredient a compound selected from the group consisting of a compound represented by Formula 3, a pharmaceutically acceptable salt, an optical isomer, a hydrate and a solvate thereof:
[Formula 3]

delete delete According to claim 5,
The food composition is suitable for sepsis-induced fever, hypoxemia, death syndrome, tachycardia, endothelitis, myocardial infarction, hyperconfusion, altered mental state, vascular collapse and organ damage, acute respiratory distress syndrome, coagulopathy, heart failure, renal failure, shock or reducing or ameliorating symptoms of coma.

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