WO2018074880A2 - Composition pharmaceutique de prévention ou de traitement de la pneumonie, comprenant un dérivé de quinolin-4-one ou un sel pharmaceutiquement acceptable associé en tant que principe actif - Google Patents

Composition pharmaceutique de prévention ou de traitement de la pneumonie, comprenant un dérivé de quinolin-4-one ou un sel pharmaceutiquement acceptable associé en tant que principe actif Download PDF

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Publication number
WO2018074880A2
WO2018074880A2 PCT/KR2017/011637 KR2017011637W WO2018074880A2 WO 2018074880 A2 WO2018074880 A2 WO 2018074880A2 KR 2017011637 W KR2017011637 W KR 2017011637W WO 2018074880 A2 WO2018074880 A2 WO 2018074880A2
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Prior art keywords
acetyl
chloro
quinolin
nitroquinolin
branched
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PCT/KR2017/011637
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English (en)
Korean (ko)
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WO2018074880A3 (fr
Inventor
박철민
송종환
이선경
장수진
김형준
셤데이비드
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Korea Research Institute of Chemical Technology KRICT
Institut Pasteur Korea
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Korea Research Institute of Chemical Technology KRICT
Institut Pasteur Korea
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Priority claimed from KR1020170097569A external-priority patent/KR101915550B1/ko
Priority claimed from KR1020170097574A external-priority patent/KR101891315B1/ko
Application filed by Korea Research Institute of Chemical Technology KRICT, Institut Pasteur Korea filed Critical Korea Research Institute of Chemical Technology KRICT
Publication of WO2018074880A2 publication Critical patent/WO2018074880A2/fr
Publication of WO2018074880A3 publication Critical patent/WO2018074880A3/fr
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    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4706—4-Aminoquinolines; 8-Aminoquinolines, e.g. chloroquine, primaquine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin

Definitions

  • the present invention relates to a pharmaceutical composition for preventing or treating pneumonia, which comprises a quinoline 4-one derivative or a pharmaceutically acceptable salt thereof as an active ingredient.
  • Pneumonia is an inflammation of the lungs caused by infections caused by microorganisms such as bacteria, viruses, and fungi. Pulmonary symptoms such as cough, sputum caused by the release of inflammatory substances, dyspnea due to impaired breathing, and digestive symptoms such as nausea, vomiting and diarrhea, and headache, fatigue, muscle pain, and joint pain Global systemic disease may occur.
  • the cause of pneumonia is bacteria or viruses, and rarely can be caused by a fungus.
  • non-infectious pneumonia may be caused by chemicals or radiation therapy, but the main cause of infection is bacteria or viruses.
  • Pneumonia is very different depending on the situation where pneumonia occurs, so the method of classification may be different. Whether the bacterium that caused pneumonia is a bacterium, what kind of bacteria it is, whether the person infected with the pathogen is a young person or an old person or a healthy person, or whether it originally had a respiratory disease or an underlying disease in many organs, Pathogens can be seen in various shapes depending on where they are infected. In addition, in some cases, the symptoms and signs of pneumonia may be revealed without knowing the exact cause of the infection.
  • Common pathogens that cause pneumonia in general are pneumococci, Staphylococcus aureus, Gram-negative bacillus, and anaerobic bacteria.
  • common pathogens that cause in-hospital infection pneumonia are Pseudomonas, Staphylococcus aureus, Escherichia coli, Klebsiella, Gram-negative bacilli, and anaerobic bacteria.
  • Patent Document 1 a method for detecting pneumococci using a gene encoding cpsA having an amino acid of SEQ ID NO: 2 as a target of detection is used (Patent Document 1).
  • Treatment is based on the causative organism and antibiotics such as penicillin. However, in severe cases, even with proper antibiotics, the disease can continue to die.
  • Pneumococcal resistance to penicillin is mainly due to denaturation of penicillin-binding protein (PBP). Therefore, as the penicillin resistance rate of pneumococci increases, the resistance rate to other beta-lactam preparations, such as cephalosporin, is also likely to increase.
  • PBP penicillin-binding protein
  • Macrolides have been used as an alternative to penicillin in the treatment of pneumococci, including erythromycin, clarithromycin and azithro-mycin.
  • pneumococcal bacteria as well as atypical bacteria such as mycoplasma, chlamydia and legionella have high antimicrobial activity and have been used in many cases when infections caused by these bacteria are suspected.
  • Macrolide resistance to pneumococci is caused by the acquisition of resistance genes (ermB, mefA) or by degeneration of RNA or protein.
  • macrolide resistance caused by pneumococcal ermB gene acquisition mainly indicates high resistance (MIC ⁇ 32 ⁇ g / ml), and thus macrolide is ineffective for infection by these strains.
  • the inventors of the present invention while studying a substance having antimicrobial activity against pneumococcus resistant to a variety of drugs, specifically multidrug-resistant S. pneumoniae including erythromycin resistance, it was confirmed that the quinoline 4-one derivative exhibits antimicrobial activity against pneumococci , S. aureus and methicillin resistant S. aureus (MRSA), also confirmed that the antibacterial and completed the present invention.
  • MRSA methicillin resistant S. aureus
  • compositions for the prevention or treatment of pneumonia comprising a compound represented by the formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.
  • R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are as defined herein.
  • the present invention also provides a health functional food composition for preventing or improving pneumonia, which comprises a compound represented by the following Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
  • R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are as defined herein.
  • the present invention provides a method for preventing or treating pneumonia, comprising the step of administering a pharmaceutical composition or a nutraceutical composition containing the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient to a subject in need thereof. To provide.
  • the present invention also provides a use of a pharmaceutical composition or a nutraceutical composition containing a compound represented by the formula (1) or a pharmaceutically acceptable salt thereof in the prevention or treatment of pneumonia.
  • the quinoline 4-one derivative according to the present invention not only has excellent antimicrobial activity but also has excellent antimicrobial activity against pneumococcal bacteria having drug resistance, unlike antimicrobial agents such as erythromycin or methicillin, which are commonly used in the prior art. It can be usefully used as a pharmaceutical composition for preventing or treating pneumonia disease that occurs.
  • the present invention provides a pharmaceutical composition for preventing or treating pneumonia, comprising a compound represented by the following Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
  • n is an integer from 0-3;
  • R 1 is OH, C 1 -C 10 alkyl or C 3 -C 6 cyclo alkyl
  • R 2 , R 3 , R 4 , and R 5 are each independently hydrogen, halogen, —NO 2 , —COOH, —CN, —OH, straight or branched C 1 -C 6 alkoxy or unsubstituted or one or more; Halogen is substituted or straight or branched C 1 -C 6 alkyl;
  • R 6 is straight or branched C 1 -C 6 alkyl, or unsubstituted or substituted C 6 -C 10 aryl,
  • the substituted C 6 -C 10 aryl is a group consisting of linear, branched C 1 -C 6 alkyl substituted with halogen, unsubstituted or one or more halogen, linear or branched C 1 -C 6 alkoxy and NO 2 Substituted with one or more substituents selected from;
  • R 7 is hydrogen or straight or branched C 1 -C 6 alkyl.
  • n is an integer from 0-2;
  • R 1 is straight or branched C 1 -C 6 alkyl or C 3 -C 4 cyclo alkyl
  • R 2 , R 3 , R 4 , and R 5 are each independently hydrogen, halogen, NO 2 , straight or branched C 1 -C 3 alkoxy, or a straight or branched chain substituted with one or more halogens.
  • R 6 is straight or branched C 1 -C 4 alkyl, or unsubstituted or substituted C 6 -C 10 aryl,
  • the substituted C 6 -C 10 aryl is a group consisting of linear, branched C 1 -C 3 alkyl substituted by halogen, unsubstituted or one or more halogen, linear or branched C 1 -C 3 alkoxy and NO 2 Substituted with one or more substituents selected from;
  • R 7 is hydrogen or straight or branched C 1 -C 4 alkyl.
  • N is an integer of 0 or 1;
  • R 1 is straight or branched C 1 -C 4 alkyl or C 3 -C 4 cyclo alkyl
  • R 2 , R 3 , R 4 , and R 5 are each independently hydrogen, halogen, NO 2 or straight or branched C 1 -C 3 alkyl unsubstituted or substituted with one or more halogens;
  • R 6 is straight or branched C 1 -C 4 alkyl, or unsubstituted or substituted C 6 -C 10 aryl,
  • the substituted C 6 -C 10 aryl is a group consisting of linear, branched C 1 -C 3 alkyl substituted by halogen, unsubstituted or one or more halogen, linear or branched C 1 -C 3 alkoxy and NO 2 Substituted with one or more substituents selected from;
  • R 7 is hydrogen or straight or C 1 -C 3 alkyl.
  • n 0 or an integer of 1;
  • X is -NH-
  • R 1 is methyl, ethyl, isopropyl or cyclopropyl
  • R 2 , R 3 , R 4 , and R 5 are each independently hydrogen, fluoro, bromo, chloro, NO 2 , methyl or trifluoromethyl;
  • R 6 is methyl, tert-butyl, unsubstituted or substituted phenyl
  • the substituted phenyl may be substituted with one or more substituents selected from the group consisting of fluoro, bromo, chloro, methyl, tert-butyl or trifluoromethyl, methoxy and NO 2 .
  • Preferred examples of the quinoline 4-one derivative represented by Formula 1 according to the present invention include the following compounds.
  • Quinoline 4-one derivatives represented by Formula 1 according to the present invention can be used in the form of pharmaceutically acceptable salts.
  • acid addition salts formed with various pharmaceutically or physiologically acceptable organic or inorganic acids are useful.
  • Acid addition salts include inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid or phosphorous acid and aliphatic mono and dicarboxylates, phenyl-substituted alkanoates, hydroxy alkanoates and alkanes. Obtained from non-toxic organic acids such as dioates, aromatic acids, aliphatic and aromatic sulfonic acids.
  • Such pharmaceutically nontoxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate chloride, bromide, and iodide.
  • the acid addition salt according to the present invention is dissolved in a conventional method, for example, a derivative of Formula 1 in an excess of aqueous acid solution, and the salt is water-miscible organic solvent such as methanol, ethanol, acetone or aceto. It can be prepared by precipitation using nitrile. It may also be prepared by evaporating the solvent or excess acid from the mixture and then drying or by suction filtration of the precipitated salt.
  • a conventional method for example, a derivative of Formula 1 in an excess of aqueous acid solution
  • the salt is water-miscible organic solvent such as methanol, ethanol, acetone or aceto. It can be prepared by precipitation using nitrile. It may also be prepared by evaporating the solvent or excess acid from the mixture and then drying or by suction filtration of the precipitated salt.
  • Bases can also be used to make pharmaceutically acceptable metal salts.
  • Alkali metal or alkaline earth metal salts are obtained, for example, by dissolving the compound in an excess of alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and evaporating and drying the filtrate.
  • the metal salt it is pharmaceutically suitable to prepare lithium, sodium, potassium or calcium salt.
  • Corresponding silver salts are also obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (eg silver nitrate).
  • the pharmaceutical composition according to the present invention is penicillin, cephalosporin, aminoglycoside, benzoyl peroxide, povidone iodine, azelaic acid ), One or more auxiliary additives selected from the group consisting of retinoids, clindamycin, and erythromycin.
  • the quinoline 4-one derivative of the present invention may be administered in various oral and parenteral formulations during clinical administration, and when formulated, the commonly used fillers, extenders, binders, wetting agents, disintegrants, surfactants, etc. Prepared using diluents or excipients.
  • Formulations for oral administration include, for example, tablets, pills, hard / soft capsules, solutions, suspensions, emulsifiers, syrups, granules, elixirs, troches, and the like.
  • lubricants such as silica, talc, stearic acid and its magnesium or calcium salts and / or polyethylene glycols.
  • Tablets may also contain binders such as magnesium aluminum silicate, starch paste, gelatin, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidine, and optionally such as starch, agar, alginic acid or its sodium salt.
  • Disintegrant or boiling mixtures and / or absorbents, colorants, flavors, and sweeteners are examples of these compounds.
  • a pharmaceutical composition comprising the quinoline 4-one derivative of Formula 1 as an active ingredient may be administered parenterally, and parenteral administration may be by injection of subcutaneous injection, intravenous injection, intramuscular injection, or intrathoracic injection.
  • parenteral administration may be by injection of subcutaneous injection, intravenous injection, intramuscular injection, or intrathoracic injection.
  • the quinoline 4-one derivative of Formula 1 or a pharmaceutically acceptable salt thereof is mixed with water together with a stabilizer or a buffer to prepare a solution or suspension, which is an ampoule or vial unit. It may be prepared in a dosage form.
  • the composition may contain sterile and / or preservatives, stabilizers, emulsifiers or emulsifiers, auxiliaries such as salts and / or buffers for the control of osmotic pressure, and other therapeutically useful substances, and conventional methods of mixing, granulating It may be formulated according to the formulation or coating method.
  • the effective dosage of the compound of the present invention to the human body may vary depending on the age, weight, sex, dosage form, health condition and degree of disease of the patient, and is generally about 0.001-100 mg / kg / day, preferably Preferably 0.01-35 mg / kg / day. Based on an adult patient weighing 70 kg, it is typically 0.07-7000 mg / day, preferably 0.7-2500 mg / day, once or several times a day at regular intervals as determined by the doctor or pharmacist. Divided doses may also be administered.
  • the pharmaceutical composition of the quinoline 4-one derivative of the present invention provides a pharmaceutical composition for preventing or treating pneumonia, characterized in that it has an antimicrobial activity against drug-resistant pneumonia.
  • the drug provides a pharmaceutical composition for preventing or treating pneumonia, characterized in that the erythromycin or methicillin.
  • the drug may be penicillin, cephalosporin, aminoglycoside, benzoyl peroxide, povidone iodine, azeolaic acid, retinoid ), Clindamycin, and erythromycin may be a pharmaceutical composition for the prevention or treatment of pneumonia, characterized in that it comprises one or more drugs selected from the group consisting of, but is not limited thereto.
  • the pneumococcus provides a pharmaceutical composition for the prevention or treatment of pneumonia, characterized in that S. pneumoniae or S. aureu .
  • the pneumococcal bacteria may be Streptococcus pneumoniae (S.pneumoniae), Staphylococcus aureus (S.aureus), Klebsiella pneumoniae, Mycoplasma pneumoniae (Mycoplasma). pneumoniae), and Legionella pneumophila may be a pharmaceutical composition for the prevention or treatment of pneumonia, characterized in that it comprises one or more pneumococci selected from the group consisting of, but is not limited thereto.
  • the present invention also provides a health functional food composition for preventing or improving pneumonia, which comprises a compound represented by the following Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
  • n is an integer from 0-3;
  • R 1 is OH, C 1 -C 10 alkyl or C 3 -C 6 cyclo alkyl
  • R 2 , R 3 , R 4 , and R 5 are each independently hydrogen, halogen, —NO 2 , —COOH, —CN, —OH, straight or branched C 1 -C 6 alkoxy or unsubstituted or one or more; Halogen is substituted or straight or branched C 1 -C 6 alkyl;
  • R 6 is straight or branched C 1 -C 6 alkyl, or unsubstituted or substituted C 6 -C 10 aryl,
  • the substituted C 6 -C 10 aryl is a group consisting of linear, branched C 1 -C 6 alkyl substituted with halogen, unsubstituted or one or more halogen, linear or branched C 1 -C 6 alkoxy and NO 2 Substituted with one or more substituents selected from;
  • R 7 is hydrogen or straight or branched C 1 -C 6 alkyl.
  • n is an integer from 0-2;
  • R 1 is straight or branched C 1 -C 6 alkyl or C 3 -C 4 cyclo alkyl
  • R 2 , R 3 , R 4 , and R 5 are each independently hydrogen, halogen, NO 2 , straight or branched C 1 -C 3 alkoxy, or a straight or branched chain substituted with one or more halogens.
  • R 6 is straight or branched C 1 -C 4 alkyl, or unsubstituted or substituted C 6 -C 10 aryl,
  • the substituted C 6 -C 10 aryl is a group consisting of linear, branched C 1 -C 3 alkyl substituted by halogen, unsubstituted or one or more halogen, linear or branched C 1 -C 3 alkoxy and NO 2 Substituted with one or more substituents selected from;
  • R 7 is hydrogen or straight or branched C 1 -C 4 alkyl.
  • N is an integer of 0 or 1;
  • R 1 is straight or branched C 1 -C 4 alkyl or C 3 -C 4 cyclo alkyl
  • R 2 , R 3 , R 4 , and R 5 are each independently hydrogen, halogen, NO 2 or straight or branched C 1 -C 3 alkyl unsubstituted or substituted with one or more halogens;
  • R 6 is straight or branched C 1 -C 4 alkyl, or unsubstituted or substituted C 6 -C 10 aryl,
  • the substituted C 6 -C 10 aryl is a group consisting of linear, branched C 1 -C 3 alkyl substituted by halogen, unsubstituted or one or more halogen, linear or branched C 1 -C 3 alkoxy and NO 2 Substituted with one or more substituents selected from;
  • R 7 is hydrogen or straight or C 1 -C 3 alkyl.
  • n 0 or an integer of 1;
  • X is -NH-
  • R 1 is methyl, ethyl, isopropyl or cyclopropyl
  • R 2 , R 3 , R 4 , and R 5 are each independently hydrogen, fluoro, bromo, chloro, NO 2 , methyl or trifluoromethyl;
  • R 6 is methyl, tert-butyl, unsubstituted or substituted phenyl
  • the substituted phenyl may be substituted with one or more substituents selected from the group consisting of fluoro, bromo, chloro, methyl, tert-butyl or trifluoromethyl, methoxy and NO 2 .
  • Preferred examples of the active ingredient of the health functional food composition according to the present invention include the following compounds.
  • the quinoline 4-one derivative may be added to food supplements such as foods and beverages for the purpose of preventing or improving pneumonia disease.
  • Examples of foods to which the above-mentioned substances may be added include dairy products, various soups, drinks, meat, sausages, breads, biscuits, rice cakes, chocolate, candy, snacks, confectionery, pizza, ramen, other noodles, gums, ice cream, Beverages, alcoholic beverages and vitamin complexes, dairy products, dairy products and the like, and includes all the health functional foods in the conventional sense.
  • the quinonelin 4-one derivative of the present invention can be added to a food as it is or used with other foods or food ingredients, and can be suitably used according to conventional methods.
  • the mixing amount of the active ingredient can be suitably determined according to the purpose of use (prevention or improvement).
  • the amount of the compound in the health food can be added at 0.1 to 90 parts by weight of the total food weight.
  • the amount may be below the above range, and the active ingredient may be used in an amount above the above range because there is no problem in terms of safety.
  • the health functional beverage composition of the present invention is not particularly limited to other ingredients except for containing the compound as an essential ingredient in the indicated ratios, and may contain various flavors or natural carbohydrates as additional ingredients, such as ordinary drinks.
  • natural carbohydrates include monosaccharides such as glucose, fructose and the like; Disaccharides such as maltose, sucrose and the like; And conventional sugars such as polysaccharides such as dextrin, cyclodextrin, and sugar alcohols such as xylitol, sorbitol, and erythritol.
  • natural flavoring agents such as, tauumatin, stevia extract (e.g., Rebaudioside A, glycyrrhizin, etc.) and synthetic flavoring agents (saccharin, aspartame, etc.) can be advantageously used.
  • the proportion of natural carbohydrates is generally from about 1 g to 20 g, preferably from about 5 g to 12 g per 100 g of the composition of the present invention.
  • the quinoline 4-one derivative of the present invention includes various nutrients, vitamins, minerals (electrolytes), synthetic flavors and natural flavors such as flavoring agents, coloring and neutralizing agents (such as cheese, chocolate), pectic acid and salts thereof. , Alginic acid and salts thereof, organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohols, carbonation agents used in carbonated drinks and the like.
  • the quinoline 4-one derivative of the present invention may contain fruit flesh for the production of natural fruit juices and fruit juice beverages and vegetable beverages. These components can be used independently or in combination. The proportion of such additives is not so critical but it is generally chosen that the quinoline 4-one derivative of the present invention is in the range of 0.1 to about 20 parts by weight per 100 parts by weight.
  • the health functional food composition of the quinoline 4-one derivative of the present invention provides a health functional food composition for the prevention or improvement of pneumonia, characterized in that it has antibacterial activity against drug-resistant pneumonia.
  • the drug provides a health functional food composition for the prevention or improvement of pneumonia, characterized in that the erythromycin or methicillin.
  • the drug may be penicillin, cephalosporin, aminoglycoside, benzoyl peroxide, povidone iodine, azeolaic acid, retinoid ), Clindamycin (clindamycin), and erythromycin (erythromycin) may be a health functional food composition for the prevention or amelioration of pneumonia, characterized in that it comprises one or more drugs.
  • the pneumococcus provides a health functional food composition for the prevention or improvement of pneumonia, characterized in that S. pneumoniae or S. aureu .
  • the pneumococcal bacteria may be Streptococcus pneumoniae (S.pneumoniae), Staphylococcus aureus (S.aureus), Klebsiella pneumoniae, Mycoplasma pneumoniae (Mycoplasma). pneumoniae), and Legionella pneumophila may be a health functional food composition for the prevention or improvement of pneumonia, characterized in that it comprises one or more pneumococci selected from the group consisting of, but is not limited thereto.
  • the present invention provides a method for preventing or treating pneumonia, comprising the step of administering a pharmaceutical composition or a nutraceutical composition containing the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient to a subject in need thereof. To provide.
  • the present invention also provides a use of a pharmaceutical composition or a nutraceutical composition containing a compound represented by the formula (1) or a pharmaceutically acceptable salt thereof in the prevention or treatment of pneumonia.
  • the quinoline 4-one derivative of 1-80 according to the present invention was prepared by depositing or synthesizing from Korea Compound Bank.
  • Step 1 25 minutes of diketene (1.7 mL, 21.05 mmol) in 2-chloro-4-nitroaniline (3.4 g, 19.70 mmol) and trimethylamine (0.1 mL, 0.99 mmol) dissolved in benzene (33 mL) Put on. After refluxing for 4 hours, it was brought to room temperature and benzene was removed under reduced pressure. The remaining material was recrystallized in ethanol to give N- (2-chloro-4-nitrophenyl) -3-oxobutaneamide (2.0 g, 40% yield).
  • Step 2 N- (2-chloro-4-nitrophenyl) -3-oxobutanamide (1.1 g, 4.40 mmol) and K 2 CO 3 (0.6 g, prepared in Step 1) were added to DMF (7 mL). 4.40 mmol) and stirred at room temperature for 2 hours, followed by CS 2 (1.27 mL, 13.20 mmol) and stirred for 2 hours. MeI (2.84 mL, 8.8 mL) was added and stirred for 1 hour.
  • Step 3 2 prepared as described in Step 2 (bis (methylthio) methylene) - N - (2-chloro-4-nitro-phenyl) -3-oxo-butane amide (100 mg, 0.28 mmol) o- Put in dichlorobenzene (4 mL) and reflux for 4 h. Cooled to room temperature to give a solid, recrystallized from EtOAc to give 3-acetyl-8-chloro-2- (methylthio) -6-nitroquinolin-4 (1 H ) -one (40 mg, 0.13 mmol).
  • Step 4 3-acetyl-8-chloro-2- (methylthio) -6-nitroquinolin-4 ( 1H ) -one (100 mg, 0.32 mmol) prepared in step 3 was added with methanol (8 mL ), Oxone (0.98 g, 1.60 mmol) dissolved in water (8 mL) was added thereto, and the resultant was stirred at room temperature for 8 hours. Methanol was removed under reduced pressure, and extracted with EtOAc and water. The organic layer was dried under Na 2 SO 4 and concentrated in vacuo to afford 3-acetyl-8-chloro-2- (methylsulfinyl) -6-nitroquinolin-4 (1 H ) -one (90 mg, 86% yield). Got it.
  • Step 5 3-acetyl-8-chloro-2- (methylsulfinyl) -6-nitroquinolin-4 ( 1H ) -one (50 mg, 0.15 mmol) prepared in step 4 and 4-methoxy Benzylamine (21 mg, 0.15 mmol) was dissolved in o-dichlorobenzene (3 mL) and refluxed for 24 h. The solvent was removed from the reaction and recrystallized from EtOAc to give 3-acetyl-8-chloro-2- (4-methoxybenzylamino) -6-nitroquinolin-4 ( 1H ) -one (20 mg, 33% yield).
  • Example Chemical structure Example Chemical structure One 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80
  • Erythromycin which is well known as a pneumococcal antimicrobial agent, was prepared.
  • Streptococcus pneumoniae S.pneumoniae
  • Staphylococcus aureus S. aureus
  • erythromycin and vancomycin 100 ⁇ l of high concentration (1 mg / ml) erythromycin and vancomycin were prepared. 1 ml of erythromycin (100 ⁇ g / ml) and 1: 12.5 diluted vancomycin (80 ⁇ g / ml) diluted 1:10 with TSB were prepared. Nine 1.5 ml tubes were prepared in two sets, one set filled with 400 ⁇ l of TSB (Erithromycin Dilution Set) and the other set with 300 ⁇ l of TSB (Vancomycin Dilution Set).
  • test plate was placed in a centrifuge and rotated at 1000 rpm for 1 minute to move the drug to the bottom of each testing-well.
  • test plates and bacteria were prepared, 45 ⁇ l of the diluted bacteria were placed in each of the corresponding test wells, and anaerobic culture was performed for 16 hours without shaking at 37 ° with 5% carbon dioxide supply. After 16 hours anaerobic incubation, the test plates were removed from the incubator and allowed to cool for 30 minutes at ⁇ 25 ° (room temperature).
  • Example WT% Inh 15B% Inh 19A% Inh Example WT% Inh 15B% Inh 19A% Inh
  • Example WT% Inh 15B% Inh 19A% Inh One 107 112 90 2 108 117 95 3 105 102 104 4 106 100 104 5 103 99 96 6 96 94 97 7 24 3 -8.42 8 12 5 -3 9 108 101 94 10 105 104 104 11 103 102 103 12 13 87 -6 13 110 116 108 14 101 100 101 15 103 101 101 16 97 95 96 17 102 102 103 18 104 102 102 19 97 97 98 20 94 97 98 21 96 96 95 22 96 92 96 23 106 105 105 24 99 99 99 99 25 94 84 93 26 103 102 102 27 100 88 86 28 106 103 106 29 104 103 103 30 65 83 80 31 104 94 97 32 106 95 106 33
  • the quinoline 4-one derivative according to the present invention exhibits excellent antimicrobial activity against wild-type samples, drug-resistant samples, and erythromycin-resistant samples. From this, the quinoline 4-one derivative according to the present invention is not only an antibacterial effect against S. pneumoniae without drug resistance, but also to S. pneumoniae , which is resistant to drug resistance, especially erythromycin. Monia ( S. pneumoniae ) can be seen that the antibacterial effect is excellent.
  • the culture cultured for 6 hours after re-inoculation After confirming the absorbance of the culture cultured for 6 hours after re-inoculation, it was diluted with MHB to make 2ml of the culture medium Staphylococcus Aureus bacteria with an absorbance of 0.05. 900 ⁇ l of the prepared 2 ml was measured by absorbance to reconfirm 0.05. Then, the Staphylococcus culture medium with an absorbance of 0.05 was prepared by diluting 1: 200 with MHB in an amount necessary for the experiment.
  • test plate was placed in a centrifuge and rotated at 1000 rpm for 1 minute to move the drug to the bottom of each testing-well.
  • test plates and bacteria were prepared, 45 ⁇ l of the diluted bacteria were placed in each of the corresponding test wells and incubated for 16 hours without shaking at 37 ° with a 5% carbon dioxide supply. After 16 hours of incubation, the test plates were removed from the incubator and allowed to cool for 30 minutes at ⁇ 25 ° (room temperature). After the adhesive cover was attached to the cooled test plate, the result was obtained with a spectrophotometer 600 nm for the plate, and is shown in Table 3 below.
  • Example 4 Example 9 Example 14 Example 5 Example 15 S. aureus% Inh 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100
  • the quinoline 4-one derivative according to the present invention can be seen to exhibit excellent antimicrobial activity against wild-type Staphylococcus Oris (S. aureus) specimen.
  • Clinical strain 1-5 Clinically isolated methicillin resistant strain S. aureus (MRSA) with different antibiotic resistance profiles
  • the quinoline 4-one derivative according to the present invention is not only an antimicrobial effect against S. aureus without drug resistance, but also Staphylococcus aureus that is resistant to drug resistance, especially methicillin. It can be seen that the antibacterial effect against (S.aureus) is excellent.
  • the derivative according to the present invention can be formulated in various forms according to the purpose. Examples of preparations for the compositions of the present invention are illustrated below.
  • tablets were prepared by tableting according to a conventional method for producing tablets.
  • the capsule was prepared by filling in gelatin capsules according to the conventional method for producing a capsule.
  • the compounds of the present invention can be prepared in various forms of health functional food according to the purpose. Examples of the preparation of the health functional food for the composition of the present invention are illustrated below.
  • Brown rice, barley, glutinous rice, and yulmu were alphad by a known method, and then dried and roasted to prepare a powder having a particle size of 60 mesh.
  • Black beans, black sesame seeds, and perilla were also steamed and dried by a known method, and then ground to a powder having a particle size of 60 mesh.
  • the health functional food composition of the present invention was concentrated under reduced pressure in a vacuum concentrator to obtain a dry powder.
  • the grains, seeds, and dry powders of the compound of Formula 1 according to the present invention were prepared by blending the following ratios.
  • Seeds (7 parts by weight perilla, 8 parts by weight black beans, 7 parts by weight black sesame seeds),
  • Vitamin B6 0.5 mg
  • composition ratio of the above-mentioned vitamin and mineral mixture is mixed and formulated in a preferred embodiment with a component suitable for a relatively healthy functional food
  • the compounding ratio may be arbitrarily modified, and the above-mentioned components are mixed according to a conventional health functional food manufacturing method.
  • the granules can then be prepared and used to prepare the nutraceutical composition according to conventional methods.
  • composition ratio is a composition that is relatively suitable for a preferred beverage in a preferred embodiment
  • the composition ratio may be arbitrarily modified according to regional and ethnic preferences such as demand hierarchy, demand country, and usage.
  • the quinoline 4-one derivative according to the present invention can be used as a pharmaceutical composition for the prevention or treatment of pneumonia caused by pneumococci.

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Abstract

La présente invention concerne un dérivé de quinolin-4-one, un sel pharmaceutiquement acceptable associé, ou une composition pharmaceutique de prévention ou de traitement de la pneumonie, la composition pharmaceutique comprenant le dérivé de quinolin-4-one ou un sel pharmaceutiquement acceptable associé en tant que principe actif. Le dérivé de quinolin-4-one selon la présente invention a une excellente activité antibactérienne et, en particulier, contrairement aux agents antibactériens classiques qui sont généralement utilisés, a une excellente activité antibactérienne contre un pneumocoque ayant une résistance aux médicaments, et peut donc être utilisé avantageusement en tant que composition pharmaceutique de prévention ou de traitement d'une pneumonie provoquée par un tel pneumocoque.
PCT/KR2017/011637 2016-10-20 2017-10-20 Composition pharmaceutique de prévention ou de traitement de la pneumonie, comprenant un dérivé de quinolin-4-one ou un sel pharmaceutiquement acceptable associé en tant que principe actif Ceased WO2018074880A2 (fr)

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KR20160136393 2016-10-20
KR10-2016-0136393 2016-10-20
KR10-2017-0097569 2017-08-01
KR1020170097569A KR101915550B1 (ko) 2016-10-20 2017-08-01 퀴놀린 4-온 유도체 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는 폐렴의 예방 또는 치료용 약학적 조성물
KR10-2017-0097574 2017-08-01
KR1020170097574A KR101891315B1 (ko) 2017-08-01 2017-08-01 퀴놀린 4-온 유도체 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는 폐렴의 예방 또는 치료용 약학적 조성물

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KR20220074300A (ko) 2020-11-27 2022-06-03 재단법인 한국파스퇴르연구소 황색포도상구균 또는 장구균에 대한 항균용 조성물
US11801242B2 (en) 2018-10-09 2023-10-31 Duke University Compositions and methods for adjuvant cancer therapeutics

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AU2002305926A1 (en) * 2001-02-05 2002-10-08 Exegenics Inc. Cysteine protease inhibitors
NZ541681A (en) * 2003-02-10 2009-02-28 Bayer Healthcare Ag Treatment of bacterial diseases of the respiratory organs by locally applying ciprofloxacin and its salts
KR100574351B1 (ko) * 2004-05-18 2006-04-27 한국화학연구원 4-퀴놀린온 유도체를 포함하는 농원예용 살균제 조성물
KR100916160B1 (ko) * 2007-02-21 2009-09-08 (주)바이오버드 약제학적 항암 조성물
MX2010013310A (es) * 2008-06-04 2011-03-01 Astrazeneca Ab Derivados de heterociclil urea para el tratamiento de infecciones bacterianas.

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11801242B2 (en) 2018-10-09 2023-10-31 Duke University Compositions and methods for adjuvant cancer therapeutics
KR20220074300A (ko) 2020-11-27 2022-06-03 재단법인 한국파스퇴르연구소 황색포도상구균 또는 장구균에 대한 항균용 조성물

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