Use of a nitroxin compound in enhancing the effect of an antibacterial agent

Abstract

The present invention relates to the use of nitroxin compounds in enhancing the effect of antibacterial agents. In particular, the present invention relates to the use of a compound represented by formula (I) or a pharmaceutically acceptable salt thereof in enhancing the antibacterial effect of antibacterial agents. When the compound represented by formula (I) of the present invention is used in combination with an antibacterial agent, a synergistic or additive effect can be produced on the antibacterial agent, thereby enhancing the antibacterial effect, particularly the antibacterial effect against multi-drug resistant strains.

Description

Technical Field

[0001] The present invention relates to the use of a nitroxin compound of formula (I) or a pharmaceutically acceptable salt thereof for enhancing the antibacterial effect of an antibacterial agent, and to the use for treating a bacterial infection in combination with an antibacterial agent of a nitroxin compound of formula (I) or a pharmaceutically acceptable salt thereof.

Background Art

[0002] Infections are frequently occurring diseases that threaten human life and health, and are also one of the major complications and causes of death in multi-organ diseases. The use of anti-infective drugs has significantly reduced deaths due to infections. Commonly used anti-infective drugs include β-lactam antibiotics, quinolone antibiotics, aminoglycoside antibiotics, etc., and their mechanisms of action include inhibition of bacterial cell wall synthesis, inhibition of certain functions of cell membranes, inhibition of protein synthesis, inhibition of nucleic acid synthesis, and inhibition of folic acid synthesis.

[0003] At present, bacterial resistance is serious worldwide, and the problem of multi-drug resistant Gram-negative bacterial infections is profound. For example, Escherichia coli, Pseudomonas aeruginosa, and Acinetobacter baumannii that are resistant to carbapenem antibiotics are widespread in a wide range in clinical practice, and are difficult to treat or even impossible to treat.

[0004] Currently, there are two strategies for combating drug resistance. One is the discovery of new antimicrobial drug molecules, and the other is combination therapy.

[0005] However, a decline in the number of new antimicrobial drug molecules entering the market has been observed for about 20 years. This decline is mainly due to high development costs and increased regulatory standards for approval.

[0006] When using another adjuvant in combination with an existing antibiotic, it is possible to solve the problem that it is difficult to treat drug-resistant bacterial infections with the existing antibiotic alone, greatly reduce bacterial resistance, and benefit all mankind.

Prior Art Documents

Patent Documents

[0007]

Patent Document 1

Summary of the Invention

Means for Solving the Problems

[0008] Accordingly, in one aspect, the present invention relates to a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one antibacterial agent as active ingredients, together with a pharmaceutically acceptable carrier or excipient.

[0009]

Chemical Formula

[0010] [In the formula, Each R1 is independently selected from the group consisting of hydrogen, halogen, amino, hydroxy, thiol, cyano, nitro, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, Each R2 is independently selected from the group consisting of hydrogen, halogen, amino, hydroxy, thiol, cyano, nitro, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, n is 0, 1 or 2, m is 0, 1, 2 or 3]

[0011] The present invention also relates to the use of a pharmaceutical composition in the preparation of a medicament for the treatment of bacterial infections, particularly multi-drug resistant bacterial infections.

[0012] In another aspect, the present invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing the same in the preparation of a medicament for enhancing the antibacterial effect of an antibacterial agent.

[0013] [Chemical formula]

[0014] [Wherein, each R1 is independently selected from the group consisting of hydrogen, halogen, amino, hydroxy, thiol, cyano, nitro, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; each R2 is independently selected from the group consisting of hydrogen, halogen, amino, hydroxy, thiol, cyano, nitro, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; n is 0, 1 or 2; m is 0, 1, 2 or 3]

[0015] In another aspect, the present invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing the same in combination with at least one antibacterial agent in the preparation of a medicament for enhancing the antibacterial effect of the antibacterial agent.

[0016] [Chemical formula]

[0017] [Wherein, Each R1 is independently selected from the group consisting of hydrogen, halogen, amino, hydroxy, thiol, cyano, nitro, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl. Each R2 is independently selected from the group consisting of hydrogen, halogen, amino, hydroxy, thiol, cyano, nitro, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl. n is 0, 1 or 2. m is 0, 1, 2 or 3.

[0018] The present invention also relates to the use in the preparation of a medicament for treating bacterial infections, particularly multi-drug resistant bacterial infections, of a compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing the same in combination with at least one antibacterial agent.

[0019]

Chemical formula

[0020] [Wherein, Each R1 is independently selected from the group consisting of hydrogen, halogen, amino, hydroxy, thiol, cyano, nitro, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl. Each R2 is independently selected from the group consisting of hydrogen, halogen, amino, hydroxy, thiol, cyano, nitro, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl. n is 0, 1 or 2. m is 0, 1, 2 or 3.

[0021] In a preferred embodiment, in the compound of formula (I) of the present invention, R1 is hydrogen, halogen, C 1~10 alkyl, C 1~10 alkoxy, C 1~10 haloalkyl, C 1~10 hydroxyalkyl, C 1~10 aminoalkyl, C 3~10 cycloalkyl, 3- to 10-membered heterocyclyl, C 6~14 aryl, and 5- to 14-membered heteroaryl, and is selected from the group consisting of.

[0022] In another preferred embodiment, in the compound of formula (I) of the present invention, R1 is hydrogen, halogen, C 1~6 alkyl, C 1~6 alkoxy, C 1~6 haloalkyl, C 1~6 hydroxyalkyl, C 1~6 aminoalkyl, C 3~6 cycloalkyl, 3- to 6-membered heterocyclyl, C 6~10 aryl, and 5- to 10-membered heteroaryl, and is selected from the group consisting of.

[0023] In another preferred embodiment, in the compound of formula (I) of the present invention, R1 is hydrogen, halogen, C 1~6 alkyl, C 1~6 alkoxy, and C 1~6 haloalkyl, and is selected from the group consisting of.

[0024] In a particularly preferred embodiment, in the compound of formula (I) of the present invention, R1 is selected from hydrogen.

[0025] In another preferred embodiment, in the compound of formula (I) of the present invention, R2 is hydrogen, halogen, C 1~10 alkyl, C 1~10 alkoxy, C 1~10 haloalkyl, C 1~10 hydroxyalkyl, C 1~10 aminoalkyl, C 3~10 cycloalkyl, 3- to 10-membered heterocyclyl, C 6~14 aryl, and 5- to 14-membered heteroaryl, and is selected from the group consisting of.

[0026] In another preferred embodiment, in the compound of formula (I) of the present invention, R2 is hydrogen, halogen, C 1~6 alkyl, C 1~6 alkoxy, C 1~6 haloalkyl, C 1~6 hydroxyalkyl, C 1~6 aminoalkyl, C 3~6 cycloalkyl, 3- to 6-membered heterocyclyl, C 6~10 selected from the group consisting of aryl and 5- to 10-membered heteroaryl.

[0027] In another preferred embodiment, in the compound of formula (I) of the present invention, R2 is hydrogen, halogen, C 1~6 alkyl, C 1~6 alkoxy and C 1~6 selected from the group consisting of haloalkyl.

[0028] In a particularly preferred embodiment, in the compound of formula (I) of the present invention, R2 is halogen.

[0029] In a specific embodiment, in the compound of formula (I) of the present invention, n is 1 or 2.

[0030] In another specific embodiment, in the compound of formula (I) of the present invention, m is 0 or 1.

[0031] In a particularly preferred embodiment, in the compound of formula (I) of the present invention, each R1 is independently hydrogen, each R2 is independently halogen, n is 1 or 2, and m is 1.

[0032] In another preferred embodiment, the compound of formula (I) of the present invention is

[0033]

Chemical formula

[0034] selected from the group consisting of.

[0035] In another preferred embodiment, the antibacterial agent of the present invention is one or more selected from the group consisting of carbapenem antibiotics, polypeptide antibiotics, fluoroquinolone antibiotics, non-fluoroquinolone antibiotics, aminoglycoside antibiotics and glycopeptide antibiotics.

[0036] In a specific embodiment, the carbapenem antibiotic is meropenem.

[0037] In another specific embodiment, the polypeptide antibiotic is polymyxin.

[0038] In another specific embodiment, the fluoroquinolone antibiotic is levofloxacin.

[0039] In another specific embodiment, the non-fluoroquinolone antibiotic is nalidixic acid or nemonoxacin.

[0040] In another specific embodiment, the aminoglycoside antibiotic is gentamicin.

[0041] In another specific embodiment, the glycopeptide antibiotic is vancomycin.

[0042] In a preferred embodiment, the antibacterial agent of the present invention is selected from the group consisting of carbapenem antibiotics and polypeptide antibiotics.

[0043] In another specific embodiment, the antibacterial agent of the present invention is selected from the group consisting of polymyxin and meropenem.

[0044] In a preferred embodiment, the pharmaceutical composition according to the present invention is an antibacterial pharmaceutical composition.

[0045] In another preferred embodiment, the bacteria of the present invention are Gram-negative bacteria such as Escherichia coli, Pseudomonas aeruginosa, and Acinetobacter baumannii; preferably, multi-drug resistant Gram-negative bacteria; more preferably, multi-drug resistant bacteria resistant to carbapenem antibiotics such as multi-drug resistant Escherichia coli, Pseudomonas aeruginosa, and Acinetobacter baumannii.

[0046] In a specific embodiment, the bacteria of the present invention are selected from strains of the genus Escherichia, and the strains of the genus Escherichia are preferably Escherichia coli, and Escherichia coli is non-resistant Escherichia coli and / or resistant Escherichia coli, preferably resistant Escherichia coli, more preferably one or more of carbapenem-resistant Escherichia coli, quinolone-resistant Escherichia coli, aminoglycoside-resistant Escherichia coli, and glycopeptide-resistant Escherichia coli.

[0047] In another specific embodiment, the bacteria of the present invention are preferably selected from strains of the genus Acinetobacter, and the strains of the genus Acinetobacter are preferably Acinetobacter baumannii, and Acinetobacter baumannii is non-resistant Acinetobacter baumannii and / or resistant Acinetobacter baumannii, preferably resistant Acinetobacter baumannii, more preferably carbapenem-resistant Acinetobacter baumannii.

[0048] In a specific embodiment, in the pharmaceutical composition or use according to the present invention, the compound of formula (I) is

[0049]

Chemical formula

[0050] and the antibacterial agent is selected from the group consisting of meropenem and polymyxin.

[0051] In another specific embodiment, in the pharmaceutical composition or use according to the present invention, the compound of formula (I) is

[0052]

Chemical formula

[0053] and the antibacterial agent is selected from the group consisting of polymyxin and meropenem, particularly polymyxin.

[0054] In another specific embodiment, in the pharmaceutical composition or use according to the present invention, the compound of formula (I) is

[0055]

Chemical formula

[0056] and the antibacterial agent is polymyxin.

[0057] In another specific embodiment, in the pharmaceutical composition or use according to the present invention, the compound of formula (I) is

[0058]

Chemical formula

[0059] and the antibacterial agent is meropenem.

[0060] In another specific embodiment, in the pharmaceutical composition or use according to the present invention, the compound of formula (I) is

[0061]

Chemical formula

[0062] and the antibacterial agent is polymyxin.

[0063] In another specific embodiment, in the use according to the present invention, the compound of formula (I) is

[0064]

Chemical formula

[0065] and the antibacterial agent is meropenem.

[0066] In another specific embodiment, in the pharmaceutical composition or use according to the present invention, the compound of formula (I) is

[0067]

Chemical formula

[0068] and the antibacterial agent is polymyxin.

[0069] In another specific embodiment, in the use according to the present invention, the compound of formula (I) is

[0070]

Chemical formula

[0071] and the antibacterial agent is meropenem.

[0072] In a specific embodiment, in the use according to the present invention, the compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing the same is administered simultaneously, continuously or separately with the antibacterial agent.

[0073] The present invention further relates to the use of a compound or a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing the same in the preparation of a medicament for enhancing the antibacterial effect of an antibacterial agent, wherein the compound is

[0074]

Chemical formula

[0075] selected from the group consisting of, and the antibacterial agent is selected from the group consisting of polymyxin and meropenem.

[0076] The present invention relates to the use of a compound in combination with an antibacterial agent in the preparation of a medicament for treating bacterial infections, wherein the compound is

[0077]

Chem.

[0078] selected from the group consisting of, wherein the antibacterial agent is selected from the group consisting of polymyxin and meropenem, and the bacterial infection is preferably a multi-drug resistant bacterial infection, also relates to use.

[0079] The present invention further relates to the use of a compound

[0080]

Chem.

[0081] and a combination of polymyxin or meropenem in the preparation of a medicament for the treatment of bacterial infections, wherein the bacterial infection is preferably a multi-drug resistant bacterial infection, and the bacteria are preferably Acinetobacter baumannii, more preferably resistant Acinetobacter baumannii, and particularly preferably carbapenem-resistant Acinetobacter baumannii, also relates to use.

[0082] The present invention further relates to the use of a compound

[0083]

Chem.

[0084] and a combination of polymyxin or meropenem in the preparation of a medicament for the treatment of bacterial infections, wherein the bacterial infection is preferably a multi-drug resistant bacterial infection, and the bacteria are preferably Acinetobacter baumannii, more preferably resistant Acinetobacter baumannii, and particularly preferably carbapenem-resistant Acinetobacter baumannii, also relates to use.

[0085] The present invention further relates to the use of a compound

[0086]

Chem.

[0087] And use of a combination of meropenem in the preparation of a medicament for treating bacterial infections, wherein the bacterial infection is preferably a multi-drug resistant bacterial infection, and the bacteria are preferably Acinetobacter baumannii and Escherichia coli, more preferably resistant Acinetobacter baumannii and Escherichia coli, particularly preferably carbapenem-resistant Acinetobacter baumannii, carbapenem-resistant Escherichia coli, quinolone-resistant Escherichia coli, aminoglycoside-resistant Escherichia coli and glycopeptide-resistant Escherichia coli, also relates to the use.

[0088] The term "β-lactam antibiotic" refers to a large class of antibiotics having a β-lactam ring in their chemical structures, including penicillins and cephalosporins most commonly used in clinical practice, as well as newly developed atypical β-lactam antibiotics such as cephamycin, thienamycin, monobactam, etc.

[0089] The term "quinolone antibiotic" refers to synthetic antibacterial drugs containing the basic structure of 4-quinolone such as fleroxacin, ofloxacin, ciprofloxacin, levofloxacin, etc.

[0090] The term "aminoglycoside antibiotic" refers to a class of antibiotics such as streptomycin, gentamicin, tobramycin, kanamycin, amikacin, etc. having a molecular structure in which an aminocyclitol and one or more amino sugar molecules are linked by a glycosidic bond to form a glycoside.

[0091] The term "carbapenem antibiotic" has a structure similar to the penicillin ring of penicillin, except that the sulfur atom of the thiazole ring is replaced by carbon, there is an unsaturated double bond between C2 and C3, and its 6-hydroxyethyl side chain is in a trans conformation, such as imipenem, meropenem, panipenem, ertapenem, biapenem, doripenem, etc.

[0092] The term "Gram-negative bacteria" refers to bacteria that show a red color in the Gram staining reaction, such as Escherichia coli, Pseudomonas aeruginosa, Proteus bacillus vulgaris, Shigella dysenteriae, Klebsiella pneumoniae, Bacterium burgeri, Haemophilus influenzae, Haemophilus parainfluenzae, Moraxella catarrhalis, Acinetobacter, Yersinia, Legionella pneumophila, Bordetella pertussis, Bordetella parapertussis, Shigella, Pasteurella, Vibrio cholerae, Vibrio parahaemolyticus, Plesiomonas shigelloides, etc.

[0093] The term "multi-drug resistance" refers to resistance to one drug and cross-resistance to multiple drugs with different structures and functions. "Multi-drug resistant bacteria" refers to microorganisms that are resistant to three or more classes of antimicrobial drugs (such as aminoglycosides, macrolides, and β-lactams) with different mechanisms, rather than three types of the same class.

[0094] The term "bacterial infection" refers to an infection caused by the invasion of bacteria into the human body. Bacterial infections cover a wide range of areas and can be either local infections or systemic infections. Examples of local infections include bacterial infections limited to a part, such as furuncle, carbuncle, bedsore, and bacterial infections limited to one organ, such as pneumonia, gastritis, enteritis, dermatitis. Examples of systemic infections include bacteremia, sepsis, pyosepticemia, etc. "Multi-drug resistant bacterial infection" refers to an infection caused by the invasion of multi-drug resistant bacteria into the human body.

[0095] In this specification, polymyxin is polymyxin E having the molecular formula of C 52 H 98 N 16 O 13 and has antibacterial effects against Gram-negative bacteria such as Pseudomonas aeruginosa, Escherichia coli, Klebsiella pneumoniae, Haemophilus, Enterobacter, Salmonella, Shigella, Bordetella pertussis, Pasteurella, and Vibrio. Polymyxin E is a basic polypeptide antibiotic produced by Bacillus polymyxa colistin variant, has a strong bactericidal effect on Gram-negative bacteria, can treat animal feeding diseases caused by various pathogens, and is characterized by a good antibacterial spectrum, high efficiency, and low toxicity.

[0096] C 17 H 25 Meropenem described in this specification having the molecular formula of C

[0097] "Alkyl" refers to a saturated aliphatic hydrocarbon group, including straight-chain and branched-chain groups having the specified number of carbon atoms. Alkyl generally has 1 to 20 carbon atoms (C1-C 20 alkyl), preferably 1 to 12 carbon atoms (C1-C 12(alkyl), more preferably containing 1 to 8 carbon atoms (C1-C8 alkyl) or 1 to 6 carbon atoms (C1-C6 alkyl) or 1 to 4 carbon atoms (C1-C4 alkyl). Non-limiting examples of alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and their various branched isomers. The alkyl may be a substituted alkyl or an unsubstituted alkyl. When substituted, the substituent may be substituted at any available connection point. Suitable optional substituents for alkyl include, but are not limited to, halogen, amino, nitro, cyano, hydroxy, thiol, carboxy, alkoxycarbonyl, oxo, thio, alkoxy, aryloxy, heteroaryloxy, haloalkyl, haloalkoxy, hydroxyalkyl, alkylamino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl.

[0098] "Alkoxy" refers to an -O-(alkyl) group, where alkyl is as defined above. Non-limiting examples of alkoxy include methoxy, ethoxy, propoxy, and butoxy. Alkoxy may be substituted or unsubstituted alkoxy. When substituted, the substituents are preferably one or more groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkyloxy, heterocyclyloxy, cycloalkylthio, heterocyclylthio, carboxy, and alkoxycarbonyl.

[0099] The term "haloalkyl" refers to alkyl substituted by one or more halogens, where alkyl is as defined above.

[0100] The term "haloalkoxy" refers to alkoxy substituted by one or more halogens, where alkoxy is as defined above.

[0101] The term "hydroxy" refers to an -OH group.

[0102] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0103] The term "amino" refers to an -NH2 group.

[0104] The term "thiol" refers to an -SH group.

[0105] "Pharmaceutical composition" refers to a mixture of one or more physiologically / pharmaceutically acceptable salts of a compound according to the present invention or other chemical components, and other components such as physiologically / pharmaceutically acceptable carriers and excipients.

[0106] The term "pharmaceutically acceptable salt" refers to salts of the compounds of the present invention that are safe and effective in mammals and have the desired biological activity.

[0107] In accordance with conventional methods in the field of the present invention, the compounds of the present invention can form pharmaceutically acceptable base addition salts or acid addition salts with an alkali or an acid. Examples of the alkali include inorganic alkalis and organic alkalis. Examples of the acceptable organic alkalis include diethanolamine, ethanolamine, N-methylglucamine, triethanolamine, tromethamine and the like. Examples of the acceptable inorganic alkalis include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide and the like. Examples of the acid include inorganic acids and organic acids. Examples of the acceptable inorganic acids include hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid and the like. Examples of the acceptable organic acids include acetic acid, trifluoroacetic acid, formic acid, ascorbic acid and the like.

[0108] A pharmaceutical composition containing an active ingredient can be in a form suitable for oral administration, such as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs. The oral composition can be prepared according to any known method in the technology of preparing pharmaceutical compositions. Such compositions can contain one or more components selected from the group consisting of sweeteners, flavoring agents, coloring agents and preservatives in order to provide a palatable and pleasant pharmaceutical formulation. Tablets contain the active ingredient admixed with non-toxic pharmaceutically acceptable excipients suitable for the preparation of tablets. These excipients can be inert excipients such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate, etc.; granulating agents and disintegrants such as microcrystalline cellulose, cross-linked sodium carboxymethyl cellulose, corn starch or alginic acid, etc.; binders such as starch, gelatin, polyvinylpyrrolidone or acacia, etc.; and lubricants such as magnesium stearate, stearic acid or talc, etc. Tablets can be plain tablets or coated tablets by known techniques that can mask the drug flavor or delay the disintegration and absorption of the active ingredient in the gastrointestinal tract, thereby achieving sustained release over a long period. For example, water-soluble flavor masking materials such as hydroxypropylmethylcellulose or hydroxypropylcellulose can be used, or sustained release materials such as ethylcellulose, cellulose acetate butyrate, etc. can be used.

[0109] Oral formulations can also be provided as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin, etc., or as soft gelatin capsules in which the active ingredient is mixed with a water-soluble carrier such as polyethylene glycol or an oil medium such as peanut oil, liquid paraffin or olive oil, etc.

[0110] The aqueous suspension contains the active ingredient admixed with an excipient suitable for the preparation of the aqueous suspension. Such excipients include suspending agents such as sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, sodium alginate, polyvinyl pyrrolidone and acacia; natural phosphatides such as lecithin, or condensation products of alkylene oxides and fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide and long-chain aliphatic alcohols, for example heptadecaethyleneoxy cetanol, or condensation products of ethylene oxide and partial esters derived from fatty acids and hexitol, for example polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide and partial esters derived from fatty acids and hexitol anhydrides, for example polyoxyethylene sorbitan monooleate, which are dispersing agents or water-retaining agents. The aqueous suspension can also contain one or more preservatives such as ethyl paraben or n-propyl paraben, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents such as sucrose, saccharin or aspartame.

[0111] The oil suspension can be formulated by suspending the active ingredient in a vegetable oil such as peanut oil, olive oil, sesame oil or coconut oil, or a mineral oil such as liquid paraffin. The oil suspension can contain a thickening agent such as beeswax, solid paraffin or cetyl alcohol. The above sweetening agents and flavoring agents can be added to provide a palatable formulation. These compositions can be preserved by the addition of an antioxidant such as butylated hydroxyanisole or α-tocopherol.

[0112] The active ingredient admixed with a dispersing agent or wetting agent, a suspending agent or one or more preservatives can be prepared as a dispersible powder or granule suitable for the preparation of an aqueous suspension by the addition of water. Suitable dispersing agents or wetting agents and suspending agents are as described above. Additional excipients such as sweetening agents, flavoring agents and coloring agents can also be added. These compositions are preserved by the addition of an antioxidant such as ascorbic acid.

[0113] The pharmaceutical composition can take the form of an oil-in-water emulsion. The oil phase can be a vegetable oil such as olive oil or peanut oil, or a mineral oil such as liquid paraffin or a mixture thereof. Suitable emulsifiers can be natural phosphatides such as soybean lecithin, and esters or partial esters of fatty acids and hexitol anhydrides, such as sorbitan monooleate, and condensation products of said partial esters and ethylene oxide, such as polyoxyethylene sorbitol monooleate. The emulsion can also contain sweeteners, flavoring agents, preservatives and antioxidants. Syrups and elixirs can be formulated using sweeteners such as glycerol, propylene glycol, sorbitol or sucrose. Such formulations can also contain buffering agents, preservatives, coloring agents and antioxidants.

[0114] The pharmaceutical composition can take the form of a sterile injectable aqueous solution. Acceptable vehicles and solvents that can be used include water, Ringer's solution and isotonic saline. The sterile injectable preparation can be a sterile oil-in-water microemulsion in which the active ingredient is dissolved in the oil phase. For example, the active ingredient can first be dissolved in a mixture of soybean oil and lecithin, and then the oil solution can be introduced into a mixture of water and glycerol and processed to form a microemulsion. The injectable solution or microemulsion can be introduced into the patient's bloodstream by local bolus injection. Alternatively, it may be advantageous to administer the solution or microemulsion so as to maintain a constant circulating concentration of the compound of the present invention. To maintain such a constant concentration, a continuous intravenous delivery device can be used.

[0115] The pharmaceutical composition can be in the form of a sterile injectable aqueous or oily suspension for intramuscular and subcutaneous administration. Such suspensions can be formulated according to known techniques using the above-mentioned suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation can also be a sterile injectable solution or suspension prepared in a non-toxic parenterally acceptable diluent or solvent such as a solution prepared in 1,3-butanediol. Furthermore, a sterile non-volatile oil can be readily used as a solvent or suspending medium. For this purpose, any compounding non-volatile oil containing synthetic monoglycerides or diglycerides can be utilized. Furthermore, fatty acids such as oleic acid can also be utilized in the preparation of injection solutions.

[0116] It is well known to those skilled in the art that the dosage of a drug depends on various factors including but not limited to the activity of the following specific compounds, the age of the patient, the weight of the patient, the general health status of the patient, the behavior of the patient, the diet of the patient, the administration time, the administration route, the excretion rate, drug combinations, etc. Furthermore, the optimal treatment such as the treatment mode, the daily dose of the active compound or the type of pharmaceutically acceptable salt can be verified according to traditional treatment regimens.

[0117] Compared with the prior art, the technical solution of the present invention has the following advantages. The compound of formula (I) or its pharmaceutically acceptable salt is combined with an antibacterial agent and shows a synergistic or additive effect against bacteria, especially multi-drug resistant bacteria such as Acinetobacter baumannii when combined with the antibacterial agent, thereby facilitating the treatment of bacterial infections and thus having broad prospects for clinical application.

Mode for Carrying Out the Invention

[0118] In the absence of a clear definition, technical terms in the present invention have the meanings commonly understood by those skilled in the art.

[0119] Hereinafter, the present invention will be further described by examples, but the present invention is not limited to the scope of the examples.

[0120] In the following examples where specific conditions are not specified, the experimental methods are carried out according to conventional methods and conditions or according to product specifications. Known reagents, solvents, and materials in the examples can be synthesized by methods known in the art or are commercially available products.

[0121] Preparation Example 1: Preparation of 6-bromo-5-chloro-7-nitroquinolin-8-ol (1)

[0122]

Chemical formula

[0123] Step 1: Preparation of 6-bromo-5-chloro-8-methoxyquinoline (1b) 4-Bromo-5-chloro-2-methoxyaniline (1a) (3.80 g, 16.1 mmol), sodium 3-nitrobenzenesulfonate (4.34 g, 19.3 mmol), and glycerol (2.96 mL, 40.2 mmol) were successively added to sulfuric acid (70% by mass) (40.4 mL) at room temperature. The resulting mixture was stirred at 140 °C for 4 hours and cooled to room temperature. The pH of the aqueous phase was adjusted to about 8 - 9 with an aqueous sodium hydroxide solution (1.0 M). The resulting mixture was extracted with dichloromethane (50.0 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain crude 6-bromo-5-chloro-8-methoxyquinoline (1b) (3.80 g, crude yield 87%).

[0124] Step 2: Preparation of 6-bromo-5-chloro-8-methoxy-7-nitroquinoline (1c) Nitric acid (65 mass %) (8.4 mL, 198.0 mmol) was slowly added dropwise to a solution of crude 6-bromo-5-chloro-8-methoxyquinoline (1b) (1.80 g, 6.6 mmol) in acetic anhydride (30.0 mL) at 0 °C, and the mixture was stirred for 30 minutes. Sulfuric acid (98 mass %) (1.20 mL, 22.6 mmol) was slowly added dropwise. The reaction mixture was stirred at 0 °C for 30 minutes, then warmed to room temperature, stirred for 48 hours, and then cooled to 0 °C. The pH of the aqueous phase was adjusted to about 8 - 9 with an aqueous sodium hydroxide solution (1.0 M). The resulting mixture was extracted with ethyl acetate (50.0 mL × 3). The combined organic phases were washed with saturated brine (50.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (gradient elution, eluent: petroleum ether / ethyl acetate = 9 / 1 → 2 / 1) to obtain 6-bromo-5-chloro-8-methoxy-7-nitroquinoline (1c) (0.551 g, yield 24%).

[0125] Step 3: Preparation of 6-bromo-5-chloro-7-nitroquinolin-8-ol (1) 6-Bromo-5-chloro-7-nitro-8-methoxyquinoline (1c) (1.65 g, 5.21 mmol) and lithium chloride (2.2 g, 52.4 mmol) were added to N,N-dimethylformamide (15.0 mL) at room temperature. The reaction mixture was stirred at 120 °C for 1 hour, cooled to room temperature, and concentrated under reduced pressure to remove the organic solvent. Water (25.0 mL) was added to the obtained residue, stirred for 5 minutes, and filtered under reduced pressure. The filter cake was washed with water (5.0 mL × 2) and dried in vacuo to obtain 6-bromo-5-chloro-7-nitroquinolin-8-ol (Compound 1) (1.41 g, yield 89%). 1 H NMR (400 MHz, DMSO-d6) δ: 8.70 (dd, J = 4.4, 1.6 Hz, 1 H), 8.41 (dd, J = 8.6, 1.4 Hz, 1 H), 7.68 (dd, J = 8.4, 4.0 Hz, 1 H). MS calculated values: 301.91, 303.91; MS measured values: 303.0, 305.0 [M+H] + .

[0126] Preparation Example 2: Preparation of 6-chloro-5-fluoro-7-nitroquinolin-8-ol (2)

[0127]

Chemical formula

[0128] Step 1: Preparation of 2-amino-4-fluoro-5-chlorophenol (2b) 2-Nitro-4-fluoro-5-chlorophenol (2a) (1.92 g, 10.0 mmol) was added to a mixture of tetrahydrofuran (60.0 mL) and water (60.0 mL) at room temperature. Sodium dithionite (85% by mass) (12.3 g, 60.0 mmol) was added portionwise. The reaction mixture was stirred at room temperature for 1 hour and extracted with ethyl acetate (30.0 mL × 3). The organic phases were combined, washed with saturated brine (20.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (gradient elution, eluent: petroleum ether / ethyl acetate = 100% / 0 → 3 / 1) to obtain 2-amino-4-fluoro-5-chlorophenol (2b) (0.892 g, yield 55%).

[0129] Step 2: Preparation of 5-fluoro-6-chloroquinolin-8-ol (2c) 2-Amino-4-fluoro-5-chlorophenol (2b) (0.892 g, 5.5 mmol), sodium 3-nitrobenzenesulfonate (1.48 g, 6.57 mmol) and glycerol (1.27 g, 13.8 mmol) were successively added to sulfuric acid (70 wt%) (8.0 mL) at room temperature. The resulting mixture was stirred at 140 °C for 4 h and cooled to room temperature. The pH of the aqueous phase was adjusted to about 8 - 9 with an aqueous sodium hydroxide solution (6.0 M). The resulting mixture was extracted with dichloromethane (20.0 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (gradient elution, eluent: petroleum ether / ethyl acetate = 100% / 0 → 7 / 1) to give 5-fluoro-6-chloroquinolin-8-ol (2c) (0.411 g, yield 38%).

[0130] Step 3: Preparation of 5-fluoro-6-chloro-8-methoxyquinoline (2d) Methyl iodide (0.17 mL, 2.73 mmol) was slowly added dropwise to a suspension of 5-fluoro-6-chloroquinolin-8-ol (2c) (0.411 g, 2.1 mmol) and potassium carbonate (0.58 g, 4.2 mmol) in N,N-dimethylformamide (6.0 mL) at room temperature. The resulting mixture was stirred for 16 h and concentrated under reduced pressure to remove the organic solvent. Water (30.0 mL) was added to the resulting residue and the mixture was extracted with dichloromethane (10.0 mL × 3). The combined organic phases were washed with saturated brine (10.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (gradient elution, eluent: petroleum ether / ethyl acetate = 100% / 0 → 3 / 1) to give 5-fluoro-6-chloro-8-methoxyquinoline (2d) (0.412 g, yield 94%).

[0131] Step 4: Preparation of 5-fluoro-6-chloro-7-nitro-8-methoxyquinoline (2e) Nitric acid (65 mass%) (0.8 mL, 11.7 mmol) was slowly added dropwise to a solution of 5-fluoro-6-chloro-8-methoxyquinoline (2d) (0.412 g, 1.95 mmol) in acetic anhydride (10.0 mL) at 0 °C, and the mixture was stirred for 10 minutes. Sulfuric acid (98 mass%) (0.12 mL, 2.25 mmol) was slowly added dropwise. The reaction mixture was warmed to room temperature, stirred for 16 hours, and then cooled to 0 °C. The pH of the aqueous phase was adjusted to about 8 - 9 with an aqueous sodium hydroxide solution (6.0 M). The resulting mixture was extracted with dichloromethane (20.0 mL × 3). The combined organic phases were washed with saturated brine (20.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (gradient elution, eluent: petroleum ether / ethyl acetate = 100% / 0 → 5 / 1) to obtain 5-fluoro-6-chloro-7-nitro-8-methoxyquinoline (2e) (84.0 mg, yield 17%).

[0132] Step 5: Preparation of 5-fluoro-6-chloro-7-nitroquinolin-8-ol (2) 5-Fluoro-6-chloro-7-nitro-8-methoxyquinoline (2e) (84.0 mg, 0.39 mmol) and lithium chloride (162.0 mg, 3.9 mmol) were added to N,N-dimethylformamide (2.0 mL) at room temperature. The reaction mixture was stirred at 130 °C for 1 hour, cooled to room temperature, and concentrated under reduced pressure to remove the organic solvent. Water (2.0 mL) was added to the obtained residue, stirred for 3 minutes, and filtered under reduced pressure. The obtained filter cake was washed with water (0.5 mL × 2) and dried in vacuo to obtain 5-fluoro-6-chloro-7-nitroquinolin-8-ol (Compound 2) (77.0 mg, yield 82%). 1 H NMR (400 MHz, DMSO-d6) δ: 8.69 (d, J = 3.2 Hz, 1H), 8.25 (d, J = 8.3 Hz, 1H), 7.63 (dt, J = 12.8, 6.4 Hz, 1H). MS calculated value: 241.99; MS measured value: 243.1 [M+H] + .

[0133] Preparation Example 3: Preparation of 5-Chloro-7-nitro-8-hydroxyquinoline (Compound A)

[0134]

Chemical formula

[0135] Compound A is a known compound and was prepared according to the method of Example 1 in US Patent Application Publication No. 20080312278.

[0136] Test Example 1 Effect of Compound 1 in combination with meropenem against drug-resistant Acinetobacter baumannii This experiment was designed to determine the minimum inhibitory concentration (MIC) of Compound 1 in combination with meropenem against Acinetobacter baumannii (a strain resistant to carbapenem antibiotics) and to calculate the fractional inhibitory concentration (FIC) index.

[0137] The related materials and methods are as follows.

[0138] 1. Test compounds

[0139]

Table 1

[0140] 2. Strains Test bacteria: A total of 9 strains of Acinetobacter baumannii, all of which are resistant to carbapenem antibiotics (e.g., meropenem) and are clinical isolates, were provided by Shanghai Junji Medical Laboratory Co., Ltd.

[0141] 3. Antibiotic susceptibility test method According to the recommendations of the Clinical and Laboratory Standards Institute (CLSI), the minimum inhibitory concentration (MIC) of Compound 1 in combination with meropenem against the above strains was determined using the microdilution method designed by the checkerboard method, and the fractional inhibitory concentration (FIC) index was calculated.

[0142] (1) Preparation of antimicrobial agent formulations and drug susceptibility plates Compound 1 was dissolved in dimethyl sulfoxide to obtain Standard Stock Solution I with a concentration of 1280 mg / L. Standard Stock Solution I was diluted to 512 mg / L with sterile water to obtain Serial Dilution Tube Solution I. Serial Dilution Tube Solution I was subjected to a 1:1 serial dilution with sterile water to obtain Standard Solution I with a concentration gradient ranging from 512 to 0.25 mg / L.

[0143] Meropenem was dissolved in sterile water to obtain Standard Stock Solution II with a concentration of 5120 mg / L. Standard Stock Solution II was diluted to 1024 mg / L with sterile water to obtain Serial Dilution Tube Solution II. Serial Dilution Tube Solution II was subjected to a 1:1 serial dilution with sterile water to obtain Standard Solution II with a concentration gradient ranging from 1024 to 0.5 mg / L.

[0144] 50 μL of solution was taken from each tube of Standard Solution I and added to the drug susceptibility plate starting from the second well in each row (in each row, the concentration of Compound 1 increased from the second well to the last well). 50 μL of solution was taken from each tube of Standard Solution II and added to the drug susceptibility plate starting from the second well in each column (in each column, the concentration of meropenem increased from the second well to the last well). As a result, a checkerboard cross of different concentrations of the two drugs was formed (however, neither Compound 1 nor meropenem was present in the intersection well of the first row and the first column. Only the wells in the first row excluding the intersection well contained Compound 1, and only the wells in the first column excluding the intersection well contained meropenem. Excluding the above wells, the remaining wells contained Compound 11 and meropenem). After mixing the two drugs in equal volumes, the concentration gradient ranges were reduced to 256 - 0.125 mg / L (Compound 1) and 512 - 0.25 mg / L (meropenem), respectively.

[0145] According to the above process, the volume of the drug solution in each well containing only one drug on the drug sensitivity plate was 50 μL. Therefore, 50 μL of sterilized water was added to each well. 100 μL of sterilized water was added to the cross wells of the first row and the first column. Then, 100 μL of the bacterial solution (formulated according to step (3)) was added to all the wells of the drug sensitivity plate and mixed. Therefore, the gradient range was reduced to 128 - 0.06 mg / L (compound 1) and 256 - 0.125 mg / L (meropenem).

[0146] (2) Culture medium for the bacterial solution: Cation-adjusted Mueller-Hinton broth (CAMHB), product of BBL (USA), batch number 9015952

[0147] (3) Method for formulating the bacterial solution: According to the direct colony suspension method, using physiological saline, the test bacteria cultured overnight were prepared in a 0.5 McFarland turbidity tube. Then, the obtained solution was diluted 100-fold with the above culture medium. 100 μL of the obtained bacterial solution was thoroughly mixed with the solution (100 μL) in each well of the drug sensitivity plate, and the final inoculum size was 10 5 CFU / mL.

[0148] (4) Culture conditions: Incubate at 35 ± 2 °C for 20 hours in air

[0149] 4. Results and evaluation (1) The experimental results were determined according to the standard method of CLSI 2019 M100, 29th edition.

[0150] (2) Calculation formula for the combined growth inhibition concentration index: FIC = MIC of drug A in the combination / MIC of drug A alone + MIC of drug B in the combination / MIC of drug B alone; In the formula, FIC ≤ 0.5 indicates a synergistic effect. 0.5 < FIC ≤ 1.0 indicates an additive effect. 1 < FIC ≤ 2.0 indicates an irrelevant effect. FIC > 2 indicates an antagonistic effect.

[0151] The specific experimental results are shown in Table 1 (Table 2) below. Here, Acinetobacter baumannii specifically refers to "carbapenem-resistant Acinetobacter baumannii".

[0152]

Table 2

[0153] As can be seen from Table 1 (Table 2), the combination of Compound 1 and meropenem can significantly reduce the MIC of meropenem and has an additive effect against Acinetobacter baumannii (strains resistant to carbapenem antibiotics). Therefore, it can be seen that the combination of Compound 1 and meropenem makes the treatment of bacterial infections easier and has the potential for a wide range of clinical applications.

[0154] Test Example 2 Effect of the combination of Compound 1 with polymyxin against drug-resistant Acinetobacter baumannii This experiment is designed to determine the minimum inhibitory concentration (MIC) of the combination of Compound 1 with polymyxin against carbapenem-resistant Acinetobacter baumannii and calculate the fractional inhibitory concentration (FIC) index.

[0155] The related materials and methods are as follows.

[0156] 1. Test compounds

[0157]

Table 3

[0158] 2. Strains Test bacteria: Ten strains of carbapenem-resistant Acinetobacter baumannii are clinical isolates and are provided by Shanghai Junji Medical Laboratory Co., Ltd.

[0159] 3. Antibiotic susceptibility test method According to the recommendations of the Clinical and Laboratory Standards Institute (CLSI), the minimum inhibitory concentration (MIC) of Compound 1 in combination with polymyxin against the above strains was determined using the microdilution method designed by the checkerboard method, and the fractional inhibitory concentration (FIC) index was calculated.

[0160] (1) Preparation of antimicrobial agent formulations and drug susceptibility plates Compound 1 was dissolved in dimethyl sulfoxide to obtain a standard stock solution I with a concentration of 51,200 mg / L. The standard stock solution I was subjected to a 1:1 gradient dilution with dimethyl sulfoxide to obtain a dilution solution in the concentration range of 51,200 - 25 mg / L. The corresponding concentrations were added to sterile water and diluted 100-fold to obtain a standard solution I in the concentration range of 512 - 0.25 mg / L.

[0161] Polymyxin was dissolved in sterile water to obtain a standard stock solution with a concentration of 5,120 mg / L. The polymyxin standard stock solution was subjected to a 1:1 gradient dilution with sterile water to obtain a standard solution II in the concentration range of 512 - 0.25 mg / L.

[0162] According to the method in Example 1, drug susceptibility plates were prepared with standard solution I and standard solution II, and the specific process was not repeated in this case.

[0163] (2) Culture medium for bacterial solution: Cation-adjusted Mueller-Hinton broth (CAMHB), product of BBL (USA), batch number 9015952

[0164] (3) Preparation method of bacterial solution: According to the direct colony suspension method, using physiological saline, the test bacteria cultured overnight were prepared in a 0.5 McFarland turbidity tube. Then, the obtained solution was diluted 100-fold with the above culture medium. 100 μL of the obtained bacterial solution was thoroughly mixed with the solution (100 μL) in each well of the drug susceptibility plate, and the final inoculum was 10 5 CFU / mL.

[0165] (4) Culture conditions: Incubate at 35 ± 2 °C for 20 hours in air

[0166] 4. Results and Evaluation (1) The experimental results were determined according to the standard method of CLSI 2020 M100, 30th edition.

[0167] (2) Calculation formula for the combined growth inhibition concentration index: FIC = MIC of drug A in the combination / MIC of drug A alone + MIC of drug B in the combination / MIC of drug B alone; In the formula, FIC ≤ 0.5 indicates a synergistic effect. 0.5 < FIC ≤ 1.0 indicates an additive effect. 1 < FIC ≤ 2.0 indicates an irrelevant effect. FIC > 2 indicates an antagonistic effect.

[0168] The specific experimental results are shown in Table 2 (Table 4) below. Here, Acinetobacter baumannii specifically refers to "carbapenem-resistant Acinetobacter baumannii".

[0169]

Table 4

[0170] As can be seen from Table 2 (Table 4), the combination of Compound 1 and polymyxin can significantly reduce the MIC of polymyxin and shows a synergistic effect against carbapenem-resistant Acinetobacter baumannii. Therefore, it can be seen that the combination of Compound 1 and meropenem makes the treatment of bacterial infections easier and has the potential for a wide range of clinical applications.

[0171] Test Example 3 Effect of the combination of Compound 2 and polymyxin against drug-resistant Acinetobacter baumannii This experiment was designed to determine the minimum growth inhibition concentration (MIC) of the combination of Compound 2 and polymyxin against carbapenem-resistant Acinetobacter baumannii and calculate the combined growth inhibition concentration (FIC) index.

[0172] The related materials and methods are as follows.

[0173] 1. Test compounds

[0174]

Table 5

[0175] 2. Strains Test bacteria: Ten strains of carbapenem-resistant Acinetobacter baumannii are clinical isolates and are provided by Shanghai Junji Medical Laboratory Co., Ltd.

[0176] 3. Antimicrobial susceptibility test method According to the recommendations of the Clinical and Laboratory Standards Institute (CLSI), the minimum inhibitory concentration (MIC) of compound 2 in combination with polymyxin against the above strains was determined using the microbroth dilution method designed by the checkerboard method, and the fractional inhibitory concentration (FIC) index was calculated.

[0177] (1) Preparation of antimicrobial agents and antimicrobial susceptibility plates Compound 2 was dissolved in dimethyl sulfoxide to obtain a standard stock solution I with a concentration of 51200 mg / L. The standard stock solution I was subjected to a 1:1 gradient dilution with dimethyl sulfoxide to obtain a dilution solution in the concentration range of 51200 - 25 mg / L. The corresponding concentrations were added to sterile water and diluted 100-fold to obtain a standard solution I in the concentration range of 512 - 0.25 mg / L.

[0178] Polymyxin was dissolved in sterile water to obtain a standard stock solution with a concentration of 5120 mg / L. The meropenem standard stock solution was subjected to a 1:1 gradient dilution with sterile water to obtain a standard solution II in the concentration range of 512 - 0.25 mg / L.

[0179] According to the method in Example 1, antimicrobial susceptibility plates were prepared with standard solution I and standard solution II, and the specific process was not repeated in this case.

[0180] (2) Culture medium for bacterial solution: Cation-adjusted Mueller-Hinton broth (CAMHB), product of BBL (USA), batch number 9015952

[0181] (3) Preparation method of bacterial solution: According to the direct colony suspension method, using physiological saline, the test bacteria cultured overnight were prepared in a 0.5 McFarland turbidity tube. Then, the obtained solution was diluted 100-fold with the above culture medium. 100 μL of the obtained bacterial solution was thoroughly mixed with the solution (100 μL) in each well of the drug susceptibility plate, and the final inoculum size was 10 5 CFU / mL.

[0182] (4) Culture conditions: Incubate at 35 ± 2 °C for 20 hours in air

[0183] 4. Results and evaluation (1) The experimental results were determined according to the standard method of CLSI 2020 M100, 30th edition.

[0184] (2) Calculation formula for the combined growth inhibition concentration index: FIC = MIC of drug A in the combination / MIC of drug A alone + MIC of drug B in the combination / MIC of drug B alone; In the formula, FIC ≤ 0.5 indicates a synergistic effect. 0.5 < FIC ≤ 1.0 indicates an additive effect. 1 < FIC ≤ 2.0 indicates an irrelevant effect. FIC > 2 indicates an antagonistic effect.

[0185] The specific experimental results are shown in Table 3 (Table 6) below. Here, Acinetobacter baumannii specifically refers to "carbapenem-resistant Acinetobacter baumannii".

[0186]

Table 6

[0187] As can be seen from Table 3 (Table 6), the combination of compound 2 and polymyxin can significantly reduce the MIC of polymyxin and shows a synergistic or additive effect against carbapenem-resistant Acinetobacter baumannii. Therefore, it can be seen that the combination of compound 2 and polymyxin makes the treatment of bacterial infections easier and has the potential for a wide range of clinical applications.

[0188] Test Example 4 Effect of Compound A in Combination with Meropenem against Drug-Resistant Escherichia coli This experiment was designed to determine the minimum inhibitory concentration (MIC) of Compound A in combination with meropenem against drug-resistant Escherichia coli I (a strain resistant to carbapenem antibiotics) and drug-resistant Escherichia coli II (a strain resistant to fluoroquinolone antibiotics, non-fluoroquinolone antibiotics, aminoglycoside antibiotics, glycopeptide antibiotics, and carbapenem antibiotics), and to calculate the fractional inhibitory concentration (FIC) index.

[0189] The related materials and methods are as follows.

[0190] 1. Test Compounds

[0191] [Table 7]

[0192] 2. Strains Test bacteria: Three strains of drug-resistant Escherichia coli I, namely drug-resistant Escherichia coli 18-W09-093, drug-resistant Escherichia coli 18-W37-025, and drug-resistant Escherichia coli 18-W37-032, were provided by Shanghai Junji Medical Laboratory Co., Ltd. All of these three strains are resistant to carbapenem antibiotics (e.g., meropenem).

[0193] One strain of drug-resistant Escherichia coli II, namely drug-resistant Escherichia coli 1864, was provided by the School of Pharmacy of Fudan University. This strain is resistant to fluoroquinolone antibiotics (such as levofloxacin), non-fluoroquinolone antibiotics (nalidixic acid, nemofloxacin, etc.), aminoglycoside antibiotics (such as gentamicin), glycopeptide antibiotics (such as vancomycin), and carbapenem antibiotics (such as meropenem).

[0194]

Table 8

[0195] 3. Antimicrobial susceptibility test method According to the recommendations of the Clinical and Laboratory Standards Institute (CLSI), the minimum inhibitory concentration (MIC) of compound A in combination with meropenem against the above strains was determined using the microbroth dilution method designed by the checkerboard method, and the fractional inhibitory concentration (FIC) index was calculated.

[0196] (1) Preparation of antimicrobial agent formulations and susceptibility plates Compound A was dissolved in dimethyl sulfoxide to obtain a standard stock solution I with a concentration of 1280 mg / L. The standard stock solution I was diluted to 512 mg / L with sterile water to obtain a serial dilution first tube solution I. The serial dilution first tube solution I was subjected to a 1:1 serial dilution with sterile water to obtain a standard solution I in the concentration range of 512 - 0.25 mg / L.

[0197] Meropenem was dissolved in sterile water to obtain a standard stock solution II with a concentration of 5120 mg / L. The standard stock solution II was diluted to 1024 mg / L with sterile water to obtain a serial dilution first tube solution II. The serial dilution first tube solution II was subjected to a 1:1 serial dilution with sterile water to obtain a standard solution II in the concentration range of 1024 - 0.5 mg / L.

[0198] According to the method in Example 1, susceptibility plates were prepared with standard solution I and standard solution II, and the specific process was not repeated in this case.

[0199] (2) Culture medium for bacterial solution: Cation-adjusted Mueller-Hinton broth (CAMHB), product of BBL (USA), batch number 9015952

[0200] (3) Preparation method of bacterial solution: According to the direct colony suspension method, using physiological saline, the test bacteria cultured overnight were prepared in a 0.5 McFarland turbidity tube. Then, the obtained solution was diluted 100-fold with the above-mentioned culture medium. 100 μL of the obtained bacterial solution was thoroughly mixed with the solution (100 μL) in each well of the drug susceptibility plate, and the final inoculum amount was 10 5 CFU / mL.

[0201] (4) Culture conditions: Incubate at 35 ± 2 °C for 20 hours in air

[0202] 4. Results and evaluation (1) The experimental results were determined according to the standard method of CLSI 2019 M100, 29th edition.

[0203] (2) Calculation formula for the combined growth inhibition concentration index: FIC = MIC of drug A in the combination / MIC of drug A alone + MIC of drug B in the combination / MIC of drug B alone; In the formula, FIC ≤ 0.5 indicates a synergistic effect. 0.5 < FIC ≤ 1.0 indicates an additive effect. 1 < FIC ≤ 2.0 indicates an irrelevant effect. FIC > 2 indicates an antagonistic effect.

[0204] The specific experimental results are shown in Table 4 (Table 9) below.

[0205]

Table 9

[0206] As can be seen from Table 4 (Table 9), the combination of compound A and meropenem can significantly reduce the MIC of meropenem and shows a synergistic effect against drug-resistant Escherichia coli I (a strain resistant to carbapenem antibiotics) and drug-resistant Escherichia coli II (a strain resistant to fluoroquinolone antibiotics, non-fluoroquinolone antibiotics, aminoglycoside antibiotics, glycopeptide antibiotics, and carbapenem antibiotics). Therefore, it can be seen that the combination of compound A and meropenem makes the treatment of bacterial infections easier and has the potential for a wide range of clinical applications.

[0207] Test Example 5 Effect of Compound A in Combination with Meropenem against Drug-Resistant Acinetobacter baumannii This experiment was designed to determine the minimum inhibitory concentration (MIC) of Compound A in combination with meropenem against carbapenem-resistant Acinetobacter baumannii and to calculate the fractional inhibitory concentration (FIC) index.

[0208] The related materials and methods are as follows.

[0209] 1. Test Compounds

[0210] [Table 10]

[0211] 2. Strains Test bacteria: Ten strains of carbapenem-resistant Acinetobacter baumannii, which are clinical isolates, were provided by Shanghai Junji Medical Laboratory Co., Ltd.

[0212] 3. Antimicrobial Susceptibility Testing Method According to the recommendations of the Clinical and Laboratory Standards Institute (CLSI), the minimum inhibitory concentration (MIC) of Compound A in combination with meropenem against the above strains was determined by the microdilution method designed by the checkerboard method, and the fractional inhibitory concentration (FIC) index was calculated.

[0213] (1) Preparation of Antimicrobial Agents and Antimicrobial Susceptibility Plates Compound A was dissolved in dimethyl sulfoxide to obtain a standard stock solution I with a concentration of 51200 mg / L. The standard stock solution I was subjected to a 1:1 gradient dilution with dimethyl sulfoxide to obtain a dilution solution in the concentration range of 51200 - 25 mg / L. The corresponding concentrations were added to sterile water and diluted 100-fold to obtain a standard solution I in the concentration range of 512 - 0.25 mg / L.

[0214] Meropenem was dissolved in sterile water to obtain a standard stock solution with a concentration of 5120 mg / L. The meropenem standard stock solution was subjected to a 1:1 gradient dilution with sterile water to obtain a standard solution II in a concentration range of 512 - 0.25 mg / L.

[0215] According to the method in Example 1, drug susceptibility plates were prepared with standard solution I and standard solution II, and the specific process was not repeated in this case.

[0216] (2) Culture medium for bacterial solution: Cation-adjusted Mueller-Hinton broth (CAMHB), product of BBL (USA), batch number 9015952

[0217] (3) Preparation method of bacterial solution: According to the direct colony suspension method, using physiological saline, the test bacteria cultured overnight were prepared in a 0.5 McFarland turbidity tube. Then, the obtained solution was diluted 100-fold with the above culture medium. 100 μL of the obtained bacterial solution was thoroughly mixed with the solution (100 μL) in each well of the drug susceptibility plate, and the final inoculum amount was 10 5 CFU / mL.

[0218] (4) Culture conditions: Incubate at 35 ± 2 °C for 20 hours in air

[0219] 4. Results and evaluation (1) The experimental results were determined according to the standard method of CLSI 2020 M100, 30th edition.

[0220] (2) Calculation formula for the combined growth inhibition concentration index: FIC = MIC of drug A in the combination / MIC of drug A alone + MIC of drug B in the combination / MIC of drug B alone; In the formula, FIC ≤ 0.5 indicates a synergistic effect. 0.5 < FIC ≤ 1.0 indicates an additive effect. 1 < FIC ≤ 2.0 indicates an irrelevant effect. FIC > 2 indicates an antagonistic effect.

[0221] The specific experimental results are shown in Table 5 (Table 11) below. Here, Acinetobacter baumannii specifically refers to "carbapenem-resistant Acinetobacter baumannii".

[0222]

Table 11

[0223] As can be seen from Table 5 (Table 11), the combination of Compound A and meropenem can significantly reduce the MIC of meropenem and shows a synergistic effect against carbapenem-resistant Acinetobacter baumannii. Therefore, it can be understood that the combination of Compound A and meropenem makes the treatment of bacterial infections easier and has the potential for a wide range of clinical applications.

[0224] Although specific embodiments of the present invention have been described above, those skilled in the art should understand that this is merely an example, and the protection scope of the present invention is defined by the appended claims. Those skilled in the art can make various changes or modifications to these embodiments without departing from the principles and essence of the present invention, and all these changes and modifications fall within the protection scope of the present invention.

Claims

1. A pharmaceutical composition comprising, as active ingredients, a compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one antibacterial agent, together with a pharmaceutically acceptable carrier or excipient. 【Chemical 1】 [Wherein, R 1 is each independently selected from the group consisting of hydrogen, halogen, amino, hydroxy, thiol, cyano, nitro, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, preferably hydrogen, halogen, C 1～10 alkyl, C 1～10 alkoxy, C 1～10 haloalkyl, C 1～10 hydroxyalkyl, C 1～10 aminoalkyl, C 3～10 cycloalkyl, 3- to 10-membered heterocyclyl, C 6～14 aryl and 5- to 14-membered heteroaryl, more preferably selected from the group consisting of hydrogen, halogen, C 1～6 alkyl, C 1～6 alkoxy, C 1～6 haloalkyl, C 1～6 hydroxyalkyl, C 1～6 aminoalkyl, C 3～6 cycloalkyl, 3- to 6-membered heterocyclyl, C 6～10 aryl and 5- to 10-membered heteroaryl, even more preferably selected from the group consisting of hydrogen, halogen, C 1～6 alkyl, C 1～6 alkoxy and C 1～6 haloalkyl, and most preferably hydrogen, R 2 is independently selected from the group consisting of hydrogen, halogen, amino, hydroxy, thiol, cyano, nitro, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, preferably hydrogen, halogen, C 1～10 alkyl, C 1～10 alkoxy, C 1～10 haloalkyl, C 1～10 hydroxyalkyl, C 1～10 aminoalkyl, C 3～10 cycloalkyl, 3- to 10-membered heterocyclyl, C 6～14 aryl and 5- to 14-membered heteroaryl, more preferably hydrogen, halogen, C 1～6 alkyl, C 1～6 alkoxy, C 1～6 haloalkyl, C 1～6 hydroxyalkyl, C 1～6 aminoalkyl, C 3～6 cycloalkyl, 3- to 6-membered heterocyclyl, C 6～10 aryl and 5- to 10-membered heteroaryl, even more preferably hydrogen, halogen, C 1～6 alkyl, C 1～6 alkoxy and C 1～6 haloalkyl, and most preferably halogen, n is 0, 1 or 2, preferably 1 or 2, m is 0, 1, 2 or 3, preferably 0 or 1]

2. In the compound of formula (I), R 1 is each independently hydrogen, and R 2 is each independently halogen, n is 1 or 2, and m is 1, the pharmaceutical composition according to claim 1.

3. The compound of formula (I) is 【Chemical 2】 The pharmaceutical composition according to claim 1 or 2, selected from the group consisting of

4. The antibacterial agent is one or more selected from the group consisting of carbapenem antibiotics, polypeptide antibiotics, fluoroquinolone antibiotics, non-fluoroquinolone antibiotics, aminoglycoside antibiotics and glycopeptide antibiotics, the carbapenem antibiotic is, for example, meropenem, the polypeptide antibiotic is, for example, polymyxin, the fluoroquinolone antibiotic is, for example, levofloxacin, the non-fluoroquinolone antibiotic is, for example, nalidixic acid or nemonoxacin, the aminoglycoside antibiotic is, for example, gentamicin, the glycopeptide antibiotic is, for example, vancomycin, the antibacterial agent is preferably selected from the group consisting of carbapenem antibiotics and polypeptide antibiotics, more preferably selected from the group consisting of polymyxin and meropenem, The pharmaceutical composition according to any one of claims 1 to 3.

5. The pharmaceutical composition is an antibacterial pharmaceutical composition, the bacteria are preferably selected from strains of the genus Escherichia, the strain of the genus Escherichia is preferably Escherichia coli, and Escherichia coli is non-resistant Escherichia coli and / or resistant Escherichia coli, preferably resistant Escherichia coli, more preferably one or more of carbapenem-resistant Escherichia coli, quinolone-resistant Escherichia coli, aminoglycoside-resistant Escherichia coli and glycopeptide-resistant Escherichia coli, The pharmaceutical composition according to any one of claims 1 to 4.

6. The pharmaceutical composition is an antibacterial pharmaceutical composition, the bacteria are preferably selected from strains of the genus Acinetobacter, the strain of the genus Acinetobacter is preferably Acinetobacter baumannii, and Acinetobacter baumannii is non-resistant Acinetobacter baumannii and / or resistant Acinetobacter baumannii, preferably resistant Acinetobacter baumannii, more preferably carbapenem-resistant Acinetobacter baumannii, The pharmaceutical composition according to any one of claims 1 to 4.

7. The compound of formula (I) is 【Chemical Formula 3】 The pharmaceutical composition according to any one of claims 1 to 6, wherein the antibacterial agent is selected from the group consisting of meropenem and polymyxin.

8. The compound of formula (I) is 【Chemical Formula 4】 The pharmaceutical composition according to any one of claims 1 to 6, wherein the antibacterial agent is selected from the group consisting of polymyxin and meropenem, particularly polymyxin.

9. The compound of formula (I) is 【Chemical Formula 5】 The pharmaceutical composition according to any one of claims 1 to 6, wherein the antibacterial agent is selected from the group consisting of polymyxin and meropenem, particularly meropenem.

10. Use of the pharmaceutical composition according to any one of claims 1 to 9 in the preparation of a medicament for the treatment of bacterial infections, particularly multi-drug resistant bacterial infections.

11. Use of the compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing the same in the preparation of a medicament for enhancing the antibacterial effect of an antibacterial agent. [[Chemical Formula 6]] [Wherein, R 1 is each independently selected from the group consisting of hydrogen, halogen, amino, hydroxy, thiol, cyano, nitro, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, preferably hydrogen, halogen, C 1～10 alkyl, C 1～10 alkoxy, C 1～10 haloalkyl, C 1～10 hydroxyalkyl, C 1～10 aminoalkyl, C 3～10 cycloalkyl, 3- to 10-membered heterocyclyl, C 6～14 aryl and 5- to 14-membered heteroaryl, more preferably hydrogen, halogen, C 1～6 alkyl, C 1～6 alkoxy, C 1～6 haloalkyl, C 1～6 hydroxyalkyl, C 1～6 aminoalkyl, C 3～6 cycloalkyl, 3- to 6-membered heterocyclyl, C 6～10 aryl and 5- to 10-membered heteroaryl, even more preferably hydrogen, halogen, C 1～6 alkyl, C 1～6 alkoxy and C 1～6 haloalkyl, and most preferably hydrogen, R 2 is independently selected from the group consisting of hydrogen, halogen, amino, hydroxy, thiol, cyano, nitro, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, preferably hydrogen, halogen, C 1～10 alkyl, C 1～10 alkoxy, C 1～10 haloalkyl, C 1～10 hydroxyalkyl, C 1～10 aminoalkyl, C 3～10 cycloalkyl, 3- to 10-membered heterocyclyl, C 6～14 aryl and 5- to 14-membered heteroaryl, more preferably hydrogen, halogen, C 1～6 alkyl, C 1～6 alkoxy, C 1～6 haloalkyl, C 1～6 hydroxyalkyl, C 1～6 aminoalkyl, C 3～6 cycloalkyl, 3- to 6-membered heterocyclyl, C 6～10 aryl and 5- to 10-membered heteroaryl, even more preferably hydrogen, halogen, C 1～6 alkyl, C 1～6 alkoxy and C 1～6 haloalkyl, and most preferably halogen, n is 0, 1 or 2, preferably 1 or 2, m is 0, 1, 2 or 3, preferably 0 or 1]

12. Use in the preparation of a medicament for enhancing the antibacterial effect of an antibacterial agent, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing the same is combined with at least one antibacterial agent. 【Chemical Formula 7】 [Wherein, R 1 is independently selected from the group consisting of hydrogen, halogen, amino, hydroxy, thiol, cyano, nitro, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, preferably hydrogen, halogen, C 1～10 alkyl, C 1～10 alkoxy, C 1～10 haloalkyl, C 1～10 hydroxyalkyl, C 1～10 aminoalkyl, C 3～10 cycloalkyl, 3- to 10-membered heterocyclyl, C 6～14 aryl and 5- to 14-membered heteroaryl, more preferably hydrogen, halogen, C 1～6 alkyl, C 1～6 alkoxy, C 1～6 haloalkyl, C 1～6 hydroxyalkyl, C 1～6 aminoalkyl, C 3～6 cycloalkyl, 3- to 6-membered heterocyclyl, C 6～10 aryl and 5- to 10-membered heteroaryl, even more preferably hydrogen, halogen, C 1～6 alkyl, C 1～6 alkoxy and C 1～6 haloalkyl, and most preferably hydrogen, R 2 is independently selected from the group consisting of hydrogen, halogen, amino, hydroxy, thiol, cyano, nitro, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, preferably hydrogen, halogen, C 1～10 alkyl, C 1～10 alkoxy, C 1～10 haloalkyl, C 1～10 hydroxyalkyl, C 1～10 aminoalkyl, C 3～10 cycloalkyl, 3- to 10-membered heterocyclyl, C 6～14 aryl and 5- to 14-membered heteroaryl, more preferably hydrogen, halogen, C 1～6 alkyl, C 1～6 alkoxy, C 1～6 haloalkyl, C 1～6 hydroxyalkyl, C 1～6 aminoalkyl, C 3～6 cycloalkyl, 3- to 6-membered heterocyclyl, C 6～10 aryl and 5- to 10-membered heteroaryl, still more preferably hydrogen, halogen, C 1～6 alkyl, C 1～6 alkoxy and C 1～6 haloalkyl, and most preferably halogen, n is 0, 1 or 2, preferably 1 or 2, m is 0, 1, 2 or 3, preferably 0 or 1]

13. Use in the preparation of a medicament for the treatment of bacterial infections, particularly multi-drug resistant bacterial infections, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing the same is combined with at least one antibacterial agent. 【Chemical Formula 8】 [Wherein, R 1 is each independently selected from the group consisting of hydrogen, halogen, amino, hydroxy, thiol, cyano, nitro, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, preferably hydrogen, halogen, C 1～10 alkyl, C 1～10 alkoxy, C 1～10 haloalkyl, C 1～10 hydroxyalkyl, C 1～10 aminoalkyl, C 3～10 cycloalkyl, 3- to 10-membered heterocyclyl, C 6～14 aryl and 5- to 14-membered heteroaryl, more preferably hydrogen, halogen, C 1～6 alkyl, C 1～6 alkoxy, C 1～6 haloalkyl, C 1～6 hydroxyalkyl, C 1～6 aminoalkyl, C 3～6 cycloalkyl, 3- to 6-membered heterocyclyl, C 6～10 aryl and 5- to 10-membered heteroaryl, even more preferably hydrogen, halogen, C 1～6 alkyl, C 1～6 alkoxy and C 1～6 haloalkyl, and most preferably hydrogen, R 2 is each independently selected from the group consisting of hydrogen, halogen, amino, hydroxy, thiol, cyano, nitro, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, preferably hydrogen, halogen, C 1～10 alkyl, C 1～10 alkoxy, C 1～10 haloalkyl, C 1～10 hydroxyalkyl, C 1～10 aminoalkyl, C 3～10 cycloalkyl, 3- to 10-membered heterocyclyl, C 6～14 aryl and 5- to 14-membered heteroaryl, more preferably hydrogen, halogen, C 1～6 alkyl, C 1～6 alkoxy, C 1～6 haloalkyl, C 1～6 hydroxyalkyl, C 1～6 aminoalkyl, C 3～6 cycloalkyl, 3- to 6-membered heterocyclyl, C 6～10 aryl and 5- to 10-membered heteroaryl, even more preferably hydrogen, halogen, C 1～6 alkyl, C 1～6 alkoxy and C 1～6 haloalkyl, and most preferably halogen. n is 0, 1 or 2, preferably 1 or 2, m is 0, 1, 2 or 3, preferably 0 or 1]

14. In the compound of formula (I), R 1 is each independently hydrogen, R 2 is each independently halogen, n is 1 or 2, and m is 1, the use according to claim 12 or 13.

15. The compound of formula (I) is 【Chemical Formula 9】 Selected from the group consisting of

16. The antibacterial agent is one or more selected from the group consisting of carbapenem antibiotics, polypeptide antibiotics, fluoroquinolone antibiotics, non-fluoroquinolone antibiotics, aminoglycoside antibiotics, and glycopeptide antibiotics; the carbapenem antibiotic is, for example, meropenem, the polypeptide antibiotic is, for example, polymyxin, the fluoroquinolone antibiotic is, for example, levofloxacin, the non-fluoroquinolone antibiotic is, for example, nalidixic acid or nemonoxacin, the aminoglycoside antibiotic is, for example, gentamicin, and the glycopeptide antibiotic is, for example, vancomycin; the antibacterial agent is preferably selected from the group consisting of carbapenem antibiotics and polypeptide antibiotics, more preferably selected from the group consisting of polymyxin and meropenem, the use according to any one of claims 12 to 15.

17. The bacterium is a gram-negative bacterium such as Escherichia coli, Pseudomonas aeruginosa, and Acinetobacter baumannii; preferably, a multi-drug resistant gram-negative bacterium; more preferably, a multi-drug resistant bacterium resistant to carbapenem antibiotics such as multi-drug resistant Escherichia coli, Pseudomonas aeruginosa, and Acinetobacter baumannii, the use according to any one of claims 14 to 16.

18. The compound of formula (I) is 【Chemical 10】 and the antibacterial agent is selected from the group consisting of meropenem and polymyxin, the use according to any one of claims 12 to 17.

19. The compound of formula (I) is 【Chemical Formula 11】 and the antibacterial agent is selected from the group consisting of polymyxin and meropenem, particularly polymyxin, the use according to any one of claims 12 to 17.

20. The compound of formula (I) is 【Chemical Formula 12】 and the antibacterial agent is meropenem, the use according to any one of claims 12 to 17.

21. The compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing the same is administered simultaneously, continuously, or separately with the antibacterial agent, the use according to any one of claims 12 to 20.

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