KR101124625B1 - A 4-[3-Chloro-pyrazin-2-yl-hydrazonomethyl]-benzene-1,3-diol, and a use as inhibitor of beta-Ketoacyl acyl carrier protein synthaseKAS thereof - Google Patents

Abstract

The present invention is a compound having a novel beta-ketoacyl acyl carrier protein synthase III (β-Ketoacyl acyl carrier protein synthase III, KAS III) inhibitory activity 4-[(3-Chloro-pyrazin-2-yl) -hydrazonomethyl ] -benzene-1,3-diol.

Beta-ketoacyl acyl transfer protein synthase, antibiotics, fatty acid synthesis

Description

-4-[(3-chloro-prazine-2-yl) -hydrazonomethyl] -benzene-1,3-diol and its beta-ketoacyl acyl group transfer protein synthase use as inhibitors {A 4- [ (3-Chloro-pyrazin-2-yl) -hydrazonomethyl] -benzene-1,3-diol, and a use as inhibitor of beta-Ketoacyl acyl carrier protein synthase (KAS) approximately}

The present invention provides a compound 4-[(3-chloro-prazin-2-yl) -hydrazo having a novel beta-ketoacyl acyl group transport protein synthase III (KAS III) inhibitory activity. Nomethyl] -benzene-1,3-diol and its use.

In chemotherapy of bacterial infections, antibiotics such as rifampicin, kanamycin, streptomycin, biomycin, capreomycin, and cycloserine are used as antibacterial agents.

In chemotherapy of bacterial infections, it is a serious problem that the bacteria causing the infection become drug resistant. There is a strong desire for new chemotherapeutic agents that are effective against infectious agents of drug resistant acidophilic bacteria.

Moreover, there is a strong demand for a new chemotherapy that is effective for infectious diseases of atypical anti-acid bacteria that have not been established.

For this reason, unlike the known antibiotic substance used conventionally, the discovery or manufacture of the novel compound which has a novel chemical structure and shows favorable property, such as an excellent antimicrobial effect, is strongly desired.

In general, beta-ketoacyl acyl transfer protein synthase III is a protein that initiates the synthesis of fatty acids in bacteria and receives beta-ketoacyl acyl transfer protein (Ketoacyl) by receiving an acyl group from malonyl-acyl transfer protein (malonyl-ACP). -ACP) (FIG. 1).

The formation of beta-ketoacyl acyl transfer proteins initiates fatty acid synthesis, and these fatty acids form cell walls such as bacteria and mammals. Therefore, it inhibits cell wall formation of various bacteria through inhibition of beta-ketoacyl acyl transfer protein synthase ( Prog . Lipid) . Res . 2001, 40, 467; J. of Biol . Chem . 2003, 19, 51494).

In 2001, Professor Charles O. Rock of the University of Tennesse, U.S.A., revealed that thiolactomycin, a type II fatty acid synthesis inhibitor, showed an antibiotic effect by inhibiting the activity of KAS III protein, which suggests the potential and potential of KAS III as a target protein. Presented. This is published in the Journal of Biological Chemistry ( J. of Biol . Chem . 2001, 276 , 6551-6559).

International patent WO / 2002/055661 has developed a beta-ketoacyl acyl transfer protein synthase III inhibitor that mimics a beta-lactam family of compounds used as an antibiotic and has been found to be useful as an antibiotic. In recent international patent application WO / 2008/061399, oxo-dihydro pyrrol carboxylic acid and its derivatives have been proposed as novel beta-ketoacyl acyl transfer protein synthase III inhibitors and their anti-bioactivity has been demonstrated. In 2002, Smithkline, a multinational pharmaceutical company, found in the international patent WO / 2002/09651 that dichloro phenyl-acetic acid-based compounds inhibit beta-ketoacyl acyl transfer protein synthase III and are useful as excellent antibiotics. In 2004, the WO / 2004/041189 patent found that furancarboxylic acids and their derivatives inhibited beta-ketoacyl acyl protein synthase III, inhibiting fatty acid production, and thus having an excellent effect on breast and prostate cancers. Proved.

The present invention has been made in view of the above necessity, and an object of the present invention is to provide a compound that inhibits beta-ketoacyl acyl transfer protein synthase III.

It is another object of the present invention to provide compounds which can be used as antibiotics by inhibiting fatty acid synthesis.

In order to achieve the above object, a compound of Chemical Formula 1 (hereinafter also referred to as 'YKA3036') is provided.

[Formula 1]

The present invention also provides a pharmaceutical composition comprising the above compound, a derivative thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

'Derivative' in the present invention is the most widely used and is a similar compound obtained by chemically changing a part of a certain compound. Usually, it refers to a compound in which a hydrogen atom or a specific atomic group in the compound is substituted by another atom or atomic group.

In a preferred embodiment of the present invention, the derivative is preferably YKA3032, 3033 or 3037 of the compounds described in FIG. 3, but is not limited thereto.

In one embodiment of the invention, the composition preferably inhibits beta-ketoacyl acyl transfer protein synthase III (KAS III), but is not limited thereto.

In another aspect, the present invention provides a pharmaceutical composition for preventing or treating infectious diseases caused by a microorganism comprising an effective amount of the compound of Formula 1 or a pharmaceutically acceptable salt thereof.

In one embodiment of the invention, the microorganism is E. coli, Staphylococcus aureus, Staphylococcus aureus, Staphylococcus aureus (MRSA) resistant to methicillin, Enterococcus whiskers showing resistance to vancomycin (VREF) ) And Enterococcus whicalis are preferably, but not limited to, a microorganism selected from the group consisting of.

The methicillin-resistant Staphylococcus aureus (MRSA) is a specific strain of Staphylococcus aureus bacteria that has expressed antibiotic resistance against all penicillins, including methicillin.

Vancomycin was developed and used in the 1950s when the staphylococcus aureus became resistant to methicillin, a replacement for penicillin. It is a yellowish brown or brown powder, injected intravenously for the treatment of severe infectious diseases of Staphylococcus aureus resistant to other antibiotics. It is said to have the strongest effect among humans developed antibiotics against disease.

Methicilline Resistance Staphyllococus Aureus (MRSA), also known as the `` death bacterium, '' is a staphylococcus aureus resistant to methicillin-based antibiotics, because most patients who die or die from hospital infections are infected with it. Antibiotic resistance refers to a condition in which bacteria have their own viability against antibiotics. The penicillin resistance rate of 84% means that 84 bacteria survive when penicillin is administered to 100 bacteria. In Korea, especially the abuse and abuse of antibiotics is serious, it is known that the rate of resistance is high. Vancomycin is the only antibiotic that can fight MRSA.

In 1996, the world's first vancomycin resistance Staphyllococus Aureus (VRSA) was discovered in Japan that was resistant to this antibiotic. VRSA, also called `` super bacteria, '' can't be cured with a single antibiotic when it penetrates a weakened body of immunity, and even a combination of several antibiotics can't convince you of a cure, eventually leading to fatal sepsis.

Unless otherwise stated, the term "prophylaxis" or "treatment" as used herein refers to the reversal, alleviation, or progression of the disease or condition to which the term applies, or one or more symptoms of the disease or condition. Means inhibiting or preventing.

Unless stated otherwise, as used herein, the term or phrase “bacterial infection”, or “infection” or “infectious disease” includes:

Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, Staphylococcus aureus, Enterococcus pecalis, Enterococcus faecalis E. faecium, Enterococcus cassellflavus, Staphylococcus epidermidis, Staphylococcus hemolyticus or Peptostreptococcus species pneumonia, otitis media, sinusitis, bronchitis, tonsillitis and mastoiditis associated with infection by spp.);

Pharyngitis associated with infection by Streptococcus pyogenes, Groups C and G streptococci, Corynebacterium diptheriae, or Actinobacillus haemolyticum , Rheumatic fever and glomerulonephritis;

Respiratory tract infections associated with infection by Mycoplasma pneumoniae, Legionella pneumophila, Streptococcus pneumoniae, Haemophilus influenzae or Chlamydia pneumoniae;

Staphylococcus aureus, star, including strains resistant to known antibiotics such as, but not limited to, beta-lactam, vancomycin, aminoglycosides, quinolone, chloramphenicol, tetracycline and macrolides Blood and tissue infections, including endocarditis and osteomyelitis caused by E. durans, E. durans, E. durans, Filococcus haemolyticus, Enterococcus pecalis, Enterococcus pecalis;

Staphylococcus aureus, coagulase-negative staphylococci (ie, Staphylococcus epidermidis, Staphylococcus hemolyticus, etc.), Streptococcus piogenes, Streptococcus agalactia (Sterptococcus agalactiae), Streptococcal groups CF (Micro-colonie streptocokai), Viridans streptococci, Corynebacterium minutissimum, Clostridium spp. Simple skin and soft tissue infections and abscesses associated with infection by Clostridium spp., Or Bartonella henselae, and puerperal fever;

Simple acute urinary tract infections associated with infection by Staphylococcus aureus, coagulase-negative Staphylococcus spp., Or Enterococcus spp .; urethritis and cervicitis;

Neiserria gonorrhea by Chlamydia trachomatis, Haemophilus ducreyi, Treponema pallidum, Ureaplasma urealyticum or Neisseria gonorrhea Diseases transmitted by sexual activity associated with infection;

Toxin disease associated with Staphylococcus aureus (food poisoning and toxin shock syndrome) or infection with group A, B, and C streptococci;

Ulcers associated with infection by Helicobacter pylori; systemic fever syndrome associated with infection by Borrelia recurrentis;

Lyme disease associated with infection by Borrelia burgdorferi; Chlamydia trachomatis, Neisseria gonorhea, Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus piogenes, hemophil Conjunctivitis, keratitis and folliculitis associated with infection by Rheumatic influenza or Listeria spp .;

Disseminated mycobacterium avium complex (MAC) disease associated with infection by Mycobacterium avium or Mycobacterium intracellulare;

Mycobacterium tuberculosis, Mycobacterium leprae, Mycobacterium paratuberculosis, Mycobacterium Kansasii ) Or infection caused by Mycobacterium keloni;

Gastroenteritis associated with infection by Campylobacter jejuni; intestinal protozoa associated with infection by Cryptosporidium spp .;

Periodontal infection associated with infection by Viridans streptococcal; chronic cough associated with infection by Bordetella pertussis;

Gas round bottoms associated with infection by Clostridium perfringens or Bacteroides spp .; And

Atherosclerosis or cardiovascular disease associated with infection by Helicobacter Philoly or Chlamydia pneumoniae.

Bacterial and protozoan infections that can be treated or prevented in animals, and diseases associated with such infections include the following diseases:

Respiratory diseases of cattle associated with infection by Pasteurella haemolytica, Pasteurella multocida, Mycoplasma bovis or Bordetella;

Bovine bowel disease associated with infection by protozoa (ie, coccidia, cryptosporidia, etc.);

Mastitis of cows associated with infection by the Staphylococcus aureus, Streptococcus uberis, Streptococcus agalactia, Streptococcus disgalactia, Corynebacterium or Enterococcus;

Swine respiratory disease associated with infection by the Actinobacillus pleuropneumoniae, Pasteurella multocida or Mycoplasma genus;

Swine intestinal disease associated with infection by Lawsonla intracellularis, Salmonella or Serpulina hyodysinteriae;

Bovine decompensation associated with infection by Fusobacterium spp .;

Bovine hairy warts associated with infection by Fusobacterium necrophorum or Bacteroides nodosus; epidemic cold of cattle associated with infection by Moraxella bovis;

Preterm birth of cattle associated with infection by protozoa (ie, neosporium);

Skin and soft tissue infections in dogs and cats associated with infection with Staphylococcus epidermidis, Staphylococcus intermedius, coagulase negative Staphylococcus spp. Or Pasteurella multocida; And

Infection by Alcaligenes spp., Bacteroides spp., Clostridium spp., Enterobacter spp., Eubacterium, Peptostreptococcus, Porphyromanas or Prevotella Or mouth infections in dogs and cats associated with.

Other bacterial and protozoal infections and diseases associated with such infections that can be treated or prevented in accordance with the methods of the present invention are described in JP Sanford et al., The Sanford Guide To Antimicrobial Therapy, 26th Ed., Antimicrobial Therapy. , Inc.) (1996).

In one embodiment of the present invention, the infectious disease is selected from the group consisting of staphylococcal food poisoning, cellulitis, lymphangitis, urinary tract infection, meningitis, peritonitis, cystitis, respiratory disease, otitis media, pneumonia, purulent inflammation and sepsis It is not limited to this.

In one embodiment of the present invention, the effective amount is preferably 1 to 512 µg / mL, but is not limited thereto.

The compound of Formula 1 of the present invention may be prepared from a production method known in the art using starting materials and catalysts known in the art, and may also be directly extracted from legumes such as 칡 and licorice. In one embodiment of the present invention, virtual screening using a computer in a database as described in Example 1 and then purchased from the company (ChemBridge Corp., San Diego, USA).

Hereinafter, the present invention will be described.

The present invention relates to a novel compound that inhibits beta-ketoacyl acyl group transfer protein synthase III and the use of the compound, which exhibits an antibiotic effect by inhibiting bacterial cell wall formation and killing the bacteria.

Hereinafter, the present invention will be described in detail.

In one embodiment of the present invention, where optically active centers are present in the compounds of the present invention, the present invention discloses, as individual specific embodiments, all individual optically active forms and mixtures thereof, and their corresponding racemates. do. Racemates can be prepared using known methods (see Advanced Organic Chemistry: 3rd Edition: author J March, p104-107), including the formation of diastereomeric derivatives with suitable optically active auxiliary groups followed by separation and decomposition of the auxiliary groups. Can be separated into individual optically active forms.

The compounds according to the invention may contain one or more asymmetrically substituted carbon atoms. The presence of one or more such asymmetric centers (chiral centers) in the compound of Formula 1 can lead to stereoisomers, in which case the invention relates to all stereoisomers, including enantiomers and diastereomers, and racemic mixtures thereof. It is to be understood that it extends to the mixture, including.

When tautomers (tautomers) are present in the compounds of the present invention, the present invention discloses all individual tautomeric forms and mixtures thereof as individual specific embodiments.

As described above, the compounds of the present invention are beta-ketoacyl acyl transfer protein producing enzyme inhibitors.

The compounds of the present invention may be provided as pharmaceutically acceptable salts. As these salts are acid addition salts formed with pharmaceutically acceptable free acids. The compound represented by Formula 1 may form a pharmaceutically acceptable acid addition salt according to a conventional method in the art. Organic acids and inorganic acids may be used as the free acid, hydrochloric acid, bromic acid, sulfuric acid or phosphoric acid may be used as the inorganic acid, and citric acid, acetic acid, lactic acid, tartaric acid, maleic acid, or fumaric acid may be used as the organic acid. (fumaric acid), formic acid, propionic acid, oxalic acid, trifluoroacetic acid, benzoic acid, gluconic acid, methanesulfonic acid, glycolic acid, succinic acid, 4-toluenesulfonic acid, galluxuronic acid, embonic acid, glutamic acid or aspartic acid Can be used.

In another aspect, suitable salts are alkali metal salts such as sodium or potassium, alkaline earth metal salts such as calcium or magnesium, or base salts such as organic amine salts such as triethylamine.

They may also be provided as in vivo hydrolyzable esters. These are pharmaceutically acceptable esters that hydrolyze in the human body to produce the parent compound. Such esters can be identified, for example, by intravenous administration of the test compound to the test animal followed by examination of the body fluids of the test animal. Suitable in vivo hydrolyzable esters for carboxy include methoxymethyl and for hydroxy include formyl and acetyl, especially acetyl.

Beta-ketoacyl acyl group transfer protein-producing enzyme inhibitor compounds (compounds of Formula 1) or pharmaceutically acceptable salts thereof or in vivo hydrolyzable compounds for therapeutic treatment (including prophylactic treatment) of mammals including humans To use an ester, it is generally formulated as a pharmaceutical composition according to standard pharmaceutical guidelines.

Therefore, in another aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention (compound of formula 1) or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof and a pharmaceutically acceptable carrier.

The products according to the invention can be used as medicaments, for example in the form of pharmaceutical preparations for enteric or parenteral administration. For example, the product according to the invention can be used orally in the form of tablets, coated tablets, dragees, hard and soft gelatin capsules, solutions, emulsions or suspensions; Into the rectum in the form of suppositories; Or parenterally, in the form of an injection solution.

The pharmaceutical preparations have a herbal dosage form in combination with other substances useful for the treatment of the substance according to the invention, with suitable nontoxic, inert, therapeutically compatible solid or liquid carrier materials, and, if necessary, with conventional pharmaceutical adducts. As such, it can be produced in a manner familiar to a person skilled in the art.

Both inorganic and organic carrier materials are suitable as such carrier materials. Thus, for example, lactose, corn starch or derivatives thereof, talc, stearic acid or its salts can be used as carrier materials for tablets, coated tablets, dragees and hard gelatin capsules. Examples of suitable carriers for soft gelatin capsules are vegetable oils, waxes, fats and semisolid and liquid polyols (but no carrier is required for soft gelatin capsules depending on the nature of the active ingredient). Examples of suitable carrier materials for the production of solutions and syrups are water, polyols, sucrose, invert sugar and glucose. Examples of suitable carrier materials for injection include water, alcohols, polyols, glycerol and vegetable oils. Examples of suitable carrier materials for suppositories include natural or hardened oils, waxes, fats and semisolid or liquid polyols.

Conventional preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavors, salts that change the osmotic pressure, buffers, masking agents and antioxidants are considered as pharmaceutical additives.

For oral administration, the compounds of Formula 1 and their respective salts are preferably provided as lyophilized or dry powder with conventional carriers such as water and isotonic saline for dilution.

The pharmaceutical compositions of the invention can be administered by standard methods for the disease or condition to be treated, for example by oral, topical, parenteral, buccal, nasal, vaginal or rectal administration or by inhalation. To this end, the compounds of the invention can be prepared by means known in the art, for example tablets, capsules, aqueous or oily solutions, suspensions, emulsions, creams, ointments, gels, nasal sprays, suppositories, fine powders or inhalable aerosols. And, in the form of sterile aqueous or oily solutions or suspensions or sterile emulsions for parenteral use (including intravenous, intramuscular or infusion).

The pharmaceutical compositions of the present invention may contain or co-administer (simultaneously or sequentially) in addition to the compounds of the present invention and also useful for treating one or more of the diseases or conditions mentioned above.

The pharmaceutical compositions of the present invention will generally be administered to humans such that the daily dose is between 0.1 and 100 mg / kg body weight (preferably between 0.5 and 50 mg / kg body weight). Such daily doses may be administered in divided doses as needed and the exact amount and route of administration of the compound administered will depend on the weight, age and sex of the patient to be treated and the particular disease or condition to be treated according to principles known in the art. do.

Unit dosage forms will typically contain about 1 to 1000 mg of a compound of the present invention. Therefore in another aspect the present invention provides a compound of formula (1) or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof for use in or as a therapeutic method for human or animal therapeutic treatment. The present invention discloses use in the treatment of a disease or condition mediated by one or more beta-ketoacyl acyl group transfer protein producing enzymes.

It is contemplated that the invention described herein is not limited to the particular methods, protocols, and reagents described as being varied. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the scope of the present invention in any way.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in practicing or testing the present invention, the preferred methods, devices, and materials are described below.

In the practice of the present invention, many conventional techniques of molecular biology and cell biology are used. These techniques are well known and are described, for example, in Current Protocols in Molecular Biology, Volumes I, II and III, 1997 (F. M. Ausubel ed.); Sambrook et al., 1989, Molecular Cloning: A Laboratory Manual, Second Edition, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N. Y.

As can be seen from the above solution and the following examples, the present invention is utilized as an antibiotic by inhibiting fatty acid synthesis using a compound that ultimately inhibits beta-ketoacyl acyl transfer protein synthase III.

Hereinafter, the present invention will be described in more detail with reference to non-limiting examples. However, the following examples are described to help the understanding of the present invention, the scope of the present invention is not to be construed as limited by the following examples.

< Example  1> Using protein-based activated skeleton Virtual drug discovery  efficiency

Pharmacophores are three-dimensional arrays of chemical groups (or features) that drugs (ligands) must have in order to be effective against a target disease or target protein. In particular, in order for a compound to bind well with a protein and increase or inhibit its activity, the definition of an active skeleton is very important. The active skeleton consists of a kind of features called hydrogen bond donor (HBA), hydrogen bond acceptor (HBD), and hydrophobic site (Lipo), and they are properly combined to form a map.

YKA3028 (4-[(5-Trifluoromethyl-pyridin-2-yl) -hydrazonomethyl] -benzene-1,3-diol, filed No. 10-2009-0123794, filed for inhibition of KAS III through a second virtual drug search After confirming that the compound is finally a KAS III inhibitor, construct and search a compound database consisting of YKA3028 analogues of derivatives (analogues) of the existing active skeletal map to generate beta-ketoacyl acyl transfer protein. A potential substance was reselected as an enzyme III inhibitor.

The library for virtual drug discovery was configured in the form of Accelrys' Catalyst / CatDB, and the compound was well tuned to find multiple conformations of three-dimensional structures to include all chemically compatible conformers.

Using the Cerius2 / SBF module of Accelrys of the present invention was carried out using a single map finally selected nine candidates (YKA3032 ~ YKA3038) as a KAS III inhibitor candidate (FIG. 3).

< Example  2> Fluorescence spectroscopy  Calculation of the coupling constant used

10 μM of KAS III was dissolved in 150 mM Sodiumphosphate, 100 mM NaCl, and pH 8.0 buffer, and the concentration and fluorescence intensity were recorded while adding small amounts of inhibitor until the final concentration of the protein and inhibitor was 1: 100. The binding constant K was calculated using the following equation.

Where F ₀ and F are the intensity of the fluorescence signal detected at 324 nm with and without inhibitors, respectively, and n is the number of inhibitors in the protein.

Results: E. coli of YKA3036 among 9 candidates for KAS III K for KAS III (ecKAS III) was found to be 19 nM and 0.12 μM for E. faecalis KAS III (efKAS III), which strongly binds to KAS III. The experimental results are shown in FIG. 4.

< Example  3> minimum inhibitory concentration ( minimal inhibitory concentration , MIC Determination of Anti-Bioactivity through Measurement

It is possible to measure the growth of bacteria in control plate and antibiotic-free plate under the condition that the concentration of bacteria is uniform. The results are summarized through at least 3 replicates. Antibiotics were measured by dilution method (micro dilution method).

Antibiotic effects were measured primarily for 16 selected compounds. Strain used in the experiment is a representative gram-negative bacteria (Gram-negative) Escherichia coli (E. coli, KCTC 1682), Gram-positive Staphylococcus aureus ( S. aureus , KCTC 1621), Enterococcus faecalis ( E. faecalis , KCTC 2011) was used as the resistant strain, Methicillin-resistant staphylococcus aureus (MRSA, CCARM3114), and Vancomycin-resistant enterococcus faecalis (VREF, clinical isolated) was also investigated. For comparison, thiolactomycin (TLM), a known antibiotic and known to have KAS inhibitory effect, was used as a reference substance. Antibiotic effectiveness of the TLM tends affected depending on the strain of the strain is known to be effective antibiotics does not develop resistance to E. coli, by default, the IC ₅₀ value for the KAS III is known about 10μM.

Antimicrobial activity of YKA3036 showed 1 ~ 512㎍ / mL activity in 4 strains and Enterococcus. Very good activity of 1 µg / mL was observed in faecalis and MRSA. The experimental results are shown in FIG. 5.

1 is a representation of the reaction scheme of fatty acid synthesis by KAS III protein in bacteria.

2 is a diagram showing the structure of a known KAS III inhibitor.

3 is a structural diagram of seven candidate substances selected through virtual drug search.

4 shows the binding constant (K) for KAS III using fluorescence spectroscopy. For YKA3036, K for ecKASIII is 19 nM and 0.12 μM for efKAS III. .

5 is a diagram showing the results of anti-bioactivity measurement by measuring the minimum inhibitory concentration (MIC) in various bacteria. TLM (Thiolactomycin) was used as a control compound.

Claims (5)

delete delete Resistant to E. coli, Staphylococcus aureus, Staphylococcus aureus, methicillin resistant to methicillin, and vancomycin containing an effective amount of a compound of Formula 1 A pharmaceutical composition for preventing or treating an infectious disease caused by a microorganism selected from the group consisting of visible enterococcus whicalis (VREF) and enterococcus whicalis.

[Formula 1] delete The pharmaceutical composition of claim 3, wherein the effective amount is 1 to 512 µg / mL.

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