Pharmaceutical composition for preventing or treating penicillin-based compound-resistant bacteria-mediated diseases comprising oxazolidinone derivative

Abstract

A pharmaceutical composition according to one aspect comprises an oxazolidinone derivative or a pharmaceutically acceptable salt thereof, and thus can exhibit excellent prophylactic or therapeutic effects on diseases mediated by bacteria having resistance to penicillin-based compounds, and in particular, when used in combination with one or more antibiotics, can exhibit excellent effects such as an increase in overall healing rate, elimination of mediating bacteria, inhibition of an increase in severity, inhibition of occurrence of adverse events, an increase in safety, an increase in tolerability, and the like. Accordingly, the composition can be used as a therapeutic agent for penicillin-based compound-resistant bacteria-mediated diseases such as bacteremia, sepsis, endocarditis, and the like.

Description

Pharmaceutical composition for the prevention or treatment of penicillin-resistant bacteria-mediated diseases comprising oxazolidinone derivatives

[0001] The present invention relates to a pharmaceutical composition for the prevention or treatment of penicillin-resistant bacteria-mediated diseases comprising an oxazolidinone derivative.

[0002]

[0003] Staphylococcus aureus (S. aureus) is a common pathogen causing infections in the human body. It primarily colonizes the nasopharynx, skin, nasal cavity, and gastrointestinal tract. As a pathogen causing various infections such as skin and soft tissue infections, pneumonia, osteoarthritis, and bacteremia, it is reported to be a major causative agent of healthcare-associated infections. With the increasing use of catheters or artificial devices and invasive procedures, severe infections caused by S. aureus are on the rise. Furthermore, since many of these strains exhibit resistance to existing antibiotics, appropriate antibiotic treatment is becoming difficult. Since the first appearance of methicillin-resistant Staphylococcus aureus (MRSA) in 1961, antibiotic resistance has developed rapidly, leading to an increase in the frequency of MRSA infections (Choo EJ, 2018; Lee YJ, 2010).

[0004] MRSA bacteremia is a severe bloodstream infection that shows a high mortality rate among various infectious diseases (Ortwine JK, 2018). The mortality rate due to MRSA bacteremia is approximately 20 to 40%, and it is known to be more difficult to treat and have a higher fatality rate compared to S. aureus bacteremia (Holubar M, 2016). Therefore, the rapid administration of appropriate antibiotics plays an important role in improving patient survival rates.

[0005] The Infectious Diseases Society of America (IDSA) guidelines recommend intravenous vancomycin or daptomycin therapy for a minimum of 14 days to a maximum of 42 days as a first-line treatment for MRSA bacteremia, and recommend administering a high dose of daptomycin (10 mg / kg / day) first in the event of vancomycin treatment failure, as well as combination therapy with other antibiotics such as gentamycin, rifampicin, linezolid, and β-lactam antibiotics (Liu C, 2011).

[0006] Vancomycin is a glycopeptide antibiotic that exhibits a bactericidal effect by inhibiting bacterial cell wall synthesis and is currently the primary antibiotic used for the treatment of MRSA bacteremia. However, compared to oxacillin, vancomycin has a slower bactericidal action, lower permeability to lung tissues and the central nervous system, and an increase in the Minimum Inhibitory Concentration (MIC) against MRSA known as 'MIC Creep,' so there are limitations to treating MRSA bacteremia with vancomycin alone (Liu C, 2011, Paiva JA, 2017). With vancomycin, a good therapeutic effect can be expected only when the area under the curve (AUC) / MIC is maintained at least above 400; therefore, if the MIC of the causative bacteria rises, the AUC must also rise. However, recently isolated MRSA strains often have increased MICs of 1 or 2 mcg / mL, making it difficult to maintain an AUC / MIC of 400 or higher, which is leading to an increased failure rate of vancomycin treatment. Furthermore, the dosage must be increased in the treatment of bacteremia accompanied by severe infections such as infectious endocarditis, osteomyelitis, and pneumonia, which entails the problem of increased renal toxicity (Nguyen HM, 2010). In addition, due to the increased frequency of vancomycin use, the incidence of resistant strains with reduced susceptibility to vancomycin (heterogenous vancomycin intermediate S. aureus, hVISA) is increasing, necessitating research on the development of new antibiotics and combination therapies to effectively treat multidrug-resistant S. aureus infections (Nguyen HM, 2010; Howden B, 2015).

[0007] Recently, several antibiotics with antimicrobial activity against MRSA have been newly developed and are being used in clinical practice. Currently, daptomycin, a cyclic lipopeptide antibiotic, is being considered as an alternative to vancomycin; however, it is not recommended for the treatment of respiratory infections due to its poor penetration into lung tissues, and rhabdomyolysis has been reported as a side effect (Ortwine JK, 2018; Liu C, 2011). Additionally, while newly developed drugs for the treatment of MRSA bacteremia have demonstrated non-inferiority compared to vancomycin, no drug has been proven to be more effective than vancomycin for the treatment of MRSA bacteremia to date. Furthermore, because these new drugs have disadvantages such as high costs and serious side effects, vancomycin is currently used as the first-line treatment for MRSA bacteremia (Paiva JA, 2017; Tong SYC, 2016; Vardakas, 2012).

[0008] Meanwhile, antibiotic combination therapy aims to reduce the development of resistance and enhance antimicrobial efficacy through different mechanisms of action. However, daptomycin, beta-lactam antibiotics, and linezolid, which are considered alternatives when vancomycin treatment fails, have all failed to demonstrate an enhancement in antimicrobial efficacy in combination therapy with vancomycin (Nguyen HM, 2010; Deresinski S, 2009; Tong SY, 2020). In particular, regarding linezolid, as its clinical usage frequency increases, the emergence of linezolid-resistant S. aureus and enterococci is increasingly being reported in the United States and Europe. Furthermore, the long-term use of linezolid is being significantly restricted due to issues such as monoamine oxidase inhibition and myelotoxicity, including thrombocytopenia, anemia, and neutropenia (Ortwine JK, 2018; Lee Hyun-hee, et al., 2014; Pillai SK, et al., 2002).

[0009] Therefore, there is a need to develop new oxazolidinone antibiotics that can overcome the resistance problems of linezolid and improve toxicity issues.

[0010]

[0011] One aspect provides a pharmaceutical composition for the prevention or treatment of penicillin-resistant bacterial-mediated diseases comprising an oxazolidinone derivative represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof:

[0012] [Chemical Formula 1]

[0013]

[0014] (In the above chemical formula 1,

[0015] The above X is a chemical bond, -(CH2) n - or -(CH2) n C(=O)- igo;

[0016] The above n is an integer from 0 to 2;

[0017] The above R is hydrogen or a pentagonal or hexaagonal heteroaryl selected from the following structures;

[0018] ;

[0019] The above R1 to R 25 are independently hydrogen, (C1-C6) alkyl, (C3-C6) cycloalkyl, -OH, -NR 31 R 32 , -C(=O)R 33 , -(CH2) m OH, -C=NOH, -CN, -NO2 or halogen;

[0020] The above R 31 and R 32 are independently hydrogen, (C1-C6) alkyl, or -C(=O)H;

[0021] The above R 33 It is hydrogen, -OH, -NH2, or (C1-C6) alkyl;

[0022] The above m is one integer from 1 to 6;

[0023] The above Q is -OH, -NHC(=O)R 41 or -NHC(=O)OR 41 is;

[0024] The above R 41 It is a (C1-C6) alkyl.

[0025] Another aspect is to provide an antibiotic composition for the prevention or treatment of penicillin-resistant bacteria-mediated diseases comprising an oxazolidinone derivative represented by the above chemical formula 1 or a pharmaceutically acceptable salt thereof.

[0026] Another aspect is an oxazolidinone derivative represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof; and

[0027] The present invention provides a pharmaceutical composition for the prevention or treatment of penicillin-resistant bacteria-mediated diseases comprising an antibiotic selected from the group consisting of vancomycin, telavancin, dalbavancin, oritavancin, daptomycin, tigecycline, doxycycline, minocycline, omadacycline, clindamycin, imipenem, meropenem, ertapenem, doripenem, ciprofloxacin, levofloxacin, moxifloxacin, delafloxacin, rifampicin, rifabutin, and rifapentine.

[0028] Another aspect is an oxazolidinone derivative represented by the above chemical formula 1 or a pharmaceutically acceptable salt thereof; and

[0029] The present invention provides an antibiotic composition for the prevention or treatment of penicillin-resistant bacteria-mediated diseases comprising an antibiotic selected from the group consisting of vancomycin, telavancin, dalbavancin, oritavancin, daptomycin, tigecycline, doxycycline, minocycline, omadacycline, clindamycin, imipenem, meropenem, ertapenem, doripenem, ciprofloxacin, levofloxacin, moxifloxacin, delafloxacin, rifampicin, rifabutin, and rifapentine.

[0030] Another aspect provides a method for preventing or treating penicillin-resistant bacteria-mediated diseases, comprising the step of administering an oxazolidinone derivative represented by the above chemical formula 1 or a pharmaceutically acceptable salt thereof to an individual in need thereof.

[0031] Another aspect provides a method for preventing or treating a disease mediated by penicillin-resistant bacteria, comprising the step of administering an antibiotic composition comprising an oxazolidinone derivative represented by the above chemical formula 1 or a pharmaceutically acceptable salt thereof to an individual in need thereof.

[0032] Another aspect is an oxazolidinone derivative represented by the above chemical formula 1 or a pharmaceutically acceptable salt thereof; and

[0033] The present invention provides a method for preventing or treating penicillin-resistant bacteria-mediated diseases, comprising the step of administering an antibiotic selected from the group consisting of vancomycin, telavancin, dalbavancin, oritavancin, daptomycin, tigecycline, doxycycline, minocycline, omadacycline, clindamycin, imipenem, meropenem, ertapenem, doripenem, ciprofloxacin, levofloxacin, moxifloxacin, delafloxacin, rifampicin, rifabutin, and rifapentine to an individual in need.

[0034] Another aspect is an oxazolidinone derivative represented by the above chemical formula 1 or a pharmaceutically acceptable salt thereof; and

[0035] The present invention provides a method for preventing or treating penicillin-resistant bacteria-mediated diseases, comprising the step of administering an antibiotic composition comprising an antibiotic selected from the group consisting of vancomycin, telavancin, dalbavancin, oritavancin, daptomycin, tigecycline, doxycycline, minocycline, omadacycline, clindamycin, imipenem, meropenem, ertapenem, doripenem, ciprofloxacin, levofloxacin, moxifloxacin, delafloxacin, rifampicin, rifabutin, and rifapentine to an individual in need thereof.

[0036] Another aspect is to provide the use of an oxazolidinone derivative represented by the above formula 1 or a pharmaceutically acceptable salt thereof for the prevention or treatment of penicillin-resistant bacteria-mediated diseases.

[0037] Another aspect is to provide the use of an antibiotic composition comprising an oxazolidinone derivative represented by the above formula 1 or a pharmaceutically acceptable salt thereof for the prevention or treatment of penicillin-resistant bacteria-mediated diseases.

[0038] Another aspect is an oxazolidinone derivative represented by Formula 1 or a pharmaceutically acceptable salt thereof for the prevention or treatment of penicillin-resistant bacteria-mediated diseases; and

[0039] The invention provides a use of a pharmaceutical composition comprising an antibiotic selected from the group consisting of vancomycin, telavancin, dalbavancin, oritavancin, daptomycin, tigecycline, doxycycline, minocycline, omadacycline, clindamycin, imipenem, meropenem, ertapenem, doripenem, ciprofloxacin, levofloxacin, moxifloxacin, delafloxacin, rifampicin, rifabutin, and rifapentine.

[0040] Another aspect is an oxazolidinone derivative represented by Formula 1 or a pharmaceutically acceptable salt thereof for the prevention or treatment of penicillin-resistant bacteria-mediated diseases; and

[0041] The present invention provides the use of an antibiotic composition comprising an antibiotic selected from the group consisting of vancomycin, telavancin, dalbavancin, oritavancin, daptomycin, tigecycline, doxycycline, minocycline, omadacycline, clindamycin, imipenem, meropenem, ertapenem, doripenem, ciprofloxacin, levofloxacin, moxifloxacin, delafloxacin, rifampicin, rifabutin, and rifapentine.

[0042] Another aspect is to provide the use of an oxazolidinone derivative represented by the above formula 1 or a pharmaceutically acceptable salt thereof for the manufacture of a drug for the prevention or treatment of diseases mediated by penicillin-resistant bacteria.

[0043] Another aspect is to provide the use of an antibiotic composition comprising an oxazolidinone derivative represented by the above formula 1 or a pharmaceutically acceptable salt thereof for the manufacture of a drug for the prevention or treatment of diseases mediated by penicillin-resistant bacteria.

[0044] Another aspect is an oxazolidinone derivative represented by Formula 1 or a pharmaceutically acceptable salt thereof for the manufacture of a drug for the prevention or treatment of diseases mediated by penicillin-resistant bacteria; and

[0045] The present invention provides the use of an antibiotic composition comprising an antibiotic selected from the group consisting of vancomycin, telavancin, dalbavancin, oritavancin, daptomycin, tigecycline, doxycycline, minocycline, omadacycline, clindamycin, imipenem, meropenem, ertapenem, doripenem, ciprofloxacin, levofloxacin, moxifloxacin, delafloxacin, rifampicin, rifabutin, and rifapentine.

[0046] Another aspect is an oxazolidinone derivative represented by Formula 1 or a pharmaceutically acceptable salt thereof for the manufacture of a drug for the prevention or treatment of diseases mediated by penicillin-resistant bacteria; and

[0047] The invention provides a use of a pharmaceutical composition comprising an antibiotic selected from the group consisting of vancomycin, telavancin, dalbavancin, oritavancin, daptomycin, tigecycline, doxycycline, minocycline, omadacycline, clindamycin, imipenem, meropenem, ertapenem, doripenem, ciprofloxacin, levofloxacin, moxifloxacin, delafloxacin, rifampicin, rifabutin, and rifapentine.

[0048]

[0049] One aspect provides a pharmaceutical composition for the prevention or treatment of penicillin-resistant bacterial-mediated diseases comprising an oxazolidinone derivative represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof:

[0050] [Chemical Formula 1]

[0051]

[0052] (In the above chemical formula 1,

[0053] The above X is a chemical bond, -(CH2) n - or -(CH2) n C(=O)- igo;

[0054] The above n is an integer from 0 to 2;

[0055] The above R is hydrogen or a pentagonal or hexaagonal heteroaryl selected from the following structures;

[0056] ;

[0057] The above R1 to R 25 are independently hydrogen, (C1-C6) alkyl, (C3-C6) cycloalkyl, -OH, -NR 31 R 32 , -C(=O)R33 , -(CH2) m OH, -C=NOH, -CN, -NO2 or halogen;

[0058] The above R 31 and R 32 are independently hydrogen, (C1-C6) alkyl, or -C(=O)H;

[0059] The above R 33 It is hydrogen, -OH, -NH2, or (C1-C6) alkyl;

[0060] The above m is one integer from 1 to 6;

[0061] The above Q is -OH, -NHC(=O)R 41 or -NHC(=O)OR 41 is;

[0062] The above R 41 It is a (C1-C6) alkyl.

[0063] In one embodiment, the above R may be hydrogen.

[0064] In one embodiment, the above Q may be -OH.

[0065] In one embodiment, the oxazolidinone derivative represented by the above chemical formula 1 is

[0066] and It may be a compound represented as one selected from the group consisting of

[0067] In one embodiment, the oxazolidinone derivative represented by Formula 1 or a pharmaceutically acceptable salt thereof may be a compound represented by Formula 2 below or a pharmaceutically acceptable salt thereof:

[0068] [Chemical Formula 2]

[0069] .

[0070] The oxazolidinone derivative represented by Chemical Formula 1 above may be prepared and used in the form of a prodrug, hydrate, solvate, isomer, or pharmaceutically acceptable salt to enhance in vivo absorption or increase solubility. Accordingly, the oxazolidinone derivative or its pharmaceutically acceptable salt includes its prodrug, hydrate, solvate, isomer, or pharmaceutically acceptable salt.

[0071] The oxazolidinone derivative represented by the above chemical formula 1 may exist in a solvated form, for example, a hydrated form and a nonsolvated form, and the solvates of the oxazolidinone derivative represented by the above chemical formula 1 include all solvated forms having pharmaceutical activity.

[0072] The oxazolidinone derivative represented by Chemical Formula 1 above may comprise a prodrug form. The prodrug may be used to modify or improve the physical and / or pharmacokinetic profile of the parent compound and may be formed if it contains a suitable group or substituent that can induce the parent compound to form the prodrug. The prodrug comprises, for example, an in vivo hydrolyzable ester of the oxazolidinone derivative represented by Chemical Formula 1 and a pharmaceutically acceptable salt thereof.

[0073] Various forms of the above-mentioned prodrugs are known in the art, for example, a) literature [Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) and Methods in Enzymology, Vol. 42, p.309-396, edited by K. Widder, et al. (Academic Press, 1985)]; b) literature [A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 "Design and Application of Prodrugs", by H. Bundgaard p. 113-191 (1991)]; c) literature [H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992)]; d) literature [H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285 (1988)]; and e) You may refer to the literature [N. Kakeya, et al., Chem Pharm Bull, 32, 692 (1984)], etc.

[0074] The above prodrugs may include, for example, the following compounds.

[0075]

[0076] As shown in the example above, it can be manufactured in a form that is active in the body by attaching a phosphonate or acetyl group to a hydroxyl group, or there are methods such as attaching an amino acid or manufacturing it in the form of a carbonate. The above prodrug is mainly used when solubility or absorption is relatively low, and when modified into a prodrug, not only are solubility and absorption increased, but ADME (absorption, distribution, metabolism, excretion) and PK profile can also be improved.

[0077] The oxazolidinone derivative represented by the above chemical formula 1 has a chiral center at the C-5 position of the oxazolidinone ring. A preferred diastereomer of the above oxazolidinone derivative compound is identical to the above chemical formula 1 and can exhibit a superior MAO profile compared to the epimer compound represented by the following chemical formula 1b.

[0078] [Chemical Formula 1b]

[0079]

[0080] When any mixture of epimers on the chiral center is used, the amount used can be adjusted by taking into account the ratio of diastereomers in order to obtain the same effect with pharmaceutical activity as when using the enantiomer alone.

[0081] Since the oxazolidinone derivative represented by the above chemical formula 1 can exhibit tautomerization, even if only one possible tautomer form is expressed in the chemical formula or reaction formula, it includes any tautomer form having antibacterial activity and is not limited to just the single tautomer form used in the chemical formula or reaction formula.

[0082] The oxazolidinone derivative represented by Chemical Formula 1 above may also exhibit polymorphism and includes any polymorphic compound having antibacterial activity. The oxazolidinone derivative represented by Chemical Formula 1 above can be prepared by various known methods depending on the type of substituent, for example, according to the method exemplified in Reaction Scheme 1 or 2 below. Since the preparation method presented in Reaction Scheme 1 or 2 below is merely an example and can be easily modified by those skilled in the art depending on specific substituents, the method exemplified in Reaction Scheme 1 or 2 below does not limit the method of preparing the oxazolidinone compound represented by Chemical Formula 1 below, and unless otherwise stated, the definition of the substituent in the following reaction scheme is the same as the definition in Chemical Formula 1 above. The oxazolidinone derivative represented by Chemical Formula 1 above can be synthesized by different methods depending on Q above. For example, if the above Q is -OH, it can be synthesized according to the following reaction scheme 1, and if the above Q is N-acetyl, it can be synthesized according to the following reaction scheme 2.

[0083] Specifically, in the case of Reaction Scheme 1, compound I is synthesized by reacting difluoronitrobenzene with ethanolamine, and the alcohol and amine are protected with TBS (t-butyldimethylsilyl) or BOC, respectively (compound II). Then, the nitro group is reduced to an amine using Pd / C (compound III), and a Cbz group is attached using Cbz-Cl to synthesize compound IV. Compound IV is reacted with (R)-glycidyl butyrate and BuLi to synthesize a chiral compound V. In compound V, the alcohol group is first protected with benzoyl, then the BOC and TBS protecting groups are removed with hydrochloric acid (compound VI), and mesylation is performed to synthesize compound VII. Compound VII is reacted with hydrazine and then reacted again with trimethylorthoformate to synthesize cyclic amiderazone compound VIII. From compound VIII, the formyl group can be removed (compound IX) and various R groups can be introduced to form the linking part X and obtain an oxazolidinone derivative represented by the above chemical formula 1.

[0084] [Reaction Equation 1]

[0085]

[0086] When Q is N-acetyl, compound V synthesized in Reaction Scheme 1 is reacted with methanesulfonyl chloride (Ms-Cl) and then reacted with sodium azide (NaN3) to synthesize compound X. Compound X is converted into an amine using Pd / C under hydrogen gas, and then a cbz group is attached using Cbz-Cl to synthesize compound XII. Compound XII is treated with hydrochloric acid to remove the protecting groups boc and tbs, and then reacted with methanesulfonyl chloride (Ms-Cl) to synthesize compound XIII. Compound XIII is reacted with hydrazine and then with trimethylorthoformate to synthesize cyclic amiderazone compound XIV. After removing the protecting group cbz from compound XIV and introducing an acetyl group (compound XV), a formyl group is removed from compound XV and various R groups are introduced to obtain a compound represented by Chemical Formula 1.

[0087] [Reaction Equation 2]

[0088]

[0089] The above pharmaceutical composition may be in a form suitable for oral use (e.g., tablets, lozenges, hard or soft capsules, aqueous or oil suspensions, emulsions, dispersible powders or granules, syrups or elixirs).

[0090] Additionally, the pharmaceutical composition may contain one or more known drugs selected from other clinically useful antimicrobial agents (e.g., β-lactams, macrolides, quinolones, or aminoglycosides) and / or other anti-infective agents (e.g., antifungal triazoles or amphotericins) (i.e., by co-formulation) or may be co-administered with one or more of these known drugs. To enhance therapeutic efficacy, they may include carbapenems, e.g., meropenem or imipenem. The pharmaceutical composition may also be formulated with or co-administered with bactericidal / permeability-enhancing protein (BPI) products or efflux pump inhibitors to enhance activity against Gram-negative bacteria and bacteria resistant to antimicrobial agents.

[0091] The above pharmaceutical composition may be formulated with or co-administered with vitamins, for example, vitamin B, for example, vitamin B2, vitamin B6, vitamin B12, and folic acid. The compound of the present invention may be formulated with or co-administered with cyclooxygenase (COX) inhibitors, particularly COX-2 inhibitors. In addition, the above pharmaceutical composition may be formulated and co-administered with an antimicrobial agent active against Gram-positive or Gram-negative bacteria.

[0092] The above pharmaceutical composition can be obtained by a conventional process using conventional pharmaceutical excipients widely known in the art. Accordingly, a composition intended for oral administration may contain, for example, one or more coloring agents, sweeteners, flavoring agents, and / or preservatives. A pharmaceutical composition intended for intravenous administration may advantageously contain a suitable fungicide, antioxidant, or reducing agent, or a suitable sequestrant (for example, to enhance stability).

[0093] The composition for oral administration may be in the form of a hard gelatin capsule in which the active ingredient is mixed with an inert solid diluent, e.g., calcium carbonate, calcium phosphate, or kaolin, or in the form of a soft gelatin capsule in which the active ingredient is mixed with water or oil, e.g., peanut oil, liquid paraffin, or olive oil.

[0094] Aqueous suspensions generally comprise one or more suspending agents, e.g., sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, tragaccand gum, and acacia gum; It contains an active ingredient in a finely divided form, together with a dispersant or wetting agent, e.g., lecithin, or a condensation product of an alkylene oxide and a fatty acid (e.g., polyoxyethylene stearate), or a condensation product of an ethylene oxide and a long-chain aliphatic alcohol, e.g., heptadecaethyleneoxycetanol, or a condensation product of an ethylene oxide and a partial ester derived from a fatty acid and hexitol, e.g., polyoxyethylene sorbitol monooleate, or a condensation product of an ethylene oxide and a long-chain aliphatic alcohol, e.g., heptadecaethyleneoxycetanol, or a condensation product of an ethylene oxide and a partial ester derived from a fatty acid and hexitol, e.g., polyoxyethylene sorbitol monooleate, or a condensation product of an ethylene oxide and a partial ester derived from a fatty acid and hexitol anhydride, e.g., polyethylene sorbitan monooleate. Aqueous suspensions may contain one or more preservatives (e.g., ethyl or propyl p-hydroxybenzoate), antioxidants (e.g., ascorbic acid), coloring agents, flavoring agents and / or sweeteners (e.g., sucrose, saccharin, or aspartame).

[0095] Oil suspensions can be formulated by suspending the active ingredient in vegetable oil (e.g., arachnid oil, olive oil, sesame oil, or coconut oil) or mineral oil (e.g., liquid paraffin). Oil suspensions may also contain thickeners, such as beeswax, hard paraffin, or cetyl alcohol. Sweeteners and flavoring agents as mentioned above can be added to provide a palatable oral formulation. These compositions can be preserved by adding antioxidants such as ascorbic acid.

[0096] Dispersible powders and granules suitable for preparing aqueous suspensions by adding water contain an active ingredient along with a dispersant or wetting agent, a suspending agent, and one or more preservatives. Suitable dispersant or wetting agents and suspending agents are exemplified as previously mentioned. Additional excipients such as sweeteners, flavoring agents, and coloring agents may also be present.

[0097] For additional information regarding formulations, refer to the following literature [Reference: Chapter 25.2 in Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press 1990].

[0098] The amount of active ingredient combined with one or more excipients to produce a single dosage form will vary depending on the host being treated and the specific route of administration. For example, a formulation intended for oral administration to humans may generally contain 50 mg to 5 g of the active ingredient compound along with a convenient and appropriate amount of excipients (which may be about 5 to about 98% of the total weight of the composition). A dosage unit form will generally contain about 200 mg to about 2 g of the active ingredient. For additional information regarding the route of administration and dosage regimen, refer to the following reference [Reference: Chapter 25.3 in Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press 1990].

[0099] In one embodiment, the pharmaceutical composition may be administered intravenously, subcutaneously, or intramuscularly to each patient, for example, at a dose of 0.1 mg / kg to 20 mg / kg or 1 mg / kg to 20 mg / kg per day, and an oral dose per day that may be approximately equivalent to the parenteral dose per day may be administered to the patient, and the pharmaceutical composition may be administered 1 to 4 times per day.

[0100] The term "salt" above may be an acid addition salt formed by a free acid, an alkali metal salt (sodium salt, potassium salt, etc.), or an alkaline earth metal salt (calcium salt, magnesium salt, etc.). Inorganic acids and organic acids may be used as the free acid forming the acid addition salt. Inorganic acids may include hydrochloric acid, bromic acid, nitric acid, sulfuric acid, perchloric acid, phosphoric acid, etc., and organic acids may include citric acid, acetic acid, lactic acid, maleic acid, fumaric acid, gluconic acid, methanesulfonic acid, glyconic acid, succinic acid, tartaric acid, galacturonic acid, emvonic acid, glutamic acid, aspartic acid, oxalic acid, (D) or (L) malic acid, maleic acid, methanesulfonic acid, ethanesulfonic acid, 4-toluenesulfonic acid, salicylic acid, citric acid, benzoic acid, or malonic acid.

[0101] The above acid addition salts are, for example, acetate, aspartate, benzate, besylate, bicarbonate / carbonate, bisulfate / sulfate, borate, camsylate, citrate, edicilate, esylate, formate, fumarate, gluteptate, gluconate, glucuronate, hexafluorophosphate, hyperbenzate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, isethionate, lactate, malate, maliate, malonate, mesylate, methyl sulfate, naphthylate, 2-naphthylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate / dihydrogen phosphate, saccharate, stearate, succinate, tartrate, It may be tosylate, trifluoroacetate, aluminum, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine, or zinc salt, and specifically may be hydrochloride or trifluoroacetate.

[0102] The above acid addition salt can be prepared, for example, by dissolving an active substance in an organic solvent such as methanol, ethanol, acetone, methylene chloride, or acetonitrile and adding the organic acid or inorganic acid to produce a precipitate, which is then filtered and dried; or by vacuum distilling an organic solvent and an excess amount of acid and then drying, or by crystallizing under an organic solvent.

[0103] In addition, the above alkali metal salt or alkaline earth metal salt can be obtained, for example, by dissolving an active substance in an excess amount of an alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the undissolved compound salt, and evaporating and drying the filtrate. At this time, it is pharmaceutically suitable to prepare sodium, potassium, or calcium salts as the metal salts. In addition, the corresponding silver salt can be obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (e.g., silver nitrate).

[0104] The above term “pharmaceutically acceptable salt” means a salt prepared using a compound according to one aspect and a relatively non-toxic acid or base. When the compound contains relatively acidic functional groups, a base addition salt may be obtained by contacting a sufficient amount of base with the neutral form of the compound in a pure solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include salts of sodium, potassium, calcium, ammonium, organic amines, or magnesium, or similar salts. When the compound contains relatively basic functional groups, an acid addition salt may be obtained by contacting a sufficient amount of acid with the neutral form of the compound in a pure solution or a suitable inert solvent. Pharmaceutically acceptable acid addition salts include salts of inorganic acids such as hydrochloric acid, hydrobromide, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, or phosphoric acid, and salts of organic acids such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, souveric acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-tolylsulfonic acid, citric acid, tartaric acid, and methanesulfonic acid, and further include salts of amino acids (e.g., arginine) and salts of organic acids such as glucuronic acid.

[0105] The above pharmaceutically acceptable salts can be synthesized by conventional chemical methods from parent compounds containing an acidic or basic portion. Generally, such salts are prepared by reacting the free acid or base form of these compounds with a stoichiometrically appropriate amount of base or acid in water, an organic solvent, or a mixture of both. Generally, the medium may be a non-aqueous medium such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile.

[0106] The oxazolidinone derivative represented by the above chemical formula 1 can exhibit antibacterial activity against Gram-positive bacteria such as Staphylococcus aureus, Enterococcus faecalis, and Enterococcus faecium, and Gram-negative bacteria such as Haemophilus influenzae and Moraxella catarrhalis, which are resistant to existing antibiotics, at much lower concentrations than linezolid currently on the market.

[0107] The above term "penicillin-based compound" refers to a compound belonging to the beta-lactam group, wherein a portion of the beta-lactam arbitrarily binds to a transpeptidase that links peptidoglycan molecules, thereby causing weakening of the bacterial cell wall.

[0108] In one embodiment, the penicillin-based compound may be one or more selected from the group consisting of methicillin, dicloxacillin, oxacillin, flucloxacillin, amoxicillin, ampicillin, piperacillin, azlocillin, and carbenicillin. The pharmaceutical composition may exhibit an excellent antibiotic effect against resistant bacteria with reduced susceptibility to the penicillin-based compound.

[0109] More specifically, the penicillin-based compound may be a compound having anti-Gram-positive bacteria activity, and the penicillin-based compound having anti-Gram-positive bacteria activity may be one or more selected from the group consisting of, for example, methicillin, dicloxacillin, oxacillin, and flucloxacillin. The pharmaceutical composition may exhibit an excellent antibiotic effect against resistant bacteria with reduced susceptibility to the penicillin-based compound having anti-Gram-positive bacteria activity.

[0110] The term "resistant bacteria" refers to bacteria whose survival or proliferation is not inhibited even when treated with a specific compound, as a result of a series of biological reactions to protect themselves from the compound, such as reducing susceptibility to the compound or removing the compound.

[0111] In one embodiment, the penicillin-resistant bacterium may be selected from the group consisting of Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus pneumoniae, Streptococcus pyogenes, Enterococcus faecalis, and Enterococcus faecium, and specifically, the penicillin-resistant bacterium may be methicillin-resistant Staphylococcus aureus.

[0112] In one embodiment, the pharmaceutical composition may be administered in combination with one or more antibiotics.

[0113] In one embodiment, the antibiotic may be a glycopeptide antibiotic, a cyclic lipopeptide antibiotic, a tetracycline antibiotic, a lincosamide antibiotic, a carbapenem antibiotic, a fluoroquinolone antibiotic, or a rifamycin antibiotic.

[0114] The term "glycopeptide antibiotic" above refers to an antibiotic that inhibits bacterial cell wall synthesis, meaning an antibiotic that blocks cell wall synthesis by directly binding to the D-Ala-D-Ala terminus during the peptidoglycan synthesis process of the bacterial cell wall. The glycopeptide antibiotic may be, for example, vancomycin, telavancin, dalbavancin, or oritavancin.

[0115] The term "cyclic lipopeptide antibiotic" refers to an antibiotic that induces bacterial death by directly inserting into the bacterial cell membrane and inhibiting ATP production through the depolarization of the cell membrane. The cyclic lipopeptide antibiotic may be, for example, daptomycin.

[0116] The above term "tetracycline class antibiotic" refers to an antibiotic that targets bacterial ribosomes and induces the death of bacteria by binding to ribosomal subunits and inhibiting protein synthesis. The above tetracycline class antibiotic may be, for example, tigecycline, doxycycline, minocycline, omadacycline, or derivatives thereof.

[0117] The term "lincosamide class antibiotic" above refers to an antibiotic that targets the 50S ribosomal subunit of bacteria and induces the death of bacteria by binding to the 23S rRNA region of the 50S ribosome and inhibiting protein synthesis. The lincosamide class antibiotic may be, for example, clindamycin.

[0118] The above term "carbapenem antibiotic" refers to an antibiotic belonging to the beta-lactam class that inhibits the synthesis of the cell wall by binding to penicillin binding protein (PBP). The above carbapenem antibiotic may be, for example, imipenem, meropenem, ertapenem, or doripenem.

[0119] The above term "fluoroquinolone antibiotic" refers to an antibiotic that induces the death of bacteria by blocking DNA replication or transcription by inhibiting DNA gyrase and topoisomerase IV. The above fluoroquinolone antibiotic may be, for example, ciprofloxacin, levofloxacin, moxifloxacin, or delafloxacin.

[0120] The term "rifamycin-class antibiotic" above refers to an antibiotic that induces the death of bacteria by binding to the DNA-dependent RNA polymerase β-subunit and blocking transcription initiation. The rifamycin-class antibiotic may be, for example, rifampicin, rifabutin, or rifapentine.

[0121] In one embodiment, the antibiotic is vancomycin, telavancin, dalbavancin, oritavancin, daptomycin, tigecycline, doxycycline, minocycline, omadacycline, clindamycin, imipenem, meropenem, ertapenem, doripenem, ciprofloxacin, levofloxacin, moxifloxacin, delafloxacin, rifampicin, rifabutin, and It may be selected from the group consisting of rifapentine. When the pharmaceutical composition is administered in combination with the antibiotic, it can reduce the occurrence of resistance through different mechanisms of action, enhance the antibacterial effect, suppress the Minimum Inhibitory Concentration Creep (MIC Creep), and suppress the increase in the frequency and severity of adverse events of the pharmaceutical composition, such as myelosuppression. Taken together, it can exhibit superior therapeutic effects against diseases mediated by penicillin-resistant bacteria compared to treatment with the antibiotic or the pharmaceutical composition alone, and can increase safety and tolerability by reducing severity and adverse events.

[0122] More specifically, the antibiotic may be selected from the group consisting of vancomycin, daptomycin, fluoroquinolones, rifampicin, tigecycline, imipenem, and gentamycin. When the antibiotic is selected from the group consisting of vancomycin, daptomycin, fluoroquinolones, rifampicin, tigecycline, imipenem, and gentamycin, the minimum inhibitory concentration (MIC) of the antibiotic or the pharmaceutical composition may be improved by an excellent synergistic effect when administered in combination compared to the single administration of the pharmaceutical composition or the antibiotic. In addition, the time to clearance of the aforementioned resistant bacteria can be effectively reduced.

[0123] More specifically, the antibiotic may be vancomycin. When the antibiotic is vancomycin, the pharmaceutical composition may be administered in combination to suppress the minimum inhibitory concentration creep (MIC Creep) phenomenon for the antibiotic, and when the pharmaceutical composition and vancomycin are administered in combination, the increase in the frequency and severity of adverse events, such as bone marrow suppression adverse events, may be suppressed.

[0124] In addition, if the above antibiotic is a nephrotoxic antibiotic, for example, vancomycin, the above pharmaceutical composition has a low renal excretion rate, so renal function does not significantly affect drug elimination, which may be advantageous for co-administration.

[0125] The term "tolerability" refers to the degree to which a patient or subject can withstand side effects or discomfort when a drug is administered, and it serves as an important indicator for evaluating the efficacy and safety of a drug. Unlike "tolerance," which implies a decline in drug efficacy, tolerability refers to the body's ability to accept the drug—that is, how well it can endure it—rather than the drug's effect itself.

[0126] The term "Severity" above refers to an indicator of how serious a disease, injury, or condition is.

[0127] In one embodiment, the combined administration may be administered simultaneously, separately, or sequentially.

[0128] In one embodiment, the pharmaceutical composition and the antibiotic are 1: 0.001 to 100, 1: 0.001 to 50, 1: 0.001 to 10, 1: 0.001 to 5, 1: 0.001 to 1, 1: 0.005 to 100, 1: 0.005 to 50, 1: 0.005 to 10, 1: 0.005 to 5, 1: 0.005 to 1, 1: 0.01 to 100, 1: 0.01 to 50, 1: 0.01 to 10, 1: 0.01 to 5, 1: 0.01 to 1, 1: 0.1 to 100, 1: 0.1 to 50, 1: It may be administered in combination in a weight ratio of 0.1 to 10, 1:0.1 to 5, or 1:0.1 to 1.

[0129] In one embodiment, the penicillin-resistant bacterial-mediated disease may be a bacterial disease occurring in a tissue selected from the group consisting of dermis, hair follicles, muscles, joints, blood, endocardium, subcutaneous tissue, bone, and lungs, and may be a systemic bacterial disease.

[0130] In one embodiment, the disease mediated by penicillin-resistant bacteria may be selected from the group consisting of abscess, furuncle, bacteremia, sepsis, endocarditis, cellulitis, necrotizing soft tissue infections, osteomyelitis, septic arthritis, and pneumonia.

[0131] The term "abscess" refers to an inflammatory pocket formed by the accumulation of pus within tissue due to bacterial infection, anal gland obstruction, or weakened immunity, and can cause pain, systemic chills, fever, and edema.

[0132] The above term "furuncle" refers to inflammation that occurs when an inflammation develops in a hair follicle.

[0133] The term "bacteremia" above refers to a disease caused by the infiltration of bacteria into the bloodstream, which can be caused by medical procedures, infections, etc. Since bacteremia causes the accumulation of bacteria throughout the subject's body, it can lead to diseases such as sepsis, inflammation, and cancer.

[0134] The term "sepsis" above refers to a systemic inflammatory response syndrome that occurs when the blood is infected by bacteria that have invaded the human body.

[0135] The term "endocarditis" refers to a disease caused by inflammatory changes in the endocardium due to bacterial infection.

[0136] The term "cellulitis" refers to an acute inflammatory disease caused by the penetration of bacteria into the dermis or subcutaneous tissue of the skin, accompanied by symptoms such as red spots, swelling, warmth, tenderness, chills, fever, and muscle pain.

[0137] The term "necrotizing soft tissue infections" refers to an infectious disease in which necrosis of soft tissues, such as fascia, muscle, cellulosic glands, and skin, is induced due to bacterial infection.

[0138] The term "osteomyelitis" above refers to a disease in which bacteria or the like penetrate the bone or bone marrow and cause inflammation, and corresponds to a disease caused by infection through the bloodstream by bacteria (Staphylococcus aureus, Streptococcus pneumoniae, Haemophilus influenzae, etc.) found in upper respiratory tract infections, boils, etc.

[0139] The term "septic arthritis" is a disease in which bacteria invade the joint and form inflammation and pus, and it is a disease in which specific joints such as the knee and hip swell, turn red, are accompanied by severe pain and fever, and can cause cartilage destruction.

[0140] The term "pneumonia" above refers to a disease in which inflammation occurs in the lung tissue below the bronchioles due to bacteria, fungi, viruses, etc.

[0141] The above pharmaceutical composition can exhibit excellent therapeutic or preventive effects against diseases mediated by penicillin-resistant bacteria based on its superior antibacterial effect. Furthermore, when the above pharmaceutical composition is administered in combination with one or more of the above antibiotics, it can exhibit even superior therapeutic effects and reduce severity and adverse events, thereby increasing safety and tolerability.

[0142] In one embodiment, the pharmaceutical composition may be administered orally.

[0143] When the above pharmaceutical composition is administered orally, the oxazolidinone derivative represented by Formula 1 or a pharmaceutically acceptable salt thereof may be administered in an amount of 0.01 to 100 mg / kg, 0.01 to 50 mg / kg, 0.01 to 10 mg / kg, 0.1 to 100 mg / kg, 0.1 to 50 mg / kg, 0.1 to 10 mg / kg, 1 to 100 mg / kg, 1 to 50 mg / kg, or 1 to 10 mg / kg.

[0144] The term "prevention" above may refer to any act of suppressing or delaying the onset of penicillin-resistant bacteria-mediated diseases in an individual by administering a pharmaceutical composition according to one aspect.

[0145] The term "treatment" above may refer to any act in which the symptoms of a penicillin-resistant bacteria-mediated disease in an individual are improved or beneficially altered by the administration of a pharmaceutical composition according to one aspect.

[0146] The term "administration" above means introducing a specific substance into an individual by an appropriate method, and "individual" refers to all living organisms, including humans, rats, mice, and livestock, that are capable of harboring cancer. Specifically, the individual may be a mammal, including humans.

[0147] A pharmaceutical composition according to one aspect comprises an oxazolidinone derivative or a pharmaceutically acceptable salt thereof, and can exhibit excellent preventive or therapeutic effects against diseases mediated by bacteria resistant to penicillin compounds. In particular, when used in combination with one or more antibiotics, it can exhibit excellent effects such as increased overall cure rate, elimination of mediating bacteria, inhibition of increased severity, inhibition of adverse events, increased safety, and increased tolerability. Through this, it can be utilized as a treatment for diseases mediated by penicillin-resistant bacteria, such as bacteremia, sepsis, and endocarditis.

[0148]

[0149] In one embodiment, the antimicrobial synergistic effect of an oxazolidinone derivative represented by Chemical Formula 2 (LCB01-0371; LigaChem Biosciences; hereinafter Compound 1) with rifampicin against methicillin-resistant Staphylococcus aureus (MRSA) was verified. As a result, it was confirmed that S. aureus BAA-1720, BAA-1754, and BAA-1761 all exhibited higher bacterial reduction efficacy when used in combination than when each antibiotic was used alone, thus confirming that a synergistic effect between the two antibiotics was present (see Example 1).

[0150] In another example, the antimicrobial synergistic efficacy of Compound 1 with tigecycline against Methicillin-resistant Staphylococcus aureus (MRSA) was verified. As a result, it was confirmed that S. aureus BAA-1720, BAA-1754, and BAA-1761 all exhibited higher bacterial reduction efficacy when used in combination than when each antibiotic was used alone, thus confirming that a synergistic effect between the two antibiotics was present (see Example 2).

[0151] In another example, the antimicrobial synergistic efficacy of Compound 1 with imipenem against Methicillin-resistant Staphylococcus aureus (MRSA) was verified. As a result, it was confirmed that both S. aureus BAA-1720 and BAA-1754 exhibited higher bacterial reduction efficacy when used in combination than when each antibiotic was used alone, thus confirming that a synergistic effect between the two antibiotics was present (see Example 3).

[0152] In another example, the efficacy of co-administration of vancomycin and Compound 1 was evaluated in patients with MRSA bacteremia. As a result, positive effects were observed regarding overall healing and the time to disappearance of MRSA bacteremia in blood culture tests compared to standard vancomycin therapy (see Example 4).

[0153] In another example, the safety of combination therapy with vancomycin and Compound 1 was evaluated in patients with MRSA bacteremia. As a result, it was confirmed that the combination therapy of vancomycin and Compound 1 did not cause specific or clinically significant adverse events compared to standard vancomycin therapy, nor did it increase the frequency or severity of adverse events. In particular, mitochondrial toxicity and related adverse events, which are causes of limitations and discontinuation of long-term administration of oazolidinone antibiotics, were not observed. Accordingly, it was confirmed that acceptable safety and tolerability were secured in the safety and tolerability profile of the combination therapy of vancomycin and Compound 1 during the clinical trial period (see Example 5).

[0154]

[0155] Another aspect provides an antibiotic composition for the prevention or treatment of penicillin-resistant bacteria-mediated diseases comprising an oxazolidinone derivative represented by the above chemical formula 1 or a pharmaceutically acceptable salt thereof:

[0156] [Chemical Formula 1]

[0157]

[0158] (In the above chemical formula 1,

[0159] The above X is a chemical bond, -(CH2) n - or -(CH2) n C(=O)- igo;

[0160] The above n is an integer from 0 to 2;

[0161] The above R is hydrogen or a pentagonal or hexaagonal heteroaryl selected from the following structures;

[0162]

[0163]

[0164] The above R1 to R 25 are independently hydrogen, (C1-C6) alkyl, (C3-C6) cycloalkyl, -OH, -NR 31 R 32 , -C(=O)R 33 , -(CH2) m OH, -C=NOH, -CN, -NO2 or halogen;

[0165] The above R 31 and R 32 are independently hydrogen, (C1-C6) alkyl, or -C(=O)H;

[0166] The above R 33 It is hydrogen, -OH, -NH2, or (C1-C6) alkyl;

[0167] The above m is one integer from 1 to 6;

[0168] The above Q is -OH, -NHC(=O)R 41 or -NHC(=O)OR 41is;

[0169] The above R 41 It is a (C1-C6) alkyl.

[0170] The above terms, such as "oxazolidinone derivative," "salt," "pharmaceuticalally acceptable salt," "penicillin-based compound," "penicillin-resistant bacteria," "disease mediated by resistance," "prevention," and "treatment," are within the scope described above.

[0171] The term "antibiotic" above refers to a compound that exhibits the effect of inhibiting the growth and killing microorganisms such as bacteria, viruses, and fungi, and corresponds to one that can be used for the prevention or treatment of various infectious diseases.

[0172] In one embodiment, the antibiotic composition may have an inhibitory effect on growth or a lethal effect on one or more bacteria selected from the group consisting of Gram-positive bacteria and Gram-negative bacteria, and specifically, may have an inhibitory effect on growth or a lethal effect on Gram-positive bacteria. More specifically, it may have an inhibitory effect on growth or a lethal effect on one or more bacteria selected from the group consisting of Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus pneumoniae, Streptococcus pyogenes, Enterococcus faecalis, and Enterococcus faecium.

[0173] In one embodiment, the antibiotic composition comprises vancomycin, telavancin, dalbavancin, oritavancin, daptomycin, tigecycline, doxycycline, minocycline, omadacycline, clindamycin, imipenem, meropenem, ertapenem, doripenem, ciprofloxacin, levofloxacin, moxifloxacin, delafloxacin, rifampicin, rifabutin, and It may include one or more additional substances selected from the group consisting of rifapentine.

[0174] The above antibiotic composition comprises Vancomycin, Telavancin, Dalbavancin, Oritavancin, Daptomycin, Tigecycline, Doxycycline, Minocycline, Omadacycline, Clindamycin, Imipenem, Meropenem, Ertapenem, Doripenem, Ciprofloxacin, Levofloxacin, Moxifloxacin, Delafloxacin, Rifampicin, Rifabutin, and Rifapentine If one or more selected from the group are included, the development of resistance can be lowered and the antimicrobial effect enhanced through different mechanisms of action; specifically, superior therapeutic effects compared to treatment with vancomycin alone can be achieved, and safety and tolerability can be increased by reducing severity and adverse reactions.

[0175] In one embodiment, the antibiotic composition comprises vancomycin, telavancin, dalbavancin, oritavancin, daptomycin, tigecycline, doxycycline, minocycline, omadacycline, clindamycin, imipenem, meropenem, ertapenem, doripenem, ciprofloxacin, levofloxacin, moxifloxacin, delafloxacin, rifampicin, rifabutin, and It may be administered in combination with one or more selected from the group consisting of rifapentine.

[0176] The above term "concurrent administration" is within the aforementioned scope.

[0177] Antibiotics according to other modes, by comprising oxazolidinone derivatives or pharmaceutically acceptable salts thereof, can exhibit excellent prophylactic or therapeutic effects against diseases mediated by bacteria resistant to penicillin compounds, and in particular vancomycin, telavancin, dalbavancin, oritavancin, daptomycin, tigecycline, doxycycline, minocycline, omadacycline, clindamycin, imipenem, meropenem, ertapenem, doripenem, ciprofloxacin, levofloxacin, It corresponds to a formulation that can exhibit superior effects, such as increased overall cure rate, elimination of vectors, inhibition of increased severity, inhibition of adverse events, increased safety, and increased tolerability, when additionally containing or co-administering one or more selected from the group consisting of moxifloxacin, delafloxacin, rifampicin, rifabutin, and rifapentine. Through this, it can be utilized as a treatment for diseases mediated by penicillin-resistant bacteria, such as bacteremia, sepsis, and endocarditis.

[0178]

[0179] Another aspect is an oxazolidinone derivative represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof; and

[0180] Selected from the group consisting of Vancomycin, Telavancin, Dalbavancin, Oritavancin, Daptomycin, Tigecycline, Doxycycline, Minocycline, Omadacycline, Clindamycin, Imipenem, Meropenem, Ertapenem, Doripenem, Ciprofloxacin, Levofloxacin, Moxifloxacin, Delafloxacin, Rifampicin, Rifabutin, and Rifapentine Provides an antibiotic composition for the prevention or treatment of diseases mediated by penicillin-resistant bacteria, comprising an antibiotic:

[0181] [Chemical Formula 1]

[0182]

[0183] (In the above chemical formula 1,

[0184] The above X is a chemical bond, -(CH2) n - or -(CH2) n C(=O)- igo;

[0185] The above n is an integer from 0 to 2;

[0186] The above R is hydrogen or a pentagonal or hexaagonal heteroaryl selected from the following structures;

[0187]

[0188]

[0189] The above R1 to R 25 are independently hydrogen, (C1-C6) alkyl, (C3-C6) cycloalkyl, -OH, -NR 31 R 32, -C(=O)R 33 , -(CH2) m OH, -C=NOH, -CN, -NO2 or halogen;

[0190] The above R 31 and R 32 are independently hydrogen, (C1-C6) alkyl, or -C(=O)H;

[0191] The above R 33 It is hydrogen, -OH, -NH2, or (C1-C6) alkyl;

[0192] The above m is one integer from 1 to 6;

[0193] The above Q is -OH, -NHC(=O)R 41 or -NHC(=O)OR 41 is;

[0194] The above R 41 It is a (C1-C6) alkyl.

[0195] The above terms, such as "oxazolidinone derivative," "salt," "pharmaceuticalally acceptable salt," "penicillin-based compound," "penicillin-resistant bacteria," "diseases mediated by resistance," "prevention," "treatment," and "antibiotic," are within the scope described above.

[0196] An antibiotic composition according to another aspect comprises an oxazolidinone derivative or a pharmaceutically acceptable salt thereof and vancomycin, telavancin, dalbavancin, oritavancin, daptomycin, tigecycline, doxycycline, minocycline, omadacycline, clindamycin, imipenem, meropenem, ertapenem, doripenem, ciprofloxacin, levofloxacin, moxifloxacin, delafloxacin, rifampicin, It corresponds to a formulation that can exhibit excellent effects, such as increased overall cure rate, elimination of vectors, inhibition of increased severity, inhibition of adverse events, increased safety, and increased tolerability, by including an antibiotic selected from the group consisting of rifabutin and rifapentine. Through this, it can be utilized as a treatment for diseases mediated by penicillin-resistant bacteria, such as bacteremia, sepsis, and endocarditis.

[0197]

[0198] Another aspect is an oxazolidinone derivative represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof; and

[0199] Selected from the group consisting of Vancomycin, Telavancin, Dalbavancin, Oritavancin, Daptomycin, Tigecycline, Doxycycline, Minocycline, Omadacycline, Clindamycin, Imipenem, Meropenem, Ertapenem, Doripenem, Ciprofloxacin, Levofloxacin, Moxifloxacin, Delafloxacin, Rifampicin, Rifabutin, and Rifapentine Provides a pharmaceutical composition for the prevention or treatment of diseases mediated by penicillin-resistant bacteria, comprising antibiotics:

[0200] [Chemical Formula 1]

[0201]

[0202] (In the above chemical formula 1,

[0203] The above X is a chemical bond, -(CH2) n - or -(CH2) n C(=O)- igo;

[0204] The above n is an integer from 0 to 2;

[0205] The above R is hydrogen or a pentagonal or hexaagonal heteroaryl selected from the following structures;

[0206]

[0207] The above R1 to R 25 are independently hydrogen, (C1-C6) alkyl, (C3-C6) cycloalkyl, -OH, -NR 31 R 32 , -C(=O)R 33, -(CH2) m OH, -C=NOH, -CN, -NO2 or halogen;

[0208] The above R 31 and R 32 are independently hydrogen, (C1-C6) alkyl, or -C(=O)H;

[0209] The above R 33 It is hydrogen, -OH, -NH2, or (C1-C6) alkyl;

[0210] The above m is one integer from 1 to 6;

[0211] The above Q is -OH, -NHC(=O)R 41 or -NHC(=O)OR 41 is;

[0212] The above R 41 It is a (C1-C6) alkyl.

[0213] The above terms, such as "oxazolidinone derivative," "salt," "pharmaceuticalally acceptable salt," "penicillin-based compound," "penicillin-resistant bacteria," "diseases mediated by resistance," "prevention," "treatment," and "antibiotic," are within the scope described above.

[0214] A pharmaceutical composition according to another aspect comprises an oxazolidinone derivative or a pharmaceutically acceptable salt thereof and vancomycin, telavancin, dalbavancin, oritavancin, daptomycin, tigecycline, doxycycline, minocycline, omadacycline, clindamycin, imipenem, meropenem, ertapenem, doripenem, ciprofloxacin, levofloxacin, moxifloxacin, delafloxacin, rifampicin, It corresponds to a formulation that can exhibit excellent effects, such as increased overall cure rate, elimination of vectors, inhibition of increased severity, inhibition of adverse events, increased safety, and increased tolerability, by including an antibiotic selected from the group consisting of rifabutin and rifapentine. Through this, it can be utilized as a treatment for diseases mediated by penicillin-resistant bacteria, such as bacteremia, sepsis, and endocarditis.

[0215]

[0216] Another aspect provides a method for preventing or treating penicillin-resistant bacteria-mediated diseases, comprising the step of administering an oxazolidinone derivative represented by the above chemical formula 1 or a pharmaceutically acceptable salt thereof to an individual in need thereof.

[0217] The above terms "oxazolidinone derivative," "salt," "pharmaceuticalally acceptable salt," "penicillin-based compound," "penicillin-based compound resistant bacteria," "resistant bacteria-mediated disease," "prevention," "treatment," "individual," etc., are within the scope described above.

[0218] In one embodiment, the step of administering to an individual an oxazolidinone derivative represented by Formula 1 or a pharmaceutically acceptable salt thereof comprises vancomycin, telavancin, dalbavancin, oritavancin, daptomycin, tigecycline, doxycycline, minocycline, omadacycline, clindamycin, imipenem, meropenem, ertapenem, doripenem, ciprofloxacin, levofloxacin, moxifloxacin, delafloxacin, It may be performed by administering one or more selected from the group consisting of rifampicin, rifabutin, and rifapentine to an individual requiring it.

[0219] In one embodiment, the method for preventing or treating a disease mediated by penicillin-resistant bacteria comprises vancomycin, telavancin, dalbavancin, oritavancin, daptomycin, tigecycline, doxycycline, minocycline, omadacycline, clindamycin, imipenem, meropenem, ertapenem, doripenem, ciprofloxacin, levofloxacin, moxifloxacin, delafloxacin, and rifampicin. The method may further include the step of administering one or more antibiotics selected from the group consisting of Rifabutin and Rifapentine to an individual requiring them.

[0220] In one embodiment, the above vancomycin, telavancin, dalbavancin, oritavancin, daptomycin, tigecycline, doxycycline, minocycline, omadacycline, clindamycin, imipenem, meropenem, ertapenem, doripenem, ciprofloxacin, levofloxacin, moxifloxacin, delafloxacin, rifampicin, rifabutin, and The step of administering one or more antibiotics selected from the group consisting of rifapentine to an individual in need thereof may be performed prior to the step of administering an oxazolidinone derivative represented by Formula 1 or a pharmaceutically acceptable salt thereof to an individual in need thereof, and may be performed after the step of administering an oxazolidinone derivative represented by Formula 1 or a pharmaceutically acceptable salt thereof to an individual in need thereof.

[0221] According to a treatment method according to another aspect, by administering an oxazolidinone derivative represented by the above chemical formula 1 or a pharmaceutically acceptable salt thereof to an individual in need of it, excellent effects such as increased overall cure rate, elimination of mediating bacteria, inhibition of increased severity, inhibition of adverse events, increased safety, and increased tolerability can be achieved, and through this, diseases mediated by penicillin-resistant bacteria, such as bacteremia, sepsis, and endocarditis, can be treated or prevented.

[0222]

[0223] Another aspect provides a method for preventing or treating a disease mediated by penicillin-resistant bacteria, comprising the step of administering an antibiotic composition comprising an oxazolidinone derivative represented by the above chemical formula 1 or a pharmaceutically acceptable salt thereof to an individual in need thereof.

[0224] The above terms, such as "oxazolidinone derivative," "salt," "pharmaceuticalally acceptable salt," "penicillin-based compound," "penicillin-resistant bacteria," "disease mediated by resistance," "prevention," "treatment," "individual," "antibiotic," etc., are within the scope described above.

[0225] In one embodiment, the antibiotic composition comprises vancomycin, telavancin, dalbavancin, oritavancin, daptomycin, tigecycline, doxycycline, minocycline, omadacycline, clindamycin, imipenem, meropenem, ertapenem, doripenem, ciprofloxacin, levofloxacin, moxifloxacin, delafloxacin, rifampicin, rifabutin, and It may further include one or more selected from the group consisting of rifapentine.

[0226] In one embodiment, the method for preventing or treating a disease mediated by penicillin-resistant bacteria comprises vancomycin, telavancin, dalbavancin, oritavancin, daptomycin, tigecycline, doxycycline, minocycline, omadacycline, clindamycin, imipenem, meropenem, ertapenem, doripenem, ciprofloxacin, levofloxacin, moxifloxacin, delafloxacin, and rifampicin. The method may further include the step of administering one or more antibiotics selected from the group consisting of Rifabutin and Rifapentine to an individual requiring them.

[0227] In one embodiment, the above vancomycin, telavancin, dalbavancin, oritavancin, daptomycin, tigecycline, doxycycline, minocycline, omadacycline, clindamycin, imipenem, meropenem, ertapenem, doripenem, ciprofloxacin, levofloxacin, moxifloxacin, delafloxacin, rifampicin, rifabutin, and The step of administering one or more antibiotics selected from the group consisting of rifapentine to an individual in need thereof may be performed prior to the step of administering an oxazolidinone derivative represented by Formula 1 or a pharmaceutically acceptable salt thereof to an individual in need thereof, and may be performed after the step of administering an oxazolidinone derivative represented by Formula 1 or a pharmaceutically acceptable salt thereof to an individual in need thereof.

[0228] According to a treatment method according to another aspect, by administering an antibiotic comprising an oxazolidinone derivative represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof to an individual in need of it, excellent effects such as increased overall cure rate, elimination of vector bacteria, inhibition of increased severity, inhibition of adverse events, increased safety, and increased tolerability can be achieved, and through this, it can be utilized to treat or prevent diseases mediated by penicillin-resistant bacteria, such as bacteremia, sepsis, and endocarditis.

[0229]

[0230] Another aspect is an oxazolidinone derivative represented by the above chemical formula 1 or a pharmaceutically acceptable salt thereof; and

[0231] The present invention provides a method for preventing or treating a disease mediated by penicillin-resistant bacteria, comprising the step of administering an antibiotic composition to an individual in need of the same, the composition comprising an antibiotic selected from the group consisting of vancomycin, telavancin, dalbavancin, oritavancin, daptomycin, tigecycline, doxycycline, minocycline, omadacycline, clindamycin, imipenem, meropenem, ertapenem, doripenem, ciprofloxacin, levofloxacin, moxifloxacin, delafloxacin, rifampicin, rifabutin, and rifapentine.

[0232] The above terms, such as "oxazolidinone derivative," "salt," "pharmaceuticalally acceptable salt," "penicillin-based compound," "penicillin-resistant bacteria," "disease mediated by resistance," "prevention," "treatment," "individual," "antibiotic," etc., are within the scope described above.

[0233] According to a treatment method according to another aspect, by including an oxazolidinone derivative represented by the above chemical formula 1 or a pharmaceutically acceptable salt thereof and an antibiotic selected from the group consisting of vancomycin, telavancin, dalbavancin, oritavancin, daptomycin, tigecycline, doxycycline, minocycline, omadacycline, clindamycin, imipenem, meropenem, ertapenem, doripenem, ciprofloxacin, levofloxacin, moxifloxacin, delafloxacin, rifampicin, rifabutin, and rifapentine, excellent effects such as increased overall cure rate, elimination of vector bacteria, inhibition of increased severity, inhibition of adverse events, increased safety, and increased tolerability can be achieved, and thereby it can be utilized to treat or prevent diseases mediated by penicillin-resistant bacteria, such as bacteremia, sepsis, and endocarditis.

[0234]

[0235] Another aspect is an oxazolidinone derivative represented by the above chemical formula 1 or a pharmaceutically acceptable salt thereof; and

[0236] The present invention provides a method for preventing or treating a disease mediated by penicillin-resistant bacteria, comprising the step of administering an antibiotic selected from the group consisting of vancomycin, telavancin, dalbavancin, oritavancin, daptomycin, tigecycline, doxycycline, minocycline, omadacycline, clindamycin, imipenem, meropenem, ertapenem, doripenem, ciprofloxacin, levofloxacin, moxifloxacin, delafloxacin, rifampicin, rifabutin, and rifapentine to an individual in need thereof.

[0237] The above terms, such as "oxazolidinone derivative," "salt," "pharmaceuticalally acceptable salt," "penicillin-based compound," "penicillin-resistant bacteria," "disease mediated by resistance," "prevention," "treatment," "individual," "antibiotic," etc., are within the scope described above.

[0238] In one embodiment, an antibiotic composition comprising an oxazolidinone derivative represented by Formula 1 or a pharmaceutically acceptable salt thereof; and an antibiotic selected from the group consisting of vancomycin, telavancin, dalbavancin, oritavancin, daptomycin, tigecycline, doxycycline, minocycline, omadacycline, clindamycin, imipenem, meropenem, ertapenem, doripenem, ciprofloxacin, levofloxacin, moxifloxacin, delafloxacin, rifampicin, rifabutin, and rifapentine may be administered simultaneously, separately, or sequentially.

[0239] According to a treatment method according to another aspect, by including an oxazolidinone derivative represented by the above chemical formula 1 or a pharmaceutically acceptable salt thereof and an antibiotic selected from the group consisting of vancomycin, telavancin, dalbavancin, oritavancin, daptomycin, tigecycline, doxycycline, minocycline, omadacycline, clindamycin, imipenem, meropenem, ertapenem, doripenem, ciprofloxacin, levofloxacin, moxifloxacin, delafloxacin, rifampicin, rifabutin, and rifapentine, excellent effects such as increased overall cure rate, elimination of vector bacteria, inhibition of increased severity, inhibition of adverse events, increased safety, and increased tolerability can be achieved, and thereby it can be utilized to treat or prevent diseases mediated by penicillin-resistant bacteria, such as bacteremia, sepsis, and endocarditis.

[0240]

[0241] Another aspect provides the use of an oxazolidinone derivative represented by the above formula 1 or a pharmaceutically acceptable salt thereof for the prevention or treatment of diseases mediated by penicillin-resistant bacteria.

[0242] The above terms, such as "oxazolidinone derivative," "salt," "pharmaceuticalally acceptable salt," "penicillin-based compound," "penicillin-resistant bacteria," "disease mediated by resistance," "prevention," and "treatment," are within the scope described above.

[0243] In one embodiment, the oxazolidinone derivative represented by Formula 1 or a pharmaceutically acceptable salt thereof is vancomycin, telavancin, dalbavancin, oritavancin, daptomycin, tigecycline, doxycycline, minocycline, omadacycline, clindamycin, imipenem, meropenem, ertapenem, doripenem, ciprofloxacin, levofloxacin, moxifloxacin, delafloxacin, rifampicin, It may be administered in combination with one or more selected from the group consisting of rifabutin and rifapentine.

[0244] The above term "concurrent administration" is within the aforementioned scope.

[0245] According to another aspect, an oxazolidinone derivative represented by the above chemical formula 1 or a pharmaceutically acceptable salt thereof can exhibit excellent preventive or therapeutic effects against diseases mediated by bacteria resistant to penicillin compounds, and in particular vancomycin, telavancin, dalbavancin, oritavancin, daptomycin, tigecycline, doxycycline, minocycline, omadacycline, clindamycin, imipenem, meropenem, ertapenem, doripenem, ciprofloxacin, levofloxacin, It corresponds to a formulation that can exhibit superior effects, such as increased overall cure rate, elimination of vectors, inhibition of increased severity, inhibition of adverse events, increased safety, and increased tolerability, when additionally containing or co-administering one or more selected from the group consisting of moxifloxacin, delafloxacin, rifampicin, rifabutin, and rifapentine. Through this, it can be utilized as a treatment for diseases mediated by penicillin-resistant bacteria, such as bacteremia, sepsis, and endocarditis.

[0246]

[0247] Another aspect provides the use of an antibiotic composition comprising an oxazolidinone derivative represented by Formula 1 or a pharmaceutically acceptable salt thereof for the prevention or treatment of penicillin-resistant bacteria-mediated diseases.

[0248] The above terms, such as "oxazolidinone derivative," "salt," "pharmaceuticalally acceptable salt," "penicillin-based compound," "penicillin-resistant bacteria," "diseases mediated by resistance," "prevention," "treatment," and "antibiotic," are within the scope described above.

[0249] In one embodiment, the antibiotic composition comprises vancomycin, telavancin, dalbavancin, oritavancin, daptomycin, tigecycline, doxycycline, minocycline, omadacycline, clindamycin, imipenem, meropenem, ertapenem, doripenem, ciprofloxacin, levofloxacin, moxifloxacin, delafloxacin, rifampicin, rifabutin, and It may further include one or more selected from the group consisting of rifapentine.

[0250] According to another aspect, an antibiotic composition comprising an oxazolidinone derivative represented by the above chemical formula 1 or a pharmaceutically acceptable salt thereof can exhibit excellent preventive or therapeutic effects against diseases mediated by bacteria resistant to penicillin compounds, and in particular vancomycin, telavancin, dalbavancin, oritavancin, daptomycin, tigecycline, doxycycline, minocycline, omadacycline, clindamycin, imipenem, meropenem, ertapenem, doripenem, ciprofloxacin, levofloxacin, It corresponds to a formulation that can exhibit superior effects, such as increased overall cure rate, elimination of vectors, inhibition of increased severity, inhibition of adverse events, increased safety, and increased tolerability, when additionally containing or co-administering one or more selected from the group consisting of moxifloxacin, delafloxacin, rifampicin, rifabutin, and rifapentine. Through this, it can be utilized as a treatment for diseases mediated by penicillin-resistant bacteria, such as bacteremia, sepsis, and endocarditis.

[0251]

[0252] Another aspect is an oxazolidinone derivative represented by Formula 1 or a pharmaceutically acceptable salt thereof for the prevention or treatment of penicillin-resistant bacteria-mediated diseases; and

[0253] The present invention provides a use of an antibiotic composition comprising an antibiotic selected from the group consisting of vancomycin, telavancin, dalbavancin, oritavancin, daptomycin, tigecycline, doxycycline, minocycline, omadacycline, clindamycin, imipenem, meropenem, ertapenem, doripenem, ciprofloxacin, levofloxacin, moxifloxacin, delafloxacin, rifampicin, rifabutin, and rifapentine.

[0254] The above terms, such as "oxazolidinone derivative," "salt," "pharmaceuticalally acceptable salt," "penicillin-based compound," "penicillin-resistant bacteria," "diseases mediated by resistance," "prevention," "treatment," and "antibiotic," are within the scope described above.

[0255] Antibiotic compositions according to another aspect can exhibit excellent effects such as increased overall cure rate, elimination of vectors, inhibition of increased severity, inhibition of adverse events, increased safety, and increased tolerability, and can be utilized to treat or prevent diseases mediated by penicillin-resistant bacteria, such as bacteremia, sepsis, and endocarditis.

[0256]

[0257] Another aspect is an oxazolidinone derivative represented by Formula 1 or a pharmaceutically acceptable salt thereof for the prevention or treatment of penicillin-resistant bacteria-mediated diseases; and

[0258] The present invention provides a use of a pharmaceutical composition comprising an antibiotic selected from the group consisting of vancomycin, telavancin, dalbavancin, oritavancin, daptomycin, tigecycline, doxycycline, minocycline, omadacycline, clindamycin, imipenem, meropenem, ertapenem, doripenem, ciprofloxacin, levofloxacin, moxifloxacin, delafloxacin, rifampicin, rifabutin, and rifapentine.

[0259] The above terms "oxazolidinone derivative," "salt," "pharmaceuticalally acceptable salt," "penicillin-based compound," "penicillin-resistant bacteria," "disease mediated by resistance," "prevention," "treatment," etc., are within the scope described above.

[0260] A pharmaceutical composition according to another aspect can exhibit excellent effects such as increased overall cure rate, elimination of mediating bacteria, inhibition of increased severity, inhibition of adverse events, increased safety, and increased tolerability, and can be utilized to treat or prevent diseases mediated by penicillin-resistant bacteria, such as bacteremia, sepsis, and endocarditis.

[0261]

[0262] Another aspect provides the use of an oxazolidinone derivative represented by Formula 1 or a pharmaceutically acceptable salt thereof for the manufacture of a drug for the prevention or treatment of diseases mediated by penicillin-resistant bacteria.

[0263] The above terms "oxazolidinone derivative," "salt," "pharmaceuticalally acceptable salt," "penicillin-based compound," "penicillin-resistant bacteria," "disease mediated by resistance," "prevention," "treatment," etc., are within the scope described above.

[0264] In one embodiment, the oxazolidinone derivative represented by Formula 1 or a pharmaceutically acceptable salt thereof is vancomycin, telavancin, dalbavancin, oritavancin, daptomycin, tigecycline, doxycycline, minocycline, omadacycline, clindamycin, imipenem, meropenem, ertapenem, doripenem, ciprofloxacin, levofloxacin, moxifloxacin, delafloxacin, rifampicin, It may be administered in combination with one or more selected from the group consisting of rifabutin and rifapentine.

[0265] The above term "concurrent administration" is within the aforementioned scope.

[0266] According to another aspect, an oxazolidinone derivative represented by the above chemical formula 1 or a pharmaceutically acceptable salt thereof can exhibit excellent preventive or therapeutic effects against diseases mediated by bacteria resistant to penicillin compounds, and in particular vancomycin, telavancin, dalbavancin, oritavancin, daptomycin, tigecycline, doxycycline, minocycline, omadacycline, clindamycin, imipenem, meropenem, ertapenem, doripenem, ciprofloxacin, levofloxacin, It corresponds to a formulation that can exhibit superior effects, such as increased overall cure rate, elimination of vectors, inhibition of increased severity, inhibition of adverse events, increased safety, and increased tolerability, when additionally containing or co-administering one or more selected from the group consisting of moxifloxacin, delafloxacin, rifampicin, rifabutin, and rifapentine. Through this, it can be utilized as a treatment for diseases mediated by penicillin-resistant bacteria, such as bacteremia, sepsis, and endocarditis.

[0267]

[0268] Another aspect provides the use of an antibiotic composition comprising an oxazolidinone derivative represented by the above formula 1 or a pharmaceutically acceptable salt thereof for the manufacture of a drug for the prevention or treatment of diseases mediated by penicillin-resistant bacteria.

[0269] The above terms, such as "oxazolidinone derivative," "salt," "pharmaceuticalally acceptable salt," "penicillin-based compound," "penicillin-resistant bacteria," "diseases mediated by resistance," "prevention," "treatment," and "antibiotic," are within the scope described above.

[0270] In one embodiment, the antibiotic composition comprises vancomycin, telavancin, dalbavancin, oritavancin, daptomycin, tigecycline, doxycycline, minocycline, omadacycline, clindamycin, imipenem, meropenem, ertapenem, doripenem, ciprofloxacin, levofloxacin, moxifloxacin, delafloxacin, rifampicin, rifabutin, and It may further include one or more selected from the group consisting of rifapentine.

[0271] According to another aspect, an antibiotic composition comprising an oxazolidinone derivative represented by the above chemical formula 1 or a pharmaceutically acceptable salt thereof can exhibit excellent preventive or therapeutic effects against diseases mediated by bacteria resistant to penicillin compounds, and in particular vancomycin, telavancin, dalbavancin, oritavancin, daptomycin, tigecycline, doxycycline, minocycline, omadacycline, clindamycin, imipenem, meropenem, ertapenem, doripenem, ciprofloxacin, levofloxacin, It corresponds to a formulation that can exhibit superior effects, such as increased overall cure rate, elimination of vectors, inhibition of increased severity, inhibition of adverse events, increased safety, and increased tolerability, when additionally containing or co-administering one or more selected from the group consisting of moxifloxacin, delafloxacin, rifampicin, rifabutin, and rifapentine. Through this, it can be utilized as a treatment for diseases mediated by penicillin-resistant bacteria, such as bacteremia, sepsis, and endocarditis.

[0272]

[0273] Another aspect is an oxazolidinone derivative represented by Formula 1 or a pharmaceutically acceptable salt thereof for the manufacture of a drug for the prevention or treatment of diseases mediated by penicillin-resistant bacteria; and

[0274] The present invention provides a use of an antibiotic composition comprising an antibiotic selected from the group consisting of vancomycin, telavancin, dalbavancin, oritavancin, daptomycin, tigecycline, doxycycline, minocycline, omadacycline, clindamycin, imipenem, meropenem, ertapenem, doripenem, ciprofloxacin, levofloxacin, moxifloxacin, delafloxacin, rifampicin, rifabutin, and rifapentine.

[0275] The above terms, such as "oxazolidinone derivative," "salt," "pharmaceuticalally acceptable salt," "penicillin-based compound," "penicillin-resistant bacteria," "diseases mediated by resistance," "prevention," "treatment," and "antibiotic," are within the scope described above.

[0276] Antibiotic compositions according to another aspect can exhibit excellent effects such as increased overall cure rate, elimination of vectors, inhibition of increased severity, inhibition of adverse events, increased safety, and increased tolerability, and can be utilized to treat or prevent diseases mediated by penicillin-resistant bacteria, such as bacteremia, sepsis, and endocarditis.

[0277]

[0278] Another aspect is an oxazolidinone derivative represented by Formula 1 or a pharmaceutically acceptable salt thereof for the manufacture of a drug for the prevention or treatment of diseases mediated by penicillin-resistant bacteria; and

[0279] The present invention provides a use of a pharmaceutical composition comprising an antibiotic selected from the group consisting of vancomycin, telavancin, dalbavancin, oritavancin, daptomycin, tigecycline, doxycycline, minocycline, omadacycline, clindamycin, imipenem, meropenem, ertapenem, doripenem, ciprofloxacin, levofloxacin, moxifloxacin, delafloxacin, rifampicin, rifabutin, and rifapentine.

[0280] The above terms "oxazolidinone derivative," "salt," "pharmaceuticalally acceptable salt," "penicillin-based compound," "penicillin-resistant bacteria," "disease mediated by resistance," "prevention," "treatment," etc., are within the scope described above.

[0281] A pharmaceutical composition according to another aspect can exhibit excellent effects such as increased overall cure rate, elimination of mediating bacteria, inhibition of increased severity, inhibition of adverse events, increased safety, and increased tolerability, and can be utilized to treat or prevent diseases mediated by penicillin-resistant bacteria, such as bacteremia, sepsis, and endocarditis.

[0282]

[0283] A pharmaceutical composition according to one aspect comprises an oxazolidinone derivative or a pharmaceutically acceptable salt thereof, and can exhibit excellent preventive or therapeutic effects against diseases mediated by bacteria resistant to penicillin compounds. In particular, when used in combination with one or more antibiotics, it can exhibit excellent effects such as increased overall cure rate, elimination of mediating bacteria, inhibition of increased severity, inhibition of adverse events, increased safety, and increased tolerability. Through this, it can be utilized as a treatment for diseases mediated by penicillin-resistant bacteria, such as bacteremia, sepsis, and endocarditis.

[0284]

[0285] Figure 1 is a figure verifying the antimicrobial synergistic efficacy of rifampicin and oxazolidinone derivatives against MRSA. Specifically, Figure 1a is a figure verifying the antimicrobial synergistic efficacy against S. aureus BAA-1720, Figure 1b is a figure verifying the antimicrobial synergistic efficacy against S. aureus BAA-1754, and Figure 1c is a figure verifying the antimicrobial synergistic efficacy against S. aureus BAA-1761.

[0286] Figure 2 is a figure verifying the antimicrobial synergistic efficacy of tigecycline and oxazolidinone derivatives against MRSA. Specifically, Figure 2a is a figure verifying the antimicrobial synergistic efficacy against S. aureus BAA-1720, Figure 2b is a figure verifying the antimicrobial synergistic efficacy against S. aureus BAA-1754, and Figure 2c is a figure verifying the antimicrobial synergistic efficacy against S. aureus BAA-1761.

[0287] Figure 3 is a figure verifying the antimicrobial synergistic efficacy of imipenem and oxazolidinone derivatives against MRSA. Specifically, Figure 3a is a figure verifying the antimicrobial synergistic efficacy against S. aureus BAA-1720, and Figure 3b is a figure verifying the antimicrobial synergistic efficacy against S. aureus BAA-1754.

[0288] Figure 4 shows the time to disappearance of MRSA bacteremia following the combined administration of an oxazolidinone derivative and vancomycin or the administration of vancomycin alone. Specifically, Figure 4a shows the measurement for the Full Analysis Set (FAS), and Figure 4b shows the measurement for the pre-protocol set (PPS).

[0289]

[0290] The present invention will be explained in more detail below through examples. However, these examples are intended to illustrate the invention and the scope of the invention is not limited to these examples.

[0291]

[0292] Reference Example - Preparation of Oxazolidinone Derivatives

[0293] For types of oxazolidinone derivatives and methods for preparing the same, refer to Korean Published Patent No. 10-2011-0088737 and Korean Registered Patent No. 10-1023174.

[0294] In the following preparation examples and embodiments, an oxazolidinone derivative represented by the following chemical formula 2 (LCB01-0371; LigaChem Biosciences; hereinafter Compound 1) was used as the oxazolidinone derivative:

[0295] [Chemical Formula 2]

[0296] .

[0297]

[0298]

[0299] Examples

[0300] Example 1. Verification of the synergistic antimicrobial efficacy of Ripampicin and oxazolidinone derivatives against MRSA

[0301] To verify the antimicrobial synergistic efficacy of Compound 1 with rifampicin against MRSA, methicillin-resistant Staphylococcus aureus (MRSA; BAA-1720, BAA-1754, BAA-1761) strains were used. The MRSA strains were obtained from the American Type Culture Collection (ATCC) (10801 University Boulevard Manassas, VA, 20110, USA). The MRSA strains were inoculated into cation-adjusted mueller hinton broth (212322; BD Biosciences, San Diego, CA, USA) and cultured at optical density (OD) in a rotary shaker (180 rpm, 37°C). 600 ) was cultured until it reached 0.4 to 0.6. Subsequently, the cultured bacteria were placed in cation-adjusted Mueller Hinton medium at a concentration twice as high (2X) as the final use concentration at a rate of 1.0 × 10⁻⁶ 6 A bacterial solution was prepared by diluting to a CFU / mL.

[0302] Compound 1 was dissolved in DMSO to prepare a high-concentration solution (2,560 μg / mL), which was then diluted to 320 μg / mL using DMSO and subsequently serially diluted twofold to prepare eight types of DMSO solutions at concentrations of 320, 160, 80, 40, 20, 10, or 5 μg / mL, respectively, and DMSO (0 μg / mL) was used as a negative control. Each of the eight DMSO-diluted solutions was diluted 20-fold using sterile distilled water to prepare a solution at a concentration four times higher than the final concentration used (4X).

[0303] Rifampicin (Sigma Aldrich, R3501) was also dissolved in DMSO to prepare a high-concentration solution (1,280 μg / mL). The prepared high-concentration solution was diluted to 20 μg / mL using DMSO, and then serially diluted twofold to prepare 11 solutions with concentrations of 20, 10, 5, 2.5, 1.25, 0.625, 0.313, 0.156, 0.078, 0.039, and 0.0195 μg / mL, respectively, and DMSO (0 μg / mL) was used as a negative control. Each of the 12 solutions prepared by dilution with DMSO was diluted 20-fold using sterile distilled water to prepare rifampicin solutions at a concentration four times higher than the final concentration used (4X).

[0304] To evaluate the synergistic efficacy of the combination of Compound 1 and Rifampicin, a checkerboard assay was performed. Using an 8-channel multi-pipette, 25 μL of the 4X Compound 1 solution was dispensed from row A (final concentration 4 μg / mL) to row H (final concentration 0 μg / mL) in a 96-well plate (clear, round bottom, Corning, 3788). Additionally, 25 μL of 4X concentration Rifampicin was dispensed from row A to row H using a 12-channel multi-pipette, ranging from row A (final concentration 0.25 μg / mL) to row H (final concentration 0 μg / mL). 50 μL of double-concentration bacterial suspension (S. aureus, BAA-1720, 1754, or 1761) was added to each 96-well plate containing 50 μL of a mixture of two types of antibiotics, and then gently tapped to mix well. Afterward, the plates were incubated in an incubator at 37°C for 20 hours. The next day, the colonies formed at the bottom of the 96-well plate were read to calculate the minimal inhibitory concentration (MIC) of the above compound 1 and rifampicin.

[0305] To confirm the quantitative degree of bacterial reduction, using checkerboard analysis samples, culture media administered with Compound 1 (2X, 1X, 0.5X MIC), Rifampicin (2X, 1X, 0.5X MIC), and a mixture of Compound 1 and Rifampicin (2X, 1X, 0.5X MIC) were serially diluted 10-fold using a 0.9% NaCl (Duksan Reagent, No. 81) solution, and then the stock solution to 10 8 10 μL was dropwise added to the 1x dilution range and incubated in an incubator at 37°C for 20 hours, after which the number of formed colonies was counted and Log 10 CFU / mL was calculated.

[0306] As a result, the MIC of Compound 1 against S. aureus BAA-1720 was confirmed to be 2 μg / mL, and the MIC of rifampicin was confirmed to be 0.00781 μg / mL. When the bacterial counts of each antibiotic alone and in combination were measured at 0.5X MIC, Compound 1 was 3.5 Log 10 It was confirmed that it decreased by CFU / mL, and rifampicin by 2.2 Log 10 It was confirmed that it decreased by CFU / mL. In addition, 5.2 Log when the above compound 1 and rifampicin were co-administered. 10 It was confirmed that it decreased by CFU / mL (Fig. 1a).

[0307] Meanwhile, the MIC of the above Compound 1 against S. aureus BAA-1754 was confirmed to be 2 μg / mL, and the MIC of rifampicin was confirmed to be 0.01563 μg / mL. When the bacterial counts of each antibiotic alone and in combination were measured at 0.5X MIC, the result for Compound 1 was 3.7 Log 10 It was confirmed that it decreased by CFU / mL, and rifampicin was 0.9 Log 10 It was confirmed that it decreased by CFU / mL. In addition, 8.4 Log when the above compound 1 and rifampicin were co-administered. 10 It was confirmed that it decreased by CFU / mL (Fig. 1b).

[0308] In addition, the MIC of the above Compound 1 against S. aureus BAA-1761 was confirmed to be 2 μg / mL, and the MIC of rifampicin was confirmed to be 0.01563 μg / mL. When the bacterial counts of each antibiotic alone and in combination were measured at 0.5X MIC, the results showed that Compound 1 was 2.5 Log 10 It was confirmed that it decreased by CFU / mL, and rifampicin was 0.4 Log 10 It was confirmed that it decreased by CFU / mL. In addition, 8.0 Log when the above compound 1 and rifampicin were co-administered. 10 It was confirmed that it decreased by CFU / mL (Fig. 1c).

[0309] Through this, it was confirmed that S. aureus BAA-1720, BAA-1754, and BAA-1761 all exhibited higher bacterial reduction efficacy when used in combination compared to using each antibiotic alone, thus confirming a synergistic effect between the two antibiotics. This suggests that the combined administration of the two antibiotics demonstrates an enhanced antibacterial effect.

[0310]

[0311] Example 2. Evaluation of the synergistic antimicrobial efficacy of tigecycline and oxazolidinone compounds against MRSA

[0312]

[0313] In order to verify the antimicrobial synergistic efficacy with tigecycline against MRSA using the above compound 1, a bacterial solution was prepared using the same Methicillin-resistant Staphylococcus aureus (MRSA; BAA-1720, BAA-1754, BAA-1761) strains as in Example 1.

[0314] Subsequently, Compound 1 was dissolved in DMSO in the same manner as in Example 1 to prepare a high-concentration solution (2,560 μg / mL), which was then diluted to 320 μg / mL using DMSO and subsequently serially diluted twofold to prepare 11 types of DMSO solutions with concentrations of 160, 80, 40, 20, 10, 5, 2.5, 1.25, 0.625, 0.313, and 0.156 μg / mL, respectively, and DMSO (0 μg / mL) was used as a negative control. Each of the 12 types of solutions prepared by dilution with DMSO was diluted 20-fold using sterile distilled water to prepare a solution with a concentration four times higher than the final concentration used (4X).

[0315] Meanwhile, Tigecycline (Sigma Aldrich, PHR2591) was dissolved in sterile distilled water to prepare a high-concentration solution (1,280 μg / mL). The prepared high-concentration solution was diluted to 160 μg / mL using sterile distilled water, and then serially diluted twofold to prepare 12 solutions with concentrations of 160, 80, 40, 20, 10, 5, 2.5, 1.25, 0.625, 0.313, and 0.156 μg / mL, respectively, and sterile distilled water (0 μg / mL) was used as a negative control. Each of the 12 solutions prepared by dilution with sterile distilled water was diluted 20-fold using sterile distilled water to prepare Tigecycline solutions at a concentration four times higher than the final concentration used (4X).

[0316] To evaluate the synergistic efficacy of the combination of Compound 1 and tigecycline, a checkerboard assay was performed. Using an 8-channel multi-pipette, 25 μL of the 4X solution of Compound 1 was dispensed into rows 1 through 12 of a 96-well plate (clear, round bottom, Corning, 3788), starting from row A (final concentration 4 μg / mL) to row H (final concentration 0 μg / mL) at a high concentration. Using a 12-channel multi-pipette, 25 μL of 4X concentration tigecycline was dispensed into rows A through H, starting from row 1 (final concentration 2 μg / mL) to row 12 (final concentration 0 μg / mL) at a high concentration. 50 μL of double-concentration bacterial suspension (S. aureus, BAA-1720, 1754, or 1761) was added to each of the 96-well plates containing 50 μL of a mixture of two antibiotics, and then gently tapped to mix well. The plates were then incubated in an incubator at 37°C for 20 hours in the dark. On the next day, the colonies formed at the bottom of the 96-well plates were read to calculate the minimal inhibitory concentration (MIC) of the above compound 1 and tigecycline.

[0317] To confirm the quantitative degree of bacterial reduction, using checkerboard analysis samples, culture solutions corresponding to Compound 1 at 2X, 1X, and 0.5X MIC, Tigecycline at 2X, 1X, and 0.5X MIC, and a mixture of Compound 1 and Tigecycline at 2X, 1X, and 0.5X MIC were serially diluted 10-fold using 0.9% NaCl (Duksan Reagent, No. 81) solution, and then the stock solution to 10 8 Add 10 μL dropwise to the dilution range, incubate in an incubator at 37°C for 20 hours, count the number of colonies, and Log 10 CFU / mL was calculated.

[0318] As a result, the MIC of Compound 1 against S. aureus BAA-1720 was confirmed to be 2 μg / mL, and the MIC of tigecycline was confirmed to be 0.25 μg / mL. When the bacterial counts of each antibiotic alone and in combination were measured at 0.5X MIC, Compound 1 showed 3.9 Log 10 It was confirmed that it decreased by CFU / mL, and tigecycline was 3.0 Log 10 It was confirmed that it decreased by CFU / mL. In addition, 5.3 Log when the above compound 1 and tigecycline were co-administered. 10 It was confirmed that it decreased by CFU / mL (Fig. 2a).

[0319] Meanwhile, the MIC of the above Compound 1 against S. aureus BAA-1754 was confirmed to be 2 μg / mL, and the MIC of tigecycline was confirmed to be 0.25 μg / mL. When the bacterial counts of each antibiotic alone and in combination were measured at 0.5X MIC, the result for Compound 1 was 3.0 Log 10 It was confirmed that it decreased by CFU / mL, and tigecycline was 3.0 Log 10 It was confirmed that it decreased by CFU / mL. In addition, 4.8 Log when the above compound 1 and tigecycline were co-administered. 10It was confirmed that it decreased by CFU / mL (Fig. 2b).

[0320] In addition, the MIC of Compound 1 against S. aureus BAA-1761 was found to be 2 μg / mL, and the MIC of tigecycline was confirmed to be 0.25 μg / mL. When the bacterial counts of each antibiotic alone and in combination were measured at 0.5X MIC, Compound 1 showed a value of 3.6 Log 10 It was confirmed that it decreased by CFU / mL, and tigecycline was 3.1 Log 10 It was confirmed that it decreased by CFU / mL. In addition, 4.9 Log when the above compound 1 and tigecycline were co-administered. 10 It was confirmed that it decreased by CFU / mL (Fig. 2c).

[0321] Through this, it was confirmed that S. aureus BAA-1720, BAA-1754, and BAA-1761 all exhibited higher bacterial reduction efficacy when used in combination compared to using each antibiotic alone, confirming a synergistic effect between the two antibiotics. This suggests that the combined administration of the two antibiotics demonstrates an enhanced antibacterial effect.

[0322]

[0323] Example 3. Evaluation of the synergistic antimicrobial efficacy of imipenem and oxazolidinone derivatives against MRSA

[0324]

[0325] To verify the antimicrobial synergistic efficacy with imipenem against MRSA using the above compound 1, methicillin-resistant Staphylococcus aureus (MRSA; BAA-1720, BAA-1754) strains were used, and a bacterial solution was prepared in the same manner as in Example 1.

[0326] Subsequently, Compound 1 was dissolved in DMSO to prepare a high-concentration solution (2,560 μg / mL). The prepared high-concentration solution was diluted to 320 μg / mL using DMSO, and then serially diluted twofold to prepare seven types of DMSO solutions at concentrations of 320, 160, 80, 40, 20, 10, or 5 μg / mL, respectively, and DMSO (0 μg / mL) was used as a negative control. Each of the eight solutions prepared by dilution with DMSO was diluted 20-fold using sterile distilled water to prepare a solution at a concentration four times higher than the final concentration used (4X).

[0327] Meanwhile, imipenem (Sigma Aldrich, PHR1796) was also dissolved in sterile distilled water to prepare a high-concentration solution (10,240 μg / mL). The prepared high-concentration solution was serially diluted twofold using sterile distilled water to produce 11 solutions at concentrations of 10,240, 5,120, 2,560, 1,280, 640, 320, 160, 80, 40, 20, or 10 μg / mL, respectively, and sterile distilled water (0 μg / mL) was used as a negative control. Each of the 12 solutions prepared by dilution with sterile distilled water was diluted 20-fold using sterile distilled water to prepare imipenem solutions at a concentration four times higher than the final concentration used (4X).

[0328] To evaluate the synergistic efficacy of the combination of Compound 1 and Imipenem, a checkerboard assay was performed. Using an 8-channel multi-pipette, 25 μL of the 4X Compound 1 solution was dispensed from row A (final concentration 4 μg / mL) to row H (final concentration 0 μg / mL) in a 96-well plate (clear, round bottom, Corning, 3788). Then, 25 μL of 4X concentration Imipenem was dispensed from row A to row H using a 12-channel multi-pipette, starting from row 1 (final concentration 128 μg / mL) to row H (final concentration 0 μg / mL) in a high concentration. 50 μL of double-concentration bacterial suspension (S. aureus, BAA-1720 or 1754) was added to each of the 96-well plates containing 50 μL of a mixture of two antibiotics, and then gently tapped to mix well. Afterward, the plates were incubated in an incubator at 37°C for 20 hours. On the next day, the colonies formed at the bottom of the 96-well plates were read to calculate the minimal inhibitory concentration (MIC) of the above compound 1 and imipenem.

[0329] To confirm the quantitative degree of bacterial reduction, using checkerboard analysis samples, culture solutions corresponding to Compound 1 at 2X, 1X, and 0.5X MIC, Imipenem at 2X, 1X, and 0.5X MIC, and the mixture of Compound 1 and Imipenem at 2X, 1X, and 0.5X MIC were serially diluted 10-fold using a 0.9% NaCl (Duksan Reagent, No. 81) solution, and then the stock solution to 10 8 Add 10 μL dropwise to the dilution range, incubate in an incubator (37℃) for 20 hours, count the number of colonies, and Log 10 CFU / mL was calculated.

[0330] As a result, the MIC of Compound 1 against S. aureus BAA-1720 was confirmed to be 2 μg / mL, and the MIC of imipenem was confirmed to be 64 μg / mL. When the bacterial counts of each antibiotic alone and in combination were measured at 0.5X MIC, Compound 1 showed a value of 2.1 Log. 10 It was confirmed that it decreased by CFU / mL, and imipenem was 0.9 Log 10 It was confirmed that it decreased by CFU / mL. In addition, 4.5 Log when the above compound 1 and imipenem were co-administered. 10 It was confirmed that it decreased by CFU / mL (Fig. 3a).

[0331] Meanwhile, the MIC of the above Compound 1 against S. aureus BAA-1754 was confirmed to be 2 μg / mL, and the MIC of imipenem was confirmed to be 8 μg / mL. When the bacterial counts of each antibiotic alone and in combination were measured at 0.5X MIC, the result for Compound 1 was 1.2 Log 10 It was confirmed that it decreased by CFU / mL, and imipenem was 1.9 Log 10 It was confirmed that it decreased by CFU / mL. In addition, 5.4 Log when the above compound 1 and imipenem were co-administered. 10 It was confirmed that it decreased by CFU / mL (Fig. 3b).

[0332] Through this, it was confirmed that both S. aureus BAA-1720 and BAA-1754 exhibited higher bacterial reduction efficacy when used in combination compared to using each antibiotic alone, confirming a synergistic effect between the two antibiotics. This suggests that the combined administration of the two antibiotics demonstrates an enhanced antibacterial effect.

[0333]

[0334] Example 4. Evaluation of the efficacy of combination therapy with vancomycin and oxazolidinone derivative compounds in patients with MRSA bacteremia

[0335]

[0336] A multicenter, randomized, double-blind, parallel-design, Phase 2a clinical trial was conducted to evaluate the safety and efficacy of combination therapy with vancomycin and Compound 1 compared to standard vancomycin therapy in patients with MRSA bacteremia. Specifically, regarding Compound 1, the LCB01-0371 product containing approximately 400 mg per 715 mg tablet was used; vancomycin hydrochloride was initially administered intravenously as a concomitant at an initial dose of 15 to 20 mg / kg, followed by the subsequent AUC / MIC of vancomycin concentration BMD The capacity was adjusted and used to maintain 400 to 600.

[0337]

[0338] Screening tests and procedures were conducted after the subjects voluntarily gave written consent to participate in this clinical trial. Patients who started empirical antibiotics within 96 hours prior to randomization (however, antibiotics effective against MRSA such as vancomycin within 72 hours) were eligible for enrollment, and patients who met the selection and exclusion criteria, including those who tested positive for MRSA at least once via blood culture, were enrolled in this clinical trial and randomized in a 1:1 ratio to either the test group (the group receiving compound 1 and vancomycin in combination) or the control group [the vancomycin standard treatment group (specifically, the group receiving placebo of compound 1 and vancomycin in combination)]. Randomized subjects could receive the investigational drug for up to 42 days (at least 14 days) depending on their assigned treatment group. If the investigator determined that a change to an antibiotic other than vancomycin was necessary for the treatment of MRSA bacteremia after the start of treatment, a switch to daptomycin was possible. After administering vancomycin or daptomycin for at least 14 days following the switch, a change to an oral antibiotic for MRSA treatment, excluding the oxazolidinone class, was possible at the investigator's discretion. If the antibiotic was changed according to the above criteria, scheduled visits were to be continued.

[0339] As the subjects were hospitalized, the planned schedule and procedures, including tests for pharmacokinetic evaluation, were carried out at each evaluation point. Additionally, after the completion of the administration of the investigational drug, visits were conducted for the end of treatment (EOT) and test of cure (TOC) to perform tests and procedures for evaluating efficacy and safety.

[0340] For the efficacy evaluation, primary and secondary efficacy analyses were performed on a total of 25 subjects, including 34 subjects in the Full Analysis Set (FAS), which was the primary efficacy evaluation group, and 25 subjects in the Per-Protocol Set (PPS). In addition, subgroup analyses were conducted on the primary and secondary efficacy endpoints (time to overall cure and MRSA bacteremia clearance), provided that the subgroup analyses were performed only for the FAS.

[0341]

[0342] 1) Primary efficacy evaluation results

[0343] The composite response rate was measured at Day 14 after the start of administration of the investigational drug.

[0344] As a result, in FAS, overall healing was confirmed in 9 out of 15 patients (60%) in the test group administered vancomycin and oxazolidinone derivative compounds, and in 10 out of 19 patients (52.63%) in the control group administered vancomycin alone. From this, the difference in ratio between the two groups (test group-control group) was 7.37% [95% CI: (32.29, 83.66)], confirming that the overall healing effect is superior when vancomycin and oxazolidinone derivative compounds are administered together. Meanwhile, in PPS, overall healing was confirmed in 9 out of 11 patients (81.82%) in the test group administered vancomycin and oxazolidinone derivative compounds, and in 9 out of 14 patients (64.29%) in the control group administered vancomycin alone. From this, the difference in the ratio between the two groups (test group-control group) was 17.53% [95% CI: (-16.37, 51.44)], confirming that the healing effect of the combination of vancomycin and oxazolidinone derivative compounds was superior to that of vancomycin alone in PPS.

[0345]

[0346] Meanwhile, when evaluating the proportion of subjects who showed overall healing among those who switched to daptomycin, at Day 7, overall healing was confirmed in 1 out of 4 subjects (25%) in the test group, but in 0 out of 7 subjects (0%) in the control group, and at Day 14, overall healing was confirmed in 1 out of 4 subjects (25%) in the test group and in 0 out of 7 subjects (0%) in the control group. In addition, at the end of treatment (EOT), overall healing was confirmed in 3 out of 4 subjects (75%) in the test group and in 4 out of 7 subjects (57.14%) in the control group.

[0347] The difference in the ratio between the two groups (test group-control group) was 25.00% [95% CI: (-17.43, 67.43)] at Day 7, 10.71% [95% CI: (-39.01, 60.44)] at Day 14, and 17.86% [95% CI: (-38.22, 73.93)] at the end of treatment (EOT) visit, confirming that the test group was significantly higher than the control group at all time points.

[0348]

[0349] In addition, when measuring the proportion of subjects who showed overall healing among those who switched to oral antibiotics excluding the oxazolidinone class after vancomycin (including daptomycin switching), it was confirmed that there were no subjects in any group who switched to oral antibiotics after vancomycin (including daptomycin switching).

[0350] In addition, the proportion of subjects who showed overall healing based on whether oral antibiotics (for MRSA) were administered 14 days after the administration of the investigational drug was measured, and it was confirmed that there were no subjects in any group who switched to oral antibiotics for the treatment of MRSA bacteremia 14 days after the administration of the investigational drug.

[0351]

[0352] In addition, the proportion of subjects showing overall healing was measured based on whether the primary lesion was removed. Among subjects who had the primary lesion removed, overall healing was confirmed in 3 out of 4 subjects (75%) in the test group and 2 out of 6 subjects (33.3%) in the control group at Day 7, and in 2 out of 4 subjects (50%) in the test group and 2 out of 6 subjects (33.3%) in the control group at Day 14. Meanwhile, at the end of treatment (EOT), overall healing was confirmed in 3 out of 4 subjects (75%) in the test group and 3 out of 6 subjects (50%) in the control group. Therefore, among subjects who had the primary lesion removed, the difference in the ratio between the two groups (test group-control group) was 41.67% [95% CI: (-15.11, 98.44)] at Day 7, 16.67% [95% CI: (-45.17, 78.50)] at Day 14, and 25.00% [95% CI: (-33.32, 83.32)] at the end of treatment (EOT) visit, confirming that the rate was significantly higher in the test group compared to the control group.

[0353] Meanwhile, for subjects whose primary lesions were not removed, overall healing was confirmed in 4 out of 11 (36.36%) of the test group and 4 out of 13 (30.77%) of the control group at Day 7, and in 7 out of 11 (63.64%) of the test group and 8 out of 13 (61.54%) of the control group at Day 14. Meanwhile, at the end of treatment (EOT), overall healing was confirmed in 9 out of 11 (81.82%) of the test group and 11 out of 13 (84.62%) of the control group. Therefore, the difference in the ratio between the two groups (test group-control group) was 5.59% [95% CI: (-32.32, 43.51)] at Day 7, 2.10% [95% CI: (-36.73, 40.92)] at Day 14, and -2.80% [95% CI: (-32.87, 27.27)] at the end of treatment (EOT) visit, confirming that it was higher in the test group compared to the control group.

[0354]

[0355] In addition, the proportion of subjects showing overall healing among subjects without complications was measured. As a result, at Day 7, overall healing was confirmed in 6 out of 11 subjects (54.55%) in the test group and 6 out of 17 subjects (35.29%) in the control group, and at Day 14, overall healing was confirmed in 7 out of 11 subjects (63.64%) in the test group and 9 out of 17 subjects (52.94%) in the control group. Meanwhile, at the end of treatment (EOT), overall healing was confirmed in 10 out of 11 subjects (90.91%) in the test group and 12 out of 17 subjects (70.59%) in the control group. The difference in the ratio between the two groups (test group-control group) was 19.25% [95% CI: (-17.92, 56.43)] at Day 7, 10.70% [95% CI: (-26.33, 47.72)] at Day 14, and 20.32% [95% CI: (-7.21, 47.85)] at the end of treatment (EOT) visit, confirming that the test group was significantly higher than the control group.

[0356]

[0357] In addition, the proportion of subjects who showed overall healing based on whether they received antiviral or antifungal treatment during the clinical trial period was measured. For subjects who received antiviral or antifungal treatment during the clinical trial period, overall healing was confirmed in 3 out of 3 subjects (100%) in the test group and 2 out of 6 subjects (33.33%) in the control group at Day 7, and in 3 out of 3 subjects (100%) in the test group and 4 out of 6 subjects (66.67%) in the control group at Day 14. Meanwhile, at the end of treatment (EOT), overall healing was confirmed in 3 out of 3 subjects (100%) in the test group and 4 out of 6 subjects (66.67%) in the control group. Therefore, the difference in the ratio between the two groups (test group-control group) was 66.67% [95% CI: (28.95, 100.00)] at Day 7 and 33.33% [95% CI: (-4.39, 71.05)] at Day 14 and the end of treatment (EOT) visit, confirming that it was significantly higher in the test group compared to the control group.

[0358]

[0359] 2) Secondary efficacy evaluation results

[0360] As a result of measuring the proportion of subjects showing overall healing at each evaluation point up to the end of treatment (EOT), for FAS, at Day 7, overall healing was observed in 7 out of 15 subjects (46.67%) in the test group and 6 out of 19 subjects (31.58%) in the control group, and at the end of treatment, in 12 out of 15 subjects (80%) in the test group and 14 out of 19 subjects (73.68%) in the control group. In other words, the difference in the proportion between the two groups for FAS (test group vs. control group) was 15.09% [95% CI: (-17.69, 47.86)] at Day 7 and 6.32% [95% CI: (-22.00, 34.63)] at the end of treatment (EOT) visit, confirming that it was higher in the test group compared to the control group.

[0361] Meanwhile, in the case of PPS, overall healing was observed in 6 out of 11 patients (54.55%) in the test group and 5 out of 14 patients (35.71%) in the control group at Day 7, and at the end of treatment, in 10 out of 11 patients (90.91%) in the test group and 12 out of 14 patients (85.71%) in the control group. Therefore, in PPS as well, it was confirmed that the test group showed a higher rate compared to the control group, with 18.83% [95% CI: (-19.84, 57.51)] at Day 7 and 5.19% [95% CI: (-19.80, 30.19)] at the end of treatment (EOT) visit.

[0362]

[0363] The proportion of subjects confirmed to be MRSA negative twice in a row based on blood culture results at the time of the end-of-treatment (EOT) visits on Day 3, Day 5, Day 7, Day 14, and the end-of-treatment (EOT) was measured, and the study group showed a higher rate of bacteremia elimination compared to the control group at all visits during the FAS. Specifically, in the study group, 8 out of 14 subjects (57.14%) at Day 3, 9 out of 13 subjects (69.23%) at Day 5, 7 out of 13 subjects (53.85%) at Day 7, 9 out of 11 subjects (81.82%) at Day 14, and 12 out of 15 subjects (80%) at the end-of-treatment visit were confirmed to be MRSA negative twice in a row. In contrast, in the control group, 6 out of 18 patients (33.33%) at Day 3, 11 out of 18 patients (61.11%) at Day 5, 6 out of 17 patients (35.29%) at Day 7, 11 out of 14 patients (78.57%) at Day 14, and 14 out of 19 patients (73.68%) at the end of treatment were confirmed to be negative for MRSA twice in a row. That is, the difference in the proportion of subjects between the two groups (test group-control group) who tested negative for MRSA in two consecutive blood culture tests at FAS at each time point from Day 3 to the end of treatment (EOT) visit was 23.81% [95% CI: (-10.05, 57.67)] at Day 3, 8.12% [95% CI: (-25.59, 41.83)] at Day 5, 18.55% [95% CI: (-16.81, 53.91)] at Day 7, 3.25% [95% CI: (-28.08, 34.58)] at Day 14, and 6.32% [95% CI: (-22.00, 34.63)] at the end of treatment (EOT) visit, confirming that the rate was higher in the test group compared to the control group.

[0364] Meanwhile, in the PPS, 5 out of 10 patients (50%) at Day 3, 8 out of 11 patients (72.73%) at Day 5, 6 out of 11 patients (54.55%) at Day 7, 9 out of 11 patients (81.82%) at Day 14, and 10 out of 11 patients (90.91%) at the end of treatment were confirmed to be MRSA negative for two consecutive times. On the other hand, in the control group, 5 out of 14 patients (35.71%) at Day 3, 8 out of 14 patients (57.14%) at Day 5, 5 out of 14 patients (35.71%) at Day 7, 10 out of 13 patients (76.92%) at Day 14, and 12 out of 14 patients (85.71%) at the end of treatment were confirmed to be MRSA negative for two consecutive times. In other words, the difference in the proportion of subjects between the two groups (test group-control group) was 14.29% [95% CI: (-25.59, 54.16)] at Day 3, 15.58% [95% CI: (-21.36, 52.53)] at Day 5, 18.83% [95% CI: (-19.84, 57.51)] at Day 7, 4.90% [95% CI: (-27.42, 37.21)] at Day 14, and 5.19% [95% CI: (-19.80, 30.19)] at the end of treatment (EOT) visit, confirming that the test group was higher than the control group at all time points.

[0365]

[0366] The proportion of subjects showing persistent MRSA bacteremia in blood culture tests at Day 3, Day 5, Day 7, and Day 14 was measured. In the FAS, for the test group, 6 out of 14 subjects (42.86%) at Day 3, 4 out of 13 subjects (30.77%) at Day 5, 1 out of 13 subjects (7.69%) at Day 7, and 0 out of 11 subjects (0%) at Day 14. On the other hand, for the control group, 12 out of 18 subjects (66.67%) at Day 3, 7 out of 18 subjects (38.89%) at Day 5, 3 out of 17 subjects (17.65%) at Day 7, and 2 out of 14 subjects (14.29%) at Day 14. That is, the difference in the proportion of subjects showing persistent MRSA bacteremia in blood culture tests between the two groups (test group-control group) from Day 3 to Day 14 was -23.81% [95% CI: (-57.67, 10.05)] at Day 3, -8.12% [95% CI: (-41.83, 25.59)] at Day 5, -9.95% [95% CI: (-33.15, 13.24)] at Day 7, and -14.29% [95% CI: (-32.62, 4.04)] at Day 14, confirming that the proportion of subjects showing persistent MRSA bacteremia in the test group was significantly reduced.

[0367] Meanwhile, in the PPS, for the test group, it was confirmed that 5 out of 10 people (50%) at Day 3, 3 out of 11 people (27.27%) at Day 5, 0 out of 11 people (0%) at Day 7, and 0 out of 11 people (0%) at Day 14. On the other hand, for the control group, it was confirmed that 9 out of 14 people (64.29%) at Day 3, 6 out of 14 people (42.86%) at Day 5, 3 out of 14 people (21.43%) at Day 7, and 2 out of 13 people (15.38%) at Day 14. That is, the difference in the ratio between the two groups (test group-control group) was -14.29% [95% CI: (-54.16, 25.59)] at Day 3, -15.58% [95% CI: (-52.53, 21.36)] at Day 5, -21.43% [95% CI: (-42.92, 0.07)] at Day 7, and -15.38% [95% CI: (-35.00, 4.23)] at Day 14, confirming that the control group was higher than the test group at all time points, it was confirmed that the proportion of subjects showing persistent MRSA bacteremia in the test group was significantly reduced.

[0368]

[0369] Meanwhile, when measuring the time to disappearance of MRSA bacteremia, the median time from the date of the first blood culture test confirming MRSA positivity prior to randomization in FAS to the date of the first blood culture test confirming negative results was 7.00 days [95% CI: (3.00, 14.00)] in the test group and 8.00 days [95% CI: (4.00, 18.00)] in the control group, confirming that it was higher in the control group compared to the test group (Fig. 4a). In addition, in PPS, the median time was 4.00 days [95% CI: (3.00, 14.00)] in the test group and 7.00 days [95% CI: (4.00, 18.00)] in the control group, confirming that it was significantly higher in the control group compared to the test group (Fig. 4b).

[0370]

[0371] 3) Secondary efficacy evaluation of subgroups

[0372] The time to the disappearance of MRSA bacteremia in blood culture tests was measured in subjects who switched to daptomycin. Specifically, among subjects who switched to daptomycin, the median time to the disappearance of MRSA bacteremia in blood culture tests was 12.50 days [95% CI: (7.00, NA)] in the test group and 18.00 days [95% CI: (9.00, NA)] in the control group, confirming that it was significantly higher in the control group compared to the test group.

[0373] Meanwhile, when measuring the time to disappearance of MRSA bacteremia in blood culture tests based on whether the primary lesion was removed, the median time to disappearance of MRSA bacteremia in subjects with confirmed disappearance of MRSA bacteremia in blood tests among subjects with removed primary lesions was 7.00 days [95% CI: (3.00, NA)] for the test group and 18.00 days [95% CI: (3.00, NA)] for the control group, confirming that it was significantly higher in the control group compared to the test group.

[0374] In addition, among subjects who did not have the primary lesion removed and whose blood test confirmed the disappearance of MRSA bacteremia, the median time to disappearance of MRSA bacteremia was 7.00 days [95% CI: (3.00, 14.00)] for the test group and 5.00 days [95% CI: (4.00, 14.00)] for the control group, with no significant difference between the two groups.

[0375]

[0376] Meanwhile, among subjects without complications in whom the disappearance of MRSA bacteremia was confirmed by blood culture, the median time to disappearance of MRSA bacteremia was 7.00 days [95% CI: (3.00, 14.00)] for the test group and 6.00 days [95% CI: (4.00, 18.00)] for the control group, with no significant difference between the two groups.

[0377]

[0378] As a result of measuring the time to disappearance of MRSA bacteremia in blood culture tests according to whether antiviral or antifungal treatment was received during the clinical trial period, among subjects who received antiviral or antifungal treatment during the clinical trial period and whose disappearance of MRSA bacteremia in blood culture tests was confirmed, the median time to disappearance of MRSA bacteremia was 4.00 days [95% CI: (3.00, NA)] for the test group and 6.00 days [95% CI: (3.00, NA)] for the control group, confirming that the control group was higher than the test group.

[0379] Meanwhile, among subjects who did not receive antiviral or antifungal treatment during the clinical trial period, when the disappearance of MRSA bacteremia was confirmed by blood culture, the median time to disappearance of MRSA bacteremia was 8.00 days [95% CI: (3.00, 15.00)] for the test group and 9.00 days [95% CI: (5.00, 21.00)] for the control group, confirming that the control group had a higher time compared to the test group.

[0380] In summary, the therapeutic effect of combination therapy with vancomycin and the above compound 1 was evaluated in patients with MRSA bacteremia. Compared to standard therapy with vancomycin monotherapy, there was a tendency for an increase in the overall cure rate and a shortening of the time to disappearance of MRSA bacteremia in blood culture tests.

[0381]

[0382] Example 5. Safety evaluation of combination therapy of vancomycin and oxazolidinone derivative compounds in patients with MRSA bacteremia

[0383]

[0384] Safety evaluation analysis was performed on a safety set (SS) that included subjects who received the investigational drug at least once.

[0385] The incidence of Treatment-Emergent Adverse Events (TEAEs) was 72.22% (13 / 18 patients, 42 cases) in the test group and 80.00% (16 / 20 patients, 50 cases) in the control group, of which the incidence of Adverse Drug Reactions (ADRs) for which a causal relationship with the investigational drug could not be ruled out was 22.22% (4 / 18 patients, 4 cases) in the test group and 45.00% (9 / 20 patients, 15 cases) in the control group. When the ADRs were classified according to the preferred term (PT), in the test group, 'diarrhea' was identified at 11.11% (2 / 18 patients, 2 cases), and 'nausea' and 'pruritus' were both identified at 5.56% (1 / 18 patients, 1 case). In the control group, 'pruritus' was identified at 15.00% (3 / 20 patients, 3 cases), followed by 'anemia' at 10.00% (2 / 20 patients, 2 cases). None of the reported ADRs were serious adverse drug reactions (SADRs), and it was confirmed that the incidence of ADRs was significantly higher in the control group compared to the test group.

[0386]

[0387] The incidence of TEAE that caused discontinuation of administration was 5.56% (1 / 18 patients, 1 case) in the test group and 5.00% (1 / 20 patients, 1 case) in the control group, and 'depressed level of consciousness' was identified as 5.56% (1 / 18 patients, 1 case) in the test group and 'endocarditis' as 5.00% (1 / 20 patients, 1 case) in the control group.

[0388] When classifying TEAEs by severity, the test group ranged from 'grade 1' to 'grade 3', with no 'grade 4' or 'grade 5' cases. The control group was reported as ranging from 'grade 1' to 'grade 5', with one case each of grade 4 and grade 5.

[0389] In addition, three cases of 'anemia' and one case of 'platelet count decreased' were observed in the test group in relation to oxazolidinone antibiotics, but all of these adverse reactions were determined to be unrelated to the investigational drug.

[0390]

[0391] In summary, safety evaluations of the entire study population revealed that the combination therapy of vancomycin and Compound 1 did not cause specific or clinically significant adverse events compared to vancomycin monotherapy, and did not increase the frequency or severity of adverse events. Furthermore, mitochondrial toxicity and related adverse events, which are the causes of limitations and discontinuation of long-term administration of oxazolidinone antibiotics, were not observed. Accordingly, during the course of this clinical trial, the combination therapy of vancomycin and Compound 1 demonstrated a clinically acceptable safety and tolerability profile, and no adverse trends were observed in terms of overall safety and tolerability compared to vancomycin monotherapy.

Claims

1. A pharmaceutical composition for the prevention or treatment of penicillin-resistant bacterial-mediated diseases comprising an oxazolidinone derivative represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof: [Chemical Formula 1] (In the above chemical formula 1, The above X is a chemical bond, -(CH2) n - or -(CH2) n C(=O)- igo; The above n is an integer from 0 to 2; The above R is hydrogen or a pentagonal or hexaagonal heteroaryl selected from the following structures; ; The above R1 to R 25 are independently hydrogen, (C1-C6) alkyl, (C3-C6) cycloalkyl, -OH, -NR 31 R 32 , -C(=O)R 33 , -(CH2) m OH, -C=NOH, -CN, -NO2 or halogen; The above R 31 and R 32 are independently hydrogen, (C1-C6) alkyl, or -C(=O)H; The above R 33 It is hydrogen, -OH, -NH2, or (C1-C6) alkyl; The above m is one integer from 1 to 6; The above Q is -OH, -NHC(=O)R 41 or -NHC(=O)OR 41 is; The above R 41 It is a (C1-C6) alkyl.

2. A pharmaceutical composition according to claim 1, wherein R is hydrogen.

3. A pharmaceutical composition according to claim 1, wherein Q is -OH.

4. A pharmaceutical composition according to claim 1, wherein the oxazolidinone derivative represented by Chemical Formula 1 is represented by the following Chemical Formula 2: [Chemical Formula 2] .

5. A pharmaceutical composition according to claim 1, wherein the penicillin-based compound is one or more selected from the group consisting of methicillin, dicloxacillin, oxacillin, and flucloxacillin.

6. A pharmaceutical composition according to claim 1, wherein the penicillin-resistant bacteria are selected from the group consisting of Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus pneumoniae, Streptococcus pyogenes, Enterococcus faecalis, and Enterococcus faecium.

7. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is administered in combination with one or more antibiotics.

8. In claim 7, the antibiotic is vancomycin, telavancin, dalbavancin, oritavancin, daptomycin, tigecycline, doxycycline, minocycline, omadacycline, clindamycin, imipenem, meropenem, ertapenem, doripenem, ciprofloxacin, levofloxacin, moxifloxacin, delafloxacin, rifampicin, rifabutin, and A pharmaceutical composition selected from the group consisting of rifapentine.

9. A pharmaceutical composition according to claim 7, wherein the combined administration is administered simultaneously, separately, or sequentially.

10. A pharmaceutical composition according to claim 7, wherein the pharmaceutical composition and the antibiotic are administered in combination in a weight ratio of 1:0.001 to 100.

11. A pharmaceutical composition according to claim 1, wherein the disease mediated by penicillin-resistant bacteria is selected from the group consisting of abscess, furuncle, bacteremia, sepsis, endocarditis, cellulitis, necrotizing soft tissue infections, osteomyelitis, septic arthritis, and pneumonia.

12. A pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is administered orally.

13. Antibiotic composition for the prevention or treatment of penicillin-resistant bacterial-mediated diseases comprising an oxazolidinone derivative represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof: [Chemical Formula 1] (In the above chemical formula 1, The above X is a chemical bond, -(CH2) n - or -(CH2) n C(=O)- igo; The above n is an integer from 0 to 2; The above R is hydrogen or a pentagonal or hexaagonal heteroaryl selected from the following structures; The above R1 to R 25 are independently hydrogen, (C1-C6) alkyl, (C3-C6) cycloalkyl, -OH, -NR 31 R 32 , -C(=O)R 33 , -(CH2) m OH, -C=NOH, -CN, -NO2 or halogen; The above R 31 and R 32 are independently hydrogen, (C1-C6) alkyl, or -C(=O)H; The above R 33 It is hydrogen, -OH, -NH2, or (C1-C6) alkyl; The above m is one integer from 1 to 6; The above Q is -OH, -NHC(=O)R 41 or -NHC(=O)OR 41 is; The above R 41 It is a (C1-C6) alkyl.

14. The antibiotic composition of claim 13, wherein the antibiotic composition is administered in combination with one or more antibiotics selected from the group consisting of vancomycin, telavancin, dalbavancin, oritavancin, daptomycin, tigecycline, doxycycline, minocycline, omadacycline, clindamycin, imipenem, meropenem, ertapenem, doripenem, ciprofloxacin, levofloxacin, moxifloxacin, delafloxacin, rifampicin, rifabutin, and rifapentine.

15. An oxazolidinone derivative represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof; and Antibiotic composition for the prevention or treatment of penicillin-resistant bacterial-mediated diseases comprising an antibiotic selected from the group consisting of vancomycin, telavancin, dalbavancin, oritavancin, daptomycin, tigecycline, doxycycline, minocycline, omadacycline, clindamycin, imipenem, meropenem, ertapenem, doripenem, ciprofloxacin, levofloxacin, moxifloxacin, delafloxacin, rifampicin, rifabutin, and rifapentine: [Chemical Formula 1] (In the above chemical formula 1, The above X is a chemical bond, -(CH2) n - or -(CH2) n C(=O)- igo; The above n is an integer from 0 to 2; The above R is hydrogen or a pentagonal or hexaagonal heteroaryl selected from the following structures; The above R1 to R 25 are independently hydrogen, (C1-C6) alkyl, (C3-C6) cycloalkyl, -OH, -NR 31 R 32 , -C(=O)R 33 , -(CH2) m OH, -C=NOH, -CN, -NO2 or halogen; The above R 31 and R 32 are independently hydrogen, (C1-C6) alkyl, or -C(=O)H; The above R 33 It is hydrogen, -OH, -NH2, or (C1-C6) alkyl; The above m is one integer from 1 to 6; The above Q is -OH, -NHC(=O)R 41 or -NHC(=O)OR 41 is; The above R 41 It is a (C1-C6) alkyl.

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