KR102051449B1 - 4'-phosphopantetheinyl transferase enzyme inhibitors derived from Mycobacterium tuberculosis and pharmaceutical composition for use in preventing or treating tuberculosis containing the same as an active ingredient - Google Patents

Abstract

The present invention relates to a 4'-phosphopantetheinyl transferase enzyme inhibitor derived from Mycobacterium tuberculosis and a pharmaceutical composition for preventing or treating tuberculosis containing the same as an active ingredient, according to the present invention. Compounds can significantly inhibit 4'-phosphopanthethenyl transferase enzyme to remove Mycobacterium tuberculosis through an immune response in the body, thereby having an effect that can be used for the prevention or treatment of tuberculosis.

Description

4'-phosphopantetheinyl transferase enzyme inhibitors derived from Mycobacterium tuberculosis and pharmaceutical composition for use in Mycobacterium tuberculosis 4'-phosphopanthethenyl transferase enzyme inhibitor and its active ingredient preventing or treating tuberculosis containing the same as an active ingredient}

The present invention relates to a 4'-phosphopantetheinyl transferase enzyme inhibitor derived from Mycobacterium tuberculosis and a pharmaceutical composition for preventing or treating tuberculosis containing the same as an active ingredient.

Tuberculosis includes tuberculosis bacteria including Mycobacterium tuberculosis, Mycobacterium bovis, Mycobacterium microti, and Mycobacterium africanum (M.africanum). Mycobacterium tuberculosis-complex) (MTB-C) is a chronic infectious disease.

It is estimated that one third of the world's population is infected with Mycobacterium tuberculosis and approximately 800 million new cases occur each year. Most infected people are asymptomatic and about one-tenth of them develop, and more than half of them die if they are not treated properly. A typical symptom is a cough with chilled phlegm, chills, cold sweats, and weight loss that can affect any organ in the body, causing a variety of symptoms depending on the affected organ.

The most common anti-tuberculosis agents prescribed for the treatment of tuberculosis are isoniazid, rifampicin, pyrazineamide and etambutol. Treatment by them often takes several months and can be extended as needed. In addition, in order to reduce the risk of developing resistance to tuberculosis drugs, a combination of various antibiotics is prescribed, but even in this case, the treatment of latent tuberculosis is very difficult, and multi-drug resistant tuberculosis bacteria (MDR-TB, isoniazid) And tuberculosis bacteria that do not die in primary treatment drugs such as rifampicin. Accordingly, there is a need for a lead substance for a new target group to replace the existing drug.

Recently, 4'-phosphopantetheinyl transferase has been studied as a new target group. When tuberculosis enters the body, macrophages and the like try to maintain the body's health, but various specific lipids on the surface of the tuberculosis cause the body's immune system to evade the 4'-phosphopantetheinyl transferase protein. It is an upper central regulator of body-forming enzymes and effectively inhibiting it allows the removal of Mycobacterium tuberculosis through the body's immune response. Recent studies have demonstrated that 4'-phosphopantetheinyl Transferase is necessary for the replication and survival of Mycobacterium tuberculosis (Non-Patent Document 1). Research teams in France, the United States, and New Zealand have also targeted 4'-phosphopantetheinyl Transferase to develop anti-tuberculosis drugs. There is no lead material reported so far.

Therefore, the present inventors designed an inhibitor based on the three-dimensional structure of the target protein and the mutual binding of two ligands bound thereto for the development of an anti-tuberculosis drug targeting 4'-phosphopantetheinyl transferase, and thus derived a compound with high inhibition potential By performing an in vitro assay to confirm the inhibitory effect was completed the present invention.

PLOS Pathogen. 2012 Dec; 8 (12): e1003097.

It is an object of the present invention to provide novel 4'-phosphopantetheinyl transferase enzyme inhibitor compounds or pharmaceutically acceptable salts thereof.

Another object of the present invention to provide a pharmaceutical composition for the prevention or treatment of tuberculosis containing the compound as an active ingredient.

Another object of the present invention to provide a health functional food for the prevention or improvement of tuberculosis containing the compound as an active ingredient.

In order to achieve the above object,

The present invention provides a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof.

[Formula 1]

In Chemical Formula 1,

이고,R ¹ is unsubstituted or substituted 5-10 each ring heteroaryl containing one or more hetero atoms selected from the group consisting of N, O and S or

ego,

The substituted 5-10 each ring heteroaryl consists of hydrogen, straight or branched chain C _1-10 alkyl, straight or branched chain C _1-10 alkoxy, nitro, nitrile, halogen and N, O and S 5-10 cyclic heteroaryl substituted with one or more substituents selected from the group consisting of unsubstituted 5-10 cyclic heteroaryl containing one or more hetero atoms selected from the group,

A ¹ and A ² are independently hydrogen, linear or branched C _1-10 alkyl, linear or branched C _1-10 alkoxy, nitro, nitrile, halogen or A ¹ and A ² are linked to N To form an unsubstituted 5-10 cyclic heterocycloalkyl comprising at least one hetero atom selected from the group consisting of O and S;

Q is S, O or CH ₂ ,

M is S, O, CH ₂ or NH,

K is CH or N,

B ¹ , B ² and B ³ are independently hydrogen, straight or branched chain C _1-10 alkyl, straight or branched chain C _1-10 alkoxy, nitro, nitrile or halogen.

The present invention also provides a pharmaceutical composition for the prevention or treatment of tuberculosis containing the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

Furthermore, the present invention provides a health functional food for preventing or improving tuberculosis containing the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

Compounds according to the present invention can significantly inhibit the 4'-phosphopanthethenyl transferase enzyme to remove Mycobacterium tuberculosis through the body's immune response, thereby having an effect that can be used for the prevention or treatment of tuberculosis.

1 is a three-dimensional structure of the proteins of Mycobacterium tuberculosis PptT (4'-phosphopantetheinyl transferase) and Mycobacterium smegmatis PptT.
Figure 2 is a graph of the results of activity inhibition experiments using 6-NOBP (6-nitro-1,2-benzopyrone) as a control.
FIG. 3 shows the results of activity inhibition experiments by varying the% (v / v) of dimethyl sulfoxide (DMSO) to find the optimal reaction conditions using 6-NOBP (6-nitro-1,2-benzopyrone) as a control. It is a graph.
Figure 4 shows the process of confirming the inhibition of BpsA (Blue-pigment synthetase) activity of the example compounds.
5 is a result graph of the PptT activity inhibition evaluation experiment of Example 1.
6 is a graph showing the results of the PptT activity inhibition evaluation experiment of Example 2. FIG.
7 is a result graph of the PptT activity inhibition evaluation experiment of Example 3.
8 is a result graph of the PptT activity inhibition evaluation experiment of Example 4.

Hereinafter, the present invention will be described in detail.

The present invention provides a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof.

[Formula 1]

In Chemical Formula 1,

이고,R ¹ is unsubstituted or substituted 5-10 each ring heteroaryl containing one or more hetero atoms selected from the group consisting of N, O and S or

ego,

The substituted 5-10 each ring heteroaryl consists of hydrogen, straight or branched chain C _1-10 alkyl, straight or branched chain C _1-10 alkoxy, nitro, nitrile, halogen and N, O and S 5-10 cyclic heteroaryl substituted with one or more substituents selected from the group consisting of unsubstituted 5-10 cyclic heteroaryl containing one or more hetero atoms selected from the group,

A ¹ and A ² are independently hydrogen, linear or branched C _1-10 alkyl, linear or branched C _1-10 alkoxy, nitro, nitrile, halogen or A ¹ and A ² are linked to N To form an unsubstituted 5-10 cyclic heterocycloalkyl comprising at least one hetero atom selected from the group consisting of O and S;

Q is S, O or CH ₂ ,

M is S, O, CH ₂ or NH,

K is CH or N,

B ¹ , B ² and B ³ are independently hydrogen, straight or branched chain C _1-10 alkyl, straight or branched chain C _1-10 alkoxy, nitro, nitrile or halogen.

Preferably,

이고,R ¹ is unsubstituted or substituted 5-8 each ring heteroaryl containing one or more hetero atoms selected from the group consisting of N, O and S or

ego,

The substituted 5-8 heterocyclic heteroaryl consists of hydrogen, straight or branched chain C _1-5 alkyl, straight or branched chain C _1-5 alkoxy, nitro, nitrile, halogen and N, O and S 5-8 angular ring heteroaryl substituted with one or more substituents selected from the group consisting of unsubstituted 5-8 angular ring heteroaryl containing one or more hetero atoms selected from the group,

A ¹ and A ² are independently hydrogen, linear or branched C _1-5 alkyl, linear or branched C _1-5 alkoxy, nitro, nitrile, halogen or A ¹ and A ² are linked N To form an unsubstituted 5-8 cyclic heterocycloalkyl comprising at least one hetero atom selected from the group consisting of O and S;

Q is S, O or CH ₂ ,

M is S, O, CH ₂ or NH,

K is CH or N,

Wherein B ^1, B ² and B ³ are independently hydrogen, straight or alkoxy, nitro of branched alkyl, linear or branched C _1-5 of C _1-5, a nitrile or a halogen.

More preferably,

,

,

또는

이고,R ¹ is

,

,

or

ego,

Q is S or CH ₂ ,

M is S or O,

K is N or CH,

B ¹ is -Cl or -CH ₃ ,

B ² and B ³ is independently —H or —CH ₃ .

Most preferably,

The compound represented by Formula 1 is any one selected from the following compound group.

(1) N- (1- (6- (4H-1,2,4-triazol-4-yl) pyridin-2-yl) vinyl) -5- (benzo [d] thiazol-2-yl) 2-methylbenzeneamine;

(2) N- (5- (benzo [d] oxazol-2-yl) -2-chlorophenylcarbamothioyl) -4-fluorobenzamide;

(3) 3-chloro-N- (3- (5,7-dimethylbenzo [d] oxazol-2-yl) -2-methylphenylcarbamothioyl) benzamide; And

(4) N- (4-chloro-3- (oxazolo [4,5-b] pyridin-2-yl) phenylcarbamothioyl) -2,3-dihydrobenzo [b] [1,4] dioxine -6-carboxamide.

The compound represented by Formula 1 of the present invention can be used in the form of a pharmaceutically acceptable salt, and as the salt, an acid addition salt formed by a pharmaceutically acceptable free acid is useful. Acid addition salts include inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid, phosphorous acid, aliphatic mono and dicarboxylates, phenyl-substituted alkanoates, hydroxy alkanoates and alkanes. It is obtained from non-toxic organic acids such as dioate, aromatic acids, aliphatic and aromatic sulfonic acids and the like, organic acids such as acetic acid, benzoic acid, citric acid, lactic acid, maleic acid, gluconic acid, methanesulfonic acid, 4-toluenesulfonic acid, tartaric acid, fumaric acid and the like. Examples of such pharmaceutically nontoxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate chloride, bromide, eye Odide, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suve Latex, sebacate, fumarate, maleate, butyne-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitro benzoate, hydroxybenzoate, Methoxybenzoate, phthalate, terephthalate, benzenesulfonate, toluenesulfonate, chloro Zensulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycolate, malate, tartrate, methanesulfonate, propanesulfonate, naphthalene- 1-sulfonate, naphthalene-2-sulfonate, mandelate and the like.

The acid addition salt according to the present invention can be prepared by a conventional method, for example, a precipitate produced by dissolving a derivative of Formula 1 in an organic solvent such as methanol, ethanol, acetone, dichloromethane, acetonitrile and adding an organic or inorganic acid. The solvent may be prepared by filtration and drying, or the solvent and excess acid may be distilled under reduced pressure, dried, and then crystallized under an organic solvent.

Bases can also be used to make pharmaceutically acceptable metal salts. Alkali metal or alkaline earth metal salts are obtained, for example, by dissolving a compound in an excess of alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and evaporating and drying the filtrate. At this time, it is pharmaceutically suitable to prepare sodium, potassium or calcium salt as the metal salt. Corresponding salts are also obtained by reacting alkali or alkaline earth metal salts with a suitable negative salt (eg silver nitrate).

Furthermore, the present invention includes not only the compound represented by Formula 1 and pharmaceutically acceptable salts thereof, but also solvates, stereoisomers, hydrates, and the like that can be prepared therefrom.

The present invention also provides a pharmaceutical composition for the prevention or treatment of tuberculosis containing the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient. Here, the compound is characterized in that to prevent or treat tuberculosis by inhibiting the 4'-phosphopantetheinyl transferase (4'-phosphopantetheinyl Transferase), specific types of tuberculosis, tuberculosis tuberculosis, adrenal tuberculosis There are renal tuberculosis, epididymal tuberculosis, lymphatic tuberculosis, laryngeal tuberculosis, middle ear tuberculosis, intestinal tuberculosis, multidrug-resistant tuberculosis, pulmonary tuberculosis, tuberculosis, bone tuberculosis, throat tuberculosis, lymph node tuberculosis, lung disease, breast tuberculosis or spinal tuberculosis.

In addition, the tuberculosis may be characterized in that the tuberculosis caused by multidrug-resistant tuberculosis bacteria.

In addition, in the pharmaceutical composition according to the present invention, the compound represented by Formula 1, or a pharmaceutically acceptable salt thereof may be administered in various dosage forms, oral and parenteral, in the case of clinical administration. It may be prepared using diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, surfactants, etc. which are commonly used.

Formulations for oral administration include, for example, tablets, pills, hard / soft capsules, solutions, suspensions, emulsifiers, syrups, granules, elixirs, troches, and the like. , Dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine), lubricants such as silica, talc, stearic acid and its magnesium or calcium salts and / or polyethylene glycols. Tablets may contain binders such as magnesium aluminum silicate, starch paste, gelatin, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidine and the like, optionally with bores such as starch, agar, alginic acid or its sodium salt, and the like. Release or boiling mixtures and / or absorbents, colorants, flavors, and sweeteners.

Pharmaceutical compositions comprising the compound represented by Formula 1 as an active ingredient may be administered parenterally, and parenteral administration may be by injection of subcutaneous injection, intravenous injection, intramuscular injection, or intrathoracic injection.

In this case, the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof is mixed with water with a stabilizer or a buffer to prepare a parenteral formulation, and prepared as a solution or suspension, and it is an ampule or vial unit dosage form. It can be prepared by. The compositions may contain sterile and / or preservatives, stabilizers, hydrating or emulsifying accelerators, auxiliaries such as salts and / or buffers for the control of osmotic pressure, and other therapeutically useful substances, and conventional methods of mixing, granulating It may be formulated according to the formulation or coating method.

Furthermore, the dosage of the compound represented by Formula 1 of the present invention or a pharmaceutically acceptable salt thereof to the human body may vary depending on the age, weight, sex, dosage form, health condition and degree of disease of the patient. Based on an adult patient of 70 kg, it is generally 0.1-1000 mg / day, preferably 1-500 mg / day, and once or several times a day at regular time intervals as determined by the doctor or pharmacist. It may be administered in divided doses.

In another aspect, the present invention provides a health food for preventing or improving tuberculosis comprising the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.

Here, the tuberculosis is tuberculosis, skin tuberculosis, adrenal tuberculosis, kidney tuberculosis, epididymal tuberculosis, lymphatic tuberculosis, laryngeal tuberculosis, middle ear tuberculosis, intestinal tuberculosis, multidrug-resistant tuberculosis, pulmonary tuberculosis, biliary tuberculosis, bone tuberculosis, throat tuberculosis, lymph node tuberculosis, lung , Breast tuberculosis or spinal tuberculosis.

Hereinafter, the present invention will be described in detail by Examples and Experimental Examples.

However, the following Examples and Experimental Examples are only illustrative of the present invention, the present invention is not limited by the following Examples and Experimental Examples.

< Example 1> N -(1- (6- (4H-1,2,4- Triazole -4-yl) pyridin-2-yl) vinyl) -5- (benzo [d] thiazol-2-yl) -2-methylbenzeneamine

The title compound was provided by the Korea Compound Bank.

< Example  2> N- (5- ( Benzo [d] oxazole -2- days) -2- Chlorophenylcarbamothioyl )-4- Fluorobenzamide

The title compound was provided by the Korea Compound Bank.

< Example  3> 3- Chloro -N- (3- (5,7- Dimethylbenzo [d] oxazole -2- days) -2- Methylphenylcarbamothioyl Benzamide

The title compound was provided by the Korea Compound Bank.

< Example  4> N- (4- Chloro -3- ( Oxazolo [4,5-b] pyridine -2-yl) phenylcarbamothioyl) -2,3-dihydrobenzo [b] [1,4] dioxine-6-carboxamide

The title compound was provided by the Korea Compound Bank.

Specific structures of the compounds of Examples 1 to 4 are shown in Table 1 below.

Example Chemical structure One

2

3

4

< Experimental Example  1> 4'- Phosphopanthetenyl Transferase  (4'- phosphopantetheinyl  transferase: PptT Inhibitor selection and activity inhibition evaluation

1-1. Experiment preparation

(1) Mass expression of E. coli of 4'-phosphopantetheinyl transferase (PptT) derived from Mycobacterium tuberculosis

The PptT gene (Rv2794c) was inserted into the pET21a plasmid and cloned into E. coli cell line BL21 (DE3). After incubating E. coli in Luria Broth medium at 37 ° C, IPTG was added at a time point of OD600 of about 0.7 to express PptT and incubated at 16 ° C for 20 hours.

(2) Purification and Isolation of PptT Proteins

After centrifugation of the cultured Escherichia coli, the cells were stored at minus 80 ° C, and then crushed by ultrasound, and then purified first using IMAC (Immobilized metallo-affinity chromatography), followed by SEC (Size exclusion chromatography) method. Final purification. The buffer solution containing PptT was composed of 50 mM Tris-HCl (pH 8.0), 200 mM NaCl.

(3) Screening of Inhibitor Substances

Inhibitors were designed based on the three-dimensional structure of 4'-phosphopantetheinyl Transferase protein and the mutual binding of two ligands.

1-2. Experiment method

(1) Inhibitor detection through BpsA (Blue-pigment synthetase) assay

Before the mass compound assay, 6-NOBP (6-nitroso-1,2-benzopyrone), a reference material, was used to determine the optimal reaction conditions for the accuracy of enzyme activity and to filter out false positive compounds. 2 and FIG. 3. Through this, 32% (v / v) of DMSO (dimethyl sulfoxide) was added to confirm that the reaction was continued and stable.

In addition, to determine whether the PptT inhibition assay presented in the present invention specifically inhibits PptT with specificity or nonspecific binding to the substrate BpsA (Blue-pigment synthetase), resulting inhibition of BpsA (Blue- After pre-reacting the pigment synthetase) and the CoA-PptT conjugate to activate the BpsA (Blue-pigment synthetase) protein, which is a substrate, the assay was performed as shown in FIG. Through this, it was confirmed that all of the leading materials presented in the present invention did not inhibit BpsA (Blue-pigment synthetase).

(2) Determination of PptT Inhibitory Activity (IC ₅₀ )

The assay was performed using a 96 well plate, and each well was tested to include 100 μM -0.001μM inhibitor at the final concentration. The experiment was carried out with 73 μl of various components in each well: 2 μM PptT, 50 mM Tris (pH 8.0), 20 μM CoA, 8 mM L-glutamine, 5 mM ATP, 10 mM MgCl ₂ , 32% (v / v) dimethyl sulfoxide (DMSO). 25 μl BpsA (Blue-pigment synthetase) protein solution (composition: 50 mM Tris-HCl, pH 8.0, 8 mM L-glutamine, 5 mM ATP, 10 mM MgCl ₂ , 20% (v / v) Dimethyl sulfoxide) The enzyme reaction was started at 25 ℃. Thirty minutes after the enzyme reaction, the absorbance values of each well were read at 590 nm using SpectraMax M5 (Molecular Devices), and the absorbances of compounds and buffers were measured separately to correct the values and normal PptT activity was not inhibited. As a reference, inhibition of PptT activity of each compound was measured. The IC ₅₀ (inhibitory concentration at 50%) was calculated using GraphPad Prism software.

1-3. Experiment result

PptT inhibitors and respective IC ₅₀ values discovered through the results are shown in Table 2 below, and the graphs of the results are shown in FIGS.

Example IC ₅₀ (μM) One 0.635 2 0.7955 3 2.282 4 1.817

On the other hand, the compound represented by Formula 1 according to the present invention can be formulated in various forms according to the purpose. The following are some examples of formulation methods containing the compound represented by Formula 1 according to the present invention as an active ingredient, but the present invention is not limited thereto.

< Formulation example  1> Preparation of Pharmaceutical Formulations

1-1. Powder  Produce

500 mg of compound of formula 1

Lactose 100 mg

Talc 10 mg

The above ingredients are mixed and filled in an airtight cloth to prepare a powder.

1-2. Manufacture of tablets

500 mg of compound of formula 1

Corn starch 100 mg

Lactose 100 mg

2 mg magnesium stearate

After mixing the above components, tablets are prepared by tableting according to a conventional method for preparing tablets.

1-3. Manufacture of capsule

500 mg of compound of formula 1

Corn starch 100 mg

Lactose 100 mg

2 mg magnesium stearate

According to a conventional capsule preparation method, the above ingredients are mixed and filled into gelatin capsules to prepare capsules.

1-4. Preparation of Injectables

500 mg of compound of formula 1

Appropriate sterile distilled water for injection

pH adjuster

According to the conventional method for preparing an injection, the amount of the above ingredient is prepared per ampoule (2 ml).

1-5. Liquid  Produce

100 mg of compound of Formula 1

10 g of isomerized sugar

5 g of mannitol

Purified water

According to the conventional method of preparing a liquid solution, each component is added to the purified water to dissolve, the lemon flavor is added appropriately, the above components are mixed, purified water is added, the whole is adjusted to 100 ml by the addition of purified water, and then filled into a brown bottle. The liquid is prepared by sterilization.

Claims (11)

delete delete delete A pharmaceutical composition for the prevention or treatment of tuberculosis containing any one compound selected from the following compound group or a pharmaceutically acceptable salt thereof as an active ingredient:
(1) N- (1- (6- (4H-1,2,4-triazol-4-yl) pyridin-2-yl) vinyl) -5- (benzo [d] thiazol-2-yl) 2-methylbenzeneamine;
(2) N- (5- (benzo [d] oxazol-2-yl) -2-chlorophenylcarbamothioyl) -4-fluorobenzamide;
(3) 3-chloro-N- (3- (5,7-dimethylbenzo [d] oxazol-2-yl) -2-methylphenylcarbamothioyl) benzamide; And
(4) N- (4-chloro-3- (oxazolo [4,5-b] pyridin-2-yl) phenylcarbamothioyl) -2,3-dihydrobenzo [b] [1,4] dioxine -6-carboxamide.
delete The method of claim 4, wherein
The compound is a pharmaceutical composition, characterized in that to prevent or treat tuberculosis by inhibiting 4'-phosphopantetheinyl transferase (4'-phosphopantetheinyl transferase).
The method of claim 4, wherein
The tuberculosis may include eye tuberculosis, skin tuberculosis, adrenal tuberculosis, kidney tuberculosis, epididymal tuberculosis, lymphatic tuberculosis, laryngeal tuberculosis, middle ear tuberculosis, intestinal tuberculosis, multidrug-resistant tuberculosis, pulmonary tuberculosis, biliary tuberculosis, bone tuberculosis, throat tuberculosis, lymph node tuberculosis, lung A pharmaceutical composition, characterized in that it is breast tuberculosis or spinal tuberculosis.
The method of claim 4, wherein
The tuberculosis is a pharmaceutical composition, characterized in that the tuberculosis caused by multidrug-resistant tuberculosis bacteria.
A health food for preventing or improving tuberculosis, comprising the compound of claim 4 or a pharmaceutically acceptable salt thereof as an active ingredient.
The method of claim 9,
The tuberculosis may include eye tuberculosis, skin tuberculosis, adrenal tuberculosis, kidney tuberculosis, epididymal tuberculosis, lymphatic tuberculosis, laryngeal tuberculosis, middle ear tuberculosis, intestinal tuberculosis, multidrug-resistant tuberculosis, pulmonary tuberculosis, biliary tuberculosis, bone tuberculosis, throat tuberculosis, lymph node tuberculosis, lung Health foods, characterized in that the tuberculosis or vertebral tuberculosis. delete

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