KR102031409B1 - Pharmaceutical composition for treating the non-tuberculous mycobacterial infectious diseases - Google Patents

Abstract

The present invention relates to a pharmaceutical composition for treating an infectious disease caused by non-tuberculosis mycobacteria, and more particularly to a pharmaceutical composition for treating an infectious disease caused by non-tuberculosis mycobacteria containing a sulfonamide compound represented by Formula 1 as an active ingredient. It is about.

Description

Pharmaceutical composition for treating the non-tuberculous mycobacterial infectious diseases}

The present invention relates to a pharmaceutical composition for treating non-tuberculous mycobacteria (NTM) infection diseases, including Mycobacterium abscessus .

Non-tuberculosis mycobacteria (Nontuberculous mycobacteria, NTM) refers to mycobacteria other than the M. tuberculosis is (M. tuberculosis) and nabyeonggyun (M. leprae), unlike the M. tuberculosis that are found only within a host animal wherein the non-tuberculosis mycobacteria as well as the animal kingdom soil It is normally present in the environment such as water and water, and about 150 kinds are known at present. Non-TB disease is classified into pulmonary disease, lymphadenitis, skin, soft tissue, osteoinfection, and disseminated disease by clinical practice, and lung disease accounts for more than 90%.

Infectious diseases caused by non-TB antibiotics show differences in the incidence of pathogens in different countries. In the United States and Japan, M. avium complex (MAC) is the most common infection, and M. kansasii is reported second, M. fortuitum , M. marinum , M. xenopi , M. chelonae, M. gordonae Many have been reported. In Korea, infection with MAC is the most common, followed by M. abscessus , and M. fortuitum and M. chelonae. And the like have been reported.

With the development of anti-tuberculosis agents disclosed in Patent Literature 1, the incidence and mortality rates of Mycobacterium tuberculosis have been continuously decreasing since the 1990s, whereas non-TB antibiotics have been increasing rapidly. Is showing. The incidence of NTB lung disease, which was around 5% in the early 1990s, has now increased to 20%. In the case of tuberculosis, the treatment rate is more than 90%, whereas in non-tuberculosis mycobacteria, the rate of separation of drug-resistant bacteria is very high and the treatment rate is less than 50% due to the difficulty of requiring long-term treatment for 2 years or more.

In case of infection by non-tuberculosis mycobacterium, it is resistant to commonly used primary anti-tuberculosis drugs and susceptible to antibiotics such as amikacin, sepocithin, imipenem, and macrolide clarithromycin. In particular, M. abscessus , which is the second most common in Korea, is not only resistant to all anti-tuberculosis drugs but also has a very low cure rate of less than 10 percent despite treatment with antibiotics such as amikacin and oral antibiotics, clarithromycin. The treatment rate is showing.

This cause is due to the high drug resistance of M. abscessus as well as induced resistance to clarithromycin, the only oral antibiotic. Therefore, it is necessary to develop a new drug that can be susceptible to M. abscessus , which has high drug resistance.

Therefore, the inventors of the present invention, while showing an inhibitory activity against non-tuberculosis mycobacteria, consequently trying to develop a pharmaceutical composition that can be usefully used in the treatment of non-tuberculosis mycobacterial infection diseases, The compounds represented showed excellent inhibitory activity against non-tuberculosis mycobacterium bacterium, confirming their usefulness in the treatment of diseases related thereto, and completed the present invention.

Republic of Korea Patent Publication 10-2016-0130706

An object of the present invention is to provide a pharmaceutical composition for treating non-tuberculous mycobacterial infectious disease comprising a sulfonamide derivative.

Another object of the present invention is to provide an antimicrobial composition against non-tuberculosis antibacterial bacterium comprising a sulfonamide derivative.

In order to achieve the above object,

The present invention provides a pharmaceutical composition for treating non-TB tuberculosis infectious disease comprising a compound represented by Formula 1 below, or a pharmaceutically acceptable salt thereof as an active ingredient.

[Formula 1]

In Chemical Formula 1,

R ¹ and R ² are independently hydrogen, halogen, unsubstituted or substituted one or more halogen of C _1-10 straight or branched alkyl, C _1-10 straight or branched alkylcarbonyl, -CH (OH) -A ¹ , -CH (NH ₂ ) -A ² , or -CH (B ¹ ) A ³ ,

Wherein A ¹ , A ² and A ³ are independently C _1-5 straight or branched alkyl, and B ¹ is C _1-5 straight or branched alkoxyamine;

R ³ is C _1-10 straight or branched alkoxy unsubstituted or substituted with one or more halogens; And

R ⁴ and R ⁵ are independently hydrogen or halogen.

In addition, the present invention provides an antimicrobial composition against non-TB tuberculosis comprising a compound represented by the following formula (1), or a pharmaceutically acceptable salt thereof as an active ingredient.

[Formula 1]

In Chemical Formula 1,

R ¹ and R ² are independently hydrogen, halogen, unsubstituted or substituted one or more halogen of C _1-10 straight or branched alkyl, C _1-10 straight or branched alkylcarbonyl, -CH (OH) -A ¹ , -CH (NH ₂ ) -A ² , or -CH (B ¹ ) A ³ ,

Wherein A ¹ , A ² and A ³ are independently C _1-5 straight or branched alkyl, and B ¹ is C _1-5 straight or branched alkoxyamine;

R ³ is C _1-10 straight or branched alkoxy unsubstituted or substituted with one or more halogens; And

R ⁴ and R ⁵ are independently hydrogen or halogen.

The compound represented by the formula (1) according to the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same as an active ingredient shows an excellent antibacterial effect against non-tuberculosis mycobacteria, in particular oral or parenteral administration (intraperitoneal injection) The antimicrobial effect is excellent in) can be usefully used as a therapeutic agent for non-TB infection.

Figure 1 is an experiment of the antimicrobial activity of the compound K13787 in macrophages of M. abscessus of Example 1 of the present invention, showed excellent antimicrobial effect in infected macrophages.
Fig. 2 shows the intraperitoneal administration of clarithromycin and Example 1 compound K13787 to mice infected with M. abscessus and the changes in the intratracheal bacterial counts of the subjects. The antimicrobial effect was confirmed.
3 and 4 are the results of assaying the therapeutic effect of the animal individual of Example 1 compound K13787, confirming the therapeutic effect of Example 1 compound K13787 as a change in the survival rate of M. abscessus infected mice. There were two methods of intraperitoneal administration and oral administration. Both methods showed statistical significance, and especially the best treatment effect in the abdominal cavity.

Hereinafter, the present invention will be described in detail.

The present invention provides a pharmaceutical composition for treating non-TB tuberculosis infectious disease comprising a compound represented by Formula 1 below, or a pharmaceutically acceptable salt thereof as an active ingredient.

[Formula 1]

In Chemical Formula 1,

R ¹ and R ² are independently hydrogen, halogen, unsubstituted or substituted one or more halogen of C _1-10 straight or branched alkyl, C _1-10 straight or branched alkylcarbonyl, -CH (OH) -A ¹ , -CH (NH ₂ ) -A ² , or -CH (B ¹ ) A ³ ,

Wherein A ¹ , A ² and A ³ are independently C _1-5 straight or branched alkyl, and B ¹ is C _1-5 straight or branched alkoxyamine;

R ³ is C _1-10 straight or branched alkoxy unsubstituted or substituted with one or more halogens; And

R ⁴ and R ⁵ are independently hydrogen or halogen.

Preferably,

R ¹ and R ² are independently hydrogen, halogen, unsubstituted or substituted one or more halogen of C _1-6 straight or branched alkyl, or C _1-6 straight or branched alkylcarbonyl;

R ³ is C _1-6 linear or branched alkoxy; And

R ⁴ and R ⁵ are independently hydrogen or fluoro.

More preferably,

R ¹ and R ² are independently methylcarbonyl, fluoro, or trifluoromethyl;

R ³ is methoxy; And

R ⁴ and R ⁵ are independently hydrogen or fluoro.

Even more preferably,

R ¹ is methylcarbonyl;

R ² is fluoro or trifluoromethyl;

R ³ is methoxy;

R ⁴ is hydrogen or fluoro; And

R ⁵ is hydrogen or fluoro.

Most preferably,

The compound represented by Chemical Formula 1 is a compound represented by the following Chemical Formula 2, or a compound represented by the following Chemical Formula 3.

[Formula 2]

;

[Formula 3]

.

The compound represented by Formula 1 of the present invention may be used in the form of a pharmaceutically acceptable salt, and acid addition salts formed by pharmaceutically acceptable free acid are useful as salts. 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, chlorobene Sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycolate, malate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1 Sulfonates, naphthalene-2-sulfonates, 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, optical isomers, hydrates, and the like that can be prepared therefrom.

The compound represented by Formula 1 according to the present invention may be administered in various formulations, oral and parenteral, during clinical administration. In the case of parenteral administration, it can be administered by intravenous injection, subcutaneous injection, intramuscular injection, intraperitoneal injection, transdermal administration, mucosal injection or eye drop. When formulated, it is prepared using conventional diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrating agents, surfactants, and the like.

Solid form preparations for oral administration include tablets, patients, powders, granules, capsules, troches, and the like, which form at least one excipient such as starch, calcium carbonate, water, or the like. It is prepared by mixing cross, lactose or gelatin. In addition to simple excipients, lubricants such as magnesium styrate talc are also used. Liquid preparations for oral administration include suspensions, solvents, emulsions, or syrups, and may include various excipients, such as wetting agents, sweeteners, fragrances, and preservatives, in addition to commonly used simple diluents, water and liquid paraffin. have.

Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, suppositories, and the like. As the non-aqueous solvent and the suspension solvent, propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like can be used. As the base of the suppository, witepsol, macrogol, tween 61, cacao butter, laurin butter, glycerol, gelatin and the like can be used.

In addition, the effective dosage of the compound of the present invention to the human body may vary depending on the age, weight, sex, dosage form, health condition and degree of disease of the patient, and is generally about 0.001 to 100 mg / kg / day, preferably Preferably 0.01-35 mg / kg / day. Based on an adult patient with a weight of 70 kg, it is generally 0.07 ~ 7000 mg / day, preferably 0.7 ~ 2500 mg / day, once a day at regular intervals depending on the judgment of the doctor or pharmacist Multiple doses may be administered.

According to another aspect of the present invention, the present invention is characterized in that it comprises a suitable carrier, excipients and diluents commonly used in the manufacture of a pharmaceutical composition comprising the compound represented by the formula (1). Carriers, excipients and diluents that may be included in the compositions of the present invention include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium diacid, calcium silicate, cellulose Uss, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methyl hydroxy benzoate, propyl hydroxy benzoate, talc, magnesium stearate and mineral oil.

The compound represented by the formula (1) according to the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same as an active ingredient shows an excellent antibacterial effect against non-tuberculosis mycobacteria, in particular oral or parenteral administration (intraperitoneal injection) The antimicrobial effect is excellent in) can be usefully used as a therapeutic agent for non-TB infection.

As a result of measuring the minimum inhibitory concentration (MIC) represented by the example compound of the present invention against non-tuberculosis antibacterial bacterium to prove the above effect, Example 1 and Example 2 of the sulfonamide series according to the present invention The compound was shown to be more susceptible to all non-tuberculosis mycobacteria compared to isoniazid (INH) and rifampicin (RIF) used as a control (see Table 1 of Experimental Example 1).

In addition, as a result of measuring the intracellular survival (ICS) by treating the example compound according to the present invention, the experimental group Example 1 compound (K13787) treated group was 24 hours (** p <0.05) and 48 It was shown to significantly inhibit bacterial growth in macrophages at time (*** p <0.001) (see FIG. 1 of Experimental Example 2).

Furthermore, as a result of experiments to confirm the in vivo effect on M. abscessus -infected mice, the experimental group of Example 1 compound was found to have a 10-fold or more bacteriostatic effect and increased mouse survival (Experimental Example 3). 2, 3 and 4).

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

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

< Example  1> N- (2-acetyl-6- Fluorophenyl )-8- Fluoro -5- Methoxy - [1,2,4] triazolo [1,5-f] pyrimidine Preparation of 2-Sulfonamide

Example 1 A compound was prepared.

< Example  2> N- (2-acetyl-6- ( Trifluoromethyl ) Phenyl) -8- Fluoro -5- Methoxy Preparation of [[1,2,4] triazolo [1,5-f] pyrimidine-2-sulfonamide

Example 2 A compound was obtained from the Korean Compound Bank.

(cas no. 1982346-86-0)

< Experimental Example  1> To non-tuberculosis  About In vitro  Check the effect

In order to determine the minimum inhibitory concentration (MIC) represented by the example compound of the present invention against non-tuberculosis mycobacteria, the following experiment was performed.

Middlebrook 7H10 supplemented with 10% OADC (oleic acid, albumin, dextrose, catalase; Becton Dickinson) at 37 ° C with non-tuberculosis mycobacteria ( M. avium , M. intracellulare , M. kansasii , M. fortuitum , M. abscessus ) After incubation in agar medium (Difco), each colony was inoculated in Middlebrook 7H9 liquid medium supplemented with 0.2% glycerol, 0.05% Tween 80 (Sigma-Aldrich), and 10% OADC and rotated to the late log phase. Bottle cultures. The culture was dispensed in 1 mL each cryovial, and stored at -70 ° C. After vial was dissolved, live colony forming units (cfu) were measured in Middlebrook 7H9 medium to determine the number of viable bacteria. The antimicrobial effect was measured by tube dilution method. Briefly, Middlebrook 7H9 liquid medium was dispensed 1 ml per test tube and the compound was diluted 2-fold stepwise. Each of the frozen bacteria was dissolved and added to 10 ⁴ cfu per test tube to observe whether the bacteria grow while cultivating the minimum concentrations that inhibit the growth of the cells are shown in Table 1 below.

TABLE 1

Table 1 shows the results of confirming the inhibitory effect of the Example 1 compound (K13787) and Example 2 compound (K13798) of the present invention on non-TB tuberculosis. All five anti -tuberculosis bacteria ( M. avium, M. intracellulare , M. kansasii , M. fortuitum , M. abscessus ) showed excellent antimicrobial effects.

As shown in Table 1, Example 1 and Example 2 compounds of the sulfonamide series according to the present invention are more uniform in all non-TB tuberculosis species compared to isoniazid (INH) and rifampicin (RIF) used as controls. It was shown to show sensitivity.

In particular, the two species, M. avium and M. abscessus , which have the highest clinical isolation rate of non-tuberculosis mycobacterium in Korea, show high inhibitory concentration and insensitivity to asoniazid and rifampicin, whereas sulfonamide according to the present invention The series of Examples 1 and 2 compounds were shown to exhibit very low inhibitory concentrations.

< Experimental Example  2> To non-tuberculosis  For Ex vivo  Check the effect

The intracellular survival (ICS) was measured as follows by treating the example compound according to the present invention.

NTM strains, like Mycobacterium tuberculosis, survive and multiply in macrophages. Therefore, the proliferation of NTM bacteria proliferating in macrophages should be suppressed. To determine this, mouse bone marrow-derived macrophages were infected with M. abscessus , one of the NTM strains, for 5 hours by adding a multiplicity of infection (MOI) of 5 cells per cell. After washing three times with PBS to remove the bacteria from the outside of the cell, clarithromycin (clarithromycin, CLR), oral antibiotics for non-tuberculous antibiotics (Ctrl) as a negative control (Ctrl) and non-tuberculous antibiotics as a positive control group Experiment was performed by dividing the 50 μg / ml concentration treatment group into the 50 μg / ml concentration treatment group of Example 1 Compound (K13787). After 0, 24, and 48 hours after cell infection, cells were burst with distilled water, diluted 10-fold with 7H9 medium, and inoculated in 7H10 solid medium to measure intracellular bacterial counts (cfu).

As shown in FIG. 1,

The number of bacteria in bone marrow-derived macrophages was decreased in both the control and experimental groups treated with antibiotics at 24 and 48 hours after infection compared to the negative control group. In particular, the positive control group clarithromycin treated group (CLR) showed the largest bacterial count reduction, experimental group Example 1 compound (K13787) treated group also 24 hours (** p <0.05) and 48 hours (*** p <0.001) significantly inhibited the growth of bacteria in macrophages.

< Experimental Example  3> M. abscessus on  For infected mice In vivo  Check the effect

The following experiments were performed to determine the survival and survival curves in the lung and spleen of M. abscessus infected mice.

Example 1 In order to confirm the antimicrobial effect of the compound (K13787) against M. abscessus in animal subjects, nine 6-week-old mice (C57BL / 6) were infected with 1.4 × 10 ⁷ bacteria per individual, and the infected mice The negative control group was 2% polyethylene glycol (PEG) used as a solution, the positive control group was classified as 200 mg / kg of clarithromycin (CLR), and the experimental group was Example 1 compound (K13787). ) Was administered at the same 200 mg / kg dose. For drug administration, clarithromycin and Example 1 compound (K13787) were used after dissolving in 2% polyethylin glycol. 24 hours after infection, 48 hours twice intraperitoneally administered, on day 4 mice were sacrificed to separate the lungs and spleen and pulverized through a tissue mill. The lysates of the tissues pulverized with PBS were step-diluted in multiples of 10 and dipped into 7H10 solid medium to measure the number of bacteria (cfu) inside the tissues.

In addition, 45 mice were infected with the same amount of M. abscessus by the same method, and divided into three groups, one group per 15 mice, and the control group, the negative control group and the clarithromycin-treated group, the positive control group and the experimental group. Example 1 Compound (K13787) was separated into administration groups. Dose was dosed at the same 200 mg / kg dose. As the route of administration, intraperitoneal (IP) administration was used in the first experimental group and oral (Oral) administration in the second experimental group. The same administration method was administered twice in 24 hours after infection and 48 hours after intraperitoneal and oral administration. Subsequent survival of the mice was recorded and plotted in FIGS. 3 (intraperitoneal administration) and 4 (oral administration).

As shown in Figure 2,

Compared to the negative control group (Vehicle Control, VC), the bacterial counts of M. abscessus were reduced in both the lung and spleen of mice treated with clarithromycin (CLR) and the experimental group administered with Example 1 compound (K13787). It confirmed that there was. It was confirmed that the effect of the positive control group, clarithromycin-administered group was 100 times more bacteria reduction effect than the negative control group, Example 1 compound in the experimental group was also confirmed to have a 10 times or more bacteria reduction effect. The statistical significance of the antimicrobial effects identified with both drug groups was *** P <0.001.

3 and 4,

Both intraperitoneal and oral administration confirmed increased survival rates of mice. In both treatment methods, the positive control group, clarythromycin-administered group showed the highest survival rate, but the compound of Example 1 (K13787) was also found to increase the mouse survival rate. Nonetheless, intraperitoneal administration showed higher survival among the experimental groups. Statistical significance for the increase in the survival rate of the mouse compound of Example 1 (K13787) experimental group was expressed as * p <0.01, ** p <0.05, *** p <0.001.

Preparation Example 1 Preparation of Pharmaceutical Formulation

<1-1> Preparation of Powder

2 g of a compound represented by Formula 1

1 g lactose

After mixing the above components, the airtight cloth was filled to prepare a powder.

<1-2> Preparation of Tablet

100 mg of compound represented by formula (1)

Corn starch 100 mg

Lactose 100 mg

2 mg magnesium stearate

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

<1-3> Preparation of Capsule

100 mg of compound represented by formula (1)

Corn starch 100 mg

Lactose 100 mg

2 mg magnesium stearate

After mixing the above components, the capsule was prepared by filling in gelatin capsules according to the conventional method for producing a capsule.

<1-4> Preparation of Injection Solution

10 μg / ml of the compound represented by Formula 1

Dilute hydrochloric acid BP until pH 3.5

Injectable sodium chloride BP up to 1 ml

The compound according to the invention was dissolved in an appropriate volume of sodium chloride BP for injection, the pH of the resulting solution was adjusted to pH 3.5 with dilute hydrochloric acid BP, and the volume was adjusted with sodium chloride BP for injection and thoroughly mixed. The solution was filled into a 5 ml Type I ampoule made of clear glass, dissolved under glass, enclosed under an upper grid of air, and sterilized by autoclaving at 120 ° C. for at least 15 minutes to prepare an injection solution.

Claims (10)

A compound represented by Formula 2, or a pharmaceutically acceptable salt thereof; or
A compound represented by Formula 3, or a pharmaceutically acceptable salt thereof; In the pharmaceutical composition for the treatment of non-tuberculosis mycobacterial infectious disease comprising as an active ingredient,
The non-TB bacterium is Mycobacterium intracellulare ( Mycobacterium intracellulare ), Mycobacterium kansasii , Mycobacterium fortuitum , or Pharmaceutical composition for the treatment of non-tuberculosis mycobacterial infectious disease, characterized in that Mycobacterium abscessus :
[Formula 2]
; And

[Formula 3]
.
delete delete delete delete delete The method of claim 1,
The non-tuberculosis mycobacterium tuberculosis is Mycobacterium abscessus ( Mycobacterium abscessus ) characterized in that the pharmaceutical composition for treating non-tuberculosis mycobacterial infection disease.
The method of claim 1,
The non-tuberculosis mycobacterial infection disease is a lung disease, lymphadenitis, skin, soft tissue, osteoinfection, or disseminated disease (disseminated disease) characterized in that the pharmaceutical composition for treating non-tuberculosis mycobacterial infection.
A compound represented by Formula 2, or a pharmaceutically acceptable salt thereof; or
A compound represented by Formula 3, or a pharmaceutically acceptable salt thereof; In the antimicrobial composition against non-TB tuberculosis bacterium containing as an active ingredient,
The non-TB bacterium is Mycobacterium intracellulare ( Mycobacterium intracellulare ), Mycobacterium kansasii , Mycobacterium fortuitum , or Antimicrobial composition against non-tuberculosis mycobacterium characterized in that Mycobacterium abscessus :
[Formula 2]
; And

[Formula 3]
. delete