KR20210076521A - Composition for preventing or treating tuberculosis comprising Telacebec and Macozinone - Google Patents

Abstract

The present invention relates to a composition for preventing or treating tuberculosis containing telacebec (Q203) and macozinone (PBTZ169) as active components. More specifically, more improved (synergism) anti-tuberculosis activity is confirmed by combining telacebec and macozinone with a different death mechanism in phase 2 clinical trials, below the minimum inhibitory concentration of each compound. A combination therapy of two types of telacebec and macozinone has high potential and marketability to be used as a very important combination therapy for tuberculosis treatment in humans in the future.

Description

A composition for preventing or treating tuberculosis comprising telacebec and macozinone as active ingredients TECHNICAL FIELD

The present invention relates to a composition for preventing or treating tuberculosis containing Telacebec (Q203) and Macozinone (PBTZ169) as active ingredients.

Tuberculosis (TB) is a single bacterial disease that is the most deadly infectious disease in human history. More than one-third of the world's population is infected with Mycobacterium tuberculosis, which refers to the pathogenic bacteria that cause tuberculosis. The World Health Organization (WHO) recognizes tuberculosis as one of the three major infectious diseases that threaten human health, and 9 million new cases of tuberculosis occur each year, of which about 1.5 million die. It has been reported that Recently, the treatment of tuberculosis has become difficult due to the increase of multidrug-resistant Mycobacterium tuberculosis and extensively-drug-resistant Mycobacterium tuberculosis, and Totally-drug-resistant Mycobacterium tuberculosis that is resistant to all drugs has also emerged. So the situation is getting more serious. As such, drug-resistant tuberculosis not only increases the cost of treatment, but also lowers the treatment efficiency, which threatens to develop into intractable tuberculosis.

In Korea, the incidence of tuberculosis significantly decreased until 2000 due to the tuberculosis control project over the past 50 years, but the number of new cases has not decreased in the last 10 years. It is estimated that there are about 15 million tuberculosis carriers in Korea, and about 39,000 new cases occur every year. Of these, about 2300 die from tuberculosis, and 50% of the total infectious disease mortality is known to be due to tuberculosis. In addition, the mortality and incidence rate of tuberculosis is the highest among the 30 OECD member countries.

The biggest problem in the treatment of tuberculosis is when Mycobacterium tuberculosis acquires drug resistance. Currently, MDR-TB is emerging as a serious health problem, and the fact that the tuberculosis infection rate has not decreased in Korea in recent years is closely related to the fact that the number of MDR-TB patients is not decreasing. ^{Since one mutant appears every 10 6} cell divisions of Mycobacterium tuberculosis, at least two or more, if possible, four or more drugs should be used in combination. Nevertheless, if resistance to one drug develops, there is no special countermeasure against chemotherapy. That's the biggest problem. Currently, several types of second-line anti-tuberculosis drugs have been developed, but none of them can replace first-line drugs in terms of effectiveness. Therefore, the development of a new anti-tuberculosis drug with a different mechanism of action from existing drugs is an urgent task.

PCT International Patent Publication WO2018-226512 (published on December 13, 2018)

An object of the present invention is Telacebec (Telacebec; Q203) or a pharmaceutically acceptable salt thereof; And to provide a pharmaceutical composition or health functional food composition for preventing or treating tuberculosis containing macozinone (PBTZ169) or a pharmaceutically acceptable salt thereof as an active ingredient.

In order to achieve the above object, the present invention is Telacebec (Q203) represented by the following formula (1) or a pharmaceutically acceptable salt thereof; And it provides a pharmaceutical composition for preventing or treating tuberculosis containing macozinone (PBTZ169) or a pharmaceutically acceptable salt thereof represented by the following Chemical Formula 2 as an active ingredient.

[Formula 1]

[Formula 2]

In addition, the present invention is Telacebec (Q203) represented by the formula (1) or a pharmaceutically acceptable salt thereof; And it provides a health functional food composition for preventing or improving tuberculosis containing macozinone (PBTZ169) or a pharmaceutically acceptable salt thereof represented by Formula 2 as an active ingredient.

The present invention relates to a composition for preventing or treating tuberculosis containing telacebec (Q203) and macozinone (PBTZ169) as active ingredients, and more specifically, having different death mechanisms in phase 2 clinical trials. Telasebec and macozinone were combined below the minimum inhibitory concentration of each compound to confirm more improved (synergism) anti-tuberculosis activity. The combination therapy of the two Telasevec and Macozinone combinations has high potential and marketability to be used as a very important combination therapy for the treatment of tuberculosis in humans in the future.

1 shows the results of inhibiting the growth of Mycobacterium tuberculosis according to the combination treatment of Telacebec (Q203) and Macozinone (PBTZ169).
2 shows the results of inhibiting the growth of Mycobacterium tuberculosis on agar plates according to the combination treatment of telasebec and macozinone.
Figure 3 shows the results of inhibition of Mycobacterium tuberculosis growth according to the combination treatment of isoniazid (isoniazid) and rifampicin (rifampicin).
4 shows the results of inhibition of Mycobacterium tuberculosis growth on agar plates according to the combination treatment of isoniazid and rifampicin.
5 shows the results of inhibiting the growth of Mycobacterium tuberculosis according to the combination treatment of telasebec and rifampicin.

The present invention is Telacebec (Q203) represented by the following formula (1) or a pharmaceutically acceptable salt thereof; And it provides a pharmaceutical composition for preventing or treating tuberculosis containing macozinone (PBTZ169) or a pharmaceutically acceptable salt thereof represented by the following Chemical Formula 2 as an active ingredient.

[Formula 1]

[Formula 2]

Preferably, the composition may include telasebec at a concentration of 0.2 to 1.6 nM and macozinone at a concentration of 0.1 to 0.4 nM, but is not limited thereto.

Preferably, the composition can enhance the antibacterial activity against Mycobacterium tuberculosis, due to the synergistic effect of the combination of telasebec and macozinone.

Preferably, the tuberculosis is multidrug-resistant (MDR) tuberculosis, extensively drug-resistant (XDR) tuberculosis, pulmonary tuberculosis, pleural tuberculosis, lymph node tuberculosis, brain tuberculosis, intestinal tuberculosis, spinal tuberculosis or renal tuberculosis. may be, but is not limited thereto.

As used herein, the term "pharmaceutically acceptable salt" refers to a salt having a safety and efficacy profile suitable for administration to humans. Specifically, it is a pharmaceutically acceptable salt of telacevec or macozinone, in specific forms derived from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, phosphorous acid and mixtures thereof. salts as well as salts derived from organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, and aliphatic and aromatic sulfonic acids, but include Not limited.

When the composition of the present invention is a pharmaceutical composition, the pharmaceutical composition may include a pharmaceutically acceptable carrier in addition to the active ingredient of the present invention. , lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methyl cellulose, methyl hydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, mineral oil, and the like, but is not limited thereto. In addition, the pharmaceutical composition may further include a lubricant, a wetting agent, a sweetening agent, a flavoring agent, an emulsifying agent, a suspending agent, a preservative, and the like as additives.

The method of administration of the pharmaceutical composition is determined according to the severity of symptoms, and a topical administration method is generally preferred. In addition, the dosage of the active ingredient in the pharmaceutical composition may vary depending on the route of administration, the degree of disease, the age, sex, weight, etc. of the patient, and may be administered once to several times a day.

The pharmaceutical composition may be administered to mammals such as rats, mice, livestock, and humans by various routes. Any mode of administration can be envisaged, for example, by oral, rectal or intravenous, intramuscular, subcutaneous, intrauterine dural or intracerebroventricular injection.

The pharmaceutical composition may be prepared in a unit dose form by formulating using a pharmaceutically acceptable carrier and/or excipient, or may be prepared by internalizing in a multi-dose container. In this case, the formulation may be in the form of a solution, suspension, or emulsion, or in the form of an elixirs, extracts, powders, granules, tablets, warning agents, lotions, ointments, and the like.

In addition, the present invention is Telacebec (Q203) represented by the following formula (1) or a pharmaceutically acceptable salt thereof; And it provides a health functional food composition for preventing or improving tuberculosis containing macozinone (PBTZ169) or a pharmaceutically acceptable salt thereof represented by the following Chemical Formula 2 as an active ingredient.

[Formula 1]

[Formula 2]

In addition, when the composition of the present invention is a health functional food composition, the health functional food composition may be provided in the form of powder, granule, tablet, capsule, syrup, beverage or pill, and the health functional food composition is effective in the present invention. It is used together with other foods or food additives in addition to the ingredients, and may be appropriately used according to a conventional method. The mixed amount of the active ingredient may be suitably determined according to the intended use thereof, for example, prophylactic, health or therapeutic treatment.

The effective dose of the active ingredient contained in the health functional food composition may be used according to the effective dose of the pharmaceutical composition, but in the case of long-term intake for health and hygiene or health control, it may be less than the above range. And it is certain that the active ingredient can be used in an amount beyond the above range because there is no problem in terms of safety.

The type of health functional food is not particularly limited, and examples include meat, sausage, bread, chocolate, candy, snacks, confectionery, pizza, ramen, other noodles, gum, dairy products including ice cream, various soups, beverages, tea , drinks, alcoholic beverages, and vitamin complexes.

Hereinafter, the present invention will be described in more detail through examples. These examples are only for illustrating the present invention in more detail, and it will be apparent to those of ordinary skill in the art that the scope of the present invention is not limited by these examples according to the gist of the present invention. .

<Experimental example>

The following experimental examples are intended to provide experimental examples commonly applied to each embodiment according to the present invention.

One. REMA Determination of Compound Interactions by Checkerboard Assay

To determine whether a compound combination acts synergistically, antagonistically or additively, a checkerboard assay using REMA was initially performed for survival markers.

Specifically, M. tuberculosis was cultured at 37° C. in Middlebrook 7H9 medium to which ADC was added. A 100 μL medium aliquot was added to each well of a 96-well microtiter plate, and 2-fold serially diluted antibiotics were added directly to each well. The plates were then incubated at 37° C. for 5 days. Resazurin (0.025% [wt/vol]) was added to each well, and fluorescence was measured using a SpectraMax® M3 Multi-Mode Microplate Reader (Molecular Devices, CA, USA) (ex/em 560). /590 nm). MIC values were calculated using Prism 6 (GraphPad Software, Inc., La Jolla, CA).

2. Evaluation of compound interactions through bacterial growth on agar plates

As mentioned above, each of the MICs (concentrations used in the checkerboard assays) was included in the combined compound or fractions thereof to culture the bacteria. To read the bacterial viability, bacteria were inoculated into solid medium (7H10 addition), and after 3 weeks of incubation at 37°C, bacterial growth was measured.

< Example >

To determine the effect of compound combinations on Mycobacterium tuberculosis, first, the MIC of each individual compound was measured through REMA. Second, Mycobacterium tuberculosis was grown in the sub-MIC fraction of Telasebec combined with the sub-MIC fraction of several anti-TB compounds, and the compound interaction was measured through a checkerboard assay. The checkerboard experiment was performed twice, and the results of both times were found to be consistent. Interestingly, it was confirmed that the combination of telassevec and macozinone acts synergistically against Mycobacterium tuberculosis. However, no synergistic effect was observed in the combination of telacevec and rifampicin.

As shown in Figure 1, Telacebec (Q203) did not inhibit the growth of Mycobacterium tuberculosis at 0.4 nM, Macozinone (Macozinone; PBTZ169) did not inhibit the growth of Mycobacterium tuberculosis at 0.4 nM. However, the growth of Mycobacterium tuberculosis was inhibited when Telasebec 0.4 nM and Macozinone 0.4 nM were combined, and when Telasebec 0.4 nM and Macozinone 0.2 nM were combined, the growth of Mycobacterium tuberculosis was inhibited.

These results were also confirmed by the results of bacterial growth on agar plates (FIG. 2).

Telasevec did not inhibit the growth of Mycobacterium tuberculosis at 1.6 nM, did not inhibit the growth of Mycobacterium tuberculosis at 0.8 nM, and macozinone did not inhibit the growth of Mycobacterium tuberculosis at 0.2 and 0.4 nM, respectively.

However, the growth of Mycobacterium tuberculosis was inhibited when 1.6 nM of Telasevec and 0.2 nM of Macozinone were combined, and the growth of Mycobacterium tuberculosis was inhibited when 0.8 nM of Telasebec and 0.2 nM of Macozinone were combined.

Therefore, the combination of the two drugs shows a synergistic effect (synergism).

However, in the combination of isoniazid and rifampicin, the most important tuberculosis treatment currently in clinical use, a slight additive effect was observed at rifampicin 5 nM and isoniazid 62.5 nM, but telasevec and macozinone It was found that the synergism was significantly weaker than the combination of (FIG. 3).

The additive effect of the combination of isoniazid and rifampicin is also shown as a result of bacterial growth on agar plates. It can be seen that Mycobacterium tuberculosis is killed only in the combination of 2.5 nM rifampicin and 62.5 nM isoniazid ( FIG. 4 ).

In addition, Telasevec showed a slight additive effect at 0.4 nM and 0.8 nM of rifampicin in the combination of rifampicin, a representative anti-tuberculosis agent, but a significantly more synergistic effect than the combination of telasevec and macozinone ( synergism) was found to be weak (FIG. 5). In addition, as already announced in previous papers, BTZ043, the active substance that is the origin of macozinone, has only recently been approved by the FDA as an anti-tuberculosis drug and has synergism only in combination with bedaquiline (TMC207), which is used clinically. Visible was confirmed (Antimicrob Agents Chemother. 2012 Nov;56(11):5790-3). Therefore, it can be seen that the synergism seen in the combination of Telasevec and Macozinone is a specific synergistic effect that is not seen well in the combination with other antituberculosis drugs.

Claims (5)

Telacebec (Q203) represented by the following formula (1) or a pharmaceutically acceptable salt thereof; And a pharmaceutical composition for preventing or treating tuberculosis containing macozinone (PBTZ169) or a pharmaceutically acceptable salt thereof represented by the following Chemical Formula 2 as an active ingredient.
[Formula 1]

[Formula 2]

The pharmaceutical composition for preventing or treating tuberculosis according to claim 1, wherein the composition comprises telasebec at a concentration of 0.2 to 1.6 nM and macozinone at a concentration of 0.1 to 0.4 nM. The pharmaceutical composition for preventing or treating tuberculosis according to claim 1, wherein the composition enhances antibacterial activity against Mycobacterium tuberculosis due to the synergistic effect of the combination of Telasebec and Macozinone. The method of claim 1, wherein the tuberculosis is multidrug-resistant (MDR) tuberculosis, extensively drug-resistant (XDR) tuberculosis, pulmonary tuberculosis, pleural tuberculosis, lymph node tuberculosis, brain tuberculosis, intestinal tuberculosis, spinal tuberculosis, A pharmaceutical composition for preventing or treating tuberculosis, characterized in that it is selected from the group consisting of renal tuberculosis. Telacebec (Q203) represented by the following formula (1) or a pharmaceutically acceptable salt thereof; And a health functional food composition for preventing or improving tuberculosis containing macozinone (PBTZ169) or a pharmaceutically acceptable salt thereof represented by the following formula (2) as an active ingredient.
[Formula 1]

[Formula 2]

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