KR101754516B1 - Phenanthrenyl compounds and antituberculosis composition containing the same - Google Patents

Phenanthrenyl compounds and antituberculosis composition containing the same Download PDF

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KR101754516B1
KR101754516B1 KR1020160006087A KR20160006087A KR101754516B1 KR 101754516 B1 KR101754516 B1 KR 101754516B1 KR 1020160006087 A KR1020160006087 A KR 1020160006087A KR 20160006087 A KR20160006087 A KR 20160006087A KR 101754516 B1 KR101754516 B1 KR 101754516B1
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tuberculosis
dpg
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compound
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KR20160105715A (en
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남궁우
이병의
장웅식
송호연
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순천향대학교 산학협력단
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/24—Oxygen or sulfur atoms
    • C07D207/26—2-Pyrrolidones
    • C07D207/273—2-Pyrrolidones with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to other ring carbon atoms
    • C07D207/277—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/24—Oxygen or sulfur atoms
    • C07D207/26—2-Pyrrolidones
    • C07D207/273—2-Pyrrolidones with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to other ring carbon atoms
    • C07D207/277—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D207/28—2-Pyrrolidone-5- carboxylic acids; Functional derivatives thereof, e.g. esters, nitriles

Abstract

The present invention relates to a novel phenanthrene compound or derivative thereof and its use for the prevention and treatment of tuberculosis. The anti-tuberculosis active compound is characterized by its excellent activity even in resistant Mycobacterium tuberculosis strains and low cytotoxicity, and can be used as a pharmaceutical composition for preventing or treating the incidence of tuberculosis.

Figure R1020160006087

Description

TECHNICAL FIELD [0001] The present invention relates to a phenanthrenyl compound or a derivative thereof, and a pharmaceutical composition for treating tuberculosis containing the same. BACKGROUND ART [0002] PHENANTHRENYL COMPOUNDS AND ANTITUBERCULOSIS COMPOSITION CONTAINING THE SAME [0003]

The present invention relates to a pharmaceutical composition comprising a novel compound having tuberculosis therapeutic activity. Specifically, the present invention relates to a novel phenanthrene compound or derivative thereof and a pharmaceutical composition for preventing or treating the incidence of tuberculosis containing the same as an active ingredient.

Tuberculosis has a long history and is currently infected with one-third of the world's population, and can become a TB patient whenever the immune function is impaired by diseases such as AIDS. Currently, 16 million patients are estimated worldwide, and 8 million new TB patients are emerging each year. Two million people die each year.

In developed countries, tuberculosis infection rates are less than 0.1% and disease incidence is less than 25%. In our case, the prevalence of active pulmonary tuberculosis (prevalence by radiography) decreased from 5.1% in 1965 to 1.0% in 1995, and the prevalence of bacterial infections decreased from 0.94% to 0.22% To 0.5%. The death rate due to tuberculosis decreased from 10.4% in 1991 to 6.3 in 2001 per 100,000 population.

However, tuberculosis is still one of the leading causes of death in the teenager, and the principle of treatment is based on the principle of short-term therapy for 6 months. In general, triple therapy with rifampin (RFP), isoniazid (INH), pyrazinamide (PZA) and ethambutol (EMB) for four months and RFP, INH and EMB three months after two months. Initial intensive therapy For 2 months, streptomycin can be used instead of EMB. In this case, maintenance therapy is administered with RFP and INH. The re-treatment for relapsed patients is mostly susceptible to the first-line treatment, so the original drug should be used again and the treatment should be extended by 3 months beyond the initial treatment period. Re-treatment for the first-time failing person is done by taking a drug susceptibility test to exclude all the drugs used for the first treatment and to treat the new susceptible drugs that have not been used in the past with at least 3 drugs, possibly 4 drugs or more, Treat for 18 months or more.

The treatment of pulmonary tuberculosis is based on the principle of using 4 agents in order to prevent hospitalization and acquisition of tolerance. The anti - tuberculosis - resistant bacilli have mutations in one frequency for about 106 cell divisions. Therefore, the principle of multidrug combination therapy using at least two antituberculous drugs should be observed.

The biggest problem of tuberculosis treatment is that there is no special treatment method in case of resistance to primary anti-tuberculosis drugs. Although the incidence and mortality of tuberculosis has decreased dramatically due to the development of effective antituberculous drugs and the systematic management of tuberculosis, the recent trend of tuberculosis due to the development of multi-drug resistant tuberculosis (MDR-TB) and acquired immunodeficiency syndrome (AIDS) to be. MDR-TB refers to simultaneous resistance to at least two drugs including INH and RFP. The criteria for the determination are that the number of M. tuberculosis strains grown on a medium containing the drug exceeds 1% of the number of strains grown on media containing no drug.

Recently, multidrug-resistant tuberculosis has become a serious health problem. In recent years, the rate of tuberculosis infection in Korea has not decreased any more, and this is closely related to the fact that patients with multidrug-resistant tuberculosis are not decreasing. It is also known that 50% of patients with multidrug-resistant tuberculosis die. Therefore, many of the causes of tuberculosis death are caused by multidrug-resistant tuberculosis.

In 1995, the rate of resistance to INH in Korea was 9.2%. Resistance to one or more drugs was 9.9%, and resistance to two or more drugs including INH and RFP was 5.3%. They are the source of persistent drug-resistant bacteria to the community.

Although a number of second-line anti-tuberculosis drugs have been developed, there are no drugs that can replace primary drugs in terms of efficacy. Therefore, the development of new anti-tuberculosis agents with different mechanisms of action from existing drugs is a pressing issue.

Korean Registered Patent No. 10-1142054 (Apr. 25, 2012) Korean Patent No. 10-1344218 (Dec. 13, 2013)

It is an object of the present invention to provide a novel phenanthrene compound or derivative thereof. Another object of the present invention is to provide a pharmaceutical composition for preventing or treating the development of tuberculosis containing a novel phenanthrenyl compound or derivative thereof which shows therapeutic activity against resistant Mycobacterium tuberculosis as an active ingredient.

The phenanthrenyl compound according to an embodiment of the present invention is represented by the following chemical formula 1, and its derivative is represented by the following chemical formula 2.

[Chemical Formula 1]

Figure 112016005518550-pat00001

In Formula 1, R 1 represents an alkyl group having 1 to 3 carbon atoms, an aryl group having 6 to 10 carbon atoms, an aralkyl group having 6 to 12 carbon atoms, an aryl group in which one carbon atom is substituted with nitrogen, Alkyl group having 4 to 9 carbon atoms including a cycloalkyl group substituted with an alkyl group substituted with a halogen atom, R 2 is hydrogen or a methyl group, and n is an integer of 2 to 4.

(2)

Figure 112016005518550-pat00002

In Formula 2, R 1 represents an aryl group having 6 to 10 carbon atoms, an aralkyl group having 6 to 12 carbon atoms, a cycloalkyl group in which one carbon atom is substituted with nitrogen or two carbon atoms are substituted with nitrogen and oxygen, respectively And R 4 is hydrogen, a methyl group, an ethyl group, or a propane group, and n is an integer of 2 to 4.

The phenanthrenyl compound or its derivative may be any one selected from the compounds represented by the following formulas (6) to (9).

[Chemical Formula 6]

Figure 112016005518550-pat00003

(7)

Figure 112016005518550-pat00004

[Chemical Formula 8]

Figure 112016005518550-pat00005

[Chemical Formula 9]

Figure 112016005518550-pat00006

(Me in formula (9) means methyl group)

A pharmaceutical composition for preventing or treating tuberculosis according to another embodiment of the present invention comprises a phenanthrenyl compound represented by the following formula (1) or a phenanthrene compound represented by the following formula (2) as an active ingredient, Optical isomers, and their respective pharmaceutically acceptable salts.

[Chemical Formula 1]

Figure 112016005518550-pat00007

In Formula 1, R 1 represents an alkyl group having 1 to 3 carbon atoms, an aryl group having 6 to 10 carbon atoms, an aralkyl group having 6 to 12 carbon atoms, an aryl group in which one carbon atom is substituted with nitrogen, Alkyl group having 4 to 9 carbon atoms, and R 2 is hydrogen or a methyl group, n is an integer of 2 to 4,

(2)

Figure 112016005518550-pat00008

In Formula 2, R 1 represents an aryl group having 6 to 10 carbon atoms, an aralkyl group having 6 to 12 carbon atoms, a cycloalkyl group in which one carbon atom contained in the ring is substituted with nitrogen, or two carbon atoms are respectively substituted with nitrogen and oxygen And R 4 is hydrogen, a methyl group, an ethyl group, or a propane group, and n is an integer of 2 to 4.

The phenanthrene compound or derivative thereof may be any one of compounds represented by the following formulas (6) to (9).

[Chemical Formula 6]

Figure 112016005518550-pat00009

(7)

Figure 112016005518550-pat00010

[Chemical Formula 8]

Figure 112016005518550-pat00011

[Chemical Formula 9]

Figure 112016005518550-pat00012

The pharmaceutical composition for preventing or treating the onset of tuberculosis may have an anti-tuberculosis activity against resistant tuberculosis.

Resistant tuberculosis (MDR), extensively drug-resistant tuberculosis (XDR), isoniazid-resistant tuberculosis (INH-r), rifampin-resistant tuberculosis (RIF-r), pyrazinamide-resistant tuberculosis , Strep-r (Streptomycin-resistant tuberculosis), and combinations thereof.

Hereinafter, the present invention will be described in more detail.

The terms "about "," substantially ", etc. used to the extent that they are used herein are intended to be taken to mean an approximation of, or approximation to, the numerical values of manufacturing and material tolerances inherent in the meanings mentioned, Accurate or absolute numbers are used to help prevent unauthorized exploitation by unauthorized intruders of the referenced disclosure.

Throughout this specification, the term "combination thereof " included in the expression of the machine form means a combination or combination of at least one element selected from the group consisting of the constituents described in the expression of the form of a marker, And the like.

Throughout this specification, the description of "A and / or B" means "A, B, or A and B".

The inventors of the present invention have found that in a previous study, plants such as Cynanchum atorum ) is a natural product in nature and has excellent antituberculous efficacy, but it is more effective and less toxic, and ideally i) it can shorten the duration of tuberculosis treatment, or ii) And iii) to meet the requirement of relatively low side effects, iv) to develop drugs that are effective for latent tuberculosis, which may become patients by reactivation at any time. The present invention has been completed.

The phenanthrene compound or its derivative according to one embodiment of the present invention is represented by the following chemical formula 1 or chemical formula 2.

[Chemical Formula 1]

Figure 112016005518550-pat00013

Wherein R 1 represents an alkyl group having 1 to 3 carbon atoms, an aryl group having 6 to 10 carbon atoms, an aralkyl group having 6 to 12 carbon atoms, a carbon atom contained in the ring is substituted with nitrogen, And a cycloalkyl-alkyl group having 4 to 9 carbon atoms including a cycloalkyl group substituted with oxygen, R 2 is hydrogen or a methyl group, and n is an integer of 2 to 4.

In the above Formula 1, R 1 may be a benzyl derivative of any one selected from the group consisting of methyl, ethyl, propyl, vinyl, and the following formula 1-1, wherein R 1 is piperidine, methylpiperidine, May be any one selected from the group consisting of pyrrolidine, methylpyrrolidine, piperazine, methylpiperazine, morpholine, and methylmorpholine;

[Formula 1-1]

Figure 112016005518550-pat00014

In Formula 1-1, R 3 is hydrogen, a methyl group, or an ethyl group, m is an integer of 0 to 2, and p is an integer of 1 to 5.

(2)

Figure 112016005518550-pat00015

In Formula 2, R 1 represents an aryl group having 6 to 10 carbon atoms, an aralkyl group having 6 to 12 carbon atoms, a cycloalkyl group in which one carbon atom contained in the ring is substituted with nitrogen, or two carbon atoms are respectively substituted with nitrogen and oxygen And R 4 is hydrogen, a methyl group, an ethyl group, or a propane group, and n is an integer of 2 to 4.

In Formula 2, R 1 may be any one selected from the group consisting of piperidine, methylpiperidine, pyrrolidine, methylpyrrolidine, piperazine, methylpiperazine, morpholine, and methylmorpholine have.

The phenanthrenyl compound represented by Formula 1 may be a compound represented by Formula 3 below.

(3)

Figure 112016005518550-pat00016

In Formula 3, R 1 is any one selected from the group consisting of methyl, ethyl, propyl, vinyl, and Formula 1-1, and R 2 is hydrogen or a methyl group.

The phenanthrenyl compound represented by Formula 1 may be a compound represented by Formula 4 below.

[Chemical Formula 4]

Figure 112016005518550-pat00017

In Formula 4, when R 2 is hydrogen, R 1 is any one selected from the group consisting of methyl, ethyl, propyl, vinyl, and Formula 1-1, and when R 2 is a methyl group, the R 1 is any one selected from the group consisting of methyl, ethyl, propyl, vinyl, and the above-described formula (1-1).

Specifically, the phenanthrenyl compound represented by the formula (1) may be any one selected from the compounds represented by the following formulas (5) to (8).

 [Chemical Formula 5]

Figure 112016005518550-pat00018

[Chemical Formula 6]

Figure 112016005518550-pat00019

(7)

Figure 112016005518550-pat00020

[Chemical Formula 8]

Figure 112016005518550-pat00021

The derivative of the phenanthrenyl compound represented by the formula (2) may be represented by the following formula (9).

[Chemical Formula 9]

Figure 112016005518550-pat00022

In the above formula (9), Me represents a methyl group.

A pharmaceutical composition for preventing or treating tuberculosis according to another embodiment of the present invention comprises a phenanthrenyl compound or a derivative thereof represented by the following Chemical Formula 1 or 2, each of the optical isomers thereof, Acceptable salts are included as active ingredients.

[Chemical Formula 1]

Figure 112016005518550-pat00023

In Formula 1, R 1 represents an alkyl group having 1 to 3 carbon atoms, an aryl group having 6 to 10 carbon atoms, an aralkyl group having 6 to 12 carbon atoms, an aryl group in which one carbon atom is substituted with nitrogen, Alkyl group having 4 to 9 carbon atoms including a cycloalkyl group substituted with an alkyl group substituted with a halogen atom, R 2 is hydrogen or a methyl group, and n is an integer of 2 to 4.

In the above formula (1), R 1 may be a functional group having a functional group such as a methyl group, an ethyl group, a propyl group, a vinyl group, or a benzyl derivative represented by the following formula (1-1), wherein R 1 is piperidine , Methylpiperidine, pyrrolidine, methylpyrrolidine, piperazine, methylpiperazine, morpholine, and methylmorpholine;

[Formula 1-1]

Figure 112016005518550-pat00024

In Formula 1-1, R 3 is hydrogen, a methyl group, or an ethyl group, m is an integer of 0 to 2, and p is an integer of 1 to 5.

(2)

Figure 112016005518550-pat00025

In Formula 2, R 1 represents an aryl group having 6 to 10 carbon atoms, an aralkyl group having 6 to 12 carbon atoms, a cycloalkyl group in which one carbon atom is substituted with nitrogen or two carbon atoms are substituted with nitrogen and oxygen, respectively And R 4 is hydrogen, a methyl group, an ethyl group, or a propane group, and n is an integer of 2 to 4.

In Formula 2, R 1 may be any one selected from the group consisting of piperidine, methylpiperidine, pyrrolidine, methylpyrrolidine, piperazine, methylpiperazine, morpholine, and methylmorpholine have.

The phenanthrenyl compound represented by Formula 1 may be a compound represented by Formula 3 below.

(3)

Figure 112016005518550-pat00026

In Formula 3, R 1 is any one selected from the group consisting of a methyl group, an ethyl group, a propyl group, a vinyl group, and a group represented by Formula 1-1, and R 2 is hydrogen or a methyl group.

The phenanthrenyl compound represented by Formula 1 may be a compound represented by Formula 4 below.

[Chemical Formula 4]

Figure 112016005518550-pat00027

In Formula 4, wherein R 2 is hydrogen when the R 1 is a methyl group, an ethyl group, a propyl group, a vinyl group, and at least one selected from the group consisting of Formula 1-1, and wherein R 2 is when the methyl group, R 1 is any one selected from the group consisting of a methyl group, an ethyl group, a propyl group, a vinyl group, and the above-described formula (1-1).

Specifically, the phenanthrenyl compound represented by the formula (1) may be any one selected from the compounds represented by the following formulas (5) to (8).

[Chemical Formula 5]

Figure 112016005518550-pat00028

[Chemical Formula 6]

Figure 112016005518550-pat00029

(7)

Figure 112016005518550-pat00030

[Chemical Formula 8]

Figure 112016005518550-pat00031

The derivative of the phenanthrenyl compound represented by the formula (2) may be represented by the following formula (9).

[Chemical Formula 9]

Figure 112016005518550-pat00032

In the above formula (9), Me represents a methyl group.

The tuberculosis includes Tuberculosis tuberculosis, pulmonary tuberculosis, tuberculosis, bone tuberculosis, throat tuberculosis, lymph tuberculosis, breast tuberculosis, spinal tuberculosis, etc. Tuberculosis causing tuberculosis includes tuberculosis, tuberculosis, (Tubercle bacillus), and the like.

Preferably, the phenanthrenyl compound or derivative thereof may be any one selected from the compounds represented by the above formulas (6) to (9).

Specifically, the compound represented by Formula (6) can be produced by reacting (S) -methyl 1- ((2,3,6-trimethoxyphenanthrene-10-yl) methyl) -5-oxopyrrolidine- (R) -methyl 1 - ((2,3,6-trimethoxyphenanthren-10-yl) methyl) -5- oxopyrrolidine- 5-oxopyrrolidine-2-carboxylate [(R) -methyl 1 - ((2,3,6-trimethoxyphenanthren-10-yl) methyl) -5 -oxopyrrolidine-2-carboxylate], and the compound represented by Formula 7 is (S) -methyl 1- ((6- (benzyloxy) -2,3-dimethoxyphenanthrene- 5-oxopyrrolidine-2-carboxylate or (S) -methyl 1 - ((6- (benzyloxy) -2,3-dimethoxyphenanthren- (R) -methyl 1 - ((6- (benzyloxy) -2,3-dimethoxyphenanthren-10-yl) methyl) -5- oxopyrrolidine- - ((6- (benzyloxy) -2,3-dimethoxyphenanthren-10-yl) methyl) -5-oxopyrrolidine- The compound represented by the general formula (8) can be produced by reacting (S) -1 - ((6- (benzyloxy) -2,3-dimethoxyphenanthrene- 2-carboxylate] or (R) -1 - ((6- ((S) -1- (6- (benzyloxy) -2,3-dimethoxyphenanthren- Yl) methyl) -5-oxopyrrolidine-2-carboxylate [(R) -1 - ((6- (benzyloxy) -2, 3-dimethoxyphenanthren- dimethoxyphenanthren-10-yl) methyl) -5-oxopyrrolidine-2-carboxylate]. The compound represented by the above formula (9) can be obtained by reacting methyl 2- (3,4-dimethoxyphenyl) -3- (4- (phenoxymethyl) phenyl) - (4- (phenoxymethyl) phenyl) acrylate [E) -methyl 2- (3,4-dimethoxyphenyl) -3- 2- (3,4-dimethoxyphenyl) -3- (4- (phenoxymethyl) phenyl) acrylate].

The phenanthrene compound or derivative thereof may have a negative or positive value for specific rotation ([] D 25 , °), and a negative value is advantageous for the anti-tuberculosis effect.

For example, the phenanthrenyl compound or its derivative having a negative nonlinearity value can be obtained by reacting (-) - (S) -methyl 1 - ((2,3, (S) -methyl 1 - ((2,3,6-trimethoxyphenanthren-10-yl) methyl) -5-oxopyrrolidine-2-carboxylate yl) methyl) -5-oxopyrrolidine-2-carboxylate] or (-) - (R) -methyl 1 - ((2,3,6-trimethoxyphenanthrene- (R) -methyl 1 - ((2,3,6-trimethoxyphenanthren-10-yl) methyl) -5-oxopyrrolidine-2- carboxylate] 7, it is preferable that the compound represented by the formula (1) is (-) - (S) -methyl 1 - ((6- (benzyloxy) -2,3-dimethoxyphenanthrene- 2-carboxylate] [(-) - (S) -methyl 1 - ((6- (benzyloxy) -2,3-dimethoxyphenanthren-10- yl) methyl) -5-oxopyrrolidine- -) - (R) -methyl 1 - ((6- (benzyloxy) -2,3-dimethoxyphenanthrene- ) -5-oxopyrrolidine-2-carboxylate [(-) - (R) -methyl 1- (6- (benzyloxy) -2,3-dimethoxyphenanthren- 2-carboxylate], and in the case of the compound represented by Formula 8, (-) - (S) -1 - ((6- (benzyloxy) -2,3- dimethoxyphenanthrene- Methyl) -5-oxopyrrolidine-2-carboxylate [(-) - (S) -1 - ((6- (benzyloxy) -2,3-dimethoxyphenanthren- oxopyrrolidine-2-carboxylate] or (-) - (R) -1- (6- (benzyloxy) -2,3- dimethoxyphenanthrene- -Carboxylate [(-) - (R) -1 - ((6- (benzyloxy) -2,3-dimethoxyphenanthren-10-yl) methyl) -5-oxopyrrolidine-2-carboxylate]. In the case of the compound represented by Formula 9, (-) - (E) -methyl 2- (3,4-dimethoxyphenyl) -3- (4- (phenoxymethyl) phenyl) ) - (E) -methyl 2- (3,4-dimethoxyphenyl) -3- (4- (phenoxymethyl) phenyl) acrylate].

Any one compound selected from the group consisting of the phenanthrenyl compound or its derivative, the optical isomer thereof, and the pharmaceutically acceptable salt thereof has the excellent antituberculous activity.

In addition, any one compound selected from the group consisting of the phenanthrene compound or its derivative, the optical isomer thereof, and the pharmaceutically acceptable salt thereof may be used not only as a standard M. tuberculosis strain, (MDR), extensively drug-resistant tuberculosis (XDR), isoniazid-resistant tuberculosis (INH-r), rifampin-resistant tuberculosis (RIF-r), pyrazinamide-resistant tuberculosis r (Streptomycin-resistant tuberculosis).

In particular, the compound of formula (6), the compound of formula (7) and the compound of formula (9) exhibit excellent anti-tuberculosis activity even when applied at a relatively low concentration and have excellent anti-tuberculosis activity not only in standard tuberculosis strains but also in resistant tuberculosis strains. In addition, even when applied at a high concentration, there is little or no cytotoxicity, and thus the drug is highly likely to be used as a pharmaceutical composition.

The term " pharmaceutically acceptable salts " refers to those salts which retain the biological effectiveness and properties of the parent compounds and which, when administered in a single dosage, are not deleteriously biologically or otherwise undesirable can do.

For example, pharmaceutically acceptable base addition salts may be prepared from inorganic and organic bases. Salts derived from inorganic bases may include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, primary, secondary, and tertiary amines; Substituted amines including naturally occurring substituted amines; And organic amines such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, tromethamine, lysine, arginine, histidine, caffeine, procaine, The compounds of the present invention can be used in the form of hydrabamine, choline, betaine, ethylenediamine, glucosamine, N-alkylglucamine, theobromine, purine, piperazine, piperidine, Lt; RTI ID = 0.0 > of Cyclic < / RTI > It is also understood that carboxylic acid amides including other carboxylic acid derivatives such as carboxamides, lower alkyl carboxamides, di (lower alkyl) carboxamides, etc. are also useful in the practice of the present invention .

For example, pharmaceutically acceptable acid addition salts may be prepared from inorganic and organic acids. Salts derived from inorganic acids include hydrochloric acid, bromic acid, sulfuric acid, nitric acid, phosphoric acid and the like. Salts derived from organic acids include those derived from acetic, propionic, glycolic, pyruvic, oxalic, malic, malonic, succinic, maleic, fumaric, tartaric, citric, benzoic, cinnamic, But are not limited to, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and / or salicylic acid.

The pharmaceutical composition for preventing or treating the onset of tuberculosis comprises 10 mg to 10 g of the phenanthrenyl compound or derivative thereof of the present invention, each of the optical isomers thereof and the respective pharmaceutically acceptable salts thereof, And 80% (by weight). It may further comprise suitable carriers, excipients and diluents conventionally used in the manufacture of pharmaceutical compositions. Examples of carriers, excipients and diluents that can be included in the pharmaceutical composition of the present invention include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate , Cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrole, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil. The pharmaceutical composition according to the present invention can be formulated in the form of powders, granules, capsules, suspensions, emulsions, oral preparations such as syrups and sterilized injection solutions according to a conventional method. When it is formulated, it is prepared using diluents or excipients such as fillers, extenders, binders, humectants, disintegrants, surfactants and the like which are generally used. The dosage of the pharmaceutical composition for preventing or treating tuberculosis containing the phenanthrenyl compound or derivative thereof according to the present invention may vary depending on the age, sex, and body weight of the patient. The dosage may be 0.1-100 mg / kg body weight once or several times a day, and the dose may be increased or decreased depending on the administration route, disease severity, sex, weight, age, . The dose is not intended to limit the scope of the invention in any way.

The pharmaceutical composition may be administered as an individual therapeutic agent or in combination with another therapeutic agent, and may be administered sequentially or simultaneously with a conventional therapeutic agent. Specifically, it may be administered in combination with any one drug selected from the group consisting of anti-nucleophilic agents rifampin, isoniazid, pyrazinamide, EMB, streptomycin, and combinations thereof. It is important to take into account all of the above factors and administer an amount that will achieve the maximum effect in the least amount without side effects. The pharmaceutical composition may be used alone or in combination with methods using surgery, radiation therapy, hormone therapy, chemotherapy, and biological response modifiers for the inhibition of tuberculosis-related diseases.

The pharmaceutical composition may be prepared by using a physiologically acceptable adjuvant together with excipient, disintegrant, sweetener, binder, coating agent, swelling agent, lubricant, lubricant or flavoring agent .

The pharmaceutical composition may be formulated or formulated for oral or parenteral human or veterinary use, including a pharmaceutically acceptable carrier. When the pharmaceutical composition is formulated, diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, and surfactants can be used. Solid preparations for oral administration include tablets, pills, powders, granules, capsules and the like. These solid preparations can be prepared by adding to a composition comprising the compound represented by Formula 1 or the salt thereof at least one or more excipients, , Calcium carbonate, sucrose, lactose, gelatin and the like. In addition to simple excipients, lubricants such as magnesium, styrene, and talc may be used. Examples of the liquid preparation for oral use include suspensions, solutions, emulsions and syrups, and various excipients such as wetting agents, sweetening agents, fragrances and preservatives in addition to commonly used simple diluents such as water and liquid paraffin . Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations and suppositories. Non-aqueous solvents and suspensions may include vegetable oils such as propylene glycol, polyethylene glycol and olive oil, injectable esters such as ethyl oleate, and the like. Further, it can be suitably formulated according to each disease or ingredient, using appropriate methods in the art or by the methods disclosed in Remington's Pharmaceutical Science (recent edition), Mark Publishing Company, Easton PA.

The pharmaceutical composition may be administered orally or parenterally (for example, intravenously, subcutaneously, intraperitoneally, topically, etc.) according to the desired method.

In another embodiment of the present invention, the Mycobacterium tuberculosis inhibitor comprises any one compound selected from the group consisting of the phenanthrenyl compounds or derivatives thereof, the optical isomers thereof, and salts thereof, as an effective ingredient.

The description of the phenanthrene compound or its derivative represented by the formula (1) to (8) as the active ingredient is the same as the description of the pharmaceutical composition for preventing or treating the onset of tuberculosis described above, so the description thereof will be omitted . The Mycobacterium tuberculosis inhibitor may be used in vivo or in vitro .

Another embodiment of the present invention is a pharmaceutical composition for preventing or treating tuberculosis, comprising as an active ingredient any one compound selected from the group consisting of the above-described phenanthrenyl compounds or derivatives thereof, optical isomers thereof and salts thereof For the manufacture of pharmaceutical compositions. The description of the phenanthrene compound or derivative thereof represented by the formula (1) to (9), which is the effective ingredient, is the same as the description of the pharmaceutical composition for preventing or treating the onset of tuberculosis, .

Another embodiment of the present invention relates to the use of any one of the compounds selected from the group consisting of the phenanthrene compounds or derivatives thereof, the optical isomers thereof, and salts thereof as described above for the prevention or treatment of tuberculosis. The description of the phenanthrene compound or derivative thereof represented by the formula (1) to (9), which is the effective ingredient, is the same as the description of the pharmaceutical composition for preventing or treating the onset of tuberculosis, .

The method for preventing tuberculosis or treating tuberculosis, which is another embodiment of the present invention, is a method for treating tuberculosis, which comprises administering to a patient in need of such treatment a therapeutically effective amount of a compound selected from the group consisting of phenanthrene compounds or derivatives thereof, optical isomers thereof, And administering a pharmaceutical composition for preventing or treating the onset of tuberculosis. The description of the phenanthrene compound or derivative thereof represented by the formula (1) to (9), which is the effective ingredient, is the same as the description of the pharmaceutical composition for preventing or treating the onset of tuberculosis, .

The novel phenanthrenyl compound or derivative thereof of the present invention shows therapeutic activity against resistant Mycobacterium tuberculosis and has low cytotoxicity, thus being excellent in its utilization as a pharmaceutical composition for the treatment of tuberculosis.

1 is a graph showing the 1 H NMR of the compound represented by the following formula 6 (DPG-05) synthesized in Production Example 1 of the present invention.
2 is a graph showing NMR 13 C results of a compound represented by Chemical Formula 6 (DPG-05) synthesized in Preparation Example 1 of the present invention.
3 is a graph showing NMR 13 C results of a compound represented by the formula 7 (DPG-13) synthesized in Preparation Example 2 of the present invention.
4 is a view showing a synthesis process corresponding to the reaction formula 1 in the embodiment of the present invention
5 is a view showing a synthesis process corresponding to the reaction formula 2 in the embodiment of the present invention

Hereinafter, embodiments of the present invention will be described in detail with reference to the accompanying drawings so that those skilled in the art can easily carry out the present invention. The present invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein.

Manufacturing example  1: DPG - 05) of  Compound synthesis

A compound represented by Formula 6 (DPF-05) was synthesized in the same manner as shown in Scheme 1 below. In the following Scheme 1, Me is abbreviated as methyl (CH 3 ).

[Reaction Scheme 1]

Figure 112016005518550-pat00033

In Scheme 1, 3,4-dimethoxyphenylacetic acid represented by the formula DPG-a is reacted with 4-methoxybenzaldehyde represented by the formula DPG-b, Was reacted for 10 hours under N 2 with trimethylamine (Et 3 N) and ethanoic anhydride (Ac 2 O) to obtain the compound represented by the formula DPG-01 (Step: 1-1 ).

The compound represented by the formula DPG-01 was added with thionyl chloride (SOCl 2 ) and reacted for 40 minutes. After pyridine and methanol were added, the reaction was continued for 40 minutes to obtain the compound represented by the formula DPG-02 To obtain the indicated compound (Step: 1-2)

To the compound represented by the formula DPG-02 was added CH 2 Cl 2 and FeCl 3, and the reaction was carried out for 3 hours. Then, NaHCO 3 was added to obtain the compound represented by the formula DPG-03 (Step: 1-3)

The formula to the compound represented by DPG-03 was added to LiAlH 4 (lithium aluminium hydride) and THF (tetrahydrofolic acid) was reacted for 50 minutes, it was added to THF and H 2 O to obtain a compound represented by the formula DPG-04 (step : 1-4)

The reaction was carried out by adding NaI and TMSCl (chlorotrimethylsilane) to the compound represented by the formula DPG-04 and reacting for 10 minutes, adding diisopropyl glutamate or D-diisopropyl glutamate and K 2 CO 3 for 5 hours (L-diisopropyl glutamate) represented by the formula: DPG-05 (formula 6) was obtained by reacting 1,4-dioxane with methanol and KOH for 1 hour to obtain (S) -methyl 1 - ((2, 3, 6-trimethoxyphenanthrene-10-yl) methyl) -5-oxopyrrolidine- , 3,6-trimethoxyphenanthren-10-yl) methyl) -5-oxopyrrolidine-2-carboxylate; (R) -methyl 1- ((2,3,6-trimethoxyphenanthrene-10-yl) methyl) -5-oxopyrrolidine-2-carboxylate in the presence of D-diisopropyl glutamate, ( R) -methyl 1 - ((2,3,6-trimethoxyphenanthren-10-yl) methyl) -5-oxopyrrolidine-2-carboxylate] (Step: 1-5).

The compound represented by DPG-05 is the compound represented by formula (6) of the present invention, and the results of NMR analysis (1H, 13C) are shown in FIG. 1 and FIG. 2, respectively.

(E) -methyl 2- (3,4-dimethoxyphenyl) -3- (4- (phenoxymethyl) phenyl) acrylate [(E) ) -methyl 2- (3,4-dimethoxyphenyl) -3- (4- (phenoxymethyl) phenyl) acrylate was also synthesized and applied to Example 2 below.

Manufacturing example  2: DPG - 13) and  8 ( DPG - 14) of  Compound synthesis

(DPG-13) and (DPG-14) were synthesized in the same manner as shown in Reaction Scheme 2 below. Hereinafter, Me is methyl (CH 3 ) and Bn is benzylC 6 H 5 CH 2 ) in Scheme 2.

[Reaction Scheme 2]

Figure 112016005518550-pat00034

In the above scheme 2, R 1 means methyl and R 2 means benzyl.

In the above Reaction Scheme 2, isopropyl bromide ( i- PrBr), KI, K (1- (4-hydroxyphenyl) ethanone, Piceol) represented by the formula DPG- 2 CO 3, was added to DMF (dimethylformamide) to give the 1- (4-isopropoxyphenyl) ethanone (1- (4-isopropoxyphenyl) ethanone) represented by the general formula DPG-07 (step 1-1).

Trimethylamine (Et 3 N) and ethanoic anhydride (Ac 2 O) were added to the compound represented by the formula DPG-07 and the compound represented by the formula (DPG-a) To obtain a compound represented by the formula DPG-08 (process: 2-2).

The reaction is carried out by adding oxalyl chloride, C 2 Cl 2 O 2 , (ClCO) 2 , pyridine, Py, and dichloromethane (CH 2 Cl 2 ) to the compound represented by the formula DPG-08 (Pyridine, Py) and methanol were added to the reaction mixture to obtain a compound represented by the formula DPG-09 (Step: 2-3).

The compound represented by the formula DPG-09 was reacted by adding FeCl 3 , 4A molecular sieve, and CH 2 Cl 2 to the compound represented by the formula DPG-10 (step: 2-4).

Benzyl bromide (BnBr), K 2 CO 3 and acetone were added to the compound represented by the formula DPG-10 and reacted to obtain a compound represented by the formula DPG-11 (step: 2-5).

Lithium aluminum hydride (LiAlH 4 ) and tetrahydrofolic acid (THF) were added to the compound represented by the formula DPG-11 and reacted to obtain a compound represented by the formula DPG-12 (Step: 2-6).

After adding NaI, TMSCl (chlorotrimethylsilane), acetonitrile (MeCN, CH 3 CN), and 1,4-dioxane to the compound represented by the formula DPG-12, dimethylglutamate (D-glutamate hydrochloride, or dimethyl D-glutamate hydrochloride), K 2 CO 3 , acetonitrile (MeCN, CH 3 CN), and 1,4-dioxane (D) -glutamate hydrochloride (D-glutamate hydrochloride) is reacted with acetic acid (AcOH) and methanol to obtain a compound represented by the formula DPG-13 When applied, the methyl 1 - ((6- (benzyloxy) -2,3-dimethoxyphenanthrene-10-yl) methyl) -5- oxopyrrolidine- 2-carboxylate of (R) methyl-5-oxopyrrolidine-2-carboxylate] (Step: 2-7)

The compound represented by DPG-13 is the compound represented by the formula (7) of the present invention, and the NMR analysis result (13C) is shown in Fig.

When a compound represented by DPG-14 (formula 8) is reacted with a compound represented by the formula DPG-13 in an aqueous solution of acetone with trifluoroacetic acid (TFA) ) -form, dimethyl D-glutamade hydrochloride is applied, a solution of 1 - ((6- (benzyloxy) -2,3-dimethoxyphenanthrene-10-yl) methyl) 2-carboxylate] (Step: 2-8) was obtained in the same manner as in Example 1, except that the solvent was replaced with methylene chloride.

Example  1: Evaluation of antituberculous efficacy

The anti-tuberculosis efficacy of the total of 15 compounds shown in Table 1 below, including the compounds synthesized above, was evaluated.

compound constitutional formula compound constitutional formula a-1
(DPG)

Figure 112016005518550-pat00035
a-9
Figure 112016005518550-pat00036
 a-2
(DPG-01)
Figure 112016005518550-pat00037
 a-10
Figure 112016005518550-pat00038
 a-3
(DPG-02)
Figure 112016005518550-pat00039
 a-11
(DPG-12)
Figure 112016005518550-pat00040
 a-4
(DPG-03)
Figure 112016005518550-pat00041
 a-12
(DPG-13 / Formula 7)
Figure 112016005518550-pat00042
 a-5
(DPG-04)
Figure 112016005518550-pat00043
 a-13 (DPG-14
/ Formula 8)
Figure 112016005518550-pat00044
 a-6
(DPG-05 / Chemical Formula 6)
Figure 112016005518550-pat00045
 a-14
(isoniazid
/ INH)
Figure 112016005518550-pat00046
 a-7
Figure 112016005518550-pat00047
 a-15
(rifampin
/ RIF)
Figure 112016005518550-pat00048
 a-8
Figure 112016005518550-pat00049
 a-16
Figure 112016005518550-pat00050

(R) -form and (S) -form are present in the case of the compounds a-6, a-7, a-12 and a- (S) -form as well as (R) -form in the case of a-6, a-12 and a-13 in which anti-TB activity was confirmed .

Anti tuberculosis efficacy was confirmed using REMA (Resazurin microtiter assay) and MGIT assay.

REMA proceeded as follows.

Resazurin solution was prepared by adding 4 mg of resazurin sodium salt to 40 ml of sterilized water to make 0.01%, then filtered with 0.45 m filter, and stored in the refrigerator. 100 쨉 l of the compounds listed in Table 1 were added to 96 wells in which 100 쨉 l of 7H9 media (7H9 media) was dispensed, serial dilution (1.5 쨉 g / ml to 50 쨉 g / ml) H37Ra (5 x 10 < 6 > cells / ml). One week later, 30 res of resazurin solution was added to each well to confirm the anti-tubercular activity. Isoniazid (INH) and rifampin (RIF) were added at 0.5 to 2 ㎍ / ml as a positive control, and DMSO was used as a negative control.

The MGIT assay was performed as follows.

Using the MGIT 960 system, the ability of the compounds listed in Table 1 to inhibit the growth of Mycobacterium tuberculosis was confirmed. After addition of 740 to 820 [mu] l of growth supplement to 7 ml of media in the MGIT tube, each of the compounds listed in Table 1 was adjusted to a final concentration of 0.1 to 12 [mu] g / ml. After that, 100 쨉 l of M. tuberculosis H37Ra (6.4x10 cells / ml) was added, and the growth inhibitory activity of each compound was measured by measuring the growth of Mycobacterium tuberculosis with an MGIT instrument. Rifampin (5 μg / ml) was used as a positive control and DMSO was used as a negative control.

The results of the antituberculous efficacy tests confirmed by the above experiments are summarized in Table 2 below in terms of MIC (minimum inhibitory concentration, ug / ml).

compound Anti tuberculosis efficacy, MIC (μg / ml) a-1 6-12.5 a-2 (DPG-01) > 100 a-3 (DPG-02) > 100 a-4 (DPG-03) > 100 a-5 (DPG-04) > 100 a-6 (DPG-05, formula 6) 1.5 to 3.25 a-7 > 100 a-8 > 100 a-9 > 100 a-10 6-12.5 a-11 (DPG-12) > 100 a-12 (DPG-13, Formula 7) 0.78 to 1.56 a-13 (DPG-14, formula 8) 6-12.5 a-14 (isoniazid, INH) 0.006 to 0.012 a-15 (rifampin, RIF) 0.05 to 0.1 a-16
(Formula 9) 1.5 to 3.1

(DPG-05), a-12 (DPG-13), a-13 (DPG-14), and a -16 < / RTI > (Formula 9) was found to be excellent without toxicity.

Example  2: Resistant bacteria  Evaluation of anti-tuberculosis efficacy in various mycobacteria including

(DPG-05) and a-12 (DPG-13) corresponding to the formula 6 and the compound 7 represented by the excellent anti-tuberculosis activity in Example 1, and the compound of the deoxypergularinine (DPG) was compared with isoniazid (INH, a-14) and rifampin (RIF, a-15), which are commercially available anti-tuberculosis drugs, And whether or not they show activity against Mycobacterium tuberculosis.

H37Ra TB, multidrug-resistant TB (MDR), extensively drug-resistant TB (XDR), isoniazid-resistant TB (INH-r), rifampin-resistant TB -r (pyrazinamide-resistant TB) and Strep-r (Streptomycin-resistant TB) were applied. The results are summarized in Table 3 below.

compound MICs (μg / ml) H37Ra H37Rv MDR XDR a-1 (DPG) 6.25-12.5 6.25-12.5 6.25-12.5 6.25-12.5 a-6 (DPG-05, formula 6) 1.5-3.25 1.5-3.25 1.5-3.25 1.5-3.25 a-12 (DPG-13, Formula 7) 0.78-1.56 0.78-1.56 0.78-1.56 0.78-1.56 a-14 (isoniazid, INH) 0.006-0.012 0.006-0.012 25-50 > 100 a-15 (rifampin, RIF) 0.05-0.1 0.1-0.195 12.5-25 > 100 a-16
(Formula 9) 1.56-3.12 1.56-3.12 1.56-3.12 1.56-3.12 compound MICs (μg / ml) INH-r RIF-r Pyr-r Strep-r a-1 (DPG) 6.25-12.5 3.12-6.25 6.25-12.5 12.5-25 a-6 (DPG-05, formula 6) 3.15-6.25 1.5-3.25 3.15-6.25 3.15-6.25 a-12 (DPG-13, Formula 7) 0.78-1.56 0.78-1.56 0.78-1.56 0.78-1.56 a-14 (isoniazid, INH) > 100 50-100 50-100 50-100 a-15 (rifampin, RIF) 0.05-0.1 50-100 0.1-0.195 0.05-0.1 a-16
(Formula 9) 1.56-3.12 1.56-3.12 1.56-3.12 1.56-3.12

(DPG), a-6 (DPG-05, Formula 6) as compared with isoniazid (INH, a-14) or rifampin (RIF, , a-12 (DPG-13, formula 7), and a-16 (formula 9) showed relatively even MIC values in resistant strains containing resistant strains, indicating that they have excellent activity against resistant strains. In particular, in the case of a-12 (DPG-13, Formula 7), almost all the strains showed similar MIC values, indicating that they have excellent activity in various resistant bacteria.

Example  3: Evaluation of efficacy in combination with existing anti-tuberculosis drugs

The synergistic effect of a-6 (DPG-05, Chemical Formula 6) with the conventional drugs INH (isoniazid), RIF (rifampin) and streptomycin is shown in Table 4 below. The experiment proceeded in a manner similar to that of Example 2, and the cell line and drugs shown in Table 4 were used.

Strain The compound a Compound b FIC a / FIC b 1 FICI 2 Outcome Name MIC
(μg / ml) Name MIC
(μg / ml) TB H37Rv a-6
(DPG-05
/ Formula 6) 1.5-3.25 Isoniazid 0.006-0.012 1/1 2 Indifferent Rifampin 0.1-0.195 1/1 2 Indifferent Streptomycin 0.3-0.6 1/1 2 Indifferent

1. a = compound a; b = first-line anti-TB drugs

In FIC a / FIC b , FIC a = (MIC in combination of compound a and compound b) / (MIC in compound a alone) ; FIC b = (MIC when compound a and compound b are combined) / (MIC when compound b alone)

2. Fractional inhibitory concentration index (FICI) = FIC a + FIC b .

The FICI value indicates synergy when FICI ≤ 0.5, and additional or irrelevant effect when FICI> 0.5.

Example  4: Evaluation of cytotoxicity (CC 50 : 50% cytotoxicity )

Cytotoxicity was measured in fibroblasts, L929, and RAW 264.7 cells associated with infection, proliferation of tuberculosis.

10 x 10 4 cells / well were treated with each compound in DMEM medium and cultured at 24 and 48 hours. 500 μl of the medium and 5 μl of the MTT solution were added to a 24-well plate with the new medium, followed by further reaction for 4 hours. After removing the medium, formazan was dissolved in 200 μl of DMSO and the absorbance was measured at 540 nm using a microplate reader. The cytotoxicity was expressed as a 50% toxic effect (CC50, 50% Cytotoxic concentration) . All measurements were the average of three replicates and the results are shown.

compound CC 50 (μg / ml) L929 cells Raw264.7 cells a-1 (DPG) <1.5 <1.5 a-6 (DPG-05, formula 6) > 100 > 100 a-12 (DPG-13, Formula 7) > 100 > 100 a-16
(Formula 9) > 100 > 100

In the case of a-6 (DPG-05, Formula 6), a-12 (DPG-13, Formula 7) and a-16 (Formula 9) as compared with DPG of a- And it was confirmed that it exhibited remarkably low cytotoxicity.

While the present invention has been particularly shown and described with reference to exemplary embodiments thereof, it is to be understood that the invention is not limited to the disclosed exemplary embodiments, Of the right.

Claims (4)

delete delete A pharmaceutical composition for preventing or treating the development of tuberculosis, comprising a phenanthrenyl compound represented by the following formula (1), an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient;
[Chemical Formula 1]
Figure 112017049037072-pat00057

Wherein R 1 is an alkyl group having 1 carbon atom or an aralkyl group having 7 carbon atoms, R 2 is hydrogen or a methyl group, and n is an integer of 2 to 4. The method of claim 3,
The phenanthrenyl compound is any one of compounds represented by the following formulas (6) to (8) and has an anti-tuberculosis activity against resistant Mycobacterium tuberculosis.
[Chemical Formula 6]
Figure 112017049037072-pat00059

(7)
Figure 112017049037072-pat00060

[Chemical Formula 8]
Figure 112017049037072-pat00061
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