KR20120060663A - Nitroimidazole compounds, process for the preparation thereof, and pharmaceutical composition for treating tuberculosis comprising the same - Google Patents

Abstract

PURPOSE: A pharmaceutical composition containing nitroimidazole compounds for treating tuberculosis is provided to excellently suppress active and non-active tuberculous bacillus. CONSTITUTION: A nitroimidazole compound is denoted by chemical formula 1. A method for preparing the nitroimidazole compounds or pharmaceutically acceptable salt thereof comprises a step of reacting compounds of chemical formulas 3 and 4 in dimethyl formamide under the presence of potassium carbonate.

Description

NITROIMIDAZOLE COMPOUNDS, PROCESS FOR THE PREPARATION THEREOF, AND PHARMACEUTICAL COMPOSITION FOR TREATING TUBERCULOSIS COMPRISING THE SAME}

The present invention relates to a nitroimidazole compound, a pharmaceutically acceptable salt thereof, a preparation method thereof, and a pharmaceutical composition for treating tuberculosis containing the same as an active ingredient.

PA-824 is a nitroimidazole-based compound, a compound of which anti-tuberculosis effect is known and is currently under clinical research as an antituberculosis agent (see C. Kendall Stover et al ., Nature 2000, 405, 962-966). Another nitroimidazole-based compound, OPC-67683, is also in clinical research as an anti-tuberculosis agent (see Hirofumi Sasaki et al . , J. Med . Chem . 2006, 49, 7854-7860). One of the biggest reasons that nitroimidazole compounds have gained a lot of attention in the field of anti-tuberculosis drug research is its efficacy against inactive tuberculosis bacteria, which is considered to be the most important for shortening tuberculosis treatment. In particular, bicyclic nitroimidazole has been continuously studied in recent years (see William Denny et al . , J. Med. Chem . 2010, 53, 282-294), and the antituberculosis effect of nitroimidazole-based compounds A study has also been reported (see Kim Pil-ho et al . , J. Med. Chem . 2009, 52, 1317-1328) and Korean Patent Application No. 2009-103041.

Against this background, the present inventors completed the present invention by discovering a novel nitroimidazole compound which exhibits an excellent inhibitory effect on Mycobacterium tuberculosis, in particular, inactive Mycobacterium tuberculosis, compared to existing monocyclic nitroimidazole-based compounds.

Accordingly, it is an object of the present invention to provide a nitroimidazole compound or a pharmaceutically acceptable salt thereof.

Another object of the present invention is to provide a method for preparing the nitroimidazole compound or a pharmaceutically acceptable salt thereof.

Still another object of the present invention is to provide a pharmaceutical composition for treating tuberculosis containing the nitroimidazole compound or a pharmaceutically acceptable salt thereof as an active ingredient.

In order to achieve the above object, the present invention provides a nitroimidazole compound of formula (1) or a pharmaceutically acceptable salt thereof:

[Formula 1]

Where

R ¹ is 1 or 2 substituents selected from hydrogen, nitro, amino, hydroxy, C _1-6 alkyl, halo, or C _1-6 alkoxy;

When X is —CH ₂ —, Y is CH—R ² or C═O, or XY is —CH═CH— or —CH ₂ —CH ₂ —;

,

, 또는

이고;R ² is hydrogen, cyano, halo, aminocarbonyl, C _1-6 thioalkyl, C _1-6 alkylsulfonyl, hydroxy, triazolyl substituted with C _1-6 alkyl,

,

, or

ego;

R ³ is hydrogen, C _1-6 alkoxy or halo;

R ⁴ is C _1-6 alkyl, C _6-14 aryl, C _6-14 arylamino or C _3-7 cycloalkylamino;

이다.
R ⁵ is C _1-6 alkyl, C _6-14 aryl, C _6-14 arylamino, C _3-7 cycloalkylamino or

to be.

In order to achieve the above another object, the present invention provides a method for preparing the nitroimidazole compound or a pharmaceutically acceptable salt thereof.

In order to achieve the above another object, the present invention provides a pharmaceutical composition for treating tuberculosis containing the nitroimidazole compound or a pharmaceutically acceptable salt thereof as an active ingredient.

The nitroimidazole compounds of the present invention and their pharmaceutically acceptable salts can be usefully used for the treatment of tuberculosis because they exhibit excellent inhibitory effects on active and inactive Mycobacterium tuberculosis.

Hereinafter, the present invention will be described in detail.

The present invention provides a nitroimidazole compound represented by the following formula (1) and a pharmaceutically acceptable salt thereof:

Where

R ¹ is 1 or 2 substituents selected from hydrogen, nitro, amino, hydroxy, C _1-6 alkyl, halo, or C _1-6 alkoxy;

When X is —CH ₂ —, Y is CH—R ² or C═O, or XY is —CH═CH— or —CH ₂ —CH ₂ —;

,

, 또는

이고;R ² is hydrogen, cyano, halo, aminocarbonyl, C _1-6 thioalkyl, C _1-6 alkylsulfonyl, hydroxy, triazolyl substituted with C _1-6 alkyl,

,

, or

ego;

R ³ is hydrogen, C _1-6 alkoxy or halo;

R ⁴ is C _1-6 alkyl, C _6-14 aryl, C _6-14 arylamino or C _3-7 cycloalkylamino;

이다.R ⁵ is C _1-6 alkyl, C _6-14 aryl, C _6-14 arylamino, C _3-7 cycloalkylamino or

to be.

또는

이고; R¹은 수소, 할로, C_1-6 알킬 또는 C_1-6 알콕시이고; R²는 수소, 할로, 메틸설포닐, 시아노,

C_1-6 알킬 또는 아미노카보닐이고; R³은 할로 또는 C_1-6 알콕시이다. Preferably, in Chemical Formula 1, XY is

or

ego; R ¹ is hydrogen, halo, C _1-6 alkyl or C _1-6 alkoxy; R ² is hydrogen, halo, methylsulfonyl, cyano,

C _1-6 alkyl or aminocarbonyl; R ³ is halo or C _1-6 alkoxy.

Specific examples of the more preferable compound as the nitroimidazole compound of Formula 1 according to the present invention are as follows:

1) 1- (1- (2,4-dichlorophenyl) -2- (2-methoxy-4-nitro-1H-imidazol-1-yl) ethyl) -1H-1,2,3-triazole -4-yl) methanol;

2) 1- (2- (2,4-dichlorophenyl) -2- (methylthio) ethyl) -2-methoxy-4-nitro-1H-imidazole;

3) 1- (2- (2,4-dichlorophenyl) -2- (methylsulfonyl) ethyl) -2-methoxy-4-nitro-1H-imidazole;

4) N- (1- (2,4-dichlorophenyl) -2- (2-methoxy-4-nitro-1H-imidazol-1-yl) ethyl) acetamide;

5) N- (1- (2,4-dichlorophenyl) -2- (2-methoxy-4-nitro-1H-imidazol-1-yl) ethyl) benzamide;

6) 1- (1- (2,4-dichlorophenyl) -2- (2-methoxy-4-nitro-1H-imidazol-1-yl) ethyl) -3-phenylurea;

7) 1-cyclohexyl-3- (1- (2,4-dichlorophenyl) -2- (2-methoxy-4-nitro-1H-imidazol-1-yl) ethyl) urea;

8) 1- (2,4-dichlorophenyl) -2- (2-methoxy-4-nitro-1H-imidazol-1-yl) ethyl phenylcarbamate;

9) 2- (2,4-dichlorophenyl) -3- (2-methoxy-4-nitro-1H-imidazol-1-yl) propanenitrile;

10) 2- (2-bromo-4-nitro-1H-imidazol-1-yl) -1- (2,4-dichlorophenyl) ethanone;

11) (E) -1- (2,4-dichlorostyryl) -2-methoxy-4-nitro-1H-imidazole;

12) 1- (2,4-dichlorophenyl) -2- (2-methoxy-4-nitro-1H-imidazol-1-yl) ethyl cyclohexylcarbamate;

13) 1- (2,4-dichlorophenyl) -2- (2-methoxy-4-nitro-1H-imidazol-1-yl) ethylacetate;

14) 1- (2,4-dichlorophenyl) -2- (2-methoxy-4-nitro-1H-imidazol-1-yl) ethyl benzoate;

15) 1- (2- (2,4-dichlorophenyl) -2-iodoethyl) -2-methoxy-4-nitro-1H-imidazole;

16) 2- (2,4-dichlorophenyl) -3- (2-methoxy-4-nitro-1H-imidazol-1-yl) propanamide;

17) 2- (2-bromo-4-nitro-1H-imidazol-1-yl) -1-phenylethanone;

18) 2- (2-bromo-4-nitro-1H-imidazol-1-yl) -1- (2,4-dimethylphenyl) ethanone;

19) 2- (2-bromo-4-nitro-1H-imidazol-1-yl) -1- (2,4-dimethoxyphenyl) ethanone;

20) 1- (2,4-dichlorophenyl) -2- (2-methoxy-4-nitro-1H-imidazol-1-yl) ethyl (1R, 2S, 5R) -2-isopropyl-5- Methylcyclohexyl carbonate;

21) 2- (2-bromo-4-nitro-1H-imidazol-1-yl) -1- (2,4-dichlorophenyl) ethyl (7,7-dimethyl-2-oxobicyclic [2.2 .1] heptan-1-yl) methanesulfonate;

22) 2-bromo-1- (2,4-dichlorophenethyl) -4-nitro-1H-imidazole;

23) 2-bromo-1- (2,4-dichlorophenethyl) -5-nitro-1H-imidazole; And

24) 1- (2,4-dichlorophenethyl) -2-methoxy-4-nitro-1H-imidazole.

The compound of formula 1 according to the present invention includes not only pharmaceutically acceptable salts thereof, but also all possible solvates, hydrates and stereoisomers that can be prepared therefrom.

The term "halo" as used herein, means fluoro, bromo, chloro or iodo.

As used herein, the term "alkyl" refers to a linear or branched saturated C ₁ to C ₆ hydrocarbon radical chain. Specific examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl and hexyl.

As used herein, the term "alkoxy" refers to the group -ORa, where Ra is alkyl as defined above. Specific examples include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy, and the like.

The term "aryl" as used herein includes fused groups such as naphthyl, phenanthrenyl and the like, as well as C _6-14 monocyclic or bicyclic aromatic rings such as phenyl, substituted phenyl and the like. The aryl group optionally contains one or more substituents, that is, halogen, alkyl, alkoxy, hydroxy, carboxy, carbamoyl, alkyloxycarbonyl, nitro, trifluoromethyl, amino, cycloalkyl, cyano, alkyl S (O) n ( n = 1,2,3) or thiol, but is not limited thereto.

As used herein, the term “heteroaryl” refers to furyl, thienyl, thiazolyl, pyrazolyl, isoazolyl, oxazolyl, isoxazolyl, pyrrolyl, triazolyl, tetrazolyl as part of a 5-10 membered group. , Imidazolyl, 1,3,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-oxadiazolyl, 1,3,5-thiadiazolyl, 1,2, 3-thiadiazolyl, 1,2,4-thiadiazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, 1,2,4-triazineyl, 1,2,3-triazineyl, 1 , 3,5-triazinyl, cinnolinyl, pteridylyl, purinyl, 6,7-dihydro-5H- [1] pyridinyl, or 5,6,7,8-tetrahydro-quinoline- as morbid 3-yl, benzooxazolyl, benzothiazolyl, benzo [b] thiophenyl, benzisothiazolyl, benzisooxazolyl, benzimidazolyl, thianaphthenyl, isocyanaphthenyl, benzofuran Isobenzofuranyl, isoindoleyl, indolyl, indolizinyl, indazolyl, Soquinolyl, quinolyl, phthalazinyl, quinoxalinyl, quinazolinyl, pyrazolo [3,4-b] pyridinyl, or benzoxazineyl.

"Pharmaceutically acceptable salts" of the compound of Formula 1 may be prepared by conventional methods in the art, for example, hydrochloric acid, bromic acid, sulfuric acid, sodium hydrogen sulfate, phosphoric acid, nitric acid, carbonic acid, and the like. Salts with inorganic acids such as formic acid, acetic acid, propionic acid, oxalic acid, succinic acid, benzoic acid, citric acid, maleic acid, malonic acid, tartaric acid, gluconic acid, lactic acid, gestyic acid, fumaric acid, lactobionic acid, salicylic acid, or acetylsalicylic acid Salts with organic acids such as silicic acid (aspirin), salts with amino acids such as glycine, alanine, vanillin, isoleucine, serine, cysteine, cystine, aspartic acid, glutamine, lysine, arginine, tyrosine, proline, methanesulfonic acid , Salts with sulfonic acids such as ethanesulfonic acid, benzenesulfonic acid and toluenesulfonic acid, metal salts by reaction with alkali metals such as sodium and potassium, or salts with ammonium ions. It should.

The present invention also provides a method for preparing the compound of Formula 1.

According to one embodiment of the present invention, the preparation method of formula 1 comprises reacting a compound of formula 3 and formula 4 in dimethylformamide in the presence of potassium carbonate to prepare a compound of formula 1a. :

[Formula 1a]

Where

R ¹ is 1 or 2 substituents selected from hydrogen, nitro, amino, hydroxy, C _1-6 alkyl, halo, or C _1-6 alkoxy.

According to another embodiment of the present invention, the preparation method of formula 1 of the present invention,

1) reacting a compound of Formula 2 and Formula 4 to produce a compound of Formula 5; Or preparing a compound of Formula 1a by reacting a compound of Formula 3 and Formula 4, followed by reaction with sodium borohydride (NaBH ₄ ) in a methanol solvent to prepare a compound of Formula 5;

2) preparing a compound of Chemical Formula 6 by reacting the compound of Chemical Formula 5 prepared with sodium methanol (NaOMe) in a methanol solvent; And

3) reacting the prepared compound of formula 6 with a compound of formula 9 or formula 10 to produce a compound of formula 1b or formula 1c:

(3)

[Formula 4]

[Formula 1a]

[Chemical Formula 1b]

[Formula 1c]

Where

R ¹ is 1 or 2 substituents selected from hydrogen, nitro, amino, hydroxy, C _1-6 alkyl, halo, or C _1-6 alkoxy;

이고; R ⁷ is C _1-6 alkyl, C _6-14 aryl or

ego;

R ⁸ is C _6-14 aryl or C _3-7 cycloalkyl.

According to another embodiment of the present invention, the preparation method of formula 1 of the present invention,

1) reacting a compound of Formula 2 and Formula 4 to produce a compound of Formula 5; Or preparing a compound of Formula 1a by reacting a compound of Formula 3 and Formula 4, followed by reaction with sodium borohydride (NaBH ₄ ) in a methanol solvent to prepare a compound of Formula 5;

2) preparing a compound of Chemical Formula 6 by reacting the compound of Chemical Formula 5 prepared with sodium methanol (NaOMe) in a methanol solvent; And

3) preparing a compound of formula 7 by reacting the compound of formula 6 prepared in dimethylformamide (DMF) in the presence of diphenylphosphoryl azide (DPPN ₃ ); And

4) reacting the compound of Formula 7 prepared with the compound of Formula 11 to prepare a compound of Formula 1d:

[Formula 2]

(3)

[Formula 4]

[Formula 1a]

[Chemical Formula 5]

[Formula 6]

[Formula 1d]

Where

R ¹ is 1 or 2 substituents selected from hydrogen, nitro, amino, hydroxy, C _1-6 alkyl, halo, or C _1-6 alkoxy;

R ⁶ is CH ₂ OH.

According to another embodiment of the present invention, the preparation method of formula 1 of the present invention,

1) reacting a compound of Formula 2 and Formula 4 to produce a compound of Formula 5; Or preparing a compound of Formula 1a by reacting a compound of Formula 3 and Formula 4, followed by reaction with sodium borohydride (NaBH ₄ ) in a methanol solvent to prepare a compound of Formula 5;

2) preparing a compound of Chemical Formula 6 by reacting the compound of Chemical Formula 5 prepared with sodium methanol (NaOMe) in a methanol solvent; And

3) preparing a compound of formula 7 by reacting the compound of formula 6 prepared in dimethylformamide (DMF) in the presence of diphenylphosphoryl azide (DPPN ₃ ); And

4) Triethylamine (Et ₃ N) was prepared in the presence of the compound of formula 7 in the presence of propanedithiol (SH (CH ₂ ) ₃ SH) Reacting in the preparation of the compound of Formula 8; And

5) reacting the prepared compound of formula 8 with a compound of formula 9 or formula 10 to produce a compound of formula 1e or 1f:

[Formula 2]

(3)

[Formula 4]

[Formula 1a]

[Chemical Formula 5]

[Formula 6]

[Formula 7]

[Formula 8]

[Formula 9]

[Formula 10]

[Formula 1e]

(1f)

Where

R ¹ is 1 or 2 substituents selected from hydrogen, nitro, amino, hydroxy, C _1-6 alkyl, halo, or C _1-6 alkoxy;

R ⁷ is C _1-6 alkyl, C _6-14 aryl or ego;

R ⁸ is a C _{6 -14} aryl or C _{3 -7-cycloalkyl.}

Compound of formula 1 according to another embodiment of the present invention can be prepared according to the synthetic route represented by, for example, Schemes 1 and 2.

Scheme 1

In the above equations,

R ¹ is as defined above.

Scheme 2

In the above equations,

R ¹ , R ⁶ to R ⁸ are as defined above.

As shown in Scheme 1, the chlorohydrin compound of formula 2 and 2-bromo-4-nitroimidazole of formula 4 (WO 2005/077913) were converted to tetrabutylammonium iodine (TBAI) and potassium carbonate. 4-nitroimidazole compound of formula (5) can be obtained by refluxing in a solvent such as methanol or ethanol in the presence of. In this reaction, a 5-nitroimidazole compound, which is a nitro substituent regioisomer of the compound of Formula 5, can be obtained as a by-product.

In addition, the compound of Formula 5 may be obtained by other methods, specifically, the chloroacetofinone compound of Formula 3 and 2-bromo-4-nitroimidazole of Formula 4 (WO 2005/077913) The 4-nitroimidazole compound of the formula (1a) of the present invention can be obtained by stirring under reflux in dimethylformamide in the presence of potassium carbonate. The compound of Formula 1a thus prepared may be reacted with sodium borohydride (NaBH ₄ ) in a methanol solvent to obtain an alcohol compound of Formula 5.

The compound of Chemical Formula 5 prepared above may be reacted with methanol sodium (NaOMe) in a methanol solvent to obtain a 2-methoxyimidazole compound of Chemical Formula 6.

Subsequently, as shown in Scheme 2, the compound of Formula 6 may be reacted with an acyl chloride compound of Formula 9 or an isocyanate of Formula 10 to prepare compounds of Formula 1b and Formula 1c. Specifically, the compound of Formula 6 is triethylamine (Et ₃ N) and Reacting with a compound of formula 9 in a methylene chloride solvent to produce an ester compound of formula 1b; Alternatively, the compound of Formula 6 may be reacted with a compound of Formula 10 in a tetrahydrofuran solvent to prepare a carbamate compound of Formula 1c.

In addition, the compound of Chemical Formula 6 is reacted in dimethylformamide (DMF) using diphenylphosphoryl azide (DPPN ₃ ) to prepare a compound of Chemical Formula 7, and then isopropylethylamine and copper iodide (CuI) The triazole compound of Formula 1d may be prepared by cyclization with an alkyne compound of Formula 11 in an acetonitrile solvent in the presence of.

In addition, the compound of Chemical Formula 6 is reacted in dimethylformamide (DMF) in the presence of diphenylphosphoryl azide (DPPN ₃ ) to prepare a compound of Chemical Formula 7, and then propanedithiol (SH (CH ₂ ) ₃ SH Triethylamine (Et ₃ N) Reaction in to prepare a compound of formula (8). Subsequently, the amide compound of Formula 1e is prepared by reacting the prepared compound of Formula 8 with an acyl chloride compound of Formula 9; Alternatively, the urea compound of Formula 1f may be prepared by reacting the compound of Formula 8 with a compound of Formula 10 in a tetrahydrofuran solvent.

According to another embodiment of the present invention, the preparation method of Chemical Formula 1 of the present invention,

1) preparing a compound of formula 12 by reacting a compound of formula 6 in methylene chloride (CH ₂ Cl ₂ ) in the presence of mesyl chloride (MsCl) and triethylamine (Et ₃ N);

2) The compound of formula 12 prepared above was acetone in the presence of sodium iodide (NaI) Reacting in the preparation of the compound of Formula 13; And

3) reacting the prepared compound of formula 13 in dimethylformamide in the presence of potassium thioacetate (KSAc) to produce a compound of formula 1 g:

[Formula 6]

[Formula 1g]

Where

R ¹ is 1 or 2 substituents selected from hydrogen, nitro, amino, hydroxy, C _1-6 alkyl, halo, or C _1-6 alkoxy.

Compound of Formula 1 according to another embodiment of the present invention can be prepared according to the synthetic route represented by, for example, Scheme 3.

Scheme 3

In the above equations,

R ¹ is as defined above.

Hereinafter, a method for preparing a compound according to an embodiment of the present invention will be described in detail.

As shown in Scheme 3, the compound of Formula 6 is reacted in methylene chloride (CH ₂ Cl ₂ ) using mesyl chloride (MsCl) and triethylamine (Et ₃ N) to prepare a compound of Formula 12 Acetone using sodium iodide (NaI) Reaction in to prepare a compound of formula (13). Subsequently, the compound of Formula 13 may be reacted in dimethylformamide using potassium thioacetate (KSAc) to prepare a compound of Formula 1g according to the present invention.

According to another embodiment of the present invention, the preparation method of Chemical Formula 1 of the present invention,

1) preparing a compound of Formula 1h and Formula 1i by reacting a compound of Formula 14 and Formula 4 in dimethylformamide in the presence of potassium carbonate; And

2) reacting the compound of Formula 1h prepared with sodium methanol (NaOMe) in a methanol solvent to prepare a compound of Formula 1j of the present invention:

[Formula 4]

[Formula 1h]

Formula 1i]

[Formula 1j]

In the above equations,

R ¹ is as defined above.

Compound of Formula 1 according to another embodiment of the present invention can be prepared according to the synthetic route represented by, for example, Scheme 4.

Scheme 4

In the above equations,

R ¹ is as defined above.

Hereinafter, a method for preparing a compound according to an embodiment of the present invention will be described in detail.

As shown in Scheme 4, the compound of Formula 14 and 2-bromo-4-nitroimidazole of Formula 4 (WO 2005/077913) were prepared in a dimethylformamide solvent in the presence of potassium carbonate. The 4-nitroimidazole compound of formula 1h can be obtained by stirring at 占 폚. In this reaction, 5-nitroimidazole compound of formula 1i, which is a nitro substituent regioisomer of compound of formula 1h, may be obtained as a by-product. The compound of Chemical Formula 1h prepared above may be reacted with sodium methanol (NaOMe) in a methanol solvent to obtain 2-methoxyimidazole compound of Chemical Formula 1j of the present invention.

On the other hand, the present invention provides a pharmaceutical composition for treating tuberculosis, which contains a nitroimidazole compound or a pharmaceutically acceptable salt thereof as an active ingredient.

A pharmaceutical composition comprising the nitroimidazole compound and a pharmaceutically acceptable salt thereof according to the present invention can be administered orally or parenterally during clinical administration and can be used in the form of a general pharmaceutical formulation. It can be prepared using diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, surfactants used as.

Solid preparations for oral administration may be prepared by mixing at least one excipient such as starch, calcium carbonate, sucrose, lactose or gelatin and the like with one or more nitroimidazole compounds according to the present invention. Can be. In addition to simple excipients, lubricants such as magnesium stearate or talc may also be used.

Liquid preparations for oral administration include suspensions, solutions, emulsions or syrups, and in addition to commonly used simple diluents such as water and liquid paraffin, various excipients can be used, such as wetting agents, sweeteners, fragrances or preservatives. have.

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

In addition, the human dose of the pharmaceutical composition for treating tuberculosis according to the present invention may vary depending on the age, weight, sex, dosage form, health condition and degree of disease of the patient, and when the weight is 70 kg based on an adult patient. In general, it is 0.1 to 1000 mg / day, preferably 1 to 500 mg / day, and may be dividedly administered once to several times a day at regular time intervals.

[Example]

Hereinafter, the present invention will be described in more detail with reference to the following examples. However, the following examples are only for illustrating the present invention, and the scope of the present invention is not limited thereto.

Example 1: 1- (1- (2,4-dichlorophenyl) -2- (2-methoxy-4-nitro-1H-imidazol-1-yl) ethyl-1H-1,2,3-tria Preparation of zol-4-yl) methanol

Step 1: Preparation of 2-bromo-4-nitroimidazole

4-nitroimidazole (25 g, 221 mmol) and sodium bicarbonate (37.1 g, 442 mmol) were diluted in water (600 mL), bromine (30 mL, 620 mmol) was added dropwise at room temperature, and the reaction mixture was The reaction was carried out at 40 ° C. for 12 hours. The solid of the reaction mixture was filtered, washed three times with toluene and dried under reduced pressure to give 2,5-dibromo-4-nitroimidazole in a yield of 39.8 g (67%).

Then, the prepared 2,5-dibromo-4-nitroimidazole (39.8 g, 149 mmol) was diluted in water (450 mL), and sodium iodide (223 g, 1486 mmol) was added thereto, and refluxed for 12 hours. Stirred. After the temperature was lowered to room temperature, the solid in the reaction mixture was filtered, washed with water, and dried under reduced pressure to obtain 2-bromo-5-iodo-4-nitroimidazole in a yield of 37.6 g (80%). The prepared 2-bromo-5-iodo-4-nitroimidazole (20 g, 63 mmol) was diluted in ethanol (190 mL), followed by triethylamine (26.5 mL, 190 mmol) and platinum oxide (Platinum oxide). 108 mg, 0.47 mmol) was added and reacted under a hydrogen pressure of 3 atm in a microwave reactor for 3 hours, filtered through silica gel and celite, and the filtrate was concentrated under reduced pressure. The obtained reaction mixture was diluted with ethyl acetate, washed with 10% aqueous hydrochloric acid solution, the water of the obtained organic layer was removed with anhydrous magnesium sulfate, and the filtrate was concentrated under reduced pressure. Purification with isopropyl alcohol and hexane afforded 2-bromo-4-nitroimidazole in a yield of 7.9 g (65%) (reference: WO 2005/077913).

Step 2: Preparation of 2- (2-bromo-4-nitro-1H-imidazol-1-yl) -1- (2,4-dichlorophenyl) ethanol

2-bromo-4-nitroimidazole (591 mg, 3.08 mmol), 2-chloro-1- (2,4-dichlorophenyl) ethanol (1.00 g, 4.43 mmol) and potassium carbonate (255 mg, 1.85 mmol) Was refluxed under methanol (10 mL) solvent for 12 h. The reaction was terminated by adding water, concentrated under reduced pressure, and the reaction mixture was extracted twice with ethyl acetate. The water of the obtained organic layer was removed with anhydrous magnesium sulfate, and the filtrate was concentrated under reduced pressure, and then purified using a silica gel column (ethyl acetate / hexane = 1/1) to purify 2- (2-bromo-4-nitro-1H-imidazole. -1-yl) -1- (2,4-dichlorophenyl) ethanol was obtained as a white solid in a yield of 43% (504 mg, 1.32 mmol).

Step 3: Preparation of 1- (2,4-dichlorophenyl) -2- (2-methoxy-4-nitro-1H-imidazol-1-yl) ethanol

2- (2-bromo-4-nitro-1H-imidazol-1-yl) -1- (2,4-dichlorophenyl) ethanol (0.50 g, 1.3 mmol) was added to methanol (5 mL) and then methanol Sodium (708 mg, 13 mmol) was added and reacted at room temperature for 6 hours. The reaction mixture was cooled to 0 ° C. and water was added to terminate the reaction. The reaction mixture was extracted twice with ethyl acetate. The water of the obtained organic layer was removed with anhydrous magnesium sulfate, and the filtrate was concentrated under reduced pressure, and then purified using a silica gel column (ethyl acetate / hexane = 1/2) to obtain 1- (2,4-dichlorophenyl) -2- (2- Methoxy-4-nitro-1H-imidazol-1-yl) ethanol was obtained as a white solid in 94% yield.

Step 4: Preparation of 1- (2-azido-2- (2,4-dichlorophenyl) ethyl) -2-methoxy-4-nitro-1H-imidazole

1- (2,4-dichlorophenyl) -2- (2-methoxy-4-nitro-1H-imidazol-1-yl) ethanol (258 mg, 0.776 mmol), diphenylphosphoryl azide (427 mg , 1.55 mmol), DBU (236 mg, 1.55 mmol) and a mixture of tetrahydrofuran (4 mL) were refluxed for 12 hours. Water was added to terminate the reaction, and the reaction mixture was extracted twice with ethyl acetate. The water of the obtained organic layer was removed with anhydrous magnesium sulfate, the filtrate was concentrated under reduced pressure, purified using a silica gel column (ethyl acetate / hexane = 1/2), and purified by 1- (2-azido-2- (2,4-dichloro). Phenyl) ethyl) -2-methoxy-4-nitro-1H-imidazole was obtained as a yellow solid in a yield of 48% (133 mg, 0.374 mmol).

Step 5: 1- (1- (2,4-Dichlorophenyl) -2- (2-methoxy-4-nitro-1H-imidazol-1-yl) ethyl-1H-1,2,3-triazole Preparation of -4-yl) methanol

1- (2-azido-2- (2,4-dichlorophenyl) ethyl) -2-methoxy-4-nitro-1H-imidazole (20 mg, 0.057 mmol), propargylic alcoholate; 4.8 mg, 0.086 mmol), diisopropylethylamine (37 mg, 0.29 mmol) and CuI (22 mg, 0.11 mmol) were diluted in acetonitrile (0.5 mL) and then 150 ° C using a microwave reactor (Anton Parr Synthos 3000). The reaction was carried out for 10 minutes at. The reaction mixture was concentrated under reduced pressure and purified using a silica gel column (ethyl acetate / hexane = 3/1) to obtain the compound of Example 1 as a yellow solid in a yield of 17% (4 mg, 0.0096 mmol).

¹ H NMR (CDCl ₃ ) δ 4.11 (s, 3H), 4.59 (dd, J = 14.7, 4.5 Hz, 1H), 4.75 (s, 2H), 4.98 (dd, J = 9.3, 4.5 Hz, 1H), 7.22-7.30 (m, 2 H), 7.37 (s, 1 H), 7.51 (d, J = 7.5 Hz, 2H);

¹³ C NMR (CDCl ₃ ) δ 56.5, 58.8, 60.9, 72.9, 83.2, 119.3, 124.8, 130.9, 131.1, 133.3, 135.7, 137.4, 152.7;

LC / MS [M + H ⁺ ] 413.10.

Example 2: Preparation of 1- (2- (2,4-dichlorophenyl) -2- (methylthio) ethyl) -2-methoxy-4-nitro-1H-imidazole

Step 1: Preparation of 1- (2,4-dichlorophenyl) -2- (2-methoxy-4-nitro-1H-imidazol-1-yl) ethyl methanesulfonate

1- (2,4-dichlorophenyl) -2- (2-methoxy-4-nitro-1H-imidazol-1-yl) ethanol (compound from step 3 of Example 1; 112 mg, 0.337 mmol) Mesyl chloride (0.06 mL, 0.775 mmol) was dissolved in dichloromethane (5 mL) and reacted at room temperature for 3 hours. Water was added to terminate the reaction, and the reaction mixture was extracted twice with dichloromethane. The water of the obtained organic layer was removed with anhydrous magnesium sulfate, and the filtrate was concentrated under reduced pressure, and then recrystallized with ethyl acetate / hexane to give 1- (2,4-dichlorophenyl) -2- (2-methoxy-4-nitro-1H- Imidazol-1-yl) ethyl methanesulfonate was obtained as a white solid in 72% (99 mg) yield.

Step 2: Preparation of 1- (2- (2,4-dichlorophenyl) -2- (methylthio) ethyl) -2-methoxy-4-nitro-1H-imidazole

1- (2,4-dichlorophenyl) -2- (2-methoxy-4-nitro-1H-imidazol-1-yl) ethyl methanesulfonate (105 mg, 0.256 mmol) in methanol (3 mL) After dilution, sodium thiomethoxide (61 mg, 0.87 mmol) was added and stirred at room temperature for 12 hours. Water was added to the reaction mixture to terminate the reaction, followed by extraction twice with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, the filtrate was concentrated under reduced pressure, and the silica gel column (ethyl acetate / hexane = 1/1) was used. Purification gave the compound of Example 2 as a white solid in a yield of 38% (35 mg, 0.097 mmol).

¹ H NMR (CDCl ₃ ) δ2.01 (s, 3H), 4.02 (s, 3H), 4.08 (dd, J = 14.3, 7.0 Hz, 1H), 4.22 (dd, J = 14.3, 6.9 Hz, 1H) , 4.64 (t, J = 7.0 Hz, 1H), 7.27-7.45 (m, 4H) HRMS (ESMS) calcd for C ₁₃ H ₁₃ Cl ₂ N ₃ O ₃ S [M ⁺ ] 361.0055, found 361.0045.

Example 3: Preparation of 1- (2- (2,4-dichlorophenyl) -2- (methylsulfonyl) ethyl) -2-methoxy-4-nitro-1H-imidazole

After diluting the compound of Example 2 (30 mg, 0.082 mmol) in methylene chloride (2 mL), 77% meta-chloroperoxybenzoic acid (mCPBA; 56 mg, 0.25 mmol) was added and stirred at room temperature for 2 hours. NaHCO ₃ saturated aqueous solution was added to the reaction mixture to terminate the reaction, and the mixture was extracted twice with methylene chloride. The water of the obtained organic layer was removed with anhydrous magnesium sulfate, and the filtrate was concentrated under reduced pressure, and then purified using a silica gel column (ethyl acetate / hexane = 1/1) to give the compound of Example 3 as a white solid, 70% (23 mg, 0.0576). mmol).

¹ H NMR (CDCl ₃ ) δ 2.76 (s, 3H), 4.06 (s, 3H), 4.41 (dd, J = 14.5, 9.1 Hz, 1H), 4.83 (dd, J = 14.5, 5.5 Hz, 1H), 5.26-5.31 (m, 1H), 7.32 (s, 1H), 7.42 (dd, J = 8.5, 2.1 Hz, 1H), 7.49 (d, J = 2.1 Hz, 1H), 7.70 (d, J = 8.5 Hz , 1H);

HRMS (ESMS) calcd for C ₁₃ H ₁₃ Cl ₂ N ₃ O ₅ S [M ⁺ ] 392.9953, found 39.9943.

Example 4: Preparation of N- (1- (2,4-dichlorophenyl) -2- (2-methoxy-4-nitro-1H-imidazol-1-yl) ethyl) acetamide

Step 1: Preparation of 1- (2,4-dichlorophenyl) -2- (2-methoxy-4-nitro-1H-imidazol-1-yl) ethanamine

1- (2-azido-2- (2,4-dichlorophenyl) ethyl) -2-methoxy-4-nitro-1H-imidazole (compound from step 4 of Example 1; 82 mg, 0.23 mmol) , Propanedithiol (0.11 mL, 1.14 mmol) and triethylamine (0.16 mL, 1.14 mmol) were dissolved in methanol (9 mL) and reacted at room temperature for 3 hours. Water was added to terminate the reaction, and the reaction mixture was extracted three times with ethyl acetate. The water of the obtained organic layer was removed with anhydrous magnesium sulfate, and the filtrate was concentrated under reduced pressure, and then purified using a silica gel column (ethyl acetate / hexane = 1 / 1-5 / 1) to give 1- (2,4-dichlorophenyl) -2. -(2-methoxy-4-nitro-1H-imidazol-1-yl) ethanamine was obtained as a yellow solid as 67% (51 mg, 0.15 mmol).

Step 2: N- (1- (2,4-dichlorophenyl) -2- (2-methoxy-4-nitro-1H-imidazol-1-yl) ethyl) acetamide

1- (2,4-dichlorophenyl) -2- (2-methoxy-4-nitro-1H-imidazol-1-yl) ethanamine (50 mg, 0.15 mmol) and triethylamine (31 mg, 0.30 mmol) was diluted in methylene chloride (0.5 mL), and then acetyl chloride (14 mg, 0.18 mmol) was added at 0 ° C. and stirred at room temperature for 2 hours. Water was added to the reaction mixture to terminate the reaction, followed by extraction with methylene chloride twice. The water of the obtained organic layer was removed with anhydrous magnesium sulfate, and the filtrate was concentrated under reduced pressure, using a silica gel column (ethyl acetate / hexane = 1/4). Purification gave the compound of Example 4 as a white solid in a yield of 89% (50 mg, 0.13 mmol).

Mp = 195.7 ° C .;

¹ H NMR (CDCl ₃ ) δ 2.03 (s, 3H), 4.04 (s, 3H), 4.25 (d, J = 1.2 Hz, 1H), 4.27 (d, J = 1.7 Hz, 1H), 5.56 (dd, J = 14.3, 6.9 Hz, 1H), 6.09 (d, J = 7.6 Hz, 1H), 7.11 (d, J = 8.4 Hz, 1H), 7.24-7.27 (m, 2H), 7.36 (s, 1H), 7.46 (d, J = 2.1 Hz, 1H);

¹³ C NMR (CDCl ₃ ) δ 23.3, 47.2, 51.4, 58.1, 117.0, 127.9, 129.3, 130.3, 133.1, 133.7, 135.4, 151.0, 169.9;

HRMS (ESMS) C ₁₄ H ₁₄ Cl ₂ N ₄ O ₄ calcd for [M ⁺ ] 372.0392, found 372.0395.

Example 5: Preparation of N- (1- (2,4-dichlorophenyl) -2- (2-methoxy-4-nitro-1H-imidazol-1-yl) ethyl) benzamide

1- (2,4-dichlorophenyl) -2- (2-methoxy-4-nitro-1H-imidazol-1-yl) ethanamine (compound from step 1 of example 4: 50 mg, 0.15 mmol) And triethylamine (31 mg, 0.30 mmol) were diluted in methylene chloride (0.5 mL), and then benzoyl chloride (25 mg, 0.18 mmol) was added at 0 ° C. and stirred at room temperature for 2 hours. Water was added to the reaction mixture to terminate the reaction, followed by extraction twice with methylene chloride. The organic layer was dried with anhydrous magnesium sulfate, the filtrate was concentrated under reduced pressure, and the silica gel column (ethyl acetate / hexane = 1/3) was used. Purification gave the compound of Example 5 as a white solid in a yield of 92% (60 mg, 0.14 mmol).

Mp = 225.6 ° C .;

¹ H NMR (CDCl ₃ ) δ 4.06 (s, 3H), 4.37 (d, J = 1.5 Hz, 1H), 4.39 (d, J = 2.4 Hz, 1H), 5.75 (dd, J = 13.9, 6.8 Hz, 1H), 6.91 (d, J = 7.5 Hz, 1H), 7.19 (d, J = 8.4 Hz, 1H), 7.25-7.29 (m, 2H), 7.38 (s, 1H), 7.44-7.56 (m, 4H ), 7.72-7.74 (m, 2 H);

¹³ C NMR (CDCl ₃ ) δ 47.2, 52.3, 58.2, 116.9, 126.9, 128.0, 128.9, 129.4, 130.4, 132.4, 133.0, 133.2, 133.6, 135.5, 153.9, 167.1, 179.4;

HRMS (ESMS) C ₁₉ H ₁₆ Cl ₂ N ₄ O ₄ calcd for [M ⁺ ] 434.0549 found 434.0562.

Example 6: Preparation of 1- (1- (2,4-dichlorophenyl) -2- (2-methoxy-4-nitro-1H-imidazol-1-yl) ethyl) -3-phenylurea

1- (2,4-dichlorophenyl) -2- (2-methoxy-4-nitro-1H-imidazol-1-yl) ethanamine (compound from step 1 of example 4: 50 mg, 0.15 mmol) After diluting in tetrahydrofuran (0.5 mL), phenylisocyanate (22 mg, 0.18 mmol) was added and stirred at room temperature for 1 hour. Water was added to the reaction mixture to complete the reaction, followed by extraction twice with ethyl acetate. The organic layer was dried with anhydrous magnesium sulfate, the filtrate was concentrated under reduced pressure, and the silica gel column (ethyl acetate / hexane = 1/2) was used. Purification gave the compound of Example 6 as a white solid in a yield of 56% (38 mg, 0.084 mmol).

Mp = 234.5 ° C .;

¹ H NMR (CDCl ₃ ) δ 3.93 (s, 3H), 4.15-4.26 (m, 2H), 5.57-5.62 (m, 1H), 6.48 (d, J = 8.1 Hz, 1H), 7.00-7.05 (m , 1H), 7.11 (d, J = 8.4 Hz, 1H), 7.24-7.34 (m, 5H), 7.45 (s, 1H), 7.53 (s, 1H)

HRMS (ESMS) C ₁₉ H ₁₇ Cl ₂ N ₅ O ₄ calcd for [M ⁺ ] 449.0658 found 449.0660.

Example 7: Preparation of 1-cyclohexyl-3- (1- (2,4-dichlorophenyl) -2- (2-methoxy-4-nitro-1H-imidazol-1-yl) ethyl) urea

1- (2,4-dichlorophenyl) -2- (2-methoxy-4-nitro-1H-imidazol-1-yl) ethanamine (compound from step 1 of example 4: 50 mg, 0.15 mmol) And cyclohexyl isocyanate (23 mg, 0.18 mmol) were diluted in tetrahydrofuran (0.5 mL), and then 1.0 M potassium t-butoxide tetrahydrofuran solution (0.23 mL, 0.23 mmol) was added at 0 ° C. and 30 ° C. at room temperature. Stirred to min. Water was added to the reaction mixture to complete the reaction, followed by extraction twice with ethyl acetate. The organic layer was dried with anhydrous magnesium sulfate, the filtrate was concentrated under reduced pressure, and the silica gel column (ethyl acetate / hexane = 1/2) was used. Purification gave the compound of Example 7 as a white solid in a yield of 68% (47 mg, 0.10 mmol).

Mp = 231.8 ° C .;

¹ H NMR (CDCl ₃ ) δ 1.05-1.39 (m, 6H), 1.54-1.81 (m, 5H), 4.01 (s, 3H), 4.08 (dd, J = 14.1, 9.0 Hz, 1H), 4.21 (dd , J = 14.1, 5.3 Hz, 1H), 5.60 (dd, J = 8.6, 5.3 Hz, 1H), 7.35 (d, J = 8.4 Hz, 1H), 7.40 (dd, J = 8.4, 1.9 Hz, 1H) , 7.52 (d, J = 1.8 Hz, 1 H), 7.72 (s, 1 H);

HRMS (ESMS) C ₁₉ H ₂₃ Cl ₂ N ₅ O ₄ calcd for [M ⁺ ] 455.1127 found 455.1119.

Example 8: Preparation of 1- (2,4-dichlorophenyl) -2- (2-methoxy-4-nitro-1H-imidazol-1-yl) ethyl phenylcarbamate

1- (2,4-dichlorophenyl) -2- (2-methoxy-4-nitro-1H-imidazol-1-yl) ethanol (compound from step 3 of Example 1; 50 mg, 0.15 mmol) and Dilute phenyl isocyanate (22 mg, 0.18 mmol) in tetrahydrofuran (0.5 mL), then add 1.0 M potassium t-butoxide tetrahydrofuran solution (0.23 mL, 0.23 mmol) at 0 ° C. and stir at room temperature for 30 minutes. It was. Water was added to the reaction mixture to terminate the reaction, followed by extraction twice with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, the filtrate was concentrated under reduced pressure, and the silica gel column (ethyl acetate / hexane = 1/1) was used. Purification gave the compound of Example 8 as a white solid in a yield of 85% (58 mg, 0.13 mmol).

Mp = 175.0 ° C .;

¹ H NMR (CDCl ₃ ) δ 3.86 (s, 3H), 4.27 (d, J = 4.5 Hz 2H). 6.36 (t, J = 4.5 Hz, 1H). 7.06-7.14 (m, 2H), 7.22 (dd, J = 8.4, 1.8 Hz, 1H), 7.29-7.53 (m, 6H);

¹³ C NMR (CD ₃ OD) δ 59.0, 71.9, 120.5, 125.0, 129.3, 130.0, 130.4, 130.7, 130.9, 134.5, 135.3, 136.7, 140.0, 144.1, 153.2, 154.2;

LC / MS [M + H ⁺ ] 451.13.

Example 9: Preparation of 2- (2,4-dichlorophenyl) -3- (2-methoxy-4-nitro-1H-imidazol-1-yl) propanenitrile

1- (2,4) diluted in methylene chloride (2.0 mL) in a solution of indium trichloride (22 mg, 0.099 mmol) and trimethylsilyl cyanide (0.30 mL, 2.0 mmol) diluted in methylene chloride (0.5 mL). -Dichlorophenyl) -2- (2-methoxy-4-nitro-1H-imidazol-1-yl) ethanol (compound of step 3 of Example 1; 150 mg, 0.45 mmol) was added and kept at room temperature for 1 hour. Stirred. Water was added to the reaction mixture to terminate the reaction, followed by extraction with methylene chloride twice. The water of the obtained organic layer was removed with anhydrous magnesium sulfate, and the filtrate was concentrated under reduced pressure, using a silica gel column (ethyl acetate / hexane = 1/4). Purification gave the compound of Example 9 as a pale yellow solid in 84% (129 mg, 0.38 mmol) yield.

¹ H NMR (300 MHz, CDCl ₃ ) δ 3.86 (dd, J = 14.0, 7.1 Hz, 1H), 4.01 (s, 3H), 4.06 (dd, J = 14.0, 3.0 Hz, 1H), 5.26 (dd, J = 7.1, 2.9 Hz, 1H), 7.27-7.30 (m, 1H), 7.38 (d, J = 8.4 Hz, 1H), 7.41 (d, J = 2.0 Hz, 1H), 7.54 (s, 1H);

¹³ C NMR (CDCl ₃ ) δ 50.6, 57.8, 69.2, 118.1, 127.7, 128.7, 129.1, 131.9, 134.7, 142.4, 151.0;

HRMS (ESMS) C ₁₃ H ₁₀ Cl ₂ N ₄ O ₃ calcd for [M ⁺ ] 340.0130 found 340.0121.

Example 10 Preparation of 2- (2-Bromo-4-nitro-1H-imidazol-1-yl) -1- (2,4-dichlorophenyl) ethanone

2-chloro-1- (2,4-dichlorophenyl) ethanone (7.63 g, 34.1 mmol), 2-bromo-4-nitro-1H-imidazole (compound from step 1 of Example 1; 4.57 g, 23.9 mmol) and potassium carbonate (1.99 g, 10.4 mmol) were diluted in dimethylformamide (30 mL) and stirred at 80-85 ° C. for 3.5 hours. Water was added to the reaction mixture to terminate the reaction, followed by extraction twice with ethyl acetate. The organic layer was dried with anhydrous magnesium sulfate, the filtrate was concentrated under reduced pressure, and then recrystallized with ethyl acetate / hexane (1/2). 10 compound as a pale yellow solid in 60% yield (7.81 g, 20.6 mmol).

¹ H NMR (300 MHz, CDCl ₃ ) δ 5.49 (s, 2H), 7.45 (ddd, J = 8.4, 2.0, 0.4 Hz, 1H), 7.68 (d, J = 1.9 H, 1H), 7.74 (d, J = 8.4 Hz, 1H), 7.86 (s, 1H)

HRMS (ESMS) C ₁₁ H ₆ BrCl ₂ N ₃ O ₃ calcd for [M ⁺ ] 376.8970 found 376.8968.

Example 11: Preparation of (E) -1- (2,4-dichlorostyryl) -2-methoxy-4-nitro-1H-imidazole

The compound of Example 15 (49 mg, 0.11 mmol) and potassium thioacetate (48 mg, 0.42 mmol) were diluted in dimethylformamide (0.5 mL) and stirred at room temperature for 2 hours. Water was added to the reaction mixture to complete the reaction, followed by extraction twice with ethyl acetate. The organic layer was dried with anhydrous magnesium sulfate, the filtrate was concentrated under reduced pressure, and the silica gel column (ethyl acetate / hexane = 1/2) was used. Purification gave the compound of Example 11 as a yellow solid in a yield of 49% (17 mg, 0.054 mmol).

¹ H NMR (CDCl ₃ ) δ 4.21 (s, 3H), 7.06 (d, J = 14.7 Hz, 1H), 7.21-7.29 (m, 2H), 7.45 (s, 1H), 7.47 (d, J = 6.4 Hz, 1H), 7.88 (s, 1H);

HRMS (ESMS) C ₁₂ H ₉ Cl ₂ N ₃ O ₃ calcd for [M ⁺ ] 313.0021 found 313.0013.

Example 12 Preparation of 1- (2,4-dichlorophenyl) -2- (2-methoxy-4-nitro-1H-imidazol-1-yl) ethyl cyclohexylcarbamate

1- (2,4-dichlorophenyl) -2- (2-methoxy-4-nitro-1H-imidazol-1-yl) ethanol (compound from step 3 of Example 1; 50 mg, 0.15 mmol) and After diluting cyclohexyl isocyanate (23 mg, 0.18 mmol) in tetrahydrofuran (0.5 mL), 1.0 M potassium t-butoxide tetrahydrofuran solution (0.23 mL, 0.23 mmol) was added at 0 ° C and 30 minutes at room temperature. Stirred. Water was added to the reaction mixture to complete the reaction, followed by extraction twice with ethyl acetate. The organic layer was dried with anhydrous magnesium sulfate, the filtrate was concentrated under reduced pressure, and the silica gel column (ethyl acetate / hexane = 1/2) was used. Purification gave the compound of Example 12 as a white solid in a yield of 86% (59 mg, 0.13 mmol).

Mp = 218.1-221.4 ° C. (decomposition);

¹ H NMR (CDCl ₃ ) δ 1.07-1.41 (m, 6H), 1.48-1.77 (m, 3H), 1.85-1.97 (m, 2H), 3.40-3.46 (m, 1H), 3.90 (s, 3H) , 4.18-4.26 (m, 2H), 4.88 (d, J = 7.4 Hz, 1H), 6.26-6.29 (m, 1H), 7.06 (d, J = 8.1 Hz, 1H), 7.22 (dd, J = 8.4 , 1.8 Hz, 1H), 7.41 (s, 1H), 7.43 (d, J = 2.0 Hz, 1H);

¹³ C NMR (CDCl ₃ ) δ 24.7, 25.3, 29.7,33.2, 47.7, 50.4, 57.9, 70.1, 117.4, 119.7, 127.7, 127.8, 132.7, 133.0, 135.2, 142.8, 145.8, 151.1, 153.3;

HRMS (ESMS) C ₁₉ H ₂₂ Cl ₂ N ₄ O ₅ calcd for [M ⁺ ] 456.0967 found 456.0973.

Example 13: Preparation of 1- (2,4-dichlorophenyl) -2- (2-methoxy-4-nitro-1H-imidazol-1-yl) ethylacetate

1- (2,4-dichlorophenyl) -2- (2-methoxy-4-nitro-1H-imidazol-1-yl) ethanol (compound of step 3 of Example 1; 50 mg, 0.15 mmol) Dilute to methylene chloride (0.5 mL) and add triethylamine (31 mg, 0.30 mmol), then add acetyl chloride (14 mg, 0.18 mmol) at 0 ° C. and stir at room temperature for 30 minutes. After adding water to the reaction mixture to terminate the reaction and extracting twice with methylene chloride, the obtained organic layer was removed with anhydrous magnesium sulfate, the filtrate was concentrated under reduced pressure, and then recrystallized with ethyl acetate / hexane (1/2). 13 compound was obtained as a white solid in a yield of 89% (51 mg, 0.13 mmol).

Mp = 135.9-142.6 ° C. (decomposition);

¹ H NMR (CDCl ₃ ) δ2.04 (s, 3H), 3.94 (s, 3H), 3.96-4.21 (m, 2H), 6.32-6.35 (m, 1H), 7.11 (d, J = 8.4 Hz, 1H), 7.23-7.24 (m, 1 H), 7.38-7.45 (m, 2 H);

¹³ C NMR (CDCl ₃ ) δ 20.7, 47.4, 58.0, 69.9, 117.0, 127.8, 129.7, 132.2, 132.8, 135.5, 142.9, 151.1, 168.9;

HRMS (ESMS) C ₁₄ H ₁₃ Cl ₂ N ₃ O ₅ calcd for [M ⁺ ] 373.0232 found 373.0237.

Example 14 Preparation of 1- (2,4-dichlorophenyl) -2- (2-methoxy-4-nitro-1H-imidazol-1-yl) ethyl benzoate

1- (2,4-dichlorophenyl) -2- (2-methoxy-4-nitro-1H-imidazol-1-yl) ethanol (compound of step 3 of Example 1; 50 mg, 0.15 mmol) Dilute to methylene chloride (0.5 mL) and add triethylamine (31 mg, 0.30 mmol), then add benzoyl chloride (25 mg, 0.18 mmol) at 0 ° C. and stir at room temperature for 30 minutes. After adding water to the reaction mixture to terminate the reaction and extracting twice with methylene chloride, the obtained organic layer was removed with anhydrous magnesium sulfate, the filtrate was concentrated under reduced pressure, and then recrystallized with ethyl acetate / hexane (1/2). Compound 14 was obtained as a white solid in a yield of 81% (53 mg, 0.12 mmol).

Mp = 164.2-169.0 ° C (decomposition)

¹ H NMR (CDCl ₃ ) δ 3.88 (s, 3H), 4.35-4.37 (m, 2H), 6.32-6.35 (m, 1H), 7.18-7.24 (m, 2H), 7.37 (s, 1H), 7.48-7.54 (m, 3 H), 7.62-7.65 (m, 1 H), 8.03-8.06 (m, 2H);

HRMS (ESMS) C ₁₉ H ₂₃ Cl ₂ N ₅ O ₄ calcd for [M ⁺ ] 435.0389 found 435.0392.

Example 15 Preparation of 1- (2- (2,4-dichlorophenyl) -2-iodoethyl) -2-methoxy-4-nitro-1H-imidazole

1- (2,4-dichlorophenyl) -2- (2-methoxy-4-nitro-1H-imidazol-1-yl) ethyl methanesulfonate (compound from step 1 of example 2: 500 mg, 1.22 mmol) and NaI (549 mg, 3.66 mmol) were diluted in acetone (7 mL) and stirred under reflux for 2 hours. Water was added to the reaction mixture to complete the reaction, followed by extraction twice with ethyl acetate. The organic layer was dried with anhydrous magnesium sulfate, the filtrate was concentrated under reduced pressure, and the silica gel column (ethyl acetate / hexane = 1/2) was used. Purification gave the compound of Example 15 as a white solid in a yield of 18% (92 mg, 0.21 mmol).

¹ H NMR (CDCl ₃ ) δ 4.09 (s, 3H), 4.37 (dd, J = 14.4, 8.4 Hz, 1H), 4.53 (dd, J = 14.6, 7.3 Hz, 1H), 5.73 (t, J = 8.0 Hz, 1H), 7.30 (dd, J = 8.4, 2.1 Hz, 1H), 7.35-7.36 (m, 2H), 7.52 (d, J = 8.4 Hz, 1H);

HRMS (ESMS) C ₁₂ H ₁₀ Cl ₂ IN ₃ O ₃ calcd for [M ⁺ ] 440.9144 found 440.9118.

Example 16: Preparation of 2- (2,4-dichlorophenyl) -3- (2-methoxy-4-nitro-1H-imidazol-1-yl) propanamide

Trimethylsilyl chloride (60 mg, 0.55 mmol) was added to the compound of Example 9 (94 mg, 0.28 mmol) at 0 ° C, and water (10 mg, 0.55 mmol) was added dropwise at 0 ° C. The reaction mixture was stirred at room temperature for 2 hours, diluted with water, and extracted twice with ethyl acetate. The water of the obtained organic layer was removed with anhydrous magnesium sulfate, and the filtrate was concentrated under reduced pressure, and then purified using a silica gel column (ethyl acetate / hexane = 1/2) to give the compound of Example 16 as a pale green solid, 91% (90 mg, 0.25 mmol) in the yield.

Mp = 165.8 ° C .;

¹ H NMR (CDCl ₃ ) δ 4.09 (s, 3H), 4.37 (dd, J = 14.4, 8.4 Hz, 1H), 4.53 (dd, J = 14.6, 7.3 Hz, 1H), 5.73 (t, J = 8.0 Hz, 1H), 7.30 (dd, J = 8.4, 2.1 Hz, 1H), 7.35-7.36 (m, 2H), 7.52 (d, J = 8.4 Hz, 1H);

¹³ C NMR (CDCl ₃ ) δ 49.7, 57.9, 68.8, 118.3, 127.8, 128.1, 129.3, 132.3, 134.9, 135.9, 151.0, 189.6.

Example 17 Preparation of 2- (2-Bromo-4-nitro-1H-imidazol-1-yl) -1-phenylethanone

2-bromoacetofinone (1.00 g, 5.02 mmol), 2-bromo-4-nitro-1H-imidazole (compound from step 1 of Example 1; 804 mg, 4.19 mmol), potassium carbonate (926 mg, 6.70 mmol) and tetrabutylammonium iodine (464 mg, 1.26 mmol) were diluted in ethanol (10 mL) and stirred at 70 ° C. for 2.5 hours. Water was added to the reaction mixture to complete the reaction, followed by extraction twice with ethyl acetate. The organic layer was dried with anhydrous magnesium sulfate, the filtrate was concentrated under reduced pressure, and the silica gel column (ethyl acetate / hexane = 1/2) was used. Purification gave the compound of Example 17 as a white solid in a yield of 43% (560 mg, 1.81 mmol).

¹ H NMR (CDCl ₃ ) δ 5.50 (s, 2H), 7.60 (t, J = 7.5 Hz, 2H), 7.71-7.74 (m, 1H), 8.00 (s, 1H), 8.00-8.03 (m, 2H );

¹³ C NMR (CDCl ₃ ) δ 54.03, 121.3, 122.8, 128.1, 129.4, 133.4, 135.1, 188.7;

HRMS (ESMS) C ₁₁ H ₈ BrN ₃ O ₃ calcd for [M ⁺ ] 308.9749 found 308.9752.

Example 18 Preparation of 2- (2-bromo-4-nitro-1H-imidazol-1-yl) -1- (2,4-dimethylphenyl) ethanone

Step 1: Preparation of 2-chloro-1- (2,4-dimethylphenyl) ethanone

m-xylene (7.0 mL, 56.7 mmol), 2-chloroacetic acid (1.43 g, 15.1 mmol), phosphorus pentoxide (3 g) and alumina (Al ₂ O ₃ ; 3 g) were converted into 1,2-dichloroethane (10 mL) Diluted in and stirred at 60-85 ° C. for 4 hours. The reaction mixture was cooled to room temperature, diluted with methylene chloride, and the solid was filtered. The obtained organic layer was washed with an aqueous sodium bicarbonate solution, water was removed with anhydrous magnesium sulfate, and the filtrate was concentrated under reduced pressure, and then purified using a silica gel column (ethyl acetate / hexane = 1/10) to give 2-chloro-1- (2, The compound of 4-dimethylphenyl) ethanone was obtained as a yellow solid in a yield of 30% (827 mg, 4.53 mmol) (Ref . Syn. Comm. 2009, 39, 2702-2722).

Step 2: Preparation of 2- (2-bromo-4-nitro-1H-imidazol-1-yl) -1- (2,4-dimethylphenyl) ethanone

2-chloro-1- (2,4-dimethylphenyl) ethanone (800 mg, 4.78 mmol), 2-bromo-4-nitro-1H-imidazole (compound from step 1 of Example 1; 764 mg, 3.98 mmol), potassium carbonate (880 mg, 6.34 mmol) and tetrabutylammonium iodine (441 mg, 1.19 mmol) were diluted in ethanol (15 mL) and stirred at 60 ° C. for 2.5 hours. Water was added to the reaction mixture to complete the reaction, followed by extraction twice with ethyl acetate. The organic layer was dried with anhydrous magnesium sulfate, the filtrate was concentrated under reduced pressure, and the silica gel column (ethyl acetate / hexane = 1/2) was used. Purification gave the compound of Example 18 as a white solid in a yield of 50% (674 mg, 1.81 mmol).

¹ H NMR (CDCl ₃ ) δ 2.42 (s, 3H), 2.55 (s, 3H), 5.40 (s, 2H), 7.20 (d, J = 6.9 Hz, 2H), 7.68 (d, J = 8.4 Hz, 1H), 7.85 (s, 1 H);

¹³ C NMR (CDCl ₃ ) δ 21.6, 22.0, 55.5, 131.3, 122.9, 126.9, 128.9, 129.9, 133.9, 141.1, 144.9, 190.1;

HRMS (ESMS) C ₁₃ H ₁₂ BrN ₃ O ₃ calcd for [M ⁺ ] 337.0062 found 337.0061.

Example 19 Preparation of 2- (2-Bromo-4-nitro-1H-imidazol-1-yl) -1- (2,4-dimethoxyphenyl) ethanone

Step 1: Preparation of 2-chloro-1- (2,4-dimethoxy) ethanone

1,3-dimethoxybenzene (4.0 mL, 30 mmol), 2-chloroacetic acid (1.42 g, 15.0 mmol), phosphorus pentoxide (3 g) and alumina (Al ₂ O ₃ ; 3 g) were converted into 1,2-dichloroethane After diluting in (10 mL), the mixture was stirred under reflux for 4 hours. The reaction mixture was cooled to room temperature, diluted with methylene chloride, and the solid was filtered. The obtained organic layer was washed with an aqueous sodium bicarbonate solution, water was removed with anhydrous magnesium sulfate, the filtrate was concentrated under reduced pressure, and then purified using a silica gel column (ethyl acetate / hexane = 1/10) to give 2-chloro-1- (2 A compound of, 4-dimethoxy) ethanone was obtained as a yellow solid in a yield of 25% (798 mg, 3.72 mmol) (Ref . Syn. Comm. 2009, 39, 2702-2722).

Step 2: Preparation of 2- (2-bromo-4-nitro-1H-imidazol-1-yl) -1- (2,4-dimethoxyphenyl) ethanone

2-chloro-1- (2,4-dimethoxy) ethanone (798 mg, 3.72 mmol), 2-bromo-4-nitro-1H-imidazole (compound from step 1 of Example 1; 595 mg, 3.10 mmol), potassium carbonate (686 mg, 5.00 mmol) and tetrabutylammonium iodine (344 mg, 0.93 mmol) were diluted in ethanol (15 mL) and stirred under reflux for 2.5 hours. Water was added to the reaction mixture to terminate the reaction, followed by extraction twice with ethyl acetate. The organic layer was dried with anhydrous magnesium sulfate, the filtrate was concentrated under reduced pressure, and then silica gel column (ethyl acetate / hexane = 1/5) was used. Purification gave the compound of Example 18 as a white solid in a yield of 10% (120 mg, 0.32 mmol).

¹ H NMR (CDCl ₃ ) δ 3.91 (s, 3H), 4.02 (s, 3H), 5.35 (s, 2H), 6.73 (d, J = 2.1 Hz, 1H), 6.64 (dd, J = 9.0, 2.1 Hz, 1H), 7.79 (s, 1H), 8.01 (d, J = 8.7 Hz, 1H)

¹³ C NMR (CDCl ₃ ) δ 21.6, 22.0, 55.5, 131.3, 122.9, 126.9, 128.9, 129.9, 133.9, 141.1, 144.9, 190.1.

Example 20 1- (2,4-dichlorophenyl) -2- (2-methoxy-4-nitro-1H-imidazol-1-yl) ethyl (1R, 2S, 5R) -2-isopropyl- Preparation of 5-methylcyclohexyl carbonate

1- (2,4-dichlorophenyl) -2- (2-methoxy-4-nitro-1H-imidazol-1-yl) ethanol (compound from step 3 of Example 1; 68 mg, 0.21 mmol) and Triethylamine (26 mg, 0.6 mmol) was diluted in methylene chloride (1 mL), and then (-)-menthylchloroformate (94 mg, 0.43 mmol) was added and stirred at room temperature for 12 hours. Water was added to the reaction mixture to terminate the reaction, followed by extraction twice with methylene chloride. The organic layer was dried with anhydrous magnesium sulfate, the filtrate was concentrated under reduced pressure, and then a silica gel column (ethyl acetate / hexane = 1/5) was used. Purification gave the compound of Example 20 as a white solid in a yield of 75% (79 mg, 0.15 mmol).

¹ H NMR (300 MHz, CDCl ₃ ) δ 0.70 (dd, J = 16.6, 7.0 Hz, 3H), 0.76-1.12 (m, 3H), 0.88 (t, J = 7.1 Hz, 6H), 1.33-1.49 ( m, 2H), 1.61-1.98 (m, 4H), 3.97 (d, J = 10.5 Hz, 3H), 4.17-4.29 (m, 2H), 4.37-4.52 (m, 1H), 6.21 (m, 1H) , 6.20 (d, J = 8.4 Hz, 1H), 7.27 (d, J = 8.4 Hz, 1H), 7.45 (s, 1H), 7.48 (s, 1H);

HRMS (ESMS) C ₂₃ H ₂₉ Cl ₂ N ₃ O ₆ calcd for [M ⁺ ] 513.1433 found 513.1437.

Example 21: 2- (2-Bromo-4-nitro-1H-imidazol-1-yl) -1- (2,4-dichlorophenyl) ethyl (7,7-dimethyl-2-oxobicyclic [2.2.1] heptan-1-yl) methanesulfonate

2- (2-bromo-4-nitro-1H-imidazol-1-yl) -1- (2,4-dichlorophenyl) ethanol (compound from step 2 of Example 1; 20 mg, 0.053 mmol) and Triethylamine (120 mg, 1.19 mmol) was diluted in methylene chloride (0.5 mL), and then (+)-camphorsulfonyl chloride (110 mg, 0.44 mmol) was added and stirred at room temperature for 12 hours. Water was added to the reaction mixture to terminate the reaction, followed by extraction twice with methylene chloride. The organic layer was dried with anhydrous magnesium sulfate, the filtrate was concentrated under reduced pressure, and then a silica gel column (ethyl acetate / hexane = 1/5) was used. Purification gave the compound of Example 21 as a white solid in a yield of 64% (20 mg, 0.034 mmol).

¹ H NMR (300 MHz, CDCl ₃ ) δ 0.85 (d, J = 4.9 Hz, 3H), 1.04 (s, 3H), 1.40-1.66 (m, 3H), 1.90-2.18 (m, 2H), 2.22- 2.44 (m, 2H), 2.98 (dd, J = 15.0, 2.5 Hz, 1H), 3.52 (dd, J = 15.0, 7.8 Hz, 1H), 4.44-4.62 (m, 2H), 6.32 (m, 1H) , 7.12-7.23 (m, 1 H) 7.27-7.34 (m, 1 H), 7.47 (d, J = 2.0 Hz, 1 H), 8.01 (s, 1H);

LC / MS [M + H ⁺ ] 595.92.

Example 22 Preparation of 2-bromo-1- (2,4-dichlorophenethyl) -4-nitro-1H-imidazole

2,4-dichlorophenethylbromide (800 mg, 3.15 mmol), 2-bromo-4-nitro-1H-imidazole (compound from step 1 of Example 1; 500 mg, 2.62 mmol) and potassium carbonate (220 mg, 1.59 mmol) was diluted in dimethylformamide (5 mL) and stirred at 80 ° C. for 4 hours. Water was added to the reaction mixture to terminate the reaction, followed by extraction twice with ethyl acetate. The organic layer was dried with anhydrous magnesium sulfate, the filtrate was concentrated under reduced pressure, and then silica gel column (ethyl acetate / hexane = 1/5) was used. Purification gave the compound of Example 22 as a white solid in a yield of 70% (667 mg, 1.83 mmol).

Mp = 155.7-159.3 ° C .;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.20 (t, J = 6.9 Hz, 2H), 4.30 (t, J = 6.9 Hz, 2H), 7.25 (d, J = 8.4 Hz, 1H), 7.37 (dd, J = 8.1, 2.1 Hz, 1H), 7.60 (d, J = 2.1 Hz, 1H), 8.57 (s, 1H);

¹³ C NMR (CDCl ₃ ) δ 33.9, 48.2, 120.3, 121.2, 127.9, 129.9, 127.9, 129.9, 131.7, 131.9, 134.6, 134.8, 147.3;

HRMS (ESMS) C ₁₁ H ₈ BrCl ₂ N ₃ O ₂ calcd for [M ⁺ ] 362.9177 found 362.9177;

4-nitro isomer λ _max = 297.9 nm.

Example 23 Preparation of 2-bromo-1- (2,4-dichlorophenethyl) -5-nitro-1H-imidazole

As a by-product of the compound synthesis method of Example 22, the compound of Example 23 was obtained as a white solid in a yield of 7% (70 mg, 0.19 mml).

Mp = 131.5-131.7 ° C .;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.21 (t, J = 7.1 Hz, 2H), 4.67 (t, J = 7.1 Hz, 2H), 7.01 (d, J = 8.2 Hz, 1H), 7.18 (dd, J = 8.2, 2.1 Hz, 1H), 7.41 (d, J = 2.1 Hz, 1H), 7.96 (s, 1H);

¹³ C NMR (CDCl ₃ ) δ 33.4, 47.8, 127.7, 129.7, 131.8, 132.4, 133.4, 134.3, 135.1; HRMS (ESMS) C ₁₁ H ₈ BrCl ₂ N ₃ O ₂ calcd for [M ⁺ ] 362.9177 found 362.9182;

5-nitro isomer λ _max = 313.3 nm

Example  24: 1- (2,4- Dichlorophenethyl )-2- Methoxy 4-nitro-lH- Imidazole  Produce

After diluting the compound of Example 22 (204 mg, 0.559 mmol) in metalol (5 mL), sodium methoxide (328 mg, 6.07 mmol) was added thereto, and the mixture was stirred at room temperature for 12 hours. Water was added to the reaction mixture to complete the reaction, followed by extraction twice with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, the filtrate was concentrated under reduced pressure, and the silica gel column (ethyl acetate / hexane = 1/3) was used. Purification gave the compound of Example 24 as a white solid in a yield of 47% (83 mg, 0.26 mmol).

Mp = 225.5 ° C .;

¹ H NMR (CDCl ₃ ) δ 3.12 (t, J = 7.0 Hz, 2H), 4.03 (s, 3H), 4.04-4.09 (m, 2H), 6.94 (d, J = 8.2 Hz, 1H), 7.16 ( dd, J = 8.2, 2.1 Hz, 1H), 7.41 (d, J = 2.1 Hz, 1H);

¹³ C NMR (CDCl ₃ ) δ 33.5, 44.4, 57.9, 116.5, 127.6, 129.7, 131.6, 132.7, 134.1, 134.8, 150.9;

HRMS (ESMS) C ₁₂ H ₁₁ Cl ₂ N ₃ O ₃ calcd for [M ⁺ ] 315.0177 found 315.0165.

≪ Test Example 1 >

The efficacy of Mycobacterium tuberculosis and the toxicity against Vero cells of the compounds obtained in Examples 1 to 24 were confirmed as follows, and the results are shown in Table 1 below.

1) Efficacy on Mycobacterium tuberculosis

1-1) Measurement of Minimum Inhibitory Concentration (MIC)

In order to evaluate the efficacy of the anti-tuberculosis bacillus of the compound of the present invention was tested using the Mycobacterium tuberculosis minimum inhibition concentration measurement method (MIC) as follows.

The test subjects obtained in Examples 1 to 24 were subjected to double serial dilution using Middle Brook 7H9 liquid medium (Difco, USA), and then 50 μL each in 96-well microplates. Busy. The frozen stock of Mycobacterium tuberculosis H37Rv strain of Mycobacterium tuberculosis standard strain, Mycobacterium tuberculosis H37Rv, was inoculated in Middlebrook 7H9 liquid medium and incubated for 5 days. When the absorbance at the wavelength of 600 nm was 0.5, 50 μl of the diluted solution was inoculated in the dilution plate so that the final cell number was 2-5 × 10 ⁵ colonies / ml. The test plates were incubated at 37 ° C. for 7 days, and then 10 μl of Alamar Blue Indicator (Abd Serotec) was added to each well. After 24 hours, the color change of each well was observed to determine the lowest concentration remaining as blue as the minimum inhibitory concentration, and the results are shown in Table 1 below.

1-2) Minimum Anaerobic Concentration (MAC) Measurement

Middlebrook 7H9 medium was expressed in vitro sealed with Mycobacterium tuberculosis H37Rv recombinant Mycobacterium tuberculosis H37Rv (Collins LA et al., Antimicrob Agents Chemother . 1998 Feb; 42 (2): 344-347). It was incubated for 14 days with stirring at a speed of 150 rpm. To 2 μl of the test substance obtained in Examples 1 to 24 diluted in DMSO 128 times, 100 μl of Mycobacterium tuberculosis in an anaerobic state was added in an anaerobic chamber, and then cultured in an anaerobic state for 7 days. Subsequently, the tuberculosis bacteria were transferred to an aerobic environment, and 10 μl of the tuberculosis bacteria was diluted 10-fold in fresh Middlebrook 7H9 medium, and the fluorescence intensity was measured by a microplate fluorimeter (BMG Labtech). Subsequently, after culturing in an aerobic environment for 2 days, the fluorescence was re-measured, and the degree of growth of the bacteria was measured to determine the concentration of the test substance that inhibited the growth by 50% or more compared to the control group treated with DMSO alone, and the results are shown in the following table. 1 is shown.

2) Toxicity Test on Vero Cells

In order to evaluate the toxicity of Vero cells of the compounds of the present invention, the following experiments were carried out.

Vero cell lines (obtained from the Korean Cell Line Bank, College of Medicine, Seoul National University) were cultured logarithmically in DMEM medium. After counting and diluting the cells to 5 x 10 ⁵ cells / ml, 90 μl were dispensed into each well. Incubated for 24 hours in a carbon dioxide incubator at 37 ℃. The test substance was diluted twice in DMEM medium, and 10 μl of each concentration was dispensed. After incubation for 3 days, the medium was removed, MTT solution was added and incubated for 4 hours. After centrifugation at room temperature, the supernatant was removed, the precipitate was diluted by adding DMSO, and the absorbance was measured at 570 nm. IC ₅₀ was calculated using GraphPad software using the measured values and the results are shown in Table 1 below.

compound Molecular Weight MIC ( m g / mL) MAC ( m g / mL) IC ₅₀ ( m g / mL) Example 2 362.2316 4 16 16.3 Example 9 341.1495 One 4 62.59 Example 11 314.1242 One 16 > 100 Example 13 374.1761 2 8 > 100 Example 14 436.2455 8 Unmeasured > 100 Example 15 442.0366 One 4 62.49 Example 16 359.1648 One 8 79.06 Example 19 370.1555 8 Unmeasured > 100 Example 23 365.0101 One 8

As shown in Table 1, the nitroimidazole compound of the present invention has the best MIC value of the nitroimidazole compound described in the previously known literature (Pilho Kim et al., JMC , 2009, 52, 1317) is 6.25 μM (= 2.26 μg / mL) and MAC values of 250-500 μM (90-181 μg / mL), while the compounds of the present invention exhibit excellent anti-TB activity with a maximum MIC value of 1.0 μg / mL and a maximum MAC value of 4 μg / mL. Have. Therefore, the compounds of the present invention, while showing excellent efficacy against Mycobacterium tuberculosis, it can be seen that safe for toxicity to Vero cells.

Claims (10)

Nitroimidazole compounds represented by the following formula (1) or a pharmaceutically acceptable salt thereof:
[Formula 1]

Where
R ¹ is 1 or 2 substituents selected from hydrogen, nitro, amino, hydroxy, C _1-6 alkyl, halo, or C _1-6 alkoxy;
When X is —CH ₂ —, Y is CH—R ² or C═O, or XY is —CH═CH— or —CH ₂ —CH ₂ —;
R ² is hydrogen, cyano, halo, aminocarbonyl, C _1-6 thioalkyl, C _1-6 alkylsulfonyl, hydroxy, triazolyl substituted with C _1-6 alkyl,

,

, or

ego;
R ³ is hydrogen, C _1-6 alkoxy or halo;
R ⁴ is C _1-6 alkyl, C _6-14 aryl, C _6-14 arylamino or C _3-7 cycloalkylamino;
R ⁵ is C _1-6 alkyl, C _6-14 aryl, C _6-14 arylamino, C _3-7 cycloalkylamino or

to be. The method of claim 1,
In Chemical Formula 1,
XY is

or

ego;
R ¹ is hydrogen, halo, C _{1 -6} alkyl, C _{1 -6} alkoxy;
R ² is hydrogen, halo, methylsulfonyl, cyano,

C _1-6 alkyl or aminocarbonyl;
R ³ is halo or C _{1 -6} alkoxy, nitro imidazole compound or a pharmaceutically acceptable salt thereof, characterized in that. The method of claim 1,
A nitroimidazole compound, or a pharmaceutically acceptable salt thereof, characterized in that it is selected from the group consisting of:
1) 1- (1- (2,4-dichlorophenyl) -2- (2-methoxy-4-nitro-1H-imidazol-1-yl) ethyl) -1H-1,2,3-triazole -4-yl) methanol;
2) 1- (2- (2,4-dichlorophenyl) -2- (methylthio) ethyl) -2-methoxy-4-nitro-1H-imidazole;
3) 1- (2- (2,4-dichlorophenyl) -2- (methylsulfonyl) ethyl) -2-methoxy-4-nitro-1H-imidazole;
4) N- (1- (2,4-dichlorophenyl) -2- (2-methoxy-4-nitro-1H-imidazol-1-yl) ethyl) acetamide;
5) N- (1- (2,4-dichlorophenyl) -2- (2-methoxy-4-nitro-1H-imidazol-1-yl) ethyl) benzamide;
6) 1- (1- (2,4-dichlorophenyl) -2- (2-methoxy-4-nitro-1H-imidazol-1-yl) ethyl) -3-phenylurea;
7) 1-cyclohexyl-3- (1- (2,4-dichlorophenyl) -2- (2-methoxy-4-nitro-1H-imidazol-1-yl) ethyl) urea;
8) 1- (2,4-dichlorophenyl) -2- (2-methoxy-4-nitro-1H-imidazol-1-yl) ethyl phenylcarbamate;
9) 2- (2,4-dichlorophenyl) -3- (2-methoxy-4-nitro-1H-imidazol-1-yl) propanenitrile;
10) 2- (2-bromo-4-nitro-1H-imidazol-1-yl) -1- (2,4-dichlorophenyl) ethanone;
11) (E) -1- (2,4-dichlorostyryl) -2-methoxy-4-nitro-1H-imidazole;
12) 1- (2,4-dichlorophenyl) -2- (2-methoxy-4-nitro-1H-imidazol-1-yl) ethyl cyclohexylcarbamate;
13) 1- (2,4-dichlorophenyl) -2- (2-methoxy-4-nitro-1H-imidazol-1-yl) ethylacetate;
14) 1- (2,4-dichlorophenyl) -2- (2-methoxy-4-nitro-1H-imidazol-1-yl) ethyl benzoate;
15) 1- (2- (2,4-dichlorophenyl) -2-iodoethyl) -2-methoxy-4-nitro-1H-imidazole;
16) 2- (2,4-dichlorophenyl) -3- (2-methoxy-4-nitro-1H-imidazol-1-yl) propanamide;
17) 2- (2-bromo-4-nitro-1H-imidazol-1-yl) -1-phenylethanone;
18) 2- (2-bromo-4-nitro-1H-imidazol-1-yl) -1- (2,4-dimethylphenyl) ethanone;
19) 2- (2-bromo-4-nitro-1H-imidazol-1-yl) -1- (2,4-dimethoxyphenyl) ethanone;
20) 1- (2,4-dichlorophenyl) -2- (2-methoxy-4-nitro-1H-imidazol-1-yl) ethyl (1R, 2S, 5R) -2-isopropyl-5- Methylcyclohexyl carbonate;
21) 2- (2-bromo-4-nitro-1H-imidazol-1-yl) -1- (2,4-dichlorophenyl) ethyl (7,7-dimethyl-2-oxobicyclic [2.2 .1] heptan-1-yl) methanesulfonate;
22) 2-bromo-1- (2,4-dichlorophenethyl) -4-nitro-1H-imidazole;
23) 2-bromo-1- (2,4-dichlorophenethyl) -5-nitro-1H-imidazole; And
24) 1- (2,4-dichlorophenethyl) -2-methoxy-4-nitro-1H-imidazole. Preparing a compound of formula 1a by reacting a compound of formula 3 and formula 4 in dimethylformamide in the presence of potassium carbonate
A process for preparing the nitroimidazole compound of claim 1, or a pharmaceutically acceptable salt thereof, comprising:
(3)

[Chemical Formula 4]

[Formula 1a]

Where
R ¹ is 1 or 2 substituents selected from hydrogen, nitro, amino, hydroxy, C _1-6 alkyl, halo, or C _1-6 alkoxy. 1) reacting a compound of Formula 2 and Formula 4 to produce a compound of Formula 5; Or preparing a compound of Formula 1a by reacting a compound of Formula 3 and Formula 4, followed by reaction with sodium borohydride (NaBH ₄ ) in a methanol solvent to prepare a compound of Formula 5;
2) preparing a compound of Chemical Formula 6 by reacting the compound of Chemical Formula 5 prepared with sodium methanol (NaOMe) in a methanol solvent; And
3) preparing a compound of formula 1b or 1c by reacting the prepared compound of formula 6 with a compound of formula 9 or 10
A process for preparing the nitroimidazole compound of claim 1, or a pharmaceutically acceptable salt thereof, comprising:
(2)

(3)

[Chemical Formula 4]

[Formula 1a]

[Chemical Formula 5]

[Formula 6]

[Chemical Formula 9]

[Formula 10]

[Chemical Formula 1b]

[Chemical Formula 1c]

Where
R ¹ is 1 or 2 substituents selected from hydrogen, nitro, amino, hydroxy, C _1-6 alkyl, halo, or C _1-6 alkoxy;
R ⁷ is C _1-6 alkyl, C _6-14 aryl or

ego;
R ⁸ is C _6-14 aryl or C _3-7 cycloalkyl. 1) reacting a compound of Formula 2 and Formula 4 to produce a compound of Formula 5; Or preparing a compound of Formula 1a by reacting a compound of Formula 3 and Formula 4, followed by reaction with sodium borohydride (NaBH ₄ ) in a methanol solvent to prepare a compound of Formula 5;
2) preparing a compound of Chemical Formula 6 by reacting the compound of Chemical Formula 5 prepared with sodium methanol (NaOMe) in a methanol solvent; And
3) preparing a compound of formula 7 by reacting the compound of formula 6 prepared in dimethylformamide (DMF) in the presence of diphenylphosphoryl azide (DPPN ₃ ); And
4) preparing a compound of formula 1d by reacting the compound of formula 7 with the compound of formula 11
A process for preparing the nitroimidazole compound of claim 1, or a pharmaceutically acceptable salt thereof, comprising:
(2)

(3)

[Chemical Formula 4]

[Formula 1a]

[Chemical Formula 5]

[Formula 6]

[Formula 7]

(11)

[Formula 1d]

Where
R ¹ is 1 or 2 substituents selected from hydrogen, nitro, amino, hydroxy, C _1-6 alkyl, halo, or C _1-6 alkoxy;
R ⁶ is CH ₂ OH. 1) reacting a compound of Formula 2 and Formula 4 to produce a compound of Formula 5; Or preparing a compound of Formula 1a by reacting a compound of Formula 3 and Formula 4, followed by reaction with sodium borohydride (NaBH ₄ ) in a methanol solvent to prepare a compound of Formula 5;
2) preparing a compound of Chemical Formula 6 by reacting the compound of Chemical Formula 5 prepared with sodium methanol (NaOMe) in a methanol solvent; And
3) preparing a compound of formula 7 by reacting the compound of formula 6 prepared in dimethylformamide (DMF) in the presence of diphenylphosphoryl azide (DPPN ₃ ); And
4) Triethylamine (Et ₃ N) was prepared in the presence of the compound of formula 7 in the presence of propanedithiol (SH (CH ₂ ) ₃ SH) Reacting in the preparation of the compound of Formula 8; And
5) preparing a compound of formula 1e or 1f by reacting the prepared compound of formula 8 with a compound of formula 9 or 10
A process for preparing the nitroimidazole compound of claim 1, or a pharmaceutically acceptable salt thereof, comprising:
(2)

(3)

[Chemical Formula 4]

[Formula 1a]

[Chemical Formula 5]

[Formula 6]

[Formula 7]

[Chemical Formula 8]

[Chemical Formula 9]

[Formula 10]

[Formula 1e]

[Formula 1f]

Where
R ¹ is 1 or 2 substituents selected from hydrogen, nitro, amino, hydroxy, C _1-6 alkyl, halo, or C _1-6 alkoxy;
R ⁷ is C _1-6 alkyl, C _6-14 aryl or

ego;
R ⁸ is a C _{6 -14} aryl or C _{3 -7-cycloalkyl.} 1) preparing a compound of formula 12 by reacting a compound of formula 6 in methylene chloride (CH ₂ Cl ₂ ) in the presence of mesyl chloride (MsCl) and triethylamine (Et ₃ N);
2) The compound of formula 12 prepared above was acetone in the presence of sodium iodide (NaI) Reacting in the preparation of the compound of Formula 13; And
3) preparing a compound of formula 1g by reacting the compound of formula 13 prepared in dimethylformamide in the presence of potassium thioacetate (KSAc);
A process for preparing the nitroimidazole compound of claim 1, or a pharmaceutically acceptable salt thereof, comprising:
[Formula 6]

[Formula 12]

[Chemical Formula 13]

[Formula 1g]

Where
R ¹ is 1 or 2 substituents selected from hydrogen, nitro, amino, hydroxy, C _1-6 alkyl, halo, or C _1-6 alkoxy. 1) preparing a compound of Formula 1h and Formula 1i by reacting a compound of Formula 14 and Formula 4 in dimethylformamide in the presence of potassium carbonate; And
2) preparing the compound of Chemical Formula 1j by reacting the compound of Chemical Formula 1h with sodium methanol (NaOMe) in a methanol solvent.
A process for preparing the nitroimidazole compound of claim 1, or a pharmaceutically acceptable salt thereof, comprising:
[Chemical Formula 14]

[Chemical Formula 4]

[Formula 1h]

Formula 1i]

[Formula 1j]

Where
R ¹ is 1 or 2 substituents selected from hydrogen, nitro, amino, hydroxy, C _1-6 alkyl, halo, or C _1-6 alkoxy. A pharmaceutical composition for treating tuberculosis, comprising the nitroimidazole compound of claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient.