KR20070038309A - Deformylase inhibitor, process for the preparation thereof, and composition comprising the same - Google Patents

Abstract

The present invention provides a novel deformillase inhibitor having excellent activity or a pharmaceutically acceptable salt thereof, a preparation method thereof, and a pharmaceutical composition comprising the same as an active ingredient. Deformillase inhibitors of the present invention are effective against bacteria resistant to existing antimicrobial agents and have a broad spectrum.

Deformillase inhibitors

Description

Deformylase inhibitor, a method for preparing the same, and a composition comprising the same

The present invention relates to a novel deformillase inhibitor, and more particularly, a novel deformillase inhibitor having excellent activity or a pharmaceutically acceptable salt thereof, a preparation method thereof, and a pharmaceutical comprising the same as an active ingredient. It relates to a composition.

Deformylase is a metallopeptidase found in prokaryotes such as bacteria. Protein synthesis in prokaryotes is initiated by N-formyl methionine (fMet). After initiation of protein synthesis, the formyl group is removed by deformillase. Since this activity is essential for protein maturation, deformillase is known to be essential for bacterial growth (Chang et al., J. Bacteriol. 171: 4071-4072 (1989); Meinnel T, Blanquet S, J. Bacteriol). . 176 (23): 7387-90 ( 1994); Mazel D et al, EMBO J 13 (4):... 914-23 (1994)). However, since the initiation of protein synthesis in eukaryotes does not depend on fMet, it can be usefully used as an antimicrobial agent having a broad spectrum when developing inhibitors of deformillase.

Prior arts that disclose deformillase inhibitors include WO 02/102791 (pyrrolidine bicyclic derivatives), WO 02/102790 (N-formyl hydroxylamine derivatives), WO 01/44179 (succinate derivatives). ), WO 01/44178 (urea derivatives), WO 01/85170 (peptide derivatives) and the like are known.

Despite the prior art, there is a need for the development of new deformillase inhibitors that are effective against bacteria that are resistant to existing antimicrobial agents and have a broad spectrum.

The present invention was developed based on the above prior art, and the present invention provides a novel deformillase inhibitor having a non-peptide bond.

It is therefore an object of the present invention to provide novel compounds useful as deformillase inhibitors.

It is also an object of the present invention to provide a method for preparing the deformillase inhibitor.

It is also an object of the present invention to provide a pharmaceutical composition comprising the deformillase inhibitor as an active ingredient.

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

Wherein R ¹ is linear or branched C ₁ -C ₆ alkyl; Or C ₁ -C ₂ alkyl substituted with C ₃ -C ₆ cycloalkyl or heteroaryl,

R ² is hydrogen; Linear or branched C ₁ -C ₆ alkyl; Or benzyl,

R ³ is straight or branched C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, benzyl, phenyl, pyridinyl or oxidized pyridinyl, wherein phenyl, pyridinyl or oxidized pyridinyl is C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, hydroxy, halogen, cyano, nitro, acetyl, phenyl, trifluoromethyl, trifluoromethoxy, methanesulfonyl, piperidinyl, morpholinyl, pyrrolidinyl, And it may be substituted with 1 to 3 substituents selected from the group consisting of benzoyl.

When pyridine or oxidized pyridinyl is substituted for R ³ , a preferred structure is shown in Formula 2 above. R ⁴ , R ⁵ , R ⁶ , and R ⁷ are hydrogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, hydroxy, halogen, cyano, nitro, acetyl, phenyl, trifluoromethyl, trifluoro And may be selected from the group consisting of methoxy, methanesulfonyl, piperidinyl, morpholinyl, pyrrolidinyl, and benzoyl.

In the compounds of the present invention, preferred compounds are listed as follows:

1) N-{(2R, 4S) -2-butyl-4- [3- (5-fluoro-pyridin-2-yl) -ureido] -5-methyl-3-oxo-hexyl} -N- Hydroxy-formamide,

2) N-{(2R, 4S) -2-butyl-4- [3- (5-fluoro-1-oxy-pyridin-2-yl) -ureido] -5-methyl-3-oxo-hexyl } -N-hydroxy-formamide,

3) N-{(2R, 4S) -2-butyl-4- [3- (2-methoxy-5-methyl-phenyl) -ureido] -5-methyl-3-oxo-hexyl} -N- Hydroxy-formamide,

4) N-[(2R, 4S) -2-butyl-5-methyl-3-oxo-4- (3-phenyl-ureido) -hexyl] -N-hydroxy-formamide,

5) N-{(2R, 4S) -2-butyl-4- [3- (2-methoxy-phenyl) -ureido] -5-methyl-3-oxo-hexyl} -N-hydroxy-form amides,

6) N-{(2R, 4S) -2-butyl-4- [3- (2-fluoro-phenyl) -ureido] -5-methyl-3-oxo-hexyl} -N-hydroxy-form amides,

7) N-{(2R, 4S) -2-butyl-4- (3-cyclopentyl-ureido) -5-methyl-3-oxo-hexyl] -N-hydroxy-formamide,

8) N-{(2R, 4S) -2-butyl-4- [3- (3-methoxy-phenyl) -ureido] -5-methyl-3-oxo-hexyl} -N-hydroxy-form amides,

9) N-{(2R, 4S) -2-butyl-4- [3- (4-methoxy-phenyl) -ureido] -5-methyl-3-oxo-hexyl} -N-hydroxy-form amides,

10) N-[(2R, 4S) -2-butyl-4- (3-butyl-ureido) -5-methyl-3-oxo-hexyl] -N-hydroxy-formamide,

11) N-[(2R, 4S) -2-butyl-4- (3-t-butyl-ureido) -5-methyl-3-oxo-hexyl] -N-hydroxy-formamide,

12) N-{(2R, 4S) -2-butyl-4- [3- (2,5-dichloro-phenyl) -ureido] -5-methyl-3-oxo-hexyl} -N-hydroxy- Formamide,

13) N-{(2R, 4S) -2-butyl-5-methyl-4- [3- (5-methyl-pyridin-2-yl) -ureido] -3-oxo-hexyl} -N-hydrate Roxy-formamide,

14) N-{(2R, 4S) -2-butyl-5-methyl-4- [3- (5-methyl-1-oxy-pyridin-2-yl) -ureido] -3-oxo-hexyl} -N-hydroxy-formamide,

15) N-[(2R, 4S) -2-butyl-5-methyl-3-oxo-4- (3-pyridin-2-yl-ureido) -hexyl] -N-hydroxy-formamide,

16) N-{(2R, 4S) -2-butyl-5-methyl-3-oxo-4- [3- (1-oxy-pyridin-2-yl) -ureido} -hexyl} -N-hydric Roxy-formamide,

17) N-{(2R, 4S) -2-butyl-4- [3- (4,6-dimethyl-pyridin-2-yl) -ureido] -5-methyl-3-oxo-hexyl} -N Hydroxy-formamide,

18) N-{(2R, 4S) -2-butyl-4- [3- (4,6-dimethyl-1-oxy-pyridin-2-yl) -ureido] -5-methyl-3-oxo- Hexyl} -N-hydroxy-formamide,

19) N-[(2R, 4S) -2-butyl-4- (3-isopropyl-ureido) -5-methyl-3-oxo-hexyl] -N-hydroxy-formamide,

20) N-[(2R, 4S) -2-butyl-4- (3-isobutyl-ureido) -5-methyl-3-oxo-hexyl] -N-hydroxy-formamide,

21) N-[(2R, 4S) -4- (3-benzyl-ureido) -2-butyl-5-methyl-3-oxo-hexyl] -N-hydroxy-formamide.

The compounds of the present invention may be in the form of pharmaceutically acceptable salts, hydrates, or solvates. Examples of pharmaceutically acceptable salts that may be applied to the compounds of the present invention include hydrochloride, bromate, sulfate, methylsulfonate, p-toluenesulfonate, phosphate, acetate, citrate, succinate, lactate, tartarate, fumarate , Maleate, sodium salt, potassium salt, magnesium salt, calcium salt and the like.

In addition, by containing the member carbon of the present invention, it may be in the form of racemic or optical isomer. Accordingly, the compounds of the present invention include both such racemates and optical isomers.

The present invention includes a method for preparing the compound of Formula 1 or a pharmaceutically acceptable salt thereof. According to the present invention, the compound of Formula 1 is prepared by removing the hydroxy protecting group of the compound of Formula 3 synthesized from the following Formula 4.

In Formula 3, R ¹ , R ² and R ³ are as defined above, Y is a hydroxy protecting group.

The compound of formula 4 is reacted with a mixture of formic acid and acetic anhydride to synthesize the compound of formula 3. In this step the reaction temperature is adjusted from 0 to 25 ^o C. The compound of Formula 4 may be prepared by reacting a compound of Formula 6 or a salt thereof with -HNR ³ to prepare a compound of Formula 5, and then reacting the compound of Formula 5 with YONH ₂ .

The reaction of the compound of Formula 5 and YONH ₂ may be performed by reflux stirring in an organic solvent such as dichloromethane, acetonitrile, tetrahydrofuran, dimethyl sulfoxide, toluene, or the like without using a solvent.

In Formula 6, R ¹ And R ² is as defined above and X is chloro or imidazole. The reaction of the compound of Formula 6 with HNR ³ may be carried out by reflux stirring in an organic solvent such as dichloromethane, acetonitrile, tetrahydrofuran, dimethyl sulfoxide, toluene, and the like.

A compound of formula 6 is prepared by reacting a salt of a compound of formula 7 (e.g., hydrochloride or trifluoroacetic acid salt) with triphosgen or 1,1'-carbonyldiimidazole. . The reaction in this step can be preferably carried out in the presence of a base such as triethylamine, diisopropylethylamine, N-methylmorpholine, and the available solvents are dichloromethane, acetonitrile, tetrahydrofuran, dimethylsulfoxide, Organic solvents, such as toluene, are included.

Wherein R ¹ and R ² are as defined above and Z is an amino protecting group. Preferred example of the amino protecting group Z is t-butoxycarbonyl.

The benzyl group of the compound of Formula 8 is removed by hydrogenation under palladium / carbon conditions, and reflux stirred under piperidine / formaldehyde and lower alcohol solvent to prepare an exomethylene compound. A salt of formula 7 is prepared by removing the amino protecting group of the exomethylene compound under hydrochloric acid or trifluoroacetic acid conditions.

Wherein R ² is as defined above and Z is an amino protecting group.

Linear or branched C ₁ -C ₆ alkyl substituted with a compound of Formula 9 and sulfate or halogen; Alternatively, the compound of formula 8 may be prepared by reacting a C ₁ -C ₂ alkyl compound substituted with C ₃ -C ₆ cycloalkyl or heteroaryl in the presence of a base such as potassium carbonate.

Wherein R ² is as defined above and Z is an amino protecting group.

After reacting the compound of Formula 10 with Meldrum's acid, dicyclohexylcarbodiimide, and dimethylaminopyridine, the reaction intermediate is stirred under reflux in a solvent of benzyl alcohol and toluene or benzene. Could be manufactured.

The present invention includes an antimicrobial composition comprising a therapeutically effective amount of a compound of Formula 1 or a salt thereof and a pharmaceutically acceptable carrier. The compositions of the present invention can be used to treat bacterial infections by administering to infected patients or animals, or by use in an infected sheath. It can also be used as an ingredient in antibacterial purification or disinfectant.

The compositions of the present invention can be administered orally or parenterally. The composition for oral administration may be in various forms such as tablets, capsules, powders, granules, solutions, suspensions, gels, and the like, and may include conventional additives such as excipients, disintegrants, lubricants, and the like. The additives include conventional excipients such as syrup, gum arabic, gelatin, sorbitol, lactose, sugar, corn-starch, calcium phosphate, glycine, magnesium stearate, talc, polyethylene glycol, silica, potato starch, or sodium lauryl sulfate. General flavors or colorants. In addition, compositions for parenteral administration (eg, injections) of the compositions according to the invention may be isotonic solutions, may also be sterilized and / or may contain conventional additives such as preservatives, stabilizers and the like.

The pharmaceutical composition of the present invention may be administered to an average adult patient (about 70 kg) at a dose of about 7 mg / day to 35 g / day for the purpose of antibacterial treatment, but the dose may be changed depending on the type and condition of the disease. have. Thus, for a typical adult patient, each unit dosage form may comprise from about 0.7 mg to 2.8 g of a compound according to the invention with a suitable pharmaceutically acceptable carrier.

Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited thereto.

Example

A. Chemical Example

Example 1 N-{(2R, 4S) -2-butyl-4- [3- (5-fluoro-pyridin-2-yl) -ureido] -5-methyl-3-oxo-hexyl}- N-hydroxy-formamide

The title compound was prepared according to Scheme 1 below.

Step 1) (S) -4-t-butoxycarbonylamino-5-methyl-3-oxo-hexanoic acid benzyl ester

To a solution of N-Boc-L-valine (0.5 g, 2.3 mmol) in dichloromethane (7 ml) meldmic acid (0.33 g, 2.3 mmol), dicyclohexylcarbodiimide (0.52 g, 2.53 mmol), and 4 -Dimethylaminopyridine (0.31 g, 2.53 mmol) was added and stirred at room temperature for 4 hours. The precipitate formed after the reaction was filtered off, and the reaction solution was washed with 1N HCl aqueous solution. The separated organic layer was dehydrated with anhydrous sulfate and concentrated in vacuo. The concentrate was dissolved in toluene, benzyl alcohol was added and stirred at 80 ^° C. for 4 hours. The reaction solution was concentrated in vacuo and purified by silica gel column chromatography to yield 0.39 g (48.1%) of the title compound.

¹ H-NMR (CDCl ₃ ) δ 0.77 (d, 3H, J = 6.78 Hz), 0.97 (d, 3H, J = 6.78 Hz), 1.44 (s, 9H), 2.17 (m, 1H), 3.59 (s , 2H), 4.32 (m, 1H), 5.17 (s, 2H), 7.36 (s, 5H).

Step 2) (S) -4-t-butoxycarbonylamino-2-butyl-5-methyl-3-oxo-hexanoic acid benzyl ester

To acetone (3.7 ml) solution of (S) -4-t-butoxycarbonylamino-5-methyl-3-oxo-hexanoic acid benzyl ester (0.39 g, 1.1 mmol), potassium carbonate (0.25 g, 1.8 mmol), sodium iodide (0.017 g, 0.1 mol), and broobutane (0.18 ml, 1.67 mmol) were added and stirred at reflux for 18 hours. The precipitate was filtered off and the filtrate was concentrated. The concentrate was purified by silica gel column chromatography to yield 0.25 g (56%) of the title compound.

¹ H-NMR (CDCl ₃ ) δ 0.75 (m, 3H), 0.90 (m, 10H), 1.43 (s, 9H), 1.54 (m, 1H), 1.87 (m, 2H), 3.72 (m, 1H) , 4.37 (m, 1 H), 5.13 (m, 2 H), 7.36 (m, 5 H).

Step 3) ((S) -1-Isopropyl-3-methylene-2-oxo-heptyl) -carbamic acid t-butyl ester

To a solution of (S) -4-t-butoxycarbonylamino-2-butyl-5-methyl-3-oxo-hexanoic acid benzyl ester (7.6 g, 18.8 mmol) in ethanol (94 ml), palladium / carbon ( 1.0 g, 0.94 mmol, 10 wt%) was added, followed by stirring at room temperature in a hydrogen environment for 4 hours. The catalyst was filtered off and formaldehyde (7.0 ml, 94.2 mmol, 37 wt%) and piperidine (2.2 ml, 22.6 mmol) were added. The reaction solution was stirred for 2 hours at 80 ^° C. and cooled to room temperature. The reaction solution was concentrated under reduced pressure, and the concentrated solution was dissolved in ethyl ester, and then washed with 1N aqueous hydrochloric acid solution and saturated brine. The separated organic layer was dehydrated with anhydrous sulfate and concentrated in vacuo. The concentrate was purified by silica gel column chromatography to give 3.3 g (61%) of the title compound.

¹ H-NMR (CDCl ₃ ) δ 0.74-0.99 (m, 13H), 1.44 (s, 9H), 2.17 (m, 3H), 4.28 (m, 1H), 5.26 (s, 1H), 6.08 (s, 1H).

Step 4) (S) -3-Amino-2-methyl-5-methylene-nonan-4-one hydrochloride

((S) -1-Isopropyl-3-methylene-2-oxo-heptyl) -carbamic acid t-butyl ester (0.67 g, 2.39 mmol) in hydrochloric acid solution (2.98 ml, 11.93 mmol, 4M 1,4- Dioxane solution) was added and stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure and used in the next reaction without purification.

Step 5) imidazole-1-carboxylic acid ((S) -1-isopropyl-3-methylene-2-oxo-heptyl) -amide

To a dichloromethane solution (13 ml) of (S) -3-amino-2-methyl-5-methylene-nonan-4-one hydrochloride (step 4) 1,1-carbonyldiimidazole (0.64 g, 3.93 mmol) and triethylamine (0.4 ml, 2.88 mmol) were added and stirred at room temperature for 4 hours. The reaction solution was washed with water, and the separated organic layer was dehydrated with anhydrous sulfate, and then concentrated in vacuo. The concentrate was purified by silica gel column chromatography to yield 0.26 g (35.7%) of the title compound.

¹ H-NMR (CDCl ₃ ) δ 0.81-0.93 (m, 13H), 1.31 (m, 9H), 2.04 (m, 3H), 4.83 (m, 1H), 5.97 (s, 1H), 6.15 (s, 1H), 7.134 (s, 1H). 7.37 (s, 1 H), 8.15 (s, 1 H).

Step 6) 1-((S) -1-Isopropyl-3-methylene-2-oxo-heptyl) -3- (5-fluoro-pyridin-2-yl) -urea

2-amino-5 in a solution of toluene (4.51 ml) of imidazole-1-carboxylic acid ((S) -1-isopropyl-3-methylene-2-oxo-heptyl) -amide (0.25 g, 0.9 mmol) -Fluoropyridine (0.1 g, 0.9 mmol) was added and stirred at 80 ^° C for 5 h. The reaction solution was concentrated in vacuo and purified by silica gel column chromatography to yield 0.1 g (35%) of the title compound.

¹ H-NMR (CDCl ₃ ) δ 0.88-1.05 (m, 9H), 1.37 (m, 4H), 2.20 (m, 3H), 5.85 (m, 1H), 6.20 (s, 1H), 6.15 (s, 1H), 7.01 (s, 1H), 7.43 (s, 1H), 8.16 (s, 1H).

Step 7) 1-[(1S, 3R) -3- (Benzyloxyamino-methyl) -1-isopropyl-2-oxo-heptyl] -3- (5-fluoro-pyridin-2-yl) -urea

O-benzyl in 1-((S) -1-Isopropyl-3-methylene-2-oxo-heptyl) -3- (5-fluoro-pyridin-2-yl) -urea (0.1 g, 0.31 mmol) Hydroxyamine (0.057 g, 0.44 mmol) was added and stirred at 40 ^° C. for 24 hours. The reaction solution was purified by silica gel column chromatography, and each optical isomer was separated by silica gel thin layer chromatography ((1S, 3R) -optical isomers having a slightly larger polarity) to give 0.08 g (58%) of the title compound. Obtained.

¹ H-NMR (CDCl ₃ ) δ 0.82-1.11 (m, 9H), 1.21-1.66 (m, 6H), 2.36 (m, 2H), 2.96-3.25 (m, 2H), 4.66 (s, 2H), 4.79 (m, 1 H), 6.99 (s, 1 H), 7.33 (m, 6 H), 8.12 (s, 1 H).

Step 8) N-benzyloxy-N-{(2R, 4S) -2-butyl-5-methyl-4- [3- (5-fluoro-pyridin-2-yl) -ureido] -3-oxo -Hexyl} -formamide

1-[(1S, 3R) -3- (benzyloxyamino-methyl) -1-isopropyl-2-oxo-heptyl] -3- (5-fluoro-pyridin-2-yl) -urea (0.08 g , 0.18 mmol) was added a mixture of acetic anhydride (0.043 ml, 0.45 mmol) and formic acid (0.051 ml, 1.35 mmol, 96%), which were stirred at room temperature for 30 minutes, and stirred at room temperature for 1 hour. did. The reaction solution was washed with a saturated aqueous solution of sodium carbonate, and the separated organic layer was dehydrated with anhydrous sulfate, and then concentrated in vacuo. The concentrate was purified by silica gel column chromatography to yield 0.06 g (70%) of the title compound.

¹ H-NMR (CDCl ₃ ) δ 0.83-1.05 (m, 9H), 1.25-1.68 (m, 6H), 2.28 (m, 2H), 3.17-3.81 (m, 2H), 4.77 (m, 3H), 7.05 (s, 1 H), 7.37 (m, 6 H), 8.10 (s, 1 H), 10.00 (m, 1 H).

Step 9) N-{(2R, 4S) -2-Butyl-5-methyl-4- [3- (5-fluoro-pyridin-2-yl) -ureido] -3-oxo-hexyl} -N Hydroxy-formamide

N-benzyloxy-N-{(2R, 4S) -2-butyl-5-methyl-4- [3- (5-fluoro-pyridin-2-yl) -ureido] -3-oxo-hexyl} Palladium / carbon (0.002 g, 0.021 mmol, 10wt%) is added to a methanol (0.42 ml) solution of formamide (0.02 g, 0.042 mmol) and stirred at room temperature in a hydrogen environment for 3 hours. The catalyst was filtered off and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography to yield 0.007 g (43%) of the title compound.

¹ H-NMR (CDCl ₃ ) δ 0.78-1.08 (m, 9H), 1.25-1.37 (m, 4H), 1.61 (m, 2H), 2.43 (m, 1H), 3.21-3.95 (m, 3H), 4.71 (m, 1 H), 6.98 (s, 1 H), 7.40 (s, 1 H), 7.89 (s, 1 H), 9.6 (s, 1 H).

Example  2: N-{(2R, 4S) -2-butyl-4- [3- (5- Fluoro -One- Oxy -Pyridin-2-yl)- Eureido ] -5- methyl -3-oxo- Hexyl } -N-hydroxy- Formamide

The title compound was prepared according to Scheme 2 below.

Step 1) N-benzyloxy-N-{(2R, 4S) -2-butyl-4- [3- (5-fluoro-1-oxy-pyridin-2-yl) -ureido] -5-methyl -3-oxo-hexyl} -formamide

N-benzyloxy-N-{(2R, 4S) -2-butyl-5-methyl-4- [3- (5-fluoro-pyridin-2-yl) -ureido] -3-oxo-hexyl} To a solution of dichloromethane / methanol (1.69 ml / 0.17 ml) in formamide (0.04 g, 0.085 mmol, step 8 of Example 1) was added magnesium monoperoxyphthalate hexahydrate (0.092 g, 0.186 mmol, 80%). It was added and stirred at room temperature for 3 hours. The reaction solution was diluted with dichloromethane and washed with saturated aqueous sodium carbonate. The reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography to obtain 0.025 g (61%) of the title compound.

¹ H-NMR (CDCl ₃ ) δ 0.80-1.05 (m, 9H), 1.25-1.66 (m, 6H), 2.18 (m, 1H), 3.47 (m, 2H), 4.05-4.77 (m, 4H), 7.22 (s, 1 H), 7.85-8.10 (m, 2 H), 8.44 (m, 1 H).

Step 2) N-{(2R, 4S) -2-Butyl-4- [3- (5-fluoro-1-oxy-pyridin-2-yl) -ureido] -5-methyl-3-oxo- Hexyl} -N-hydroxy-formamide

N-benzyloxy-N-{(2R, 4S) -2-butyl-4- [3- (5-fluoro-1-oxy-pyridin-2-yl) -ureido] -5-methyl-3- Palladium / carbon (0.003 g, 0.026 mmol, 10 wt%) is added to a methanol (0.51 ml) solution of oxo-hexyl} -formamide (0.025 g, 0.051 mmol) and stirred at room temperature in a hydrogen environment for 3 hours. The catalyst was filtered off and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography to yield 0.01 g (50%) of the title compound.

¹ H-NMR (CDCl ₃ ) δ 0.76-1.05 (m, 9H), 1.25-1.65 (m, 6H), 2.17 (s, 1H), 3.49 (m, 2H), 4.00 (m, 1H), 4.80 ( s, 1H), 7.26 (s, 1H), 7.90-8.11 (m, 2H), 8.48 (m, 1H).

 The compound of the following example was synthesized using an appropriately substituted amine instead of 2-amino-5-fluoropyridine in step 6 of Example 1. In the following examples, when the oxidized pyridine was substituted, it was prepared using the same synthesis method as in Step 1 and Step 2 of Example 2.

Example 3: N-{(2R, 4S) -2-Butyl-4- [3- (2-methoxy-5-methyl-phenyl) -ureido] -5-methyl-3-oxo-hexyl}- N-hydroxy-formamide

¹ H-NMR (CDCl ₃ ) δ 0.64-1.07 (m, 9H), 1.30-1.65 (m, 6H), 2.20 (m, 4H), 3.25-4.76 (m, 6H), 5.33 (m, 1H), 6.75-6.99 (m, 3 H), 8.0 (m, 1 H), 8.48 (s, 1 H).

Example  4: N-[(2R, 4S) -2-Butyl-5-methyl-3-oxo-4- (3-phenyl-ureido) -hexyl] -N-hydroxy-formamide

¹ H-NMR (CDCl ₃ ) δ 0.59-1.03 (m, 9H), 1.30-1.68 (m, 6H), 2.21 (m, 1H), 3.10-4.43 (m, 3H), 4.75 (s, 1H), 6.10 (bs, 1 H), 6.98-7.27 (m, 5 H), 8.01 (s, 1 H), 9.05 (bs, 1 H).

Example 5: N-{(2R, 4S) -2-butyl-4- [3- (2-methoxy-phenyl) -ureido] -5-methyl-3-oxo-hexyl} -N-hydroxy Formamide

¹ H-NMR (CDCl ₃ ) δ 0.64-1.05 (m, 9H), 1.24-1.67 (m, 6H), 2.24 (s, 1H), 3.17-4.00 (m, 6H), 4.75 (m, 1H), 5.83 (m, 1 H), 6.92 (m, 4 H), 7.95 (m, 1 H), 8.70 (s, 1 H).

Example 6: N-{(2R, 4S) -2-butyl-4- [3- (2-fluoro-phenyl) -ureido] -5-methyl-3-oxo-hexyl} -N-hydroxy Formamide

¹ H-NMR (CDCl ₃ ) δ 0.58-1.15 (m, 9H), 1.32-1.70 (m, 6H), 2.24 (m, 1H), 3.26-4.42 (m, 3H), 4.78 (s, 1H), 6.47 (bs, 1H), 7.05 (m, 3H), 8.0 (m, 2H), 8.48 (s, 1H).

Example 7: N-{(2R, 4S) -2-Butyl-4- (3-cyclopentyl-ureido) -5-methyl-3-oxo-hexyl] -N-hydroxy-formamide

¹ H-NMR (CDCl ₃ ) δ 0.67-1.01 (m, 9H), 1.25 (m, 10H), 1.62 (m, 4H), 1.96 (m, 2H), 2.21 (s, 1H), 3.15-5.30 ( m, 4H).

Example 8: N-{(2R, 4S) -2-butyl-4- [3- (3-methoxy-phenyl) -ureido] -5-methyl-3-oxo-hexyl} -N-hydroxy Formamide

¹ H-NMR (CDCl ₃ ) δ 0.66-1.01 (m, 9H), 1.25-1.66 (m, 6H), 2.25 (s, 1H), 3.19-3.99 (m, 6H), 4.71 (m, 1H), 6.72-7.55 (m, 4H), 8.00 (m, 1H), 8.65 (s, 1H).

Example 9: N-{(2R, 4S) -2-butyl-4- [3- (4-methoxy-phenyl) -ureido] -5-methyl-3-oxo-hexyl} -N-hydroxy Formamide

¹ H-NMR (CDCl ₃ ) δ 0.68-0.99 (m, 9H), 1.20-1.48 (m, 6H), 2.20 (s, 1H), 3.20-4.00 (m, 6H), 4.80 (m, 1H), 6.80-7.20 (m, 4H), 7.99 (m, 1H), 8.80 (s, 1H).

Example 10: N-[(2R, 4S) -2-butyl-4- (3-butyl-ureido) -5-methyl-3-oxo-hexyl] -N-hydroxy-formamide

¹ H-NMR (CDCl ₃ ) δ 0.67-1.01 (m, 12H), 1.25-1.67 (m, 10H), 2.20 (s, 1H), 3.16-4.21 (m, 5H), 4.59 (s, 1H), 5.30 (m, 1 H).

Example 11: N-[(2R, 4S) -2-Butyl-4- (3-t-butyl-ureido) -5-methyl-3-oxo-hexyl] -N-hydroxy-formamide

¹ H-NMR (CDCl ₃ ) δ 0.81-1.00 (m, 9H), 1.25-1.59 (m, 15H), 2.20 (m, 1H), 3.14-5.10 (m, 4H).

Example 12 N-{(2R, 4S) -2-butyl-4- [3- (2,5-dichloro-phenyl) -ureido] -5-methyl-3-oxo-hexyl} -N-hydride Roxy-formamide

¹ H-NMR (CDCl ₃ ) δ 0.70-1.04 (m, 9H), 1.21-1.50 (m, 6H), 2.22 (s, 1H), 3.18-4.44 (m, 3H), 4.75 (m, 1H), 6.85-7.30 (m, 3 H), 7.99 (m, 1 H).

Example 13: N-{(2R, 4S) -2-Butyl-5-methyl-4- [3- (5-methyl-pyridin-2-yl) -ureido] -3-oxo-hexyl} -N Hydroxy-formamide

¹ H-NMR (CDCl ₃ ) δ 0.66-1.02 (m, 9H), 1.25-1.62 (m, 6H), 2.34 (m, 4H), 3.35-3.95 (m, 3H), 4.73 (m, 1H), 6.70 (s, 1 H), 7.43 (s, 1 H), 7.95 (s, 1 H), 8.10 (s, 1 H).

Example 14 N-{(2R, 4S) -2-butyl-5-methyl-4- [3- (5-methyl-1-oxy-pyridin-2-yl) -ureido] -3-oxo- Hexyl} -N-hydroxy-formamide

¹ H-NMR (CDCl ₃ ) δ 0.59-1.01 (m, 9H), 1.26-1.60 (m, 6H), 2.30 (m, 4H), 3.30-3.93 (m, 3H), 4.59 (m, 1H), 7.33 (s, 1 H), 7.85-8.00 (m, 2 H), 8.30 (m, 1 H).

Example 15 N-[(2R, 4S) -2-Butyl-5-methyl-3-oxo-4- (3-pyridin-2-yl-ureido) -hexyl] -N-hydroxy-formamide

¹ H-NMR (CDCl ₃ ) δ 0.85-1.02 (m, 9H), 1.24-1.3 (m, 6H), 2.11 (m, 1H), 3.17 (m, 1H), 3.73 (m, 2H), 4.54 ( m, 1H), 6.80 (m, 2H), 7.54 (m, 1H), 8.53 (m, 1H).

Example 16: N-{(2R, 4S) -2-butyl-5-methyl-3-oxo-4- [3- (1-oxy-pyridin-2-yl) -ureido} -hexyl} -N Hydroxy-formamide

¹ H-NMR (CDCl ₃ ) δ 0.78-1.04 (m, 9H), 1.24-1.67 (m, 6H), 2.25 (s, 1H), 3.43 (m, 2H), 3.98 (m, 1H), 4.78 ( m, 1H), 7.37-8.48 (m, 3H), 10.43 (s.1H).

Example 17 N-{(2R, 4S) -2-butyl-4- [3- (4,6-dimethyl-pyridin-2-yl) -ureido] -5-methyl-3-oxo-hexyl} -N-hydroxy-formamide

¹ H-NMR (CDCl ₃ ) δ 0.78-1.05 (m, 9H), 1.26-1.62 (m, 6H), 2.28 (s, 4H), 2.40 (s, 3H), 3.20-3.90 (m, 3H), 4.59 (m, 1 H), 6.46 (s, 1 H), 6.66 (s, 1 H), 7.84 (s, 1 H).

Example 18: N-{(2R, 4S) -2-butyl-4- [3- (4,6-dimethyl-1-oxy-pyridin-2-yl) -ureido] -5-methyl-3- Oxo-hexyl} -N-hydroxy-formamide

¹ H-NMR (CDCl ₃ ) δ 0.66-1.10 (m, 9H), 1.25-1.65 (m, 6H), 2.30 (s, 4H), 2.45 (s, 3H), 3.41-4.07 (m, 3H), 4.70 (m, 1H), 6.60 (s, 1H), 7.51 (m, 1H), 7.88-8.32 (m, 2H).

Example 19 N-[(2R, 4S) -2-Butyl-4- (3-isopropyl-ureido) -5-methyl-3-oxo-hexyl] -N-hydroxy-formamide

¹ H-NMR (CDCl ₃ ) δ 0.81-1.00 (m, 9H), 1.10-2.05 (m, 12H), 2.30 (m, 1H), 3.20-4.77 (m, 5H), 8.33 (m, 1H).

Example 20 N-[(2R, 4S) -2-Butyl-4- (3-isobutyl-ureido) -5-methyl-3-oxo-hexyl] -N-hydroxy-formamide

¹ H-NMR (CDCl ₃ ) δ 0.81-1.59 (m, 21H), 2.21 (m, 1H), 3.42-4.48 (m, 5H).

Example 21 N-[(2R, 4S) -4- (3-benzyl-ureido) -2-butyl-5-methyl-3-oxo-hexyl] -N-hydroxy-formamide

¹ H-NMR (CDCl ₃ ) δ 0.58-1.00 (m, 9H), 1.23-1.62 (m, 6H), 2.16 (m, 1H), 3.37-4.28 (m, 6H), 7.26 (m 5H).

B. Biological Examples

(1) Deformillase inhibitory activity measurement

i) Production and Purification of Deformillase

Deformillase producing strain (Novagen, USA, cat.no. 69041) was added to 30 ml LB medium (tryptone 8 g / l, yeast extract 5 g / l, NaCl 5 g / l, 1N NaOH) with ampicillin at 50 ° C. 2.5 ml) and incubated at 37 ° C. The culture was inoculated in 3 L of the same LB medium and when the OD (660 nm) reached 0.5, 1 mM isopropyl-β-D-thiogalactopyranoside was injected into the medium to induce expression. Cell pellets were harvested by centrifugation, stored at −80 ° C. for 30 minutes, resuspended in phosphate buffer solution, and disrupted by ultrasonic waves at intervals of 1 second pulse versus 8 seconds of rest. Subsequently, ultracentrifugation gave a supernatant, which was attached to an adsorption column and separated by elution buffer. The fraction containing peptide deformillase in the separated fraction was confirmed by SDS-PAGE, and eluted by gel chromatography. At this time, a buffer solution containing 5 mM NiCl ₂ was used as an enzyme source stabilizer, and purification was confirmed by SDS-PAGE and Dynamic Light Scattering. Purified enzyme source was stored and used at -80 ℃.

Ii) deformillase inhibition test

The compound prepared in Example was dissolved in dimethyl sulfoxide to 2 mM, and 7 μl was dispensed into a microtiter plate, and a buffer solution (50 mM HEPES, pH 7.0, 10 mM NaCl, 5 mM NiCl ₂ , 0.1% Triton X-100) Deformillase was diluted to 250 nM and dispensed into microtiter plates. After dispensing, the compound prepared in Example by serial dilution was diluted at a dilution ratio of 7/2 and the final amount between wells was 50 μl. After standing at room temperature for 5 minutes, 50 µl of 5 mM formyl-Met-Ala-Ser, which was used as a substrate source, was dispensed into each well and subjected to enzymatic reaction at 30 ° C for 10 minutes. After completion of the reaction, fluorescarmine at 50 ° C. and 50 μl of 50 mM borate-sodium hydroxide buffer solution (pH9.5) were added thereto, and the fluorescence was measured under the conditions of an excitation wavelength of 390 nm and an emission wavelength of 465 nm. From this value, the concentration (IC ₅₀ ) that inhibits the activity of the enzyme by 50% was measured, and the results are shown in Table 1.

compound IC ₅₀ (nM) compound IC ₅₀ (nM) Example 1 25 Example 12 10 Example 2 66 Example 13 128 Example 3 68 Example 14 57 Example 4 49 Example 15 43 Example 5 41 Example 16 77 Example 6 41 Example 17 20 Example 7 10 Example 18 95 Example 8 9 Example 19 16 Example 9 37 Example 20 30 Example 10 5 Example 21 19 Example 11 68

(2) antibacterial effect test

The minimum inhibitory concentration (MIC) of the compounds of the present invention against Haemophilus influenza (ATCC 51907), Streptococcus pneumoniae (ATCC 6305) and Moraxella catarrhalis (ATCC 43617) was measured. The compound prepared in Example was dissolved in dimethyl sulfoxide and prepared at a concentration of 2 mg / ml. At this time, actininine (Sigma, USA) and ampicillin (Sigma, USA) were used as standard antibiotics, and were prepared at a concentration of 2 mg / ml. The cultures of the specimens were inoculated in a culture medium composed of Haemophilus influenzae, Moraxella catarrhalis, 37g / l Brain Heart Infusion (Dipcosa, USA), 10 mg / l NAD, and 5 mg / l hemin, respectively, for 24 hours, 48 hours. The cells were cultured for 48 hours and inoculated in GC culture medium containing 5% horse serum for Streptococcus pneumoniae. After incubation, the cells were diluted to an amount of 1 x 10 ⁶ CFU / ml and inoculated into microtiter plates, and each of Haemophilus influenzae was inhibited after 24 hours in Moraxella catarrhalis and Streptococcus pneumoniae after 48 hours. Inhibitory concentration (MIC) values were determined. All incubations were at 37 ° C., 5% CO ₂ . Minimum inhibitory concentrations for the compounds of the present invention are shown in Table 2 below.

compound MIC (µg / ml) Streptococcus Sumoniae Haemophilus influenza Moraxella Qatarihalis Example 1 0.8 0.1 0.1 Example 2 0.4 0.1 0.1 Example 3 0.1 0.4 0.1 Example 4 0.4 0.4 0.1 Example 5 0.1 0.2 0.1 Example 6 0.2 0.1 0.1 Example 7 1.6 0.2 0.1 Example 8 0.4 0.2 0.1 Example 9 0.2 0.1 0.1 Example 10 0.4 0.1 0.1 Example 11 12.8 1.6 0.1 Example 12 0.1 0.4 0.1 Example 13 0.1 0.1 0.1 Example 14 0.1 0.2 0.1 Example 15 1.6 0.1 0.1 Example 16 0.2 0.2 0.2 Example 17 0.2 0.2 0.1 Example 18 0.1 0.4 0.1 Example 19 0.4 0.1 0.8 Example 20 3.2 0.4 1.6 Example 21 0.4 0.1 0.4

The compound according to the present invention or a pharmaceutically acceptable salt thereof is effective as an antimicrobial agent having a broad spectrum, effective against bacteria resistant to existing antimicrobial agents, by having an excellent deformylase inhibitory effect.

Claims (10)

A compound of Formula 1 or a pharmaceutically acceptable salt thereof:

Formula 1 Wherein R ¹ is linear or branched C ₁ -C ₆ alkyl; Or C ₁ -C ₂ alkyl substituted with C ₃ -C ₆ cycloalkyl or heteroaryl; R ² is hydrogen; Linear or branched C ₁ -C ₆ alkyl; Or benzyl; R ³ is straight or branched C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, benzyl, phenyl, pyridinyl or oxidized pyridinyl, wherein phenyl, pyridinyl or oxidized pyridinyl is C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, hydroxy, halogen, cyano, nitro, acetyl, phenyl, trifluoromethyl, trifluoromethoxy, methanesulfonyl, piperidinyl, morpholinyl, pyrrolidinyl, And it may be substituted with 1 to 3 substituents selected from the group consisting of benzoyl. The compound of Formula 1 or a pharmaceutically acceptable salt thereof according to claim 1, wherein when R ³ is substituted with pyridinyl or oxidized pyridinyl, R ³ is a compound of Formula 2:

Formula 2 Wherein R ⁴ , R ⁵ , R ⁶ , and R ⁷ are hydrogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, hydroxy, halogen, cyano, nitro, acetyl, phenyl, trifluoromethyl , Trifluoromethoxy, methanesulfonyl, piperidinyl, morpholinyl, pyrrolidinyl, and benzoyl can be substituted by any one selected from the group consisting of. The compound of claim 1, wherein N-{(2R, 4S) -2-butyl-4- [3- (5-fluoro-pyridin-2-yl) -ureido] -5-methyl-3-oxo-hexyl } -N-hydroxy-formamide; N-{(2R, 4S) -2-Butyl-4- [3- (5-fluoro-1-oxy-pyridin-2-yl) -ureido] -5-methyl-3-oxo-hexyl}- N-hydroxy-formamide; N-{(2R, 4S) -2-butyl-4- [3- (2-methoxy-5-methyl-phenyl) -ureido] -5-methyl-3-oxo-hexyl} -N-hydroxy Formamide; N-[(2R, 4S) -2-Butyl-5-methyl-3-oxo-4- (3-phenyl-ureido) -hexyl] -N-hydroxy-formamide; N-{(2R, 4S) -2-Butyl-4- [3- (2-methoxy-phenyl) -ureido] -5-methyl-3-oxo-hexyl} -N-hydroxy-formamide; N-{(2R, 4S) -2-Butyl-4- [3- (2-fluoro-phenyl) -ureido] -5-methyl-3-oxo-hexyl} -N-hydroxy-formamide; N-{(2R, 4S) -2-Butyl-4- (3-cyclopentyl-ureido) -5-methyl-3-oxo-hexyl] -N-hydroxy-formamide; N-{(2R, 4S) -2-Butyl-4- [3- (3-methoxy-phenyl) -ureido] -5-methyl-3-oxo-hexyl} -N-hydroxy-formamide; N-{(2R, 4S) -2-Butyl-4- [3- (4-methoxy-phenyl) -ureido] -5-methyl-3-oxo-hexyl} -N-hydroxy-formamide; N-[(2R, 4S) -2-Butyl-4- (3-butyl-ureido) -5-methyl-3-oxo-hexyl] -N-hydroxy-formamide; N-[(2R, 4S) -2-Butyl-4- (3-t-butyl-ureido) -5-methyl-3-oxo-hexyl] -N-hydroxy-formamide; N-{(2R, 4S) -2-butyl-4- [3- (2,5-dichloro-phenyl) -ureido] -5-methyl-3-oxo-hexyl} -N-hydroxy-formamide ; N-{(2R, 4S) -2-Butyl-5-methyl-4- [3- (5-methyl-pyridin-2-yl) -ureido] -3-oxo-hexyl} -N-hydroxy- Formamide; N-{(2R, 4S) -2-Butyl-5-methyl-4- [3- (5-methyl-1-oxy-pyridin-2-yl) -ureido] -3-oxo-hexyl} -N Hydroxy-formamide; N-[(2R, 4S) -2-Butyl-5-methyl-3-oxo-4- (3-pyridin-2-yl-ureido) -hexyl] -N-hydroxy-formamide; N-{(2R, 4S) -2-Butyl-5-methyl-3-oxo-4- [3- (1-oxy-pyridin-2-yl) -ureido} -hexyl} -N-hydroxy- Formamide; N-{(2R, 4S) -2-butyl-4- [3- (4,6-dimethyl-pyridin-2-yl) -ureido] -5-methyl-3-oxo-hexyl} -N-hydrate Oxy-formamide; N-{(2R, 4S) -2-butyl-4- [3- (4,6-dimethyl-1-oxy-pyridin-2-yl) -ureido] -5-methyl-3-oxo-hexyl} -N-hydroxy-formamide; N-[(2R, 4S) -2-Butyl-4- (3-isopropyl-ureido) -5-methyl-3-oxo-hexyl] -N-hydroxy-formamide; N-[(2R, 4S) -2-Butyl-4- (3-isobutyl-ureido) -5-methyl-3-oxo-hexyl] -N-hydroxy-formamide; And Of formula 1 selected from the group consisting of N-[(2R, 4S) -4- (3-benzyl-ureido) -2-butyl-5-methyl-3-oxo-hexyl] -N-hydroxy-formamide Compound or a pharmaceutically acceptable salt thereof. The compound of formula 4 is reacted with a reaction mixture of formic acid and acetic anhydride to synthesize a compound of formula 3, and then removes a hydroxy protecting group from the compound of formula 3, wherein the compound of formula 1 or Methods for preparing pharmaceutically acceptable salts:

Formula 3,

Formula 4 Wherein R ¹ , R ² , and R ³ are as defined in claim 1 and Y is a hydroxy protecting group. The method of claim 4, wherein the compound of formula 4 is prepared by reacting a compound of formula 6 or a salt thereof with -HNR ³ to prepare a compound of formula 5, and then reacting the compound of formula 5 with YONH ₂ Method for preparing a compound of Formula 1 or a pharmaceutically acceptable salt thereof characterized in that:

Formula 5,

Formula 6 Wherein R ¹ , R ² and R ³ are as defined in claim 1 and X is chloro or imidazole. The method of claim 5, wherein the compound of Formula 6 is prepared by reacting a salt of the compound of Formula 7 with triphosgen or 1,1'-carbonyldiimidazole, Method for preparing a compound of Formula 1 or a pharmaceutically acceptable salt thereof:

Formula 7 Wherein R ¹ and R ² are as defined in claim 1 and Z is an amino protecting group. The compound of formula (7) according to claim 6, wherein the benzyl group of the compound of formula (8) is removed by hydrogenation under palladium / carbon conditions, reflux stirred under piperidine / formaldehyde and lower alcohol solvent, and then de- Method for preparing a compound of formula 1 or a pharmaceutically acceptable salt thereof, characterized in that prepared by protecting:

Formula 8 Wherein R ² is as defined in claim 1 and Z is an amino protecting group. 8. A compound according to claim 7, wherein the compound of formula 8 is selected from the group consisting of linear or branched C ₁ -C ₆ alkyl substituted with sulfate or halogen; Or a C ₁ -C ₂ alkyl compound substituted with C ₃ -C ₆ cycloalkyl or heteroaryl in the presence of a base such as potassium carbonate, wherein the compound of Formula 1 or a pharmaceutically acceptable How to prepare salts:

Formula 9 Wherein R ² is as defined in claim 1 and Z is an amino protecting group. The method of claim 8, wherein the compound of formula 9 is reacted with a compound of formula 10, Meldrum's acid, dicyclohexylcarbodiimide, and dimethylaminopyridine, and then the reaction intermediate is benzyl alcohol and toluene or A process for preparing a compound of formula (1) or a pharmaceutically acceptable salt thereof, which is prepared by stirring under reflux under benzene solvent conditions:

Formula 10 Wherein R ² is as defined in claim 1 and Z is an amino protecting group. An antimicrobial composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 3 or a salt thereof and a pharmaceutically acceptable carrier.