KR20020071576A - Oxazolidinone derivatives containing pyridine substituted with heterocycle or heteroaromatic cycle and process for the preparation thereof - Google Patents

Abstract

PURPOSE: Provided are oxazolidinone derivatives containing pyridine substituted with heterocycle or heteroaromatic cycle, its pharmaceutically acceptable salts and its preparation process. The oxazolidinone derivatives have broad spectrum of antibacterial activity and low toxicity and are thus used as antibiotics. CONSTITUTION: The oxazolidinone derivative represented by the formula(1) is manufactured by the steps of: reacting trimethyl stanyl oxazolidinone of the formula(2) with a pyridine derivative of the formula(3) in the presence of palladium catalyst. A pharmaceutical composition for antibiotics contains oxazolidinone derivatives containing a pyridine ring and its pharmaceutically acceptable salts as active ingredients.

Description

Oxazolidinone derivatives comprising a pyridine ring substituted with a heterocycle or a heteroaromatic ring, and a method for preparing the same {Oxazolidinone derivatives containing pyridine substituted with heterocycle or heteroaromatic cycle and process for the preparation

The present invention provides an oxazolidinone derivative represented by the following formula (1) including a pyridine ring substituted with a heterocyclic ring or a heteroaromatic ring at position 4 of the phenyl group, and a pharmaceutically acceptable salt thereof, a method of preparing the compound, and a compound thereof. It relates to a pharmaceutical composition for an antimicrobial agent as an active ingredient.

Formula 1

(In Formula 1, R ₁ and R ₂ are as described in the specification.)

Oxazolidinone compounds are known as new synthetic antibiotics that can be administered orally rather than as fermentation products, and derivatives of various structures are known. For example, 3-phenyl-2-oxazolidinone derivatives having one or two substituents are described in USP 4,948,801, USP 4,461,773, USP 4,340,606, USP 4,476,136, USP 4,250,318, USP 4,128,654, and are represented by Formula 2 below -[(Monosubstituted) phenyl] -2-oxazolidinone derivatives are described in EP 0312000, J. Med. Chem . 32, 1673 ( 1989 ), J. Med. Chem . 33, 2569 ( 1990 ), Tetrahedron . 45,123 ( 1989 ) and the like.

In addition, Pharmacia & Upjohn synthesized oxazolidinone derivatives of the following Chemical Formulas 3 and 4 (WO 93/23384, WO 95/14684, WO 95/07271). It is scheduled for release with the approval of the FDA (Food and Drug Administration). However, conventionally synthesized 3-phenyl-2-oxazolidinone compounds have the disadvantage that their antimicrobial spectrum is not broad and toxic, and their therapeutic effect is reduced in vivo .

WO 93/09103 also discloses phenyl oxazolidinone derivatives having heterocycles such as thiazole, indole, oxazole, quinol and the like containing pyridine at position 4 of the phenyl group as shown in Formula 1, but the substituents of the heterocycle are simple It is known that not only the alkyl group or the amino group but also the effect is not sufficiently excellent.

Accordingly, the present inventors have tried to solve the above problems, as shown in the formula 1 synthesized a phenyl oxazolidinone derivative having a heteropyri or heteroaromatic ring substituted pyridine derivative at position 4 of the phenyl group, the synthesis As a result of measuring the antimicrobial activity of the compounds, the present invention was completed by finding out that the antimicrobial spectrum was broad and the antimicrobial effect was excellent.

It is an object of the present invention to provide an oxazolidinone derivative of the formula (1) comprising a pyridine derivative substituted with a heterocyclic ring or a heteroaromatic ring at position 4 of the phenyl group, a pharmaceutically acceptable salt thereof and a method for preparing the same.

It is also an object of the present invention to provide a pharmaceutical composition for antibiotics comprising an oxazolidinone derivative represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

In order to achieve the above object, in the present invention, an oxazolidinone derivative and a pharmaceutically acceptable compound containing a pyridine ring represented by the following Formula 1 including a pyridine derivative substituted with a hetero ring or a heteroaromatic ring at position 4 of the phenyl group Provide their salts.

Formula 1

In Chemical Formula 1,

R ₁ is H, F, Cl or CF ₃ ,

R ₂ is a heterocyclic ring or heteroaromatic ring substituted with R ₃ or R ₄ ,

1) a pentagonal or hexagonal heterocycle containing one or more carbon (C), nitrogen (N), or oxygen (O), preferably nitrogen or oxygen atoms alone or in two or more, or It is a ring compound containing at least one nitrogen or oxygen each, more preferably

, , , or to be.

2) a pentagonal ring consisting of carbon (C), nitrogen (N) or oxygen (O), saturated with two hydrogens on either carbon directly constituting the ring, or oxygen (ketone), Heterocylic ring consisting of a double bond with nitrogen (imino) or sulfur (thioketone), preferably

, or

(Where A, B, and D are carbon, oxygen, or nitrogen, and may be the same or different, and E may be two hydrogen, oxygen, sulfur, or nitrogen), and more preferably

, , , , , or to be.

3) Heteroaromatic ring having five or six-membered aromatic properties consisting of carbon (C), nitrogen (N), oxygen (O) or sulfur (S), preferably

Nitrogen or oxygen is a ring consisting of only one or two or a ring compound containing one or more oxygen and nitrogen each of the following are the most representative rings, more preferably

, , , , , , , , , , , , or to be.

R ₃ and R ₄ are the same as or different from each other,

(a) hydrogen, F, Cl, Br or I,

(b) alkyl groups (C _{1 to} C ₄ ) substituted or unsubstituted with one or more substituents, wherein the substituted alkyl group is hydroxyalkyl, alkoxycarbonylalkyl, trihaloalkyl, acetoxyalkyl, alkylamino Alkyl, alkoxyalkyl or methanesulfonyloxyalkyl group),

(c) an acetyl group (where the substituted acetyl group is unsubstituted or substituted acetoxy, acetyl, hydroxy, acetyl, alkoxy, acetyl, amino acetyl in C ₁ ~C ₃ alkyl-amino-acetoxy acetyl, C ₁ ~C ₃ a, ah map acetyl, acetylamino, acetyl, is a C ₁ ~C ₃ alkyl, amino, acetyl, propionyl amino, or hydroxy-propionyl group.)

(d) Ajido,

(e) hydroxy,

(f) mercapto,

(g) cyano,

(h) ketones,

(i) substituted or unsubstituted imino, wherein the substituted imino group is a hydroxyimino, alkylimino, alkoxyimino or methanesulfonyloxyimino group,

(j) -OR _5, wherein R ₅ is hydrogen, C ₁ -C ₃ alkyl, acetyl, alkoxyalkyl, hydroxy acetyl or methanesulfonyl group,

(k) -NR ₆ R _{7, wherein} R ₆ and R ₇ are each hydrogen, C ₁ -C ₄ alkyl, acetyl, alkoxyalkyl, hydroxy acetyl or methanesulfonyl group,

Preferred are triazole, tetrazole, oxazole, oxadiazole, oxazolidine, piperidine, pyrroline, imidazole or derivatives thereof.

Particularly preferred compounds among the compounds of Formula 1 are as follows.

1) (S)-[N-3- [4- [2- (1-tetrazolyl) -5-pyridinyl] -3-fluorophenyl] -2-oxo-5-oxazolidinyl] methyl acetamide (Compound of Example 1)

2) (S)-[N-3- [4- [2- [5-methyl- (1,3,4) -oxadiazol-2-yl] -5-pyridinyl] -3-fluorophenyl ] -2-oxo-5-oxazolidinyl] methyl acetamide (compound of Example 2)

3) (S)-[N-3- [4- [2- [5-methyl- (1,2,4) -oxadiazol-3-yl] pyridin-5-yl] -3-fluorophenyl ] -2-oxo-5-oxazolidinyl] methyl acetamide (compound of Example 3)

4) (S)-[N-3- [4- [2- (1-methyl-5-tetrazolyl) -5-pyridinyl] -3-fluorophenyl] -2-oxo-5-oxazolidinyl ] Methyl Acetamide (Compound of Example 4)

5) (S)-[N-3- [4- [2- (2-methyl-5-tetrazolyl) -5-pyridinyl] -3-fluorophenyl] -2-oxo-5-oxazolidinyl ] Methyl Acetamide (Compound of Example 5)

6) (S)-[N-3- [4- [2- [4-ethoxycarbonyl- (1,2,3) -triazol-1-yl] -5-pyridinyl] -3-fluoro Lophenyl] -2-oxo-5-oxazolidinyl] methyl acetamide (compound of Example 6)

7) (S)-[N-3- [4- [2- (3-pyrrolinyl) -5-pyridinyl] -3-fluorophenyl] -2-oxo-5-oxazolidinyl] methyl acet Amide (Compound of Example 7)

8) (S)-[N-3- [4- [2- [2-oxo- (1,3) -oxazolidin-3-yl] -5-pyridinyl] -3-fluorophenyl]- 2-oxo-5-oxazolidinyl] methyl acetamide (compound of Example 8)

9) (S)-[N-3- [4- [2-[(1,3) -oxazol-5-yl] -5-pyridinyl] -3-fluorophenyl] -2-oxo-5 -Oxazolidinyl] methyl acetamide (compound of Example 9)

10) (S)-[N-3- [4- [2-[(1,2,4) -oxadiazol-3-yl] -5-pyridinyl] -3-fluorophenyl] -2- Oxo-5-oxazolidinyl] methyl acetamide (compound of Example 10)

11) (S)-[N-3- [4- [2-[(1,2,3) -triazol-1yl] -5-pyridinyl] -3-fluorophenyl] -2-oxo- 5-oxazolidinyl] methyl acetamide (compound of Example 11)

12) (S)-[N-3- [4- [2- [3-methyl-2-oxo-2,3-dihydro- (1,3,4) -triazol-1-yl] -5 -Pyridinyl] -3-fluorophenyl] -2-oxo-5-oxazolidinyl] methyl acetamide (compound of Example 12)

13) (S)-[N-3- [4- [2- [2-oxo- (1,3) -imidazolidin-1-yl] -5-pyridinyl] -3-fluorophenyl] -2-oxo-5-oxazolidinyl] methyl acetamide (compound of Example 13)

14) (S)-[N-3- [4- [2- (4-hydroxy-piperidin-1-yl) -5-pyridinyl] -3-fluorophenyl] -2-oxo-5 -Oxazolidinyl] methyl acetamide (compound of Example 14)

15) (S)-[N-3- [4- [2- [2-oxo- (2,3) -dihydro- (1,3,4) -triazol-1-yl] -5-pyri Diyl] -3-fluorophenyl] -2-oxo-5-oxazolidinyl] methyl acetamide (compound of Example 15)

16) (S)-[N-3- [4- [2- [5-hydroxymethyl- (1,2,4) -oxadiazol-3-yl] -5-pyridinyl] -3-fluoro Lophenyl] -2-oxo-5-oxazolidinyl] methyl acetamide (compound of Example 16)

17) (S)-[N-3- [4- [2- (5-tetrazolyl) -5-pyridinyl] -3-fluorophenyl] -2-oxo-5-oxazolidinyl] methyl acetamide (Compound of Example 17)

18) (S)-[N-3- [4- [2- [5-methoxymethyl- (1,2,4) -oxadiazol-3-yl] -5-pyridinyl] -3-fluoro Lophenyl] -2-oxo-5-oxazolidinyl] methyl acetamide (compound of Example 18)

19) (S)-[N-3- [4- [2- [5-trichloromethyl- (1,2,4) -oxadiazol-3-yl] -5-pyridinyl] -3-fluoro Lophenyl] -2-oxo-5-oxazolidinyl] methyl acetamide (compound of Example 19)

20) (S)-[N-3- [4- [2- [5-dimethylamino- (1,2,4) -oxadiazol-3-yl] -5-pyridinyl] -3-fluoro Lophenyl] -2-oxo-5-oxazolidinyl] methyl acetamide (compound of Example 20)

21) (S)-[N-3- [4- [2- [5-amino- (1,2,4) -oxadiazol-3-yl] -5-pyridinyl] -3-fluorophenyl ] -2-oxo-5-oxazolidinyl] methyl acetamide (compound of Example 21)

22) (S)-[N-3- [4- [2- [4-acetylamino-1-piperidinyl] -5-pyridinyl] -3-fluorophenyl] -2-oxo-5-oxa Zolidinyl] methyl acetamide (compound of Example 22)

23) (S)-[N-3- [4- [2- [4-acetyloxymethylcarbonylamino-piperidin-1-yl] -5-pyridinyl] -3-fluorophenyl] -2 -Oxo-5-oxazolidinyl] methyl acetamide (compound of Example 23)

24) (S)-[N-3- [4- [2- (4-hydroxymethylcarbonylamino-piperidin-1-yl) -5-pyridinyl] -3-fluorophenyl] -2 -Oxo-5-oxazolidinyl] methyl acetamide (compound of Example 24)

25) (S)-[N-3- [4- [2- [3,4-dihydroxy-pyrrolidin-1-yl] -5-pyridinyl] -3-fluorophenyl] -2- Oxo-5-oxazolidinyl] methyl acetamide (compound of Example 25)

Chemical formulas of the oxazolidinone compounds represented by Chemical Formula 1 are shown in Table 1 below.

The oxazolidinone compound of the present invention represented by Formula 1 may be used in the form of a pharmaceutically acceptable salt, and acid salts formed by pharmaceutically acceptable free acid are useful as salts. Inorganic acids and organic acids can be used as the free acid. Hydrochloric acid, bromic acid, sulfuric acid, phosphoric acid and the like can be used as the inorganic acid, and citric acid, acetic acid, lactic acid, maleic acid, umarin acid, gluconic acid, methanesulfonic acid, glyconic acid, succinic acid, 4-toluenesulfonic acid, and gallic acid are used as the organic acid. Luteuronic acid, embonic acid, glutamic acid, aspartic acid and the like can be used.

The compound of formula 1 may also be a pharmaceutically acceptable metal salt, in particular an alkali metal salt, formed due to the base. Examples of these are sodium salts and potassium salts.

In another aspect, the present invention provides a method for preparing an oxazolidinone derivative represented by Formula 1 prepared by reacting trimethylstannyl oxazolidinone derivative (2) with a pyridine derivative (3) under a palladium catalyst.

(Wherein R ₁ , R ₂ and X are as defined above).

Specifically, the oxazolidinone derivative of the present invention

1) Converting the hydroxy group of the hydroxymethyloxazolidinone derivative (4) to an amine group to prepare an amine compound (5),

2) reacting the amine compound (5) with acetic anhydride to produce an acetyl compound (6),

3) halogenating the acetyl compound (6) to produce a halogen compound (7),

4) trimethylstannyl oxazolidinone derivative (2) was prepared by stanning the halogen compound (7) under a palladium catalyst,

5) The trimethylstannyl oxazolidinone derivative (2) is reacted with a pyridine derivative (3) under a palladium catalyst to prepare a compound represented by the formula (1).

(In the above scheme, R ₁ and R ₂ are as defined in Formula 1, X is a halogen element.)

Hereinafter, a method for preparing the oxazolidinone derivative of the present invention will be described in more detail at each step.

The hydroxymethyloxazolidinone derivative of the general formula (4) used as a starting material in the reaction can be simply synthesized by a known method. For example, the Cbz (Benzyloxycarbonyl) group may be introduced into an amine group of aniline, and then reacted with glacidyl butyrate under a strong base.

Step 1: Amination Reaction

(In the above scheme, R ₁ is as defined in Formula 1, and X is a halogen element.)

In the first step, an amine compound (5) is prepared by converting the hydroxy group of the hydroxymethyloxazolidinone derivative compound (4) into an amine group.

In order to replace the hydroxy group of the compound of formula (4) with an amine group, the hydroxy group is halogenated, azated and then substituted with an amine group.

First, a methanesulfonyl group, a paratoluenesulfonyl group or a halogen is introduced into the hydroxy group for easy substitution with azide. At this time, the reaction temperature is preferably carried out at 0 ℃.

Next, a methanesulfonyl group, a paratoluenesulfonyl group, or a compound having a halogen introduced therein is reacted with sodium azide to azide. The sodium azide used at this time is preferably added in an amount of about 1 to 3 equivalents to the compound, and is preferably reacted at 90 to 110 ° C. for 1 to 2 hours. In addition, the reaction solvent used for the reaction includes dimethylformamide, dimethyl sulfoxide or 1,4-dioxane.

Next, the azide compound is reduced using palladium or triphenyl phosphine to give the compound of formula (5). When the azide compound is reduced using palladium, it is preferable to perform the reaction under hydrogen at room temperature, and the reaction solvent may be used alone or in combination with tetrahydrofuran, methanol, and the like. In addition, when the azide compound is reduced using triphenyl phosphine, a small amount of water is added to tetrahydrofuran and refluxed for about 2 hours to prepare a compound of formula (3).

Step 2: Acetylation Reaction

(In Formula 1, R ₁ is as defined in Formula 1.)

In the second step, the amine compound of formula (5) obtained in the first step is reacted with acetic anhydride under a base to perform an acetylation reaction to obtain a compound of formula (6).

At this time, a suitable base may be used triethylamine, pyridine, diisopropylethylamine and the like.

Step 3: halogenation reaction

(In the above scheme, R ₁ is as defined in Formula 1, and X is a halogen element.)

In the third step, a halogenation reaction is carried out at position 4 of the phenyl group of the compound of formula (6) to obtain a compound of formula (7).

In the third step, the halogen to be substituted in the phenyl group is preferably iodine, wherein the iodide reaction is preferably reacted with iodine monochloride (ICl) or silver trifluoroacetic acid salt (CF ₃ COOAg) in the presence of iodine. In addition, it is preferable to perform an iodide reaction at normal temperature.

Step 4: Substitution Reaction

(In the above scheme, R ₁ is as defined in Formula 1, and X is a halogen element.)

In the fourth step, the compound of formula (7) is reacted with hexamethylditin under a palladium catalyst to give trimethylstannyl oxazolidinone derivative (2).

In the fourth step, a trimethylstannyl oxazolidinone derivative (2) in which an iodine group is substituted with a trimethylstannyl group can be obtained. As the palladium catalyst, dichlorobistriphenylphosphinepalladium (II) or tetrakistriphenylphosphinepalladium (0) can be used.

1,4-dioxane, dimethylformamide, tetrahydrofuran, etc. can be used as a reaction solvent, It is preferable to carry out reaction temperature at 90-120 degreeC.

Step 5: Condensation Reaction

Scheme 1

(In the above scheme, R ₁ and R ₂ are as defined in Formula 1, X is a halogen element.)

The oxazolidinone compounds of the present invention represented by Formula 1 are prepared by reacting trimethylstannyl oxazolidinone derivative (2) and pyridine derivative (3) in step 4 in the presence of palladium (0) or palladium (II).

As the palladium catalyst, dichlorobistriphenylphosphine palladium (II) or tetrakistriphenylphosphine palladium (0) may be used.

The reaction temperature is preferably carried out in the range of 60 to 150 ° C., and the reaction time is preferably about 30 minutes to 12 hours, and as the reaction solvent, dimethylformamide, 1,4-dioxane, tetrahydrofuran alone or It can be mixed and used.

The pyridine derivative (3) used at this time can be prepared using dibromopyridine as shown in Scheme 8, and these methods have already been reported in several documents ( J. Medicinal Chem . V41, 2399 ( 1998 ), Chem. Pharm. Bull , 314 ( 1996 ), J. Med. Chem 957 ( 2000 ), J. Med. Chem . 1230 ( 2000 ), J. Med. Chem . 1086 ( 1991 ), J. Med. Chem . 2837 ( 1997 ), J. Med. Chem . 2019 ( 1998 ))

(Wherein R ₂ and X are as defined above).

Preferably pyridine derivative (2),

1) 2- (1-tetrazolyl) -5-bromopyridine (Compound of Preparation Example 1)

2) 2- [5-methyl- (1,3,4) -oxadiazol-2-yl] -5-bromopyridine (compound of Preparation Example 2)

3) 2- [5-methyl- (1,2,4) -oxadiazol-3-yl] -5-bromopyridine (compound of Preparation Example 3)

4) 2- (1-Methyl-5-tetrazolyl) -5-bromopyridine (Compound of Preparation Example 4)

5) 2- (2-Methyl-5-tetrazolyl) -5-bromopyridine (Compound of Preparation Example 4)

6) 2- [4-carboethoxy- (1,2,3) -triazol-1-yl] -5-bromopyridine (compound of Preparation Example 5)

7) 2- (3-Pyrrolin-1-yl) -5-bromopyridine (Compound of Preparation Example 6)

8) 2- [2-oxo- (1,3) -oxazolidin-1-yl] -5-bromopyridine (compound of Preparation Example 7)

9) 2-[(1,2,4) -oxadiazol-3-yl] -5-bromopyridine (compound of Preparation Example 8)

10) 2-[(1,2,3) -triazol-1-yl] -5-bromopyridine (compound of Preparation Example 9)

11) 2- [3-Methyl-2-oxo- (2,3) -dihydro- (1,3,4) -triazol-1-yl] -5-bromopyridine (compound of Preparation 10)

12) 2- [3-t-butoxycarbonyl-2-oxo- (2,3) -dihydro-[(1,3,4) -triazol-1-yl] -5-bromopyridine ( Compound of Preparation Example 11)

13) 2- [2-oxo- (1,3) -imidazolidin-1-yl] -5-bromopyridine (compound of Preparation Example 12)

14) 2-[(1,3) -oxazol-2-yl] -5-bromopyridine (compound of Preparation Example 13)

15) 2- (4-hydroxy-piperidin-1-yl) -5-bromopyridine (compound of Preparation 14)

16) 2- [3-t-butoxycarbonyl-2-oxo- (1,3) -imidazolidin-1-yl] -5-bromopyridine (compound of Preparation 15).

The present invention also provides another method for preparing the compound of formula (1).

(Wherein R ₁ , R ₂ , R ₃ , R ₄ and X are as defined above, and L is a conventional leaving group, preferably halogen or methylcarbonyl oxy group.)

The compound of formula (1) is reacted with trimethylstannyl oxazolidinone derivative (2) and cyano pyridine derivative (10) prepared as described above to prepare a compound of formula (11), and imidized with hydroxyl amine A compound of 12) is prepared and prepared by a cyclization reaction of the compound of formula (12) with a carboxylic acid derivative (13).

Trimethylstannyl oxazolidinone derivative (2) is reacted with a cyano pyridine derivative (10) under a palladium catalyst and lithium chloride to prepare a compound of formula (11). In this case, the reaction is prepared by refluxing in an organic solvent at 100 to 120 ° C. for 4 to 10 hours, and an organic solvent such as N-methylpyrrolidine or tetrahydrofuran is used.

The compound of formula (11) prepared above is reacted in the presence of sodium hydrogen carbonate and hydroxy amine hydrochloride to prepare a compound of formula (12) containing an imine group. At this time, the reaction is prepared by reacting at reflux temperature of the solvent for 2 to 5 hours, and the solvent used may be alcohols, preferably ethanol, methanol or isopropyl alcohol.

The compound of formula (12) containing an imine group is reacted with an activated carboxylic acid derivative of formula (13) to prepare an oxazolidinone derivative of formula (1) of the present invention.

The activated carboxylic acid derivative of formula (13) is acyl chloride or acetic anhydride substituted with R ₃ or R ₄ . At this time, the reaction is prepared by reacting at reflux temperature of the solvent for 4 to 8 hours, and a preferred solvent is pyridine, tetrahydrofuran or acetone.

In another aspect, the present invention provides a pharmaceutical composition for antibiotics containing the compound of formula (1) as an active ingredient.

The present invention provides, in addition to non-toxic, inert, pharmaceutically suitable excipients, a pharmaceutical composition containing at least one compound according to the invention or consisting of at least one active compound according to the invention and a process for preparing the composition.

The compound of formula 1 may be administered orally or parenterally during clinical administration and may be used in the form of a general pharmaceutical preparation.

That is, the compound of Formula 1 of the present invention may be administered in various oral and parenteral dosage forms during actual clinical administration, and when formulated, the commonly used fillers, extenders, binders, wetting agents, disintegrating agents, surfactants, etc. Prepared using diluents or excipients. Solid form preparations for oral administration include tablets, pills, powders, granules, capsules, and the like, which form at least one excipient such as starch, calcium carbonate, Sucrose (Lucose) or lactose (Lactose), gelatin and the like are mixed and prepared. In addition to simple excipients, lubricants such as magnesium styrate talc are also used.

Oral liquid preparations include suspensions, solvents, emulsions, and syrups, and may include various excipients, such as wetting agents, sweeteners, fragrances, and preservatives, in addition to commonly used simple diluents such as water and liquid paraffin. . Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, suppositories. As the non-aqueous solvent and the suspension solvent, propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like can be used. As the base of the suppository, witepsol, macrogol, tween 61, cacao butter, laurin butter, glycerogelatin and the like can be used.

In general, in medicine, the effective dose of the compound represented by the formula (1) according to the present invention is 1.2 g / day for adults and may be administered 2-3 times a day. However, the dosage may need to be changed, and in particular, may be changed in consideration of the constitution specificity and weight of the subject to be treated, the type and depth of the disease, the nature of the formulation, the nature of the drug administration, and the duration or interval of administration.

As a result of measuring the antimicrobial activity of the oxazolidinone compound represented by Formula 1 according to the present invention, it was confirmed that the antimicrobial spectrum was wide and some compounds also had excellent in vivo effects. In addition, compounds of the present invention are Staphylococcus Kokai (Staphylococci), those resistant to existing antibiotics, Enterobacter Kokai (Enterococci), streptomycin Kokai (Streptococci) Gram-positive aerobic bacteria teroyi, as well as foil des species (Bacteroides), such as a Claus tea Lydia Humans , including anaerobic organisms such as Clostridia , and acidic microorganisms such as Mycobacterium species such as Mycobacterium tuberculosis and Mycobacterium avium And showed strong antibacterial effect on animal pathogens.

Hereinafter, the present invention will be described in detail by preparation examples and examples. However, the following examples are merely to illustrate the invention and the present invention is not limited by the examples.

Preparation Example 1 Preparation of 2- (1-tetrazolyl) -5-bromopyridine

1.0 g of 2,5-dibromopyridine was dissolved in 10 ml of 1-methyl-2-pyrrolidone, 0.5 g of 1,2,3,4-tetrazole and 1.75 g of potassium carbonate were added, followed by 3 hours at 100 ° C. Stirred. After completion of the reaction, the reaction was carried out in the same manner as in Preparation Example 3 to obtain 0.8 g of the title compound.

^OneH NMR (DMSO-d₆) δ 10.17 (s. 1 H), 8.80 (d, 1 H), 8.40 (dd, 1 H) , 8.00 (d, 1H),

Preparation Example 2 Preparation of 2- [5-methyl- (1,3,4) -oxadiazol-2-yl] -5-bromopyridine

1 g of 2- (5-tetrazolyl) -5-bromopyridine was dissolved in 10 ml of acetic anhydride and refluxed for 2 hours. After the reaction was completed, the work up was carried out in the same manner as in Preparation Example 3 to obtain 0.6 g of the title compound.

^OneH NMR (CDCl₃) 8.79 (d.1H), 8.09 (dd, 1H), 7.97 (dd, 1H) , 2.64 (s, 3H)

Preparation Example 3 Preparation of 2- [5-methyl- (1,2,4) -oxadiazol-3-yl] -5-bromopyridine

8.6 g of 2- (imino-N-hydroxyaminomethyl) -5-bromopyridine was dissolved in 250 ml of acetic anhydride and refluxed for one day. After completion of the reaction, the reaction was carried out in the same manner as in Preparation Example 3 to obtain 2.8 g of the title compound.

¹ H NMR (CDCl ₃ ) δ8.80 (dd.1H), 7.96 (dd, 2H), 2.67 (s, 3H)

Preparation Example 4 Preparation of 2- (1-methyl-5-tetrazolyl) -5-bromopyridine and 2- (2-methyl-5-tetrazolyl) -5-bromopyridine

400 mg of 2- (5-tetrazolyl) -5-bromopyridine was dissolved in 5 ml of dimethylformamide, 502 mg of iodomethane and 300 mg of potassium hydroxide were added and stirred at room temperature for 1 hour. After completion of the reaction, work up in the same manner as in Preparation Example 3 to obtain 110 (2- (1-methyl-5-tetrazolyl) -5-bromopyridine and 2- (2-methyl-5-tetrazolyl) -5-bro 220 mg of furridine were obtained, respectively.

NMR data of 2- (1-methyl-5-tetrazolyl) -5-bromopyridine

¹ H NMR (CDCl ₃ ) δ8.80 (d, 1H), 8.11 (d, 1H), 7.96 (dd, 1H), 4.42 (s, 3H)

NMR data of 2- (2-methyl-5-tetrazolyl) -5-bromopyridine

¹ H NMR (CDCl ₃ ) δ8.77 (d, 1H), 8.25 (d, 1H), 8.03 (dd, 1H), 4.48 (s, 3H)

Preparation Example 5 Preparation of 2- [4-carboethoxy- (1,2,3) -triazol-1-yl] -5-bromopyridine

100 mg of 2-azide-5-bromopyridine was dissolved in 1 ml of dimethylformamide, and 10 mg of ethylpropioate was added at room temperature, followed by reaction at 120 ° C. After completion of the reaction, work up in the same manner as in Preparation Example 3 to obtain 100 mg of the title compound.

^OneH NMR (DMSO-d₆δ8.85 (d.1H), 8.74 (dd, 1H), 8.34 (dd, 1H) , 8.06 (t, 1H), 4.38 (q, 2H), 2.03 (s.1H), 1.23 (t, 3H)

Preparation Example 6 Preparation of 2- (3-pyrroline-1-yl) -5-bromopyridine

10 g of 2,5-dibromopyridine was dissolved in 100 ml of 1-methyl-2-pyrrolidone, 3.5 ml of 3-pyrrolidine and 8.7 g of potassium carbonate were added at room temperature and stirred at 100 ° C. for 24 hours. After completion of the reaction, the reaction was carried out in the same manner as in Preparation Example 3 to obtain 8 g of the title compound.

¹ H NMR (CDCl ₃ ) δ7.48 (d.1H), 7.39 (dd, 1H), 6.21 (d, 1H), 5.89 (s, 2H), 4.15 (s, 4H)

Preparation Example 7 Preparation of 2- [2-oxo- (1,3) -oxazolindin-1-yl] -5-bromopyridine

1.2 g of 2-oxazolidone was dissolved in 20 ml of 1-methyl-2-pyrrolidone, and 3.92 g of 2,5-dibromopyridine and 3.81 g of potassium carbonate were added at room temperature and stirred at 120 ° C. for 4 hours. After completion of the reaction, the resultant was worked up in the same manner as in Preparation Example 3 to obtain 50 mg of the title compound.

¹ H NMR (DMSO-d ₆ ) δ8.33 (d.1H), 8.12 (dd, 1H), 7.79 (dd, 1H), 4.47 (m, 2H), 4.22 (m, 2H)

Preparation Example 8 Preparation of 2-[(1,2,4) -oxadiazol-3-yl] -5-bromopyridine

1.0 g of 2- (imino-N-hydroxyaminomethyl) -5-bromopyridine was dissolved in 10 ml of triethyloxoformate, and then 2 to 3 drops of trifluoroboron ether (BH ₃ etherate) were added thereto. The reaction was refluxed for 3 hours. After completion of the reaction, work up in the same manner as in Preparation Example 3 to obtain 0.7 g of the title compound.

¹ H NMR (CDCl ₃ ) δ 8.77 (brs. ² H), 8.00 (m, 2H),

Preparation Example 9 Preparation of 2-[(1,2,3) -triazol-1-yl] -5-bromopyridine

1.72 g of 2,5-dibromopyridine is dissolved in 20 ml of 1-methyl-2-pyrrolidone and 1H500 mg of-(1,2,3) -triazole and 3 g of potassium carbonate were added at room temperature and stirred at 100 ° C. for 24 hours. After completion of the reaction, the reaction was carried out in the same manner as in Preparation Example 3 to obtain 120 mg of the title compound.

^OneH NMR (DMSO-d₆) δ 8.85 (d. 1 H), 8.75 (dd, 1 H), 8.34 (dd, 1 H) , 8.06 (t, 1H), 8.00 (s, 1H)

Preparation Example 10 Preparation of 2- [3-methyl-2-oxo- (2,3) -dihydro- (1,3,4) -triazol-1-yl-yl] -5-bromopyridine

Dissolve 311 mg of 2- [2-oxo- (2,3) -dihydro- (1,3,4) -triazol-1-yl] -5-bromopyridine in dimethylformamide and 217 mg of potassium hydroxide. 366 ml of iodine methane It was slowly added dropwise at 0 ° C. After stirring at room temperature for 4 hours, the reaction was terminated and worked up in the same manner as in Preparation Example 3 to obtain 290 mg of the title compound.

^OneH NMR (DMSO-d₆δ8.62 (d.1H), 8.61 (s, 1H), 8.27 (dd, 1H) , 8.13 (d, 1H), 3.39 (s, 3H)

Production Example 11 2- [3-t-butoxycarbonyl-2-oxo- (2,3) -dihydro- (1,3,4) -triazol-1-yl] -5-bromo Preparation of Pyridine

1.6 g of 2- [2-oxo- (2,3) -dihydro- (1,3,4) -triazol-1-yl] -5-bromopyridine was dissolved in 20 ml of methylene chloride and 1.11 ml of triethylamine. After adding 3.4 g of di-tertiary-butyldicamonate and a small amount of catalyst dimethylaminopyrrolidine, the mixture was stirred at room temperature for 1 hour, and the reaction was terminated. Get 2.84 g

^OneH NMR (CDCl₃) δ 8.47 (s.1H), 8.45 (dd, 1H), 8.13 (d, 1H) , 7.91 (dd, 1H), 1.16-1.20 (m, 9H)

Preparation Example 12 Preparation of 2- [2-oxo- (1,3) -imidazolidin-1-yl] -5-bromopyridine

15.14 g of 2,5-dibromopyridine is dissolved in 50 ml of 1-methyl-2-pyrrolidone and 2-oxo-1,3-imidazolidine (2-imidazolidone, 2-imidazolidinone ) 5.0 g and potassium carbonate 16.05 g were added at room temperature, and the mixture was stirred at 100 ° C. for 24 hours. After completion of the reaction, the resultant was worked up in the same manner as in Preparation Example 3 to obtain 2.0 g of the title compound.

^OneH NMR (CDCl₃δ 8.55 (d.1H), 8.45 (s, 1H), 8.34 (d, 1H) , 8.15 (dd, 1H)

Preparation Example 13 Preparation of 2-[(1,3) -oxazol-5-yl] -5-bromopyridine

Dissolve 200 mg of 5-bromo-2-formyl pyridine (5-bromo-2-pyridinyl aldehyde) in 5.4 ml of methanol, reflux for 3 hours after adding 231 mg of tosylmethylisocyanade and 178 mg of potassium carbonate. It was. After completion of the reaction, the reaction was carried out in the same manner as in Preparation Example 3 to obtain 204 mg of the title compound.

^OneH NMR (CDCl₃) δ 8.65 (d. 1 H), 7.95 (s, 1 H), 7.89 (dd, 1 H) , 7.68 (s, 1H) , 7.56 (d, 1H)

Preparation Example 14 Preparation of 2- (4-hydroxy-piperidin-1-yl) -5-bromopyridine

10 g of 2,5-dibromopyridine was dissolved in 100 ml of 1-methyl-2-pyrrolidone, 5.2 g of 4-hydroxypiperidine and 17.5 g of potassium carbonate were added at room temperature and stirred at 100 ° C. for 3 hours. . Post-treatment was carried out in the same manner as in Preparation Example 3 after the completion of reaction to obtain 9 g of the title compound.

^OneH NMR (CDCl₃) δ 7.43 (d. 1 H), 7.38 (dd, 1 H), 6.21 (d, 1 H), 4.69 (m, 1 H) , 3.72 (m, 2H), 3.12 (m, 2H), 1.75 (m, 2H), 1.34 (m, 2H)

Preparation Example 15 Preparation of 2- [3-t-butoxycarbonyl-2-oxo- (1,3) -imidazolidin-1-yl] -5-bromopyridine

200 mg of 2- (2-oxo-1,3-imidazolidin-1-yl) -5-bromopyridine is dissolved in 2 ml of tetrahydrofuran and 300 ml of triethylamine, di-tert-butyldica 216 mg of monate was reacted at room temperature for 4 hours. After the completion of the reaction, the reaction was carried out in the same manner as in Preparation Example 3 to obtain 310 mg of the title compound.

^OneH NMR (CDCl₃) δ 8.31 (d.1H), 8,21 (d, 1H), 7.72 (dd, 1H), 3.99 (m, 2H) , 3.87 (m, 2H), 1.54 (s, 9H)

Preparation Example 16 Preparation of (R)-[N-3- (3-fluorophenyl) -2-oxo-5-oxazolidinyl] methanol

(1) Preparation of N-carbenzyloxy-3-fluoroaniline

100 g (0.90 mole) of 3-fluoroaniline was dissolved in 1 L of tetrahydrofuran (THF), 150 g (1.8 mol) of sodium hydrogen carbonate (NaHCO ₃ ) was added, followed by cooling to 0 ° C. To the solution was slowly added 154 ml (1.08 mol) of carbobenzyloxy chloride (CbzCl, N- carbobenzyloxy chloride). The reaction mixture was stirred for 2 hours while maintaining 0 ℃ and extracted by adding 0.5 L of ethylacetate (ethylacetate). The extracted organic layer was washed with brine, dehydrated with anhydrous magnesium sulfate (MgSO ₄ ) and concentrated under reduced pressure. The residue was washed twice with n- hexane to give 132 g (85%) of the title compound as white crystals.

(2) Preparation of (R)-[N-3- (3-fluorophenyl) -2-oxo-5-oxazolidinyl] methanol

132 g (0.54 mol) of N-carbenzyloxy-3-fluoroaniline obtained above were dissolved in 1.3 L of tetrahydrofuran and cooled to -78 ° C. 370 ml of n -butyllithium ( n- BuLi, 1.6 M / n -hexane, 0.59 mol) were added slowly under nitrogen and stirred for about 10 minutes. To the solution 84 ml of (R)-(-)-glycidylbutyrate (1.1 mol) was slowly added and the reaction mixture was stirred at the same temperature for 2 hours and then reacted at room temperature for 24 hours. After the reaction was completed, ammonium chloride (NH ₄ CI) solution was added to the reaction solution at room temperature, and extracted with ethyl acetate (0.5 L). The extracted organic layer was washed with brine, dehydrated with anhydrous magnesium sulfate and distilled under reduced pressure. Subsequently, the residue obtained by distillation under reduced pressure was dissolved in ethyl acetate (100 ml), and n- hexane was added to give white crystals. The white crystals were filtered off to afford 80 g (70%) of the title compound.

¹ H NMR (DMSO-d ₆ ) δ7.85 (t, 1H), 7.58 (dd, 1H), 7.23 (dd, 1H), 4.69 (m, 1H), 4.02 (t, 1H), 3.80 (dd, 1H), 3.60 (br dd, 2H).

Preparation Example 17 Preparation of (S)-[N-3- (4-trimethylstannyl-3-fluorophenyl) -2-oxo-5-oxazolidinyl] methyl acetamide

(Step 1): Preparation of (S)-[N-3- (3-fluorophenyl) -2-oxo-5-oxazolidinyl] methyl amine

(1) Preparation of (R)-[N-3- (3-fluorophenyl) -2-oxo-5-oxazolidinyl] methyl methanesulfonate

55.1 g (0.26 mol) of (R)-[N-3- (3-fluorophenyl) -2-oxo-5-oxazolidinyl] methanol obtained in Preparation Example 16 was dissolved in methylene chloride (300 ml) and 0 54.4 ml (0.39 mol) of triethylamine and 24 ml (0.312 mol) of methanesulfonyl chloride were slowly added dropwise at 占 폚. After stirring the reaction mixture for about 40 minutes at 0 ℃, water was added, extracted with chloroform, dehydrated with anhydrous magnesium sulfate, concentrated under reduced pressure and dried to give 78.3 g of the title compound.

(2) Preparation of (R)-[N-3- (3-fluorophenyl) -2-oxo-5-oxazolidinyl] methyl azide

78 g (0.27 mol) of (R)-[N-3- (3-fluorophenyl) -2-oxo-5-oxazolidinyl] methyl methanesulfonate was dissolved in 800 ml of dimethylformamide and 26.3 g of sodium azide (0.41 mol) was added and the mixture was stirred at 100 ° C for 2 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate, dehydrated, concentrated under reduced pressure and dried to give 70 g of the title compound.

(3) Preparation of (S)-[N-3- (3-fluorophenyl) -2-oxo-5-oxazolidinyl] methyl amine

70 g of (R)-[N-3- (3-fluorophenyl) -2-oxo-5-oxazolidinyl] methyl azide was dissolved in a mixed solvent of 400 ml of tetrahydrofuran and 80 ml of methanol, followed by palladium carbon. 8 g of (Pd / C) was added, stirred at room temperature under hydrogen for 24 hours, filtered and concentrated under reduced pressure to give 54.6 g of the title compound.

(Step 2): Preparation of (S)-[N-3- (3-fluorophenyl) -2-oxo-5-oxazolidinyl] methyl acetamide

54.6 g (0.26 mol) of (S)-[N-3- (3-fluorophenyl) -2-oxo-5-oxazolidinyl] methyl amine obtained in step 1 was dissolved in 500 ml of methylene chloride, and After 72.4 ml (0.52 mol) of triethylamine and 36.8 ml (0.39 mol) of acetic anhydride were added, the reaction mixture was stirred for 1 hour while maintaining the reaction temperature at 0 ° C., followed by addition of water and extraction with chloroform. The extracted organic layer was washed with brine, dehydrated and concentrated under reduced pressure to obtain an off-white powder. The resulting off-white powder was washed three times with n- hexane to give 49.6 g (76%) of the title compound.

(Step 3): Preparation of (S)-[N-3- (4-iodo-3-fluorophenyl) -2-oxo-5-oxazolidinyl] methyl acetamide

54.5 g (0.22 mol) of (S)-[N-3- (3-fluorophenyl) -2-oxo-5-oxazolidinyl] methyl acetamide obtained in step 2 was diluted with 2.5 L acetic acid and trifluoroacetic acid 700 455.7 g (2.8 mol) of iodine monochloride (ICl) dissolved in ml of a mixed solvent and dissolved in 300 ml of acetic acid was slowly added dropwise at room temperature. After stirring the reaction mixture at room temperature for 15 hours, diethyl ether was added to form a solid, and the resultant solid was dissolved in a mixed solvent of chloroform and methanol, followed by sodium thiosulfate solution and sodium hydrogen carbonate (NaHCO ₃ Washed with solution and dehydrated. The residue was concentrated under reduced pressure and dried to give 59.5 g (80.4%) of the title compound.

¹ H NMR (DMSO-d ₆ ) δ 8.23 (t, 1H), 7.82 (dd, 1H), 7.56 (dd, 1H), 7.18 (dd, 1H). 4.74 (m, 1H), 4.10 (t, 1H), 3.73 (dd, 1H), 3.40 (br dd, 2H), 1.83 (s, 3H)

(Step 4): Preparation of (S)-[N-3- (4-trimethylstannyl-3-fluorophenyl) -2-oxo-5-oxazolidinyl] methyl acetamide

660 ml of 1,4-dioxane, 50 g of (S)-[N-3- (4-iodo-3-fluorophenyl) -2-oxo-5-oxazolidinyl] methyl acetamide obtained in step 3 The solution was dissolved in 52 g of hexamethylditin ((Me ₃ Sn) ₂ ) and 9.3 g of dichlorobistriphenylphosphinepalladium (II), followed by reflux for 2 hours. Filtration was carried out using celite, concentrated under reduced pressure, and the residue was purified by column chromatography to separate 45 g of the titled compound.

¹ H NMR (DMSO-d ₆ ) δ 8.23 (t, 1H), 7.74 (dd, 1H), 7.54 (dd, 1H), 7.11 (dd, 1H). 4.74 (m, 1H), 4.10 (t, 1H), 3.73 (dd, 1H), 3.40 (br dd, 2H), 1.83 (s, 3H), 0.30 (s, 8H)

<Example 1> ( S Preparation of)-[N-3- [4- [2- (tetrazol-1-yl) -5-pyridinyl] -3-fluorophenyl] -2-oxo-5-oxazolidinyl] methyl acetamide

734 mg of ( S )-[N-3- (4-trimethylstannyl-3-fluorophenyl) -2-oxo-5-oxazolidinyl] methyl acetamide obtained in Production Example 17 was added to 8.8 ml of dimethylformamide. After dissolving, 600 mg of 2- (1-tetrazolyl) -5-bromopyridine obtained in Preparation Example 1, 0.49 ml of triethylamine and 372 mg of dichlorobistriphenylphosphinepalladium (II) were respectively added, and then 100 for 4 hours. Stir at ° C. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The extracted organic layer was washed with brine, dehydrated, filtered and concentrated under reduced pressure, and then purified by column chromatography to obtain 110 mg of the title compound.

¹ H NMR (DMSO-d ₆ ) δ 10.22 (s, 1H), 8.83 (s, 1H), 8.39 (dd, 1H), 8.30 (t, 1H), 8.15 (d, 1H), 7.76 (m, 2H ), 7.47 (dd, 1H) 4.78 (m, 1H), 4.16 (t, 1H), 3.80 (dd, 1H), 3.43 (t, 2H), 1.83 (s, 3H)

Example 2 (S)-[N-3- [4- [2- [5-methyl- (1,3,4) -oxadiazol-2-yl] -5-pyridinyl] -3- Fluorophenyl] -2-oxo-5-oxazolidinyl] methyl acetamide

1 g of ( S )-[N-3- (4-trimethylstannyl-3-fluorophenyl) -2-oxo-5-oxazolidinyl] methyl acetamide obtained in Production Example 17 was diluted with 1-methyl-2-. Dissolved in 10 ml of pyrrolidone, 600 mg of 2- (1,3,4-oxadiazole) -5-bromopyridine, 320 mg of lithium chloride, dichlorobistriphenylphosphinepalladium (II) 100 at room temperature After adding mg each, it stirred at 100 degreeC for 4 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with brine, dehydrated, filtered and concentrated under reduced pressure, and then purified by column chromatography to obtain 300 mg of the title compound.

¹ H NMR (DMSO-d ₆ ) δ 9.99 (s.1H), 8.73 (s, 1H), 8.26 (t, 1H), 7.95 (m, 2H), 7.64 (m, 2H), 7.47 (dd, 1H ), 4.78 (m, 1H), 4.16 (t, 1H), 3.80 (dd, 1H), 3.43 (t, 2H), 1.83 (s, 3H)

Example 3 (S)-[N-3- [4- [2- [5-methyl- (1,2,4) -oxadiazol-3-yl] pyridin-5-yl] -3- Fluorophenyl] -2-oxo-5-oxazolidinyl] methyl acetamide

The above example, except that 2.8 g of 2- [5-methyl- (1,2,4) -oxadiazol-3-yl] -5-bromopyridine was used instead of 2-cyano-5-bromopyridine 280 mg of the title compound were obtained in the same manner as in 2.

¹ H NMR (CDCl ₃ ) δ 8.85 (s, 1H), 8.09 (d, 1H), 7.97 (m, 1H), 7.58 (dd, 1H), 7.45 (t, 1H), 7.26 (dd, 1H), 6.50 (t, 1H), 4.81 (m, 1H), 4.10 (t, 1H), 3.84 (dd, 1H), 3.68 (m, 2H), 2.67 (s, 3H), 2.01 (s, 3H)

Example 4 (S)-[N-3- [4- [2- (1-Methyl-tetrazol-5-yl) -5-pyridinyl] -3-fluorophenyl] -2-oxo- Preparation of 5-oxazolidinyl] methyl acetamide

60 mg of the title compound was obtained by the same method as Example 2, except that 110 mg of 2- (1-methyl-5-tetrazolyl) -5-bromopyridine was used instead of 2-cyano-5-bromopyridine. .

¹ H NMR (CDCl ₃ ) δ8.89 (s, 1H), 8.29 (d, 1H), 8.00 (m, 1H), 7.61 (dd, 1H), 7.46 (t, 1H), 7.26 (dd, 1H) , 6.12 (t, 1H), 4.80 (m, 1H), 4.45 (s, 3H), 4.07 (t, 1H), 3.83 (dd, 1H), 3.67 (m, 2H), 2.02 (s, 3H)

Example 5 (S)-[N-3- [4- [2- (2-Methyl-tetrazol-5-yl) -5-pyridinyl] -3-fluorophenyl] -2-oxo- Preparation of 5-oxazolidinyl] methyl acetamide

180 mg of the title compound was obtained by the same method as Example 2, except that 220 mg of 2- (2-methyl-5-tetrazolyl) -5-bromopyridine was used instead of 2-cyano-5-bromopyridine. .

¹ H NMR (CDCl ₃ ) δ 8.85 (s, 1H), 8.34 (d, 1H), 8.00 (m, 1H), 7.56 (dd, 1H), 7.40 (t, 1H), 7.26 (dd, 1H), 4.76 (m, 1H), 4.49 (s, 3H), 4.07 (t, 1H), 3.79 (dd, 1H), 3.59 (m, 2H), 1.96 (s, 3H)

Example 6 (S)-[N-3- [4- [2- [4-ethoxycarbonyl- (1,2,3) -triazol-1-yl] -5-pyridinyl]- 3-fluorophenyl] -2-oxo-5-oxazolidinyl] methyl acetamide

Except for using 200 mg of 2- [4-ethoxycarbonyl- (1,2,3) -triazol-1-yl] -5-bromopyridine instead of 2-cyano-5-bromopyridine 60 mg of the title compound were obtained in the same manner as in Example 2.

H NMR (DMSO-d ₆ ) δ 9.02 (s, 1H), 8.59 (s, 1H), 8.16 (dd, 1H), 8.02 (dd, 1H), 7.51 (dd, 1H), 7.35 (t, 1H) , 7.29 (dd, 1H), 6.63 (t, 1H), 4.78 (m, 1H), 4.42 (tr, 2H) 4.16 (t, 1H), 3.80 (dd, 1H), 3.43 (t, 2H), 1.83 (s, 3H), 1.37 (t, 3H)

Example 7 (S)-[N-3- [4- [2- (3-pyrrolinyl) -5-pyridinyl] -3-fluorophenyl] -2-oxo-5-oxazolidinyl ] Production of Methyl Acetamide

60 mg of the title compound was obtained by the same method as Example 2, except that 200 mmg of 2- (3-pyrrolinyl) -5-bromopyridine was used instead of 2-cyano-5-bromopyridine.

¹ H NMR (CDCl ₃ ) δ 8.27 (brm, 2H), 7.53 (m, 2H), 7.40 (m, 1H), 6.49 (dd, 1H), 6.03 (s, 1H), 4.76 (m, 1H), 4.07 (t, 1H), 3.79 (dd, 1H), 3.59 (m, 2H), 3.40 (m, 2H), 1.96 (m, 2H), 1.92 (s, 3H)

Example 8 (S)-[N-3- [4- [2-2-oxo-oxazolidin-3-yl] -5-pyridinyl] -3-fluorophenyl] -2-oxo- Preparation of 5-oxazolidinyl] methyl acetamide

14 mg of the title compound was prepared in the same manner as in Example 2, except that 150 mg of 2- (2-oxo-3-oxazolidinyl) -5-bromopyridine was used instead of 2-cyano-5-bromopyridine. Got it.

¹ H NMR (CDCl ₃ ) δ 8.37 (s, 1H), 8.19 (d, 1H), 7.80 (m, 1H), 7.44 (m, 2H), 7.34 (t, 1H), 7.16 (dd, 1H), 4.67 (m, 1H), 4.41 (m, 1H), 4.23 (m, 1H), 3.91 (t, 1H), 3.74 (dd, 1H), 3.50 (m, 2H), 1.87 (s, 3H)

Example 9 (S)-[N-3- [4- [2- (5-oxazolyl) -5-pyridinyl] -3-fluorophenyl] -2-oxo-5-oxazolidinyl] Preparation of Methyl Acetamide

130 mg of the title compound was obtained by the same method as Example 2, except that 204 mg of 2- (5-oxazolyl) -5-bromopyridine was used instead of 2-cyano-5-bromopyridine.

¹ H NMR (DMSO-d ₆ ) δ 8.82 (s, 1H), 8.57 (s, 1H), 8.27 (m, 1H), 8.10 (m, 1H), 7.88 (s, 1H), 7.85 (s, 1H ), 7.68 (m, 2H), 7.44 (dd, 1H), 4.76 (m, 1H), 4.17 (t, 1H), 3.79 (dd, 1H), 3.43 (t, 2H), 1.83 (s, 3H)

Example 10 (S)-[N-3- [4- [2-[(1,2,4) -Oxadiazol-3-yl] -5-pyridinyl] -3-fluorophenyl] Preparation of 2-oxo-5-oxazolidinyl] methyl acetamide

Same method as in Example 2, except that 700 mg of 2-[(1,2,4) -oxadiazol-3-yl] -5-bromopyridine was used instead of 2-cyano-5-bromopyridine. 300 mg of the title compound were obtained.

¹ H NMR (CDCl ₃ ) δ 8.82 (t, 1H), 7.99 (m, 1H), 7.75 (dd, 1H), 7.61 (dd, 1H), 7.30 (t, 2H), 7.28 (dd, 1H), 4.76 (m, 1H), 4.06 (t, 1H), 3.80 (dd, 1H), 3.58 (m, 2H), 1.96 (s, 3H)

Example 11 (S)-[N-3- [4- [2-[(1,2,3) -triazol-1-yl] -5-pyridinyl] -3-fluorophenyl]- Preparation of 2-oxo-5-oxazolidinyl] methyl acetamide

In the same manner as in Example 2, except that 120 mg of 2-[(1,2,4) -triazol-1-yl] -5-bromopyridine was used instead of 2-cyano-5-bromopyridine. 90 mg of the title compound were obtained.

¹ H NMR (DMSO-d ₆ ) δ 8.90 (d, 1H), 8.78 (s, 1H), 8.29 (m, 3H), 8.02 (d, 1H), 7.70 (m, 2H), 7.46 (dd, 1H ), 4.76 (m, 1H), 4.17 (t, 1H), 3.79 (dd, 1H), 3.43 (t, 2H), 1.83 (s, 3H)

Example 12 (S)-[N-3- [4- [2- [3-methyl-2-oxo- (1,3,4) -triazol-1-yl] -5-pyridinyl] 3-Fluorophenyl] -2-oxo-5-oxazolidinyl] methyl acetamide

Except for using 290 mg of 2- [3-methyl-2-oxo- (1,3,4) -triazolyl-1yl] -5-bromopyridine instead of 2-cyano-5-bromopyridine 160 mg of the title compound was obtained in the same manner as in Example 2.

¹ H NMR (DMSO-d ₆ ) δ 8.68 (s, 1H), 8.66 (s, 1H), 8.27 (m, 3H), 7.64 (m, 2H), 7.46 (dd, 1H), 4.75 (m, 1H ), 4.17 (t, 1H), 3.78 (dd, 1H), 3.44 (t, 2H), 3.41 (s, 3H), 1.83 (s, 3H)

Example 13 (S)-[N-3- [4- [2- [2-oxo- (1,3) -imidazolidin-1-yl] -5-pyridinyl] -3-fluoro Rophenyl] -2-oxo-5-oxazolidinyl] methyl acetamide

150 mg of 2- [2-oxo-3-t-butyloxy carbonyl- (1,3) -imidazolidin-1-yl] -5-bromopyridine instead of 2-cyano-5-bromopyridine 25 mg of the title compound from which t-butyloxy carbonyl group was released was reacted in the same manner as in Example 2 except for using.

¹ H NMR (CDCl ₃ ) δ8.29 (s, 1H), 8.21 (dd, 1H), 7.66 (m, 1H), 7.52 ~ 7.39 (m, 2H), 7.27 (d, 1H), 7.12 (dd, 1H), 4.67 (m, 1H), 4.07-3.88 (m, 2H), 3.70 (dd, 1H), 3.50-3.27 (mt, 4H), 1.87 (s, 3H)

Example 14 (S)-[N-3- [4- [2- (4-hydroxy-piperidin-1-yl) -5-pyridinyl] -3-fluorophenyl] -2- Preparation of oxo-5-oxazolidinyl] methyl acetamide

The title compound in the same manner as in Example 2, except that 1.9 g of 2- (4-hydroxy-piperidin-1-yl) -5-bromopyridine was used instead of 2-cyano-5-bromopyridine. 400 mmg was obtained.

¹ H NMR (DMSO-d ₆ ) δ 8.27 (s.1H), 8.24-8.22 (t, 1H), 7.67 (dd, 1H), 7.52 (dd, 1H), 7.47 (dd, 1H), 6.91 (d , 1H), 4.75 (m, 1H), 4.69 (d, 1H), 4.16 (d, 1H), 4.07 (m, 2H), 3.72 (m, 2H), 3.43 (t, 2H), 3.12 (m, 2H), 1.83 (s, 3H), 1.75 (m, 2H), 1.34 (m, 2H)

Example 15 (S)-[N-3- [4- [2-oxo- (2,3) -dihydro- (1,3,4) -triazol-1-yl] -5-pyri Diyl] -3-fluorophenyl] -2-oxo-5-oxazolidinyl] methyl acetamide

2- [3-t-butoxycarbonyl-2-oxo- (2,3) -dihydro-1,3,4-triazol-1-yl] instead of 2-cyano-5-bromopyridine The reaction was conducted in the same manner as in Example 2, except that 500 mg of 5-bromopyridine was used to obtain 100 mg of the title compound from which the t-butyloxy carbonyl group was released.

¹ H NMR (DMSO-d ₆ ) δ8.60 (dd, 1H), 8.21 (m, 2H), 7.68 (d, 1H), 7.62 ~ 7.44 (dd, 1H), 4.76 (m, 1H), (t , 1H), 3.79 (dd, 1H), 3.59 (m, 2H), 3.15 (m, 2H), 1.96 (s, 3H),

Example 16 (S)-[N-3- [4- [2- [5-hydroxymethyl- (1,2,4) -oxadiazol-3-yl] -5-pyridinyl]- 3-fluorophenyl] -2-oxo-5-oxazolidinyl] methyl acetamide

(Step 1): of (S)-[N-3- [4- (2-cyano-5-pyridinyl) -3-fluorophenyl] -2-oxo-5-oxazolidinyl] methyl acetamide Produce

10.7 g of Compound (S)-[N-3- (4-trimethylstannyl-3-fluorophenyl) -2-oxo-5-oxazolidinyl] methyl acetamide prepared in Production Example 17 was diluted with 1-methyl- It was dissolved in 85 ml of 2-pyrrolidone and 4.7 g of 2-cyano-5-bromopyridine, 3.27 g of lithium chloride and 0.9 g of dichlorobistriphenylphosphinepalladium (II) were added at room temperature for 120 hours. Stirred at. After completion of the reaction was worked up in the usual manner to obtain 4.67 mg of the title compound.

¹ H NMR (DMSO-d ₆ ) δ 8.95 (s.1H), 8.26-8.22 (dd, 2H), 8.15 (d, 1H), 7.76 (m, 2H), 7.47 (dd, 1H), 4.78 (m , 1H), 4.16 (t, 1H), 3.80 (dd, 1H), 3.43 (t, 2H), 1.83 (s, 3H)

(Step 2): (S)-[N-3- (4- (2-imino-N-hydroxyaminomethyl-5-pyridinyl) -3-fluorophenyl) -2-oxo-5-oxa Preparation of Zolidinyl] methyl Acetamide

7 g of (S)-[N-3- (2-cyano-5-pyridinyl) -3-fluorophenyl) -2-oxo-5-oxazolidinyl] methyl acetamide obtained in the step was added to ethanol 100 It was dissolved in ml and 5.0 g of sodium bicarbonate and 3.4 g of hydroxy amine were added at room temperature, and the mixture was refluxed for 2 hours. After completion of the reaction, work up in the usual manner to obtain 6 g of the title compound.

¹ H NMR (DMSO-d ₆ ) δ 9.99 (s.1H), 8.73 (s, 1H), 8.26 (t, 1H), 7.95 (m, 2H), 7.64 (m, 2H), 7.47 (dd, 1H ), 4.78 (m, 1H), 4.16 (t, 1H), 3.80 (dd, 1H), 3.43 (t, 2H), 1.83 (s, 3H)

(Step 3): (S)-[N-3- [4- [2- [5-hydroxymethyl- (1,2,4) -oxadiazol-3-yl] -5-pyridinyl]- 3-fluorophenyl] -2-oxo-5-oxazolidinyl] methyl acetamide

(S)-[N-3- (4- (2-imino-N-hydroxyaminomethyl-5-pyridinyl) -3-fluorophenyl) -2-oxo-5-oxazoli obtained in the above step After dissolving 2 g of dinyl] methyl acetamide in 20 ml of acetone, 1.1 g of potassium carbonate and 0.7 ml of acetoxy acetyl chloride were added at room temperature, and the mixture was refluxed for 6 hours. After completion of the reaction, the resultant was worked up by a conventional workup method, and the obtained residue was dissolved in 20 ml of pyridine and refluxed for 7 hours. After the reaction was concentrated under reduced pressure, citric acid solution was added, extracted with ethyl acetate, washed with brine, dehydrated, filtered, and concentrated under reduced pressure and dried. The obtained compound was dissolved in methanol and 588 mg of potassium carbonate was added thereto. Reacted. After completion of the reaction, water was added, extracted with chloroform, dehydrated, filtered and concentrated under reduced pressure, and then purified by column chromatography to obtain 600 mg of the title compound.

¹ H NMR (CDCl ₃ ) δ 8.85 (s, 1H), 8.06 (d, 1H), 8.00 (dd, 1H), 7.86 (t, 1H), 7.45 (dd, 1H), 7.40 (t, 1H), 7.22 (dd, 1H), 4.80 (s, 1H) 4.76 (m, 1H), 4.07 (t, 1H), 3.79 (dd, 1H), 3.59 (m, 2H), 1.96 (s, 3H)

Example 17 (S)-[N-3- [4- [2- (5-tetrazolyl) -5-pyridinyl] -3-fluorophenyl] -2-oxo-5-oxazolidinyl] Preparation of Methyl Acetamide

Compound (S)-[N-3- [4- (2-cyano-5-pyridinyl) -3-fluorophenyl] -2-oxo-5-oxazolidinyl] methyl acet prepared in Example 16 Amide 1 g was dissolved in 15 ml of dimethylformamide, 1.10 g of sodium azide and 0.91 g of ammonium chloride were added at room temperature, followed by stirring at 120 ° C. for 2 hours. After cooling to room temperature, 4 ml of ice water and 4 ml of ethyl acetate were added, 2 g of sodium nitrate was added thereto, and the pH of the solution was adjusted to about 2 with 6N aqueous HCl solution. After stirring at room temperature for 1 hour, the mixture was extracted with ethyl acetate, the organic layer was dehydrated, filtered and concentrated, and the obtained solid was recrystallized with ethyl ether to obtain 0.8 g of the title compound.

¹ H NMR (DMSO-d ₆ ) δ 8.97 (s, 1H), 8.29 (m, 3H), 7.72 (t, 1H), 7.65 (dd, 1H), 7.47 (dd, 1H), 4.78 (m, 1H ), 4.18 (t, 1H), 3.81 (dd, 1H), 3.44 (dd, 2H), 1.83 (s, 3H)

Example 18 (S)-[N-3- [4- [2- [5-methoxymethyl- (1,2,4) -oxadiazol-3-yl] -5-pyridinyl]- 3-fluorophenyl] -2-oxo-5-oxazolidinyl] methyl acetamide

Intermediate (S)-[N-3- [4- (2-imino-N-hydroxyaminomethyl-5-pyridinyl) -3-fluorophenyl] -2-oxo-5 prepared in Example 16 -Oxazolidinyl] methyl acetamide (300 mg) was dissolved in 5 ml of pyridine, and 450 ml of methoxyacetyl chloride was added at room temperature, followed by reflux for 1 hour. After completion of the reaction, the mixture was concentrated under reduced pressure, water was added to the residue, followed by extraction with ethyl acetate. The organic layer was washed with brine, dehydrated, filtered and concentrated under reduced pressure, and then purified by column chromatography to obtain 200 mg of the title compound.

¹ H NMR (CDCl ₃ ) δ 8.86 (s, 1H), 8.22 (d, 1H), 8.00 (dd, 1H), 7.64 (m, 1H), 7.46 (t, 1H), 7.25 (dd, 1H), 6.16 (t, 1H), 4.81 (s, 1H), 4.75 (m, 1H), 4.17 (t, 1H), 3.78 (dd, 1H), 3.44 (t, 2H), 3.55 (s, 3H), 2.01 (s, 3H)

Example 19 (S)-[N-3- [4- [2- [5-trichloromethyl- (1,2,4) -oxadiazol-3-yl] -5-pyridinyl] 3-fluorophenyl] -2-oxo-5-oxazolidinyl] methyl acetamide

Intermediate (S)-[N-3- [4- (2-imino-N-hydroxyaminomethyl-5-pyridinyl) -3-fluorophenyl] -2-oxo-5 prepared in Example 16 -Oxazolidinyl] methyl acetamide (600 mg) was dissolved in trichloroacetic acid (20 ml), and trichloroacetyl chloride (34 ml) was added at 85 ° C and reacted at 95 ° C for 3 hours. After completion of the reaction, water was added, extraction was performed with ethyl acetate, and the organic layer was washed with brine, dehydrated, filtered and concentrated under reduced pressure, and then purified by column chromatography to obtain 600 mg of the title compound.

¹ H NMR (CDCl ₃ ) δ 7.99 (m, 1H), 7.75 (dd, 1H), 7.61 (dd, 1H), 7.30 (t, 2H), 7.28 (dd, 1H), 4.76 (m, 1H), 4.06 (t, 1H), 3.80 (dd, 1H), 3.58 (m, 2H), 1.96 (s, 3H)

Example 20 (S)-[N-3- [4- [2- [5-dimethylamino- (1,2,4) -oxadiazol-3-yl] -5-pyridinyl] 3-fluorophenyl] -2-oxo-5-oxazolidinyl] methyl acetamide

Compound (S)-[N-3- [4- [2- [5-trichloromethyl- (1,2,4) -oxadiazol-3-yl] -5-pyridinyl, prepared in Example 19 ] -3-fluorophenyl] -2-oxo-5-oxazolidinyl] methyl acetamide was dissolved in 5 ml of dimethylpoamide, and 2 ml of dimethylamine was added at room temperature, followed by reaction for 4 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with brine, dehydrated, filtered and concentrated under reduced pressure, and then purified by column chromatography to obtain 40 mg of the title compound.

¹ H NMR (CDCl ₃ ) δ8.85 (s, 1H), 8.34 (d, 1H), 8.00 (m, 1H), 7.56 (dd, 1H), 7.40 (t, 1H), 7.26 (dd, 1H) , 4.76 (m, 1H),, 4.07 (t, 1H), 3.79 (dd, 1H), 3.59 (m, 2H), 3.15 (s, 6H), 1.96 (s, 3H)

Example 21 (S)-[N-3- [4- [2- [5-Amino- (1,2,4) -oxadiazol-3-yl] -5-pyridinyl] -3- Fluorophenyl] -2-oxo-5-oxazolidinyl] methyl acetamide

Compound (S)-[N-3- [4- [2- [5-trichloromethyl- (1,2,4) -oxadiazol-3-yl] -5-pyridinyl, prepared in Example 19 ] -3-fluorophenyl] -2-oxo-5-oxazolidinyl] methyl acetamide (500 mg) was dissolved in 5 ml of methanol and refluxed for 24 hours after adding 273 mg of cyanogen bromide at room temperature. Water was added to terminate the reaction, followed by extraction with ethyl acetate. The organic layer was washed with brine, dehydrated, filtered and concentrated under reduced pressure, and then purified by column chromatography to obtain 13 mg of the title compound.

¹ H NMR (CDCl ₃ ) δ 8.87 (brm, 1H), 7.92 (m, 2H), 7.41 (m, 2H), 4.76 (m, 1H), 4.07 (t, 1H), 3.79 (dd, 1H), 3.59 (m, 2H), 3.40 (m, 2H), 1.96 (m, 2H),

Example 22 (S)-[N-3- [4- [2- [4-acetylamino-piperidin-1-yl] -5-pyridinyl] -3-fluorophenyl] -2- Preparation of oxo-5-oxazolidinyl] methyl acetamide

Compound (S)-[N-3- [4- [2- (4-hydroxy-piperidin-1-yl) -5-pyridinyl] -3-fluorophenyl] -prepared in Example 14- 2-oxo-5-oxazolidinyl] methyl acetamide (400 mg) in methylene chloride (5 ml), and then triethylamine (530 ml) and metasulfonyl chloride (150 ml) were added at 0 ° C. The reaction was carried out at room temperature for 3 hours. Subsequently, water was added to the reaction mixture to terminate the reaction. The mixture was extracted with ethyl acetate, and the organic layer was washed with brine, dehydrated, filtered and concentrated under reduced pressure, and dried. The dried compound (450 mg) was dissolved in 5 ml of dimethylpoamide, and then 200 mg of sodyanazide was added and reacted at 90 ° C. for 3 hours. Water was added to the reaction mixture, and after completion of the GKU reaction, the mixture was extracted with ethyl acetate and the organic layer was washed with brine, dehydrated, filtered and concentrated under reduced pressure, and then dried (300 mg) was obtained. No further purification was dissolved in 4 ml of tetrahydrofuran, water (small amount), triphenylphosphine (200 mg) were added and refluxed for 3 hours, water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with brine, dehydrated, filtered, concentrated under reduced pressure and dried to obtain (S)-[N-3- [4- [2- (4-amino-piperidin-1-yl) -5-pyridine. Diyl] -3-fluorophenyl] -2-oxo-5-oxazolidinyl] methyl acetamide (250 mg) was obtained. Methylene chloride (5 ml) was added to this compound (100 mg), triethylamine (48 ml) and acetic anhydride (36 ml) were added at 0 ° C, and the mixture was reacted at room temperature for 1 hour. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with brine, dehydrated, filtered and concentrated under reduced pressure, and then purified by column chromatography to obtain 80 mg of the title compound.

NMR (CDCl ₃ ) δ 7.69 (dd, 1H), 7.52 (dd, 2H), 7.40 (dd, 1H), 6.98 (dd, 1H), 4.76 (m, 1H), 4.07 (t, 1H), 3.79 ( dd, 1H), 3.59 (m, 2H), 3.15 (m, 2H), 2.88 (t, 2H) 1.99 (m, 2H), 1.94 (s, 3H), 1.96 (s, 3H), 1.52 (m, 2H)

Example 23 (S)-[N-3- [4- [2- (4-acetyloxymethylcarbonylamino-1-piperidinyl) -5-pyridinyl] -3-fluorophenyl]- Preparation of 2-oxo-5-oxazolidinyl] methyl acetamide

Intermediate (S)-[N-3- [4- [2- (4-amino-piperidin-1-yl) -5-pyridinyl] -3-fluorophenyl] -2 prepared in Example 22 Tetrahydrofuran (5 ml) was added to oxo-5-oxazolidinyl] methyl acetamide (300 mg), triethylamine (300 ml) and acetoxyacetyl chloride (115 ml) were added at 0 ° C., and then room temperature. The reaction was carried out for 1 hour at. After completion of the reaction, water was added, extraction was performed with ethyl acetate, and the organic layer was washed with brine, dehydrated, filtered and concentrated under reduced pressure, and then purified by column chromatography to obtain 150 mg of the title compound.

¹ H NMR (DMSO-d ₆ ) δ 7.69 (dd, 1H), 7.52 (dd, 2H), 7.40 (dd, 1H), 6.98 (dd, 1H), 4.76 (m, 1H), 4.73 (s, 2H ) 4.07 (t, 1H), 3.79 (dd, 1H), 3.59 (m, 2H), 3.15 (m, 2H), 2.88 (t, 2H), 2.16 (s, 3H), 1.99 (m, 2H), 1.96 (s, 3H), 1.52 (m, 2H)

Example 24 (S)-[N-3- [4- [2- (4-hydroxymethylcarbonylamino-piperidin-1-yl) -5-pyridinyl] -3-fluorophenyl ] -2-oxo-5-oxazolidinyl] methyl acetamide

(S)-[N-3- [4- [2- (4-acetyloxymethylcarbonylamino-1-piperidinyl) -5-pyridinyl] -3-fluorophenyl] prepared in Example 23] 150 mg of -2-oxo-5-oxazolidinyl] methyl acetamide was dissolved in 2 ml of methanol, and 200 mg of potassium carbonate was added at room temperature to react for 2 hours. After completion of the reaction, the mixture was treated in a conventional work-up manner to obtain 100 mg of the title compound.

¹ H NMR (DMSO-d ₆ ) δ 7.69 (dd, 1H), 7.49 (dd, 2H), 7.40 (dd, 1H), 6.97 (dd, 1H), 4.76 (m, 1H), 4.75 (s, 2H ) 4.08 (t, 1H), 3.74 (dd, 1H), 3.59 (m, 2H), 3.15 (m, 2H), 2.88 (t, 2H), 1.99 (m, 2H), 1.96 (s, 3H), 1.52 (m, 2H)

Example 25 (S)-[N-3- [4- [2-[(3,4) -Dihydroxy-pyrrolidin-1-yl] -5-pyridinyl] -3-fluoro Phenyl] -2-oxo-5-oxazolidinyl] methyl acetamide

(S)-[N-3- [4- [2- (3-pyrrolinyl) -5-pyridinyl] -3-fluoronyl] -2-oxo-5-oxazoli prepared in Example 7 100 mg of dinyl] methyl acetamide was dissolved in 2 ml of a mixed solvent of water / acetone / acetonitrile (1: 1: 1), and 10 mg of osmium tetroxide was added thereto at room temperature for 10 hours. After completion of the reaction, work up in a conventional work-up manner to obtain 30 mg of the title compound.

¹ H NMR (DMSO-d ₆ ) δ 8.23 (m, 2H), 7.65 (dd, 1H), 7.47 (mdd, 1H), 7.40 (dd, 1H), 4.90 (m, 1H), 4.73 (t, 1H ) 4.13 (t, 1H), 3.79 (dd, 1H), 3.59 (m, 2H), 3.20 (m, 2H), 3.15 (m, 2H), 1.96 (s, 3H),

Meanwhile, the pharmaceutical composition comprising the compound of formula 1 as an active ingredient of the present invention may be administered parenterally and orally. For example, the compound of Example 1 may be injected into a parenteral formulation as an example. Was prepared.

Preparation Example 1 Preparation of Injection Solution

Injection solution containing 10 mg of the active ingredient was prepared by the following method.

1 g of the compound of Example 1, 0.6 g of sodium chloride and 0.1 g of ascorbic acid were dissolved in distilled water to make 100 ml. The solution was bottled and sterilized by heating at 20 ° C. for 30 minutes.

The components of the injection solution are as follows.

Compound of Example 1 ... 1 g

Sodium Chloride ・ ・ ・ ・ 0.6 g

0.1 g of ascorbic acid

Distilled water ··················

Preparation Example 2 Preparation of Syrup

Syrups containing an acid addition salt of the compound of the present invention and a pharmaceutically acceptable salt thereof as an active ingredient of 2% (weight / volume) are prepared by the following method.

Acid addition salt, saccharin and sugar of the compound of Example 1 were dissolved in 80 g of warm water. After the solution was cooled, a solution consisting of glycerin, saccharin, spices, ethanol, sorbic acid and distilled water was prepared and mixed thereto. Water was added to this mixture to 100 ml.

The components of the syrup are as follows.

Acid addition salts of the compound of Example 1 2 g

Saccharin: 0.8 g ················

25.4 g of sugar

Glycerin ... 8.0 g

Spices ··················· 0.04 g

Ethanol 4.0 g

0.4 g of sorbic acid

Distilled water ·····················

Preparation Example 3 Manufacturing Method

A tablet containing 15 mg of active ingredient is prepared by the following method.

250 g of the compound of Example 1 were mixed with 175.9 g of lactose, 180 g of potato starch and 32 g of colloidal silicic acid. 10% gelatin solution was added to the mixture, which was then ground and passed through a 14 mesh sieve. It was dried and the mixture obtained by adding 160 g of potato starch, 50 g of talc and 5 g of magnesium stearate was made into a tablet.

The components of the tablet are as follows.

Compound of Example 1 ... 250 g

Lactose ········ 175.9 g

Potato starch ········· 180 g

Colloidal silicic acid 32 g

10% gelatin solution

Potato starch · 160 g

Talc · 50 g

Magnesium stearate ·········· 5

Experimental Example 1 Measurement of In Vitro Antimicrobial Activity

In order to examine the antimicrobial activity of the compounds according to the present invention, agar dilution described in the literature is resistant to methicillin and methicillin resistant Staphylococcus aureus (MRSA) and vancomycin resistant Enterobacter showed in Kokai minimum inhibitory concentration (MIC, ㎍ / ㎖) the antibacterial activity of the (VRE, vancomycin resistant Enterococci) in this case we compared the antibiotic activity in the U-100766 compound of formula (3) as a control substance (Chemotheraphy,

29 (1), 76, ( 1981 )). The results are as shown in Table 2 below.

compound Antimicrobial Activity (MIC ₅₀ , ㎍ / mL) MRSA VRE U-100766 3.13 1.56 One 0.39 0.2 2 0.39 0.2 3 0.78 0.39 4 0.78 0.2 5 0.78 0.2 8 0.2 0.1 9 0.39 0.2 10 0.39 0.2 11 0.39 0.2 12 0.78 0.2 17 > 25 25 23 0.78 0.2 MRSA: methicillin resistant Staphylococcus aureus VRE: vancomycin resistant Enterococci resistant to vancomycin

As can be seen in Table 2 , the compounds of the present invention are resistant to staphylococcus and enterocokai that are resistant to conventional antibiotics at much lower concentrations than the U-100766 compound of Formula 3, which is licensed by the US Food and Drug Administration. It can be seen that the antimicrobial activity. One characteristic of the compounds 1,3,5,6 is that in case of compounds in which tetrazole is substituted with pyridine ring, there are many differences in antimicrobial activity depending on the substitution position of tetrazole and the substituents substituted in tetrazole. You can see that.

Experimental Example 2 Oral Acute Toxicity in Mice

In order to determine the acute toxicity of the compound according to the present invention was performed the following experiment. 200 mg of each compound of Examples 3, 4, and 5 were prepared orally administered to 1 g / 10 ml / kg of 5 male ICR mice (20 g ± 2 g) at 5 weeks of age by preparing 1% of hydroxypropyl methylcellulose embryoids. The minimum lethal dose (MLD, mg / kg) was examined by observing mortality, body weight, and clinical symptoms for 2 weeks. The results are shown in Table 3 below.

compound Minimum lethal dose (MLD, mg / kg) U-100766 > 1000 Example 3 > 1000 Example 4 > 1000 Example 17 > 1000

As a result of oral acute toxicity test, all mice administered the test substance according to the present invention had no clinical symptoms and no dead animals, and also toxicity in weight change, blood test, blood biochemical test, autopsy findings, etc. No change was observed. As can be seen in Table 3 , the compounds of the present invention represented by the formula (1) was not only excellent in the antimicrobial effect but also determined to be a safe substance with a minimum lethal dose of 1 g / kg or more.

As described above, the oxazolidinone compounds represented by Chemical Formula 1 of the present invention not only have a broad antibacterial spectrum but also have resistance to conventional antibiotics, as well as Gram-positive aerobic bacteria such as Staphylocokai, Enterocokai, and Streptocokai, Excellent antimicrobial against a variety of human and animal pathogens, including anaerobic organisms such as the Teroides species and Clostridia species, and antimicrobial microorganisms such as the Mako bacterium species such as Mycobacterium tumerculosis and Mycobacterium avium The oxazolidinone compounds of the present invention can be usefully used as antibiotics because of their low toxicity and low toxicity.

Claims (8)

An oxazolidinone derivative including a pyridine ring represented by the following formula (1) and a pharmaceutically acceptable salt thereof. Formula 1 In Chemical Formula 1, R ₁ is H, F, Cl or CF ₃ , R ₂ is a heterocyclic ring or heteroaromatic ring substituted with R ₃ or R ₄ , 1) a pentagonal or hexagonal heterocycle containing one or more carbon (C), nitrogen (N), or oxygen (O), preferably nitrogen or oxygen atoms alone or in two or more, or It is a ring compound containing at least one nitrogen or oxygen each, more preferably , , , or to be. 2) a pentagonal ring consisting of carbon (C), nitrogen (N) or oxygen (O), saturated with two hydrogens on either carbon directly constituting the ring, or oxygen (ketone), Heterocylic ring consisting of a double bond with nitrogen (imino) or sulfur (thioketone), preferably , or (Where A, B, and D are carbon, oxygen, or nitrogen, and may be the same or different, and E may be two hydrogen, oxygen, sulfur, or nitrogen), and more preferably , , , , , or to be. 3) Heteroaromatic ring having five or six-membered aromatic properties consisting of carbon (C), nitrogen (N), oxygen (O) or sulfur (S), preferably Nitrogen or oxygen is a ring consisting of only one or two or a ring compound containing one or more oxygen and nitrogen each of the following are the most representative rings, more preferably , , , , , , , , , , , , or to be. R ₃ and R ₄ are the same as or different from each other, (a) hydrogen, F, Cl, Br or I, (b) alkyl groups (C _{1 to} C ₄ ) substituted or unsubstituted with one or more substituents, wherein the substituted alkyl group is hydroxyalkyl, alkoxycarbonylalkyl, trihaloalkyl, acetoxyalkyl, alkylamino Alkyl, alkoxyalkyl or methanesulfonyloxyalkyl group), (c) an acetyl group (where the substituted acetyl group is unsubstituted or substituted acetoxy, acetyl, hydroxy, acetyl, alkoxy, acetyl, amino acetyl in C ₁ ~C ₃ alkyl-amino-acetoxy acetyl, C ₁ ~C ₃ a, ah map acetyl, acetylamino, acetyl, is a C ₁ ~C ₃ alkyl, amino, acetyl, propionyl amino, or hydroxy-propionyl group.) (d) Ajido, (e) hydroxy, (f) mercapto, (g) cyano, (h) ketones, (i) substituted or unsubstituted imino, wherein the substituted imino group is a hydroxyimino, alkylimino, alkoxyimino or methanesulfonyloxyimino group, (j) -OR _5, wherein R ₅ is hydrogen, C ₁ -C ₃ alkyl, acetyl, alkoxyalkyl, hydroxy acetyl or methanesulfonyl group, (k) —NR ₆ R _{7, wherein} R ₆ and R ₇ are each hydrogen, C ₁ -C ₄ alkyl, acetyl, alkoxyalkyl, hydroxy acetyl or methanesulfonyl groups. The oxazolidinone derivative comprising a pyridine ring and a pharmaceutically acceptable salt thereof according to claim 1, wherein R ₁ is F. The oxazoli comprising a pyridine ring according to claim 1, wherein R ₂ is triazole, tetrazole, oxazole, oxadiazole, oxazolidine, piperidine, pyrroline, imidazole or derivatives thereof. Dinon derivatives and pharmaceutically acceptable salts thereof. The compound of claim 1 wherein 1) (S)-[N-3- (4- (2- (1-tetrazolyl) -5-pyridinyl) -3-fluorophenyl) -2-oxo-5-oxazolidinyl] methyl acetamide 2) (S)-[N-3- [4- [2- [5-methyl- (1,3,4) -oxadiazol-2-yl] -5-pyridinyl] -3-fluorophenyl ] -2-oxo-5-oxazolidinyl] methyl acetamide 3) (S)-[N-3- [4- [2-[-methyl- (1,2,4) -oxadiazol-3-yl] pyridin-5-yl] -3-fluorophenyl) -2-oxo-5-oxazolidinyl] methyl acetamide 4) (S)-[N-3- (4- (2- (1-methyl-5-tetrazolyl) -5-pyridinyl) -3-fluorophenyl) -2-oxo-5-oxazolidinyl ] Methyl acetamide 5) (S)-[N-3- [4- [2- [2-methyl-5-tetrazolyl] -5-pyridinyl] -3-fluorophenyl] -2-oxo-5-oxazolidinyl ] Methyl acetamide 6) (S)-[N-3- [4- [2- [4-ethoxycarbonyl- (1,2,3) -triazol-1-yl] -5-pyridinyl] -3-fluoro Lophenyl] -2-oxo-5-oxazolidinyl] methyl acetamide 7) (S)-[N-3- [4- [2- (3-prolinyl) -5-pyridinyl] -3-fluorophenyl] -2-oxo-5-oxazolidinyl] methyl acet Amide 8) (S)-[N-3- [4- [2-[-oxo-1,3-oxazolidin-1-yl] -5-pyridinyl] -3-fluorophenyl] -2-oxo -5-oxazolidinyl] methyl acetamide 9) (S)-[N-3- [4- [2- [1,3-oxazol-5-yl] -5-pyridinyl] -3-fluorophenyl] -2-oxo-5-oxa Zolidinyl] methyl acetamide 10) (S)-[N-3- [4- [2-[(1,2,4) -oxadiazol-3-yl] -5-pyridinyl] -3-fluorophenyl] -2- Oxo-5-oxazolidinyl] methyl acetamide 11) (S)-[N-3- [4- [2-[(1,2,3) -triazol-1yl] -5-pyridinyl])-3-fluorophenyl] -2-oxo -5-oxazolidinyl] methyl acetamide 12) (S)-[N-3- [4- [2- [3-methyl-2-oxo-2,3-dihydro- (1,3,4) -triazol-1-yl] -5 -Pyridinyl] -3-fluorophenyl] -2-oxo-5-oxazolidinyl] methyl acetamide 13) (S)-[N-3- [4- [2- (2-oxo-1,3-imidazolidin-1-yl) -5-pyridinyl] -3-fluorophenyl] -2 -Oxo-5-oxazolidinyl] methyl acetamide 14) (S)-[N-3- [4- [2- (4-hydroxy-piperidin-1-yl) -5-pyridinyl] -3-fluorophenyl] -2-oxo-5 -Oxazolidinyl] methyl acetamide 15) (S)-[N-3- [4- [2- [2-oxo-2,3-dihydro- (1,3,4) -triazol-1-yl] -5-pyridinyl] -3-fluorophenyl] -2-oxo-5-oxazolidinyl] methyl acetamide 16) (S)-[N-3- [4- [2- [5-hydroxymethyl- (1,2,4) -oxadiazol-3-yl] -5-pyridinyl] -3-fluoro Lophenyl] -2-oxo-5-oxazolidinyl] methyl acetamide 17) (S)-[N-3- (4- (2- (5-tetrazolyl) -5-pyridinyl) -3-fluorophenyl) -2-oxo-5-oxazolidinyl] methyl acetamide 18) (S)-[N-3- [4- [2- [5-methoxymethyl- (1,2,4) -oxadiazol-3-yl] -5-pyridinyl] -3-fluoro Lophenyl] -2-oxo-5-oxazolidinyl] methyl acetamide 19) (S)-[N-3- [4- [2- [5-trichloromethyl- (1,2,4) -oxadiazol-3-yl] -5-pyridinyl] -3-fluoro Lophenyl] -2-oxo-5-oxazolidinyl] methyl acetamide 20) (S)-[N-3- [4- [2- [5-dimethylamino- (1,2,4) -oxadiazol-3-yl] -5-pyridinyl] -3-fluoro Lophenyl] -2-oxo-5-oxazolidinyl] methyl acetamide 21) (S)-[N-3- [4- [2- [5-amino- (1,2,4) -oxadiazol-3-yl] -5-pyridinyl] -3-fluorophenyl ] -2-oxo-5-oxazolidinyl] methyl acetamide 22) (S)-[N-3- [4- [2- [4-acetylamino-1-piperidinyl] -5-pyridinyl] -3-fluorophenyl] -2-oxo-5-oxa Zolidinyl] methyl acetamide 23) (S)-[N-3- [4- [2- [4-acetyloxymethylcarbonylamino-piperidin-1-yl] -5-pyridinyl] -3-fluorophenyl] -2 -Oxo-5-oxazolidinyl] methyl acetamide 24) (S)-[N-3- [4- [2- (4-hydroxymethylcarbonylamino-piperidin-1-yl) -5-pyridinyl] -3-fluorophenyl] -2 -Oxo-5-oxazolidinyl] methyl acetamide 25) (S)-[N-3- [4- [2- [3,4-dihydroxy-1-pyrrolidinyl] -5-pyridinyl] -3-fluorophenyl] -2-oxo- An oxazolidinone derivative comprising a pyridine ring, characterized in that 5-oxazolidinyl] methyl acetamide and a pharmaceutically acceptable salt thereof. A process for producing an oxazolidinone derivative comprising a pyridine ring of formula (1) characterized by reacting trimethylstannyl oxazolidinone derivative (2) and pyridine derivative (3) under a palladium catalyst. Scheme 1 (Wherein R ₁ , R ₂ and X are as defined above). 1) Converting the hydroxy group of the hydroxymethyloxazolidinone derivative (4) to an amine group to prepare an amine compound (5), 2) reacting the amine compound (5) with acetic anhydride to produce an acetyl compound (6), 3) halogenating the acetyl compound (6) to produce a halogen compound (7), 4) trimethylstannyl derivative compound (2) is prepared by stannylating the halogen compound (7) under a palladium catalyst, 5) A method for preparing an oxazolidinone derivative comprising a pyridine ring of formula (1) characterized in that the trimethylstannyl oxazolidinone derivative (2) and the pyridine derivative (3) are reacted under a palladium catalyst. Scheme 2 (Wherein R ₁ , R ₂ and X are as defined above). Reacting with trimethylstannyl oxazolidinone derivative (2) and cyano pyridine derivative (10) to prepare a compound of formula (11), Imine with hydroxyl amine to prepare the compound of formula (12), Method for producing an oxazolidinone derivative comprising a pyridine ring, characterized in that the compound of formula (12) and a carboxylic acid derivative (12) is reacted. Scheme 8 (Wherein R ₁ , R ₂ , R ₃ , R ₄ and X are as defined above, and L is a conventional leaving group, preferably halogen or methylcarbonyl oxy group.) An pharmaceutical composition for antibiotics comprising an oxazolidinone derivative compound comprising a pyridine ring of claim 1 and a pharmaceutically acceptable salt thereof as an active ingredient.