KR100872059B1 - Novel Oxazolidinones with amidoxime or hydroxamide and Pharmaceutical Compositions and derivatives thereof - Google Patents

Abstract

The present invention relates to novel oxazolidinone derivatives represented by the general formula (1), in particular novel oxazolidinone compounds comprising amidoxime or hydroxamide groups.

[Formula 1]

The present invention also relates to a pharmaceutical composition for antibiotics containing an oxazolidinone derivative, a prodrug thereof, a hydrate thereof, a solvate thereof, an isomer thereof, and a pharmaceutically acceptable salt thereof as an active ingredient.

Oxazolidinone derivatives thereof, prodrugs thereof, hydrates thereof, solvates thereof, isomers thereof and pharmaceutically acceptable salts thereof according to the present invention have a broad antimicrobial spectrum, low toxicity, resistance to gram-positive and gram-negative bacteria Since it shows a strong antibacterial effect, it can be usefully used as an antibiotic.

Oxazolidinone, antibiotics, antibacterial, Gram-positive bacteria, Gram-negative bacteria

Description

Novel oxazolidinones with amidoxime or hydroxamide and pharmaceutical compositions and derivatives

The present invention relates to novel oxazolidinone derivatives represented by the general formula (1), in particular novel oxazolidinone compounds comprising amidoxime or hydroxamide groups.

[Formula 1]

The present invention also relates to a pharmaceutical composition for antibiotics containing an oxazolidinone derivative, a prodrug thereof, a hydrate thereof, a solvate thereof, an isomer thereof, and a pharmaceutically acceptable salt thereof as an active ingredient.

Since the discovery of penicillin, many pharmaceutical companies around the world have developed a number of antibiotics, including sulfonamides, tetracyclines, aminoglucosides, macrolides, quinolones and glycopeptides, including beta-lactam antibiotics against bacterial infections. Strains resistant to antibiotics have emerged.

There is a constant concern in the international microbiological community that the development of antibiotic resistance can lead to strains that can make antimicrobials ineffective. In general, bacterial pathogens can be classified as either Gram-positive or Gram-negative pathogens. Antibiotic compounds with effective activity against both Gram-positive and Gram-negative pathogens are generally considered to have a broad spectrum of activity. Compounds of the invention are effective against both Gram-positive pathogens and certain Gram-negative pathogens.

Gram-positive and gram-negative pathogens, such as Staphylococcus, Enterococcus, Streptococcus and Mycobacteria, are of particular importance, which causes resistant strains to them. This is because it is difficult to eradicate them from the hospital environment where they are once settled, and treatment is also difficult. Examples of such strains include methicillin resistant Staphylococcus (MRSA), methicillin resistant Coagulase negative Staphylococcus (MRCNS), penicillin resistant Streptococcus pneumoniae and multiple resistant Enterococcus faecium. There is this.

Vancomycin is the major clinically effective antibiotic for treating such resistant Gram-positive pathogens. Vancomycin is a glycopeptide and is associated with a variety of toxicities, including nephrotoxicity. And most importantly, antimicrobial resistance to vancomycin and other glycopeptides is also emerging. This resistance increases at a constant rate, making the formulation less effective in treating Gram-positive pathogens. H. Influenza and M. influenzae The emergence of resistance to agents such as β-lactams, quinolone and macrolides, which are used to treat upper respiratory tract infections, which are also caused by certain Gram-negative bacteria, including M. catarrhalis, are currently on the rise. .

Certain antimicrobial compounds containing oxazolidinone rings have already been reported. For example, oxazolidinone compounds are known synthetic derivatives that can be administered orally rather than fermentation products, and derivatives of various structures are known. For example, 3-phenyl-2-oxazolidinone derivatives having one or two substituents are described in US Pat. Nos. 4,948,801, 4,461,773, 4,340,606, 4,476,136, 4,250,318 and 4,128,654. , 3-[(monosubstituted) phenyl] -2-oxazolidinone derivatives represented by Formula A are described in European Patent EP 0312000, J. Med. Chem. 32, 1673 (1989), J. Med. Chem. 33, 2569 (1990), Tetrahedron. 45,123 (1989) and the like.

[Formula A]

Pharmacia & Upjohn also synthesized oxazolidinone derivatives of Formulas B and C (International Patent Applications WO 93/23384, WO 95/14684, WO 95/07271), and the compounds of Formula B It is an oral and injectable drug under the name Zyvox, licensed by the Food and Drug Administration (FDA) as an oxazolidinone antibiotic. However, conventionally synthesized oxazolidinone compounds have the disadvantage that their antimicrobial spectrum is not broad and toxic, and their therapeutic effect decreases in vivo. / Ml is not enough and can be used only in a limited way as an injection.

[Formula B]

[Formula C]

WO 93/09103 also discloses phenyl oxazolidinone derivatives having heterocycles such as thiazoles, indole, oxazoles, quinols and the like containing pyridine at position 4 of the phenyl group, but the substituents of the heterocycles being merely alkyl or amino groups. Drug efficacy is also known to be not good enough.

In order to solve the above problem, WO 01/94342 synthesized phenyloxazolidinone derivatives having various pyridine or phenyl derivatives at position 4 of the phenyl group, and the antibacterial activity of the synthesized compounds was measured. The effect was also confirmed to be excellent. However, oxazolidinone compounds having various pyridine derivatives at position 4 of the oxazolidinone phenyl group have a broader antimicrobial spectrum and excellent antimicrobial effect compared to Gibox, but most of them have a solubility in water of 30 µg / ml or less. Development is impossible.

In addition, the patent US 2003/0166620 issued by Dong-A Pharm introduced pyridine and pyrimidine into an oxazolidinone compound, similar to the present invention, but R3 or R4 is mainly a cyclic compound and a little to some amines, amides and ester groups. Only the degree of introduction of the substituent of is studied. Compared to these compounds, the compounds synthesized in the present invention, in particular the hydroxamide compounds can be made in the form of a salt has the advantage of improving the solubility.

[Formula D]

Also, in WO 2006/038100, various compounds have been disclosed, including a compound in which pyridine is introduced at position 4 of the oxazolidinone phenyl group and an oxime derivative is introduced at position 2 of the pyridine, as shown in the formula (E). However, no compounds with satisfactory solubility have yet been found. In particular, no studies on amidoxime or hydroxamide compounds such as the compounds of the present invention have been made.

[Formula E]

Therefore, the present inventors synthesized a novel oxazolidinone derivative to develop an antibiotic having high solubility in order to facilitate the development of oral and injectable drugs, and has a superior antimicrobial activity than conventional antibiotics, and the novel oxazoli according to the present invention. Dinon derivatives have confirmed that the antimicrobial effect is excellent and the antibacterial spectrum is significantly improved and completed the present invention.

It is therefore an object of the present invention to provide novel oxazolidinone derivatives, in particular novel oxazolidinone compounds which have increased solubility by introducing amidoxime or hydroxamide groups.

Another object of the present invention is to provide a pharmaceutical composition for antibiotics containing an oxazolidinone derivative, a prodrug thereof, a hydrate thereof, a solvate thereof, an isomer thereof, and a pharmaceutically acceptable salt thereof as an active ingredient.

The novel oxazolidinone derivatives according to the present invention are in vitro acquired pneumonia, socially acquired pneumonia, complex skin and soft tissue infections, simple skin and soft tissue infections, antibiotic resistant strains, in particular VRE (vancomycin resistant enterococcus fascium) or linezolide resistant It can be used as a therapeutic agent for infections such as sepsis caused by Enterococcus faecalis, or in combination therapy when gram (-) bacteria are included in pathogens.

The present invention relates to novel oxazolidinone derivatives represented by the following general formula (1), in particular novel oxazolidinone compounds containing amidoxime or hydroxamide groups.

[Formula 1]

The present invention also relates to a pharmaceutical composition for antibiotics containing an oxazolidinone derivative, a prodrug thereof, a hydrate thereof, a solvate thereof, an isomer thereof, and a pharmaceutically acceptable salt thereof as an active ingredient.

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

The present invention relates to a novel oxazolidinone derivative represented by the following formula (1).

[Formula 1]

[A in Formula 1 is a heteroaromatic ring substituent of the following structure;

P, Q, R, Y and Z are independently of each other C or N;

W is NH, O or S;

X is O or NH;

Except where P, Q and R are all N, and X is NH and P, Q and R are all C.]

-A- of the oxazolidinone derivative represented by Chemical Formula 1 according to the present invention is a heteroaromatic ring substituent having the following structure.

The oxazolidinone derivative compound of Formula 1 according to the present invention may be exemplified by the following compounds, but the following compounds are not intended to limit the present invention.

Exemplary oxazolidinone derivative compounds of the general formula (1) according to the present invention include the following compounds.

Reaction Scheme 1 is illustrated as a method of preparing the oxazolidinone derivative compound of Chemical Formula 1 according to the present invention, and the following preparation method does not limit the method of preparing the oxazolidinone compound of Chemical Formula 1 according to the present invention. Modifications of the following preparation methods will be apparent to those skilled in the art, and unless otherwise stated, the definitions of substituents in the following schemes are the same as defined in the above Formula 1.

As shown in Scheme 1 below, the oxazolidinone derivative compound of formula 1 according to the present invention is (S) -N-((3- (4-bromo-3-fluorophenyl) -2-oxooxazoli Dyn-5-Nyl) methyl) acetamide (I) substituted with dioxaborolane compound (II) and cyano or carboxylic esters obtained by boring with bis (pinacoleto) diboron Synthesis of Compounds (III) and (IV) Substituted with Cyano or Esters by Suzuki Coupling Using Heteroaromatic Bromine Compounds with Palladium Tetrakistriphenylphosphine (Pd (PPh ₃ ) ₄ ) can do.

In addition, for a compound which is not easy to purchase a heteroaromatic compound substituted with a cyano group, the dioxaborolane compound (II) and the heteroaromatic bromine compound substituted with an aldehyde are reacted as in the third method of Scheme 1 below. Synthesized aldehyde-substituted compound (V) and then reacted with hydroxylamine to synthesize oxime compound (VI), and then reacted with acetic anhydride (Ac ₂ O) to synthesize cyano-substituted compound (IV) can do.

The oxazolidinone derivative compound of Chemical Formula 1 may be synthesized by reacting cyano or ester-substituted compound (III) and compound (IV) with hydroxylamine.

Scheme 1

(S) -N-((3- (4-bromo-3-fluorophenyl) -2-oxooxazolidin-5-yl) methyl) acetamide (I) used as starting material in Scheme 1 Can be synthesized by the following Scheme 2.

Scheme 2

Synthesis of 2-(((S) -oxirane-2-yl) methyl) isoindoline-1,3-dione (VII) with 4-bromo-3-fluoroaniline is carried out to react 2-(( R) -3- (4-bromo-3-fluorophenyl) -2-hydroxypropyl) isoindolin-1,3-dione (VIII), followed by 1,1-carbonyldiimidazole and DMAP 2-((S) -3- (4-bromo-3-fluorophenyl) -2-oxooxazolidine-5-yl) methyl) isoindolin-1,3-dione (IX) Amine of (S) -5- (aminomethyl) -3- (4-bromo-3-fluorophenyl) oxazolidin-2-one (X) using hydrazine after forming an oxazolidinin ring The derivatives were synthesized and then acetylated under pyridine solvent to give (S) -N-((3- (4-bromo-3-fluorophenyl) -2-oxooxazolidine-5-yl) methyl) acet Amide (I) is synthesized.

The pharmaceutical composition for antibiotics according to the present invention is characterized by comprising an oxazolidinone derivative, a prodrug thereof, a hydrate thereof, a solvate thereof, an isomer thereof, and a pharmaceutically acceptable salt thereof represented by the following Chemical Formula 2. .

[Formula 2]

[A in Formula 2 is a heteroaromatic ring substituent of the following structure;

P, Q, R, Y and Z are independently of each other C or N;

W is NH, O or S;

X is O or NH;

Provided that P, Q and R are not all N.]

The oxazolidinone derivative compound of Formula 2 contained as an active ingredient in the pharmaceutical composition for antibiotics according to the present invention may be exemplified by the following compounds, but the following compounds are not intended to limit the present invention.

As the oxazolidinone derivative compound of Formula 2 contained as an active ingredient in the pharmaceutical composition for antibiotics according to the present invention, the following compounds are representative.

The oxazolidinone derivatives represented by Formula 1 or Formula 2 according to the present invention may be tautomers as well as isomers by tautomers.

The oxazolidinone derivative compound represented by Chemical Formula 2 included in the pharmaceutical composition for antibiotics according to the present invention may be used in the form of a pharmaceutically acceptable salt, and the pharmaceutically acceptable salt may be a pharmaceutically acceptable free acid ( acid addition salts formed by free acid) and sodium, potassium and calcium salts. The inorganic acid and organic acid may be used as the free acid, and the inorganic acid used may include hydrochloric acid, bromic acid, sulfuric acid, and phosphoric acid, and the organic acid used may be citric acid, acetic acid, lactic acid, maleic acid, umarin acid, gluconic acid, and methane. Sulfonic acid, glyconic acid, succinic acid, 4-toluenesulfonic acid, trifluoroacetic acid, galluxuronic acid, embonic acid, glutamic acid and aspartic acid.

Compositions of the present invention are suitable for oral use (e.g. tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), suitable for topical use. Forms (e.g. creams, ointments, gels or aqueous or oily solvents or suspensions), forms suitable for ophthalmic administration, forms suitable for inhalation administration (e.g. micronized powder or liquid aerosol), infusion administration Suitable forms for use (eg, undifferentiated powders) or suitable forms for parenteral administration (eg, as sterile aqueous or oily solvents for intravenous, subcutaneous, sublingual, intramuscular or intramuscular administration, or rectal As a suppository for administration).

In addition to the compounds of the present invention, the pharmaceutical compositions of the present invention may contain other clinically useful antibacterial agents (e.g., β-lactams, macrolides, quinolones or aminoglycosides) and / or other anti-infective agents (e.g., antifungal agents One or more known drugs selected from sexual triazoles or amphotericins) (ie, by formulating together) or co-administered with one or more known drugs. These may include carbapenems, for example meropenem or imipenem, to broaden the therapeutic efficacy. Compounds of the invention may also be formulated or co-administered with bactericidal / permeable-increasing protein (BPI) products or effluent pump inhibitors to enhance activity against gram negative bacteria and bacteria that are resistant to antimicrobial agents. May be administered.

The compounds of the present invention may also be formulated with or coadministered with vitamins such as vitamin B such as vitamin B2, vitamin B6, vitamin B12 and folic acid. The compounds of the present invention may also be formulated or co-administered with cyclooxygenase (COX) inhibitors, in particular COX-2 inhibitors. The compounds of the invention can also be formulated and coadministered with antimicrobial agents active against Gram-positive bacteria, Gram-negative bacteria.

The compositions of the present invention can be obtained by conventional procedures using conventional pharmaceutical excipients which are well known in the art. Thus, a composition intended for oral administration may contain, for example, one or more colorants, sweeteners, flavors and / or preservatives. Pharmaceutical compositions to be administered intravenously may advantageously contain (eg, to enhance stability) suitable bactericides, antioxidants or reducing agents, or suitable sequestrants.

Compositions for oral administration may be in the form of hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin, or the active ingredient in water or oil such as peanut oil, liquid paraffin or olive oil. It may be in the form of a soft gelatin capsule mixed with.

Aqueous suspending agents generally include one or more suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, tragacand gum and acacia gum; Dispersing or wetting agents, for example lecithin or condensation products of alkylene oxides with fatty acids (eg polyoxyethylene stearate), or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadeca Condensation products of ethyleneoxycetanol or partial esters derived from fatty acids and hexitols, for example polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example , Heptadecaethyleneoxycetanol, or a condensation product of ethylene oxide with partial esters derived from fatty acids and hexitol, for example polyoxyethylene sorbitol monooleate, or from ethylene oxide with fatty acids and hexitol anhydrides Condensation products with partial esters, for example polyethylene sol With the monooleate, the active ingredients in micronised form. Aqueous suspending agents include one or more preservatives (eg, ethyl or propyl p-hydroxybenzoate), antioxidants (eg, ascorbic acid), colorants, flavors, and / or sweetening agents (eg, shoe Cross, saccharin or aspartame).

Oily suspensions can be formulated by suspending the active ingredient in vegetable oils (eg arachis oil, olive oil, sesame oil or coconut oil) or mineral oils (eg liquid paraffin). Oily suspensions may contain thickening agents, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents as mentioned above, and flavoring agents may be added to provide a delicious oral preparation. These compositions can be preserved by adding antioxidants such as ascorbic acid.

Dispersible powders and granules suitable for preparing an aqueous suspending agent by adding water contain the active ingredient together with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified as mentioned above. Additional excipients may also be present, such as sweetening, flavoring and coloring agents.

For further information regarding formulations, reference may be made to Chapter 25.2 in Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press 1990.

The amount of active ingredient combined with one or more excipients to produce a single dosage form will of course vary depending upon the host being treated and the particular route of administration. For example, formulations intended for oral administration to humans generally contain 50 mg to 5 g of active compound with a convenient suitable amount of excipient, which may be about 5 to about 98% based on the total weight of the composition. can do. Dosage unit forms will generally contain about 200 mg to about 2 g of active ingredient. For further information regarding the route of administration and dosage regimen, reference may be made to Chapter 25.3 in Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press 1990.

Suitable pharmaceutical compositions of the invention are tablets or capsules containing 0.1 mg to 1 g, preferably 100 mg to 1 g of a compound of the invention, in a form suitable for oral administration in unit dosage form. Especially preferred are tablets or capsules containing 50 mg to 800 mg, in particular 100 mg to 500 mg of the compounds of the invention.

In addition, the pharmaceutical composition of the present invention is in a form suitable for intravenous, subcutaneous or intramuscular injection, for example, 0.1% w / v to 50% w / v (1 mg / ml to 500 mg) of a compound of the present invention. / ml) injectables.

Each patient may be administered intravenously, subcutaneously or intramuscularly, for example, from 0.1 mg / kg to 20 mg / kg of a compound of the invention, and the composition is administered 1 to 4 times per day. In another embodiment, the compound of the present invention is administered 1 mg / kg to 20 mg / kg per day. Intravenous, subcutaneous and intramuscular doses can be given by bolus injection. Alternatively, intravenous doses can be given by continuous infusion over time. Alternatively, each patient may be administered a daily oral dose, which may be approximately equivalent to a daily parenteral dose, and the composition is administered 1 to 4 times per day.

The oxazolidinone derivatives of the present invention are Gram-positive bacteria and Haemophilus, such as Staphylococcus aureus and Enterococcus faecalis, which are resistant to conventional antibiotics at much lower concentrations than the commercially available Pharmacia & Upzone linezolid. It exhibits antimicrobial activity against Gram-negative bacteria such as influenza and Moraxella catarrhalis, and especially against linezolide resistant Enterococcus faecalis.

Hereinafter, preferred examples and experimental examples are presented to help understand the present invention. However, the following examples and experimental examples are provided only to more easily understand the present invention, and the contents of the present invention are not limited by the following examples.

Production Example 1 (S) -N-((3- (4-bromo-3-fluorophenyl) -2-oxooxazolidine-5-yl) methyl) acetamide ((S) -N- Preparation of ((3- (4-bromo-3-fluorophenyl) -2-oxooxazolidin-5-yl) methyl) acetamide) (Compound I)

2-((R) -3- (4- Bromo -3- Fluorophenylamino ) -2-hydroxypropyl) Isoindolin -1,3- Dion  (2-((R) -3- (4- bromo -3-fluorophenylamino) -2-hydroxypropyl) isoindoline-1,3-dione) (compound VIII Manufacturing

4-bromo-3-fluoroaniline (5.0 g, 26 mmol), 2-(((S) -oxirane-2-yl) methyl) isoindoline-1,3-dione (2-(((S ) -oxiran-2-yl) methyl) isoindoline-1,3-dione (Compound VII) (38mmol) was added to 75 ml of 2-propyl alcohol and stirred under reflux for 12 hours. The resulting solid was filtered under reduced pressure and diethyl Wash with 30 ml of diethylether to give 2-((R) -3- (4-bromo-3-fluorophenyl) -2-hydroxypropyl) isoindolin-1,3-dione (Compound VIII) (6.0 g, 15 mmol, 59.76%) was obtained.

¹ H NMR (400 MHz, chloroform-d ₁ ) δ 7.86-7.84 (m, 2H), 7.78-7.76 (m, 2H), 7.21-7.17 (m, 1H), 6.43 (dd, 1H, J ₁ = 11.6 Hz, J ₂ = 2.8 Hz), 6.35 (dd, 1H, J ₁ = 8.6 Hz, J ₂ = 2.6 Hz), 5.19 (t, 1H, J = 5.4 Hz), 5.03 (d, 1H, J = 5.2 Hz ), 4.16-4.08 (m, 1H), 3.87-3.71 (m, 2H), 3.23-3.06 (m, 2H)

2-((R) -3- (4- Bromo -3- Fluorophenyl )-2- Oxooxazolidine -5-neyl) methyl ) Isoindolin -1,3- Dion  (2-(((S) -3- (4- bromo -3- fluorophenyl )-2- oxooxazolidin -5-yl) methyl) isoindoline -1,3- dione )(compound IX Manufacturing

6.0 g (15 mmol) of 2-((R) -3- (4-bromo-3-fluorophenylamino) -2-hydroxypropyl) isoindolin-1,3-dione (Compound VIII) obtained above , 3.7 g (23 mmol) of 1,1-carbonyldiimidazole and 0.93 g (7.6 mmol) of dimethylaminopyridine were sequentially added to 60 ml of tetrahydrofuran, followed by stirring under reflux for 20 hours. The reaction product was concentrated under reduced pressure, dissolved in 100 ml of ethyl acetate, washed sequentially with 50 ml of 1N-hydrochloric acid solution and 50 ml of sodium bicarbonate solution, dehydrated with sodium sulfate, concentrated under reduced pressure, and washed with 80 ml of diethyl ether. -3- (4-Bromo-3-fluorophenyl) -2-oxooxazolidine-5-yl) methyl) isoindoline-1,3-dione (Compound IX) (4.9 g, 12 mmol, 77% )

¹ H NMR (400 MHz, chloroform-d ₁ ) δ 7.86-7.84 (m, 2H), 7.75-7.73 (m, 2H), 7.49-7.45 (m, 2H), 7.12-7.09 (m, 1H), 5.00 -4.93 (m, 1H), 4.14-4.05 (m, 2H), 3.98-3.93 (m, 1H), 3.88-3.85 (m, 1H)

(S) -5- ( Aminomethyl ) -3- (4- Bromo -3- Fluorophenyl ) Oxazolidine 2-one ((S) -5- (aminomethyl) -3- (4-bromo-3-fluorophenyl) oxazolidin-2-one) (compound  X Manufacturing

2-((S) -3- (4-bromo-3-fluorophenyl) -2-oxooxazolidine-5-yl) methyl) isoindolin-1,3-dione obtained above (Compound IX ) 4.9 g (12 mmol) and hydrazine 1.2 g (23 mmol) were sequentially dissolved in 70 ml of ethyl alcohol, stirred under reflux for 1 hour, the reaction mixture was cooled to room temperature, filtered and washed with 30 ml of diethyl ether (S) -5- (Aminomethyl) -3- (4-bromo-3-fluorophenyl) oxazolidin-2-one (Compound X) (3.1 g, 10 mmol, 87%) was obtained.

¹ H NMR (400 MHz, chloroform-d ₁ ) δ 7.55-7.34 (m, 2H), 7.05 (dd, 1H, J ₁ = 8.8 Hz, J ₂ = 2.4 Hz), 6.18 (t, 1H, J = 5.2 Hz), 4.32-4.12 (m, 1H), 4.00 (t, 1H, J = 9.2 Hz), 3.74 (dd, 1H, J ₁ = 9.2 Hz, J ₂ = 6.8 Hz), 3.67-3.49 (m, 2H ), 1.99 (s, 3 H)

(S) -N-((3- (4- Bromo -3- Fluorophenyl )-2- Oxooxazolidine -5-neyl) methyl ) Acetamide  ((S) -N-((3- (4- bromo -3- fluorophenyl )-2- oxooxazolidin -5- yl ) methyl ) acetamide )(compound  I Manufacturing

3.1 g (10 mmol) of (S) -5- (aminomethyl) -3- (4-bromo-3-fluorophenyl) oxazolidin-2-one (Compound X) obtained above was dissolved in 30 ml of pyridine. After cooling to 0 ° C., 1.5 ml (20 mmol) of acetyl chloride was slowly added dropwise and stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, dissolved in 80 ml of ethyl acetate, washed sequentially with 50 ml of 1N- aqueous hydrochloric acid solution, 50 ml of sodium bicarbonate solution and 20 ml of brine, and concentrated under reduced pressure by dehydration using sodium sulfate to give the title compound (S) -N-((3- (4-Bromo-3-fluorophenyl) -2-oxooxazolidin-5-yl) methyl) acetamide (Compound I ) (3.3. G, 10 mmol, 98%) was obtained.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.77 (dd, 1H, J ₁ = J ₂ = 8.68 Hz), 7.62 (dd, 1H, J ₁ = 11.6 Hz, J ₂ = 2.4 Hz), 7.32- 7.29 (m, 1H), 4.62-4.55 (m, 1H), 4.03-3.99 (m, 1H,), 3.83-3.79 (m, 1H), 2.83-2.71 (m, 2H)

Preparation Example 2 (S) -N-((3- (3-fluoro-4- (5-formylthiophen-3-yl) phenyl) -2-oxooxazolidine-5-yl) methyl) Acetamide ((S) -N-((3- (3-fluoro-4- (5-formylthiopene-3-yl) phenyl) -2-oxooxazolidin-5-yl) methyl) acetamide) (Compound V-1 ) Manufacture

0.50 g of (S) -N-((3- (4-bromo-3-fluorophenyl) -2-oxooxazolidine-5-yl) methyl) acetamide (Compound I ) obtained in Preparation Example 1 (1.5 mmol) and 0.42 g (1.7 mmol) bis (pinacoleto) diboron, 0.44 g (4.5 mmol) potassium acetate, 10 mol% [1,1'-bis (diphenylphosphino) -ferrocene] dichloropalladium (II) 0.037 g (0.045 mmol) was added to the flask, replaced with nitrogen gas, dissolved in 15 ml of N, N-dimethylformamide, and stirred at 80 ° C. for 13 hours to form borane compound II . To this solution, 0.58 g (3.0 mmol) of 4-bromothiophene-2-carbaldehyde and 10 mol% [1,1'-bis (diphenylphosphino) -ferrocene] die 0.037 g (0.045 mmol) of chloropalladium (II) was added thereto, and 2 ml of 2M aqueous sodium carbonate solution was added thereto. After stirring at 80 ° C. for 5 hours, the mixture was cooled to room temperature, diluted with ethyl acetate, washed twice with water, washed once with brine, and the organic layer was concentrated under reduced pressure, and then columned with 5% methanol / ethyl acetate to obtain the title compound (S) -N. -((3- (3-fluoro-4- (5-formylthiophen-3-yl) phenyl) -2-oxooxazolidine-5-yl) methyl) acetamide (Compound V-1 ) (0.25 g, 0.69 mmol, 46%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.00 (s, 1H), 8.41 (s, 1H), 8.40 (s, 1H), 8.27 (t, 1H, J = 5.6 Hz), 7.85-7.80 ( m. 1 H), 7.64 (dd, 1 H, J ₁₎ = 14 Hz, J ₂ = 2.4 Hz), 7.43 (dd, 1H, J ₁ = 8.6 Hz, J ₂ = 2.2 Hz), 4.80-4.74 (m, 1H), 4.20-4.15 (m, 1H), 3.81-3.77 (m, 1H), 3.45-3.42 (m, 2H), 1.84 (s , 3H)

LCMS: 363 (M + H ⁺ ) for C ₁₇ H ₁₅ FN ₂ O ₄ S

Preparation Example 3 (S) -N-((3- (3-fluoro-4- (5-((hydroxymino) methyl) thiophen-3-yl) phenyl) -2-oxooxazolidine -5-Nyl) methyl) acetamide ((S) -N-((3- (3-fluoro-4- (5- ((hydroxylimino) methyl) thiophene-3-yl) phenyl) -2-oxooxazolidin-5 -yl) methyl) acetamide) (Compound VI- 1 )

(S) -N-((3- (3-fluoro-4- (5-formylthiophen-3-yl) phenyl) -2-oxooxazolidin-5-yl) methyl) acetamide obtained above (Compound V-1 ) 0.14 g (0.38 mmol) was dissolved in 30 ml of ethanol, 52 mg (0.75 mmol) of hydroxyl amine hydrochloride and 46 mg (0.56 mmol) of sodium acetate were added, followed by 3 ml of water. After stirring for 3 hours at room temperature, the resulting solid was washed with water and filtered to obtain the title compound (S) -N-((3- (3-fluoro-4- (5-((hydroxymino) methyl) thiophene-). 3-Nyl) phenyl) -2-oxooxazolidine-5-yl) methyl) acetamide (Compound VI- 1 ) (0.10 g, 0.27 mmol, 82%) was obtained.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.97-11.25 (m, 1H), 8.34-7.94 (m, 1H), 8.22 (t, 1H, J = 5.6 Hz), 7.86-7.73 (m. 1H ), 7.76-7.61 (m. 1H), 7.70-7.66 (m. 1H), 7.56-7.52 (m. 1H), 7.34-7.32 (m. 1H), 4.72-4.67 (m. 1H), 4.13-4.08 (m. 1H), 3.74-3.70 (m. 1H), 3.40-3.39 (m. 2H), 1.79 (s, 3H)

LCMS: 378 (M + H ⁺ ) for C ₁₇ H ₁₆ FN ₃ O ₄ S

Preparation Example 4 (S) -N-((3- (4- (5-cyanothiophen-3-yl) -3-fluorophenyl) -2-oxo oxazolidine-5-yl) methyl Preparation of acetamide ((S) -N-((3- (4- (5-cyanothiopene-3-yl) -fluorophenyl) -2-oxooxazolidin-5-yl) methyl) acetamide) (Compound IV- 1 )

(S) -N-((3- (3-fluoro-4- (5-((hydroxymino) methyl) thiophen-3-yl) phenyl) -2-oxooxazolidine obtained above 99 mg (0.26 mmol) of 5-yl) methyl) acetamide (Compound VI- 1 ) and 10 mg (0.079 mmol) of N, N-4-dimethylaminopyridine were dissolved in 3 ml of acetic anhydride, followed by stirring under reflux for 5 hours. It was. Then, the solvent was concentrated under reduced pressure, dissolved in ethyl acetate, and washed three times with water. The organic layer was concentrated under reduced pressure and columned with 5% methanol / methylene dichloride to give the title compound (S) -N-((3- (4- (5-cyanothiophen-3-yl) -3-fluorophenyl) 2-oxooxazolidine-5-yl) methyl) acetamide (Compound IV- 1 ) (57 mg, 0.16 mmol, 61%) was obtained.

¹ H NMR (DMSO-d ₆ ) δ 8.37-8.30 (m, 1H), 8.27 (t, 1H, J = 6.0 Hz), 8.08-7.98 (m. 1H), 7.83-7.74 (m, 1H), 7.65 -7.60 (m, 1H), 7.41 (dd, 1H, J ₁ = 8.6 Hz, J ₂ = 2.2 Hz), 4.79-4.73 (m, 1H), 4.19-4.14 (m, 1H), 3.80-3.76 (m, 1H), 3.45-3.42 (m, 2H), 1.84 (s , 3H)

LCMS: 360 (M + H ⁺ ) for C ₁₇ H ₁₄ FN ₃ O ₃ S

Preparation Example 5 (S) -methyl-4- (4- (5-acetamidomethyl) -2-oxooxazolidin-3-yl) -2-fluorophenyl) thiophene-2-carboxylate Preparation of ((S) -methyl-4- (4- (5- (acetamidomethyl) -2-oxooxazolidine-3-yl) -2-fluorophenyl) thiophene-2-carboxylate) (Compound III- 1 )

Synthesis of Compound II in the same manner as in Preparation Example 2, and instead of 4-bromothiophene-2-carboxaldehyde of Preparation Example 2, 4-bromo-2-methoxycarbonylthiophene was used as the title compound. of (S) - methyl-4- (4- (5-acetamido) -2-oxo-oxazolidin-3-carbonyl) -2-fluorophenyl) thiophene-2-carboxylate (compound III - 1 ) (0.29 g, 0.75 mmol, 50%) was obtained.

¹ H NMR (DMSO-d ₆ ) δ 8.21 (t, 1H, J = 6.0 Hz), 8.16 (s, 1H), 8.09 (s, 1H), 7.81-7.77 (m, 1H), 7.56 (dd, 1H , J ₁ = 14 Hz, J ₂ = 2.4 Hz), 7.34 (dd, 1H, J ₁ = 8.8 Hz, J ₂ = 2.0 Hz), 4.74-4.68 (m, 1H), 4.14-4.09 (m, 1H), 3.81 (s, 3H), 3.75-3.71 (m, 1H), 3.39-3.37 (m, 2H), 1.79 ( s, 3H),

LCMS: 393 (M + H ⁺ ) for C ₁₈ H ₁₇ FN ₂ O ₅ S

Preparation Example 6 (S) -N-((3- (3-fluoro-4- (5-formylthiophen-2-yl) phenyl) -2-oxooxazolidine-5-yl) methyl) Acetamide ((S) -N-((3- (3-fluoro-4- (5-formylthiophen-2-yl) phenyl) -2-oxooxazolidin-5-yl) methyl) acetamide) (Compound V-2 ) Manufacture

Compound II was synthesized in the same manner as in Preparation Example 2, and instead of 4-bromothiophene-2-carboxaldehyde of Preparation Example 2, 5-chlorothiophene-2-carboxaldehyde (5-chlorothiophene-2-carbaldehyde ) Is the title compound (S) -N-((3- (3-fluoro-4- (5-formylthiophen-2-yl) phenyl) -2-oxooxazolidin-5-yl) Methyl) acetamide (Compound V-2 ) (0.15 g, 0.41 mmol, 27%) was obtained.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.95 (s, 1H), 8.27 (t, 1H, J = 5.8 Hz), 8.07 (d, 1H, J = 4.0 Hz), 7.98 (t, 1H, J = 8.8 Hz), 7.77 (d, 1H, J = 4.0 Hz), 7.67 (d, 1H, J = 14.0 Hz), 7.48 (d, 1H, J = 9.2 Hz), 4.83-4.71 (m, 1H) , 4.18 (t, 1H, J = 9.0 Hz), 3.79 (dd, 1H, J ₁ = 9.2 Hz, J ₂ = 6.4 Hz), 3.44 (t, 2H, J = 5.4 Hz), 1.84 (s, 3H)

Preparation Example 7 (S) -N-((3- (3-fluoro-4- (5-((hydroxymino) methyl) thiophen-2-yl) phenyl) -2-oxooxazolidine -5-Nyl) methyl) acetamide ((S) -N-((3- (3-fluoro-4- (5-((hydroxylimino) methyl) thiophene-2-yl) phenyl) -2-oxooxazolidin-5 Preparation of -yl) methyl) acetamide) (Compound VI- 2 )

(S) -N-((3- (3-fluoro-4- (5-formylthiophen-2-yl) phenyl) -2-oxooxazolidine-5-yl) methyl obtained in Preparation Example 6 Acetamide (Compound V-2 ) was prepared by (S) -N-((3- (3-fluoro-4- (5-formylthiophen-3-yl) phenyl) -2-oxooxa of Preparation Example 3. The title compound (S) -N-((3- (3-fluoro-4- (3)) was used in the same manner as in Preparation Example 3, instead of the zolidine-5-yl) methyl) acetamide (compound V-1 ). 5-((hydroxymino) methyl) thiophen-2-yl) phenyl) -2-oxooxazolidine-5-yl) methyl) acetamide (Compound VI- 2 ) (0.13 g, 0.34 mmol, 86% )

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.04-11.29 (m, 1H), 8.33-7.82 (m, 3H), 7.64-7.32 (m, 4H), 4.88-4.66 (m, 1H), 4.25 -4.07 (m, 1H), 3.86-3.66 (m, 1H), 3.52-3.40 (m, 2H), 1.84 (s, 3H)

LCMS: C ₁₇ H ₁₆ FN ₃ O ₄ 378 (M + H ⁺ ) for S

Preparation Example 8 (S) -N-((3- (4- (5-cyanothiophen-2-yl) -3-fluorophenyl-2-oxooxazolidin-5-yl) methyl) Preparation of acetamide ((S) -N-((3- (4- (5-cyanothiopene-2-yl) -fluorophenyl) -2-oxooxazolidin-5-yl) methyl) acetamide) (Compound IV- 2 )

(S) -N-((3- (3-fluoro-4- (5-((hydroxymino) methyl) thiophen-2-yl) phenyl) -2-oxooxazoli obtained in Production Example 7 above Din-5-yl) methyl) acetamide (Compound VI- 2 ) was prepared by (S) -N-((3- (3-fluoro-4- (5-((hydroxymino)) methyl) of Preparation Example 4. The title compound (S) -N in the same manner as in Preparation Example 4, using thiophen-3-yl) phenyl) -2-oxooxazolidine-5-yl) methyl) acetamide (Compound VI- 1 ) instead. -((3- (4- (5-cyanothiophen-2-yl) -3-fluorophenyl-2-oxooxazolidin-5-yl) methyl) acetamide (Compound IV- 2 ) (0.08 g, 0.22 mmol, 69%).

LCMS: C ₁₇ H ₁₄ FN ₃ O ₃ 360 for S (M + H ⁺ )

Preparation Example 9 (S) -methyl-5- (4- (5-acetamidomethyl) -2-oxooxazolidin-3-yl) -2-fluorophenyl) thiophene-2-carboxylate Preparation of ((S) -methyl-5- (4- (5- (acetamidomethyl) -2-oxooxazolidine-3-yl) -2-fluorophenyl) thiophene-2-carboxylate) (Compound III- 2 )

Compound II was synthesized in the same manner as in Preparation Example 2, and 5-chloro-2-methoxycarbonylthiophene instead of 4-bromothiophene-2-carboxaldehyde of Preparation Example 2 was used as the title compound ( S) -Methyl-5- (4- (5-acetamidomethyl) -2-oxooxazolidin-3-yl) -2-fluorophenyl) thiophene-2-carboxylate (Compound III- 2 ) (1.6 g, 4.2 mmol, 56%) was obtained.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.27 (t, 1H, J = 6.0 Hz), 7.95 (t, 1H, J = 8.8 Hz), 7.84 (dd, 1H, J ₁ = 4.0 Hz, J ₂ = 1.2 Hz), 7.69-7.62 (m, 2H), 7.46 (dd, 1H, J ₁ = 8.8 Hz, J ₂ = 2.4 Hz), 4.85-4.68 (m, 1H), 4.17 (t, 1H, J = 9.0 Hz), 3.85 (s, 3H), 3.79 (dd, 1H, J ₁ = 9.2 Hz, J ₂ = 6.8 Hz), 3.43 (t, 2H, J = 5.6 Hz), 1.84 (s, 3H)

LCMS: C ₁₈ H ₁₇ FN ₂ O ₅ 393 (M + H ⁺ ) for S

Preparation Example 10 (S) -N-((3- (4- (6-cyanopyridin-3-yl) -3-fluorophenyl) -2-oxooxazolidine-5-yl) methyl) Preparation of acetamide (S) -N-((3- (4- (6-cyanopyridine-3-yl) 3-fluorophenyl) -2-oxooxazolidin-5-yl) methyl) acetamide) (Compound IV- 3 )

Synthesis of Compound II in the same manner as in Preparation Example 2, and instead of 4-bromothiophene-2-carboxaldehyde of Preparation Example 2, 2-cyano-5-bromopyridine was used as the title compound (S ) -N-((3- (4- (6-cyanopyridin-3-yl) -3-fluorophenyl) -2-oxooxazolidine-5-yl) methyl) acetamide (Compound IV- 3 ) (0.85 g, 2.4 mmol, 66%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.97 (s, 1H), 8.32-8.21 (m, 2H), 8.16 (d, 1H, J = 8.0 Hz), 7.77 (t, 1H, J = 8.8 Hz), 7.69 (dd, 1H, J ₁ = 13.8 Hz, J ₂ = 2.2 Hz), 7.50 (dd, 1H, J ₁ = 8.6 Hz, J ₂ = 2.2 Hz), 4.86-4.70 (m, 1H), 4.19 (t, 1H, J = 9.2 Hz), 3.80 (dd, 1H, J ₁ = 9.2 Hz, J ₂ = 6.4 Hz), 3.44 (t, 2H, J = 5.4 Hz). 1.84 (s, 3 H)

LCMS: 355 (M + H ⁺ ) for C ₁₈ H ₁₅ FN ₄ O ₃

Production Example 11 (S) -methyl-5- (4- (5- (acetamidomethyl) -2-oxooxazolidin-3-yl) -2-fluorophenyl) picolinate ((S Preparation of) -methyl-5- (4- (5- (acetamidomethyl) -2-oxooxazolidine-3-yl) -2-fluorophenyl) picolinate) (Compound III- 3 )

Compound II was synthesized in the same manner as in Preparation Example 2, and 2-methoxycarbonyl-5-bromopyridine was used instead of 4-bromothiophene-2-carboxaldehyde of Preparation Example 2 to obtain the title compound. (S) -Methyl-5- (4- (5- (acetamidomethyl) -2-oxooxazolidin-3-yl) -2-fluorophenyl) picolinate (compound III- 3 ) (0.84 g, 2.2 mmol, 48%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.92 (s, 1H), 8.28 (t, 1H, J = 5.6 Hz), 8.22-8.11 (m, 2H), 7.76 (t, 1H, J = 8.8 Hz), 7.68 (dd, 1H, J ₁ = 14.2 Hz, J ₂ = 2.0 Hz), 7.50 (dd, 1H, J ₁ = 8.8 Hz, J ₂ = 2.0 Hz), 4.84-4.78 (m, 1H), 4.19 (t, 1H, J = 9.2 Hz), 3.91 (s, 3H), 3.81 (dd, 1H, J ₁ = 9.2 Hz, J ₂ = 6.4 Hz), 3.45 (t, 2H, J = 5.4 Hz), 1.84 (s, 3 H)

LCMS: 388 (M + H ⁺ ) for C ₁₉ H ₁₈ FN ₃ O ₅

Example 1 (S) -N-((3- (3-fluoro-4- (5- (N'-hydroxycarbamimidoyl) thiophen-3-yl) phenyl) -2-oxo Oxazolidin-5-yl) methyl) acetamide ((S) -N-((3- (3-fluoro-4- (5- (N'-hydroxycarbamimidoyl) thiopene) -3-yl) phenyl) -2 -oxooxazolidin-5-yl) methyl) acetamide) (Compound 101 )

(S) -N-((3- (4- (5-cyanothiophen-3-yl) -3-fluorophenyl-2-oxooxazolidin-5-yl) synthesized in Preparation Example 4 above 57 mg (0.16 mmol) of methyl) acetamide (Compound IV- 1 ) was dissolved in 1.5 ml of ethanol, and 33 mg (0.47 mmol) of hydroxyamine hydrochloride and 25 mg (0.24 mmol) of sodium carbonate were added, followed by 2 ml of water. After stirring for 2 hours, the solvent was concentrated under reduced pressure, dissolved in ethyl acetate, washed twice with water, dried and columned with 10% methanol / dichloromethane to give the title compound (S) -N-((3- ( 3-fluoro-4- (5- (N'-hydroxycarbamidomiyl) thiophen-3-yl) phenyl) -2-oxooxazolidin-5-yl) methyl) acetamide (Compound 101 ) (16 mg, 0.04 mmol, 24%) was obtained.

¹ H NMR (DMSO-d ₆ ) δ 11.23-9.63 (m, 1H), 8.32-7.82 (m, 1H), 8.21 (t, 1H, J = 5.8 Hz), 7.79-7.62 (m, 2H), 7.57 -7.52 (m, 1H), 7.35-7.33 (m, 1H), 5.95 (s, 2H), 4.74-4.67 (m, 1H), 4.13-4.09 (m, 1H), 3.75-3.71 (m, 1H) , 3.39-3.36 (m, 2H), 1.79 (s, 3H)

LCMS: 393 (M + H ⁺ ) for C ₁₇ H ₁₇ FN ₄ O ₄ S

Example 2 (S) -4- (4- (5- (acetamidomethyl) -2-oxooxazolidin-3-yl) -2-fluorophenyl) -N-hydroxythiophene Of 2-carboxamide ((S) -4- (4- (5- (acetamido methyl) -2-oxooxazolidin-3-yl) -2-fluorophenyl) -N-hydroxythiophene-2-carboxamide) (Compound 102 ) Produce

2.4 g (35 mmol) of hydroxy amine hydrochloride dissolved in 20 ml methanol and 2.4 g (43 mmol) of potassium hydroxide dissolved in 20 ml methanol were mixed and the precipitated potassium chloride was filtered out. This filtrate was synthesized in Preparation Example 5 (S) -methyl-4- (4- (5-acetamidomethyl) -2-oxooxazolidin-3-yl) -2-fluorophenyl) thiophene Into a flask containing 0.19 g (0.48 mmol) of 2-carboxylate (Compound III- 1 ), the mixture was stirred at room temperature for 2 hours and acidified by adding 7 ml of 4N dioxane solution. The solution was concentrated under reduced pressure, solidified with 20 ml of water, washed with water and diethyl ether and dried to give the title compound (S) -4- (4- (5- (acetamidomethyl) -2-oxooxa Zolidin-3-yl) -2-fluorophenyl) -N-hydroxythiophene-2-carboxamide (Compound 102 ) (9 mg, 0.03 mmol, 5%) was obtained.

¹ H NMR (DMSO-d ₆ ) δ 11.34 (s, 1H), 9.22 (s, 1H), 8.28 (t, 1H, J = 3.8 Hz), 8.02 (s, 1H), 8.00 (s, 1H), 7.72-7.69 (m, 1 H), 7.61 (dd, 1 H, J ₁ = 9.2 Hz, J ₂ = 1.6 Hz), 7.41 (dd, 1H, J ₁ = 5.8 Hz, J ₂ = 1.4 Hz), 4.78-4.75 (m, 1H), 4.18-4.15 (m, 1H), 3.79-3.76 (m, 1H), 3.44-3.42 (m, 2H), 1.84 (s, 3H)

LCMS: 394 (M + H ⁺ ) for C ₁₇ H ₁₆ FN ₃ O ₅ S

Example 3 (S) -N-((3- (3-fluoro-4- (5- (N'-hydroxycarbamimidoyl) thiophen-2-yl) phenyl) -2-oxo Oxazolidine-5-yl) methyl) acetamide ((S) -N-((3-((3-fluoro-4- (5- (N'-hydroxycarbamimidoyl) thiopene) -2-yl) phenyl)- Preparation of 2-oxooxazolidin-5-yl) methyl) acetamide) (Compound 103 )

(S) -N-((3- (4- (5-cyanothiophen-2-yl) -3-fluorophenyl) -2-oxooxazolidin-5-yl synthesized in Preparation Example 8 above Dissolve 79 mg (0.22 mmol) of methyl) acetamide (Compound IV- 2 ) in 4 ml of ethanol, add 46 mg (0.66 mmol) of hydroxyamine hydrochloride and 35 mg (0.33 mmol) of sodium carbonate, and add 1 ml of water. It was stirred at reflux for a time. After 2 hours, the precipitate formed by pouring into 50 mL of water was filtered, washed with water and diethyl ether and dried to give the title compound ((S) -N-((3- (3-fluoro-4- (5- (N'-Hydroxycarbamimidoyl) thiophen-2-yl) phenyl) -2-oxooxazolidine-5-yl) methyl) acetamide (Compound 103 ) (21 mg, 0.05 mmol, 24%) Got it.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.70 (s, 1H), 8.26 (t, 1H, J = 5.8 Hz), 7.80 (t, 1H, J = 9.0 Hz), 7.60 (dd, 1H, J ₁ = 14.4 Hz, J ₂ = 2.0 Hz), 7.49 (d, 1H, J = 3.2 hz), 7.46 (d, 1H, J = 3.6 Hz), 7.40 (dd, 1H, J ₁ = 8.6 Hz, J ₂ = 2.2 Hz), 5.98 (s, 2H), 4.83-4.68 (m, 1H), 4.16 (t, 1H, J = 9.2 Hz), 3.77 (dd, 1H, J ₁ = 9.2 Hz, J ₂ = 6.4 Hz), 3.43 (t, 2H, J = 5.4 Hz), 1.84 (s, 3H)

LCMS: C ₁₇ H ₁₇ FN ₄ O ₄ 393 (M + H ⁺ ) for S

Example 4 (S) -5- (4- (5- (Acetamidomethyl) -2-oxooxazolidin-3-yl) -2-fluorophenyl) -N-hydroxythiophene Of 2-carboxamide ((S) -5- (4- (5- (acetamido methyl) -2-oxooxazolidin-3-yl) -2-fluorophenyl) -N-hydroxythiophene-2-carboxamide) (Compound 104 ) Produce

(S) -methyl-5- (4- (5-acetamidomethyl) -2-oxooxazolidin-3-yl) -2-fluorophenyl) thiophen-2- synthesized in Preparation Example 9 The carboxylate (Compound III-2 ) was reacted in the same manner as in Example 2 to give the title compound (S) -5- (4- (5- (acetamidomethyl) -2-oxooxazolidine-3- Nil) -2-fluorophenyl) -N-hydroxythiophene-2-carboxamide (Compound 104 ) (1.23 g, 3.2 mmol, 77%) was obtained.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.30 (bs, 1H), 9.19 (bs, 1H), 8.27 (t, 1H, J = 6.0 Hz), 7.87 (t, 1H, J = 8.8 Hz) , 7.72-7.58 (m, 2H), 7.55 (d, 1H, J = 4.0 Hz), 7.43 (dd, 1H, J ₁ = 8.8 Hz, J ₂ = 2.0 Hz), 4.85-4.69 (m, 1H), 4.17 (t, 1H, J = 9.0 Hz), 3.78 (dd, 1H, J ₁ = 9.0 Hz, J ₂ = 6.8 Hz), 3.43 (t, 2H, J = 5.4 Hz), 1.84 (s, 3H)

LCMS: C ₁₈ H ₁₇ FN ₂ O ₅ 394 (M + H ⁺ ) for S

Example 5 (S) -N-((3- (3-fluoro-4- (6- (N'-hydroxycarbamidomiyl) pyridin-3-yl) phenyl) -2-oxooxa Zolidine-5-yl) methyl) acetamide (S) -N-((3- (3-fluoro-4- (6- (N'-hydroxycarbamoyl) pyridin-3-yl) phenyl) -2-oxooxazolidin- Preparation of 5-yl) methyl) acetamide) (Compound 105 )

(S) -N-((3- (4- (6-cyanopyridin-3-yl) -3-fluorophenyl) -2-oxooxazolidine-5-yl) synthesized in Preparation Example 10 above Methyl) acetamide (Compound IV- 3 ) 0.85 g (2.39 mmol) was dissolved in 16 ml of ethanol, 0.50 g (7.2 mmol) of hydroxyamine HCl salt and 0.38 g (3.6 mmol) of sodium carbonate were added, and 4 ml of water was added. After stirring for 2 hours at reflux. After 2 hours, the precipitate formed by pouring into 50 mL of water was filtered, washed with water and diethyl ether and dried to give the title compound (S) -N-((3- (3-fluoro-4- (6- ( N'-hydroxycarbamimidoyl) pyridin-3-yl) phenyl) -2-oxooxazolidine-5-yl) methyl) acetamide (Compound 105 ) (0.49 g, 1.3 mmol, 53%) was obtained. .

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.01 (s, 1H), 8.75 (s, 1H), 8.27 (t, 1H, J = 5.6 Hz), 8.01 (d, 1H, J = 8.4 Hz) , 7.95 (d, 1H, J = 8.4 Hz), 7.70 (t, 1H, J = 9.0 Hz), 7.66 (dd, 1H, J ₁ = 14.2 Hz, J ₂ = 2.0 Hz), 7.47 (dd, 1H, J ₁ = 8.8 Hz, J ₂ = 2.0 Hz), 5.89 (s, 2H), 4.88-4.68 (m, 1H), 4.17 (t, 1H, J = 9.2 Hz), 3.80 (dd, 1H, J ₁ = 9.2 Hz, J ₂ = 6.4 Hz), 3.44 (t, 2H, J = 5.4 Hz), 1.84 (s, 3H)

LCMS: 388 (M + H ⁺ ) for C ₁₈ H ₁₈ FN ₅ O ₄

Example 6 (S) -5- (4- (5- (acetamidomethyl) -2-oxooxazolidin-3-yl) -2-fluorophenyl) -N-hydroxypinacolinamide Preparation of ((S) -5- (4- (5- (acetamidomethyl) -2-oxooxazolidin-3-yl) fluorophenyl) -N-hydroxypicolinamide) (Compound 106 )

(S) -methyl-5- (4- (5- (acetamidomethyl) -2-oxooxazolidin-3-yl) -2-fluorophenyl) picolinate synthesized in Preparation Example 11 ( Compound III- 3 ) was reacted in the same manner as in Example 2 to obtain the title compound (S) -5- (4- (5- (acetamidomethyl) -2-oxooxazolidin-3-yl)- 2-Fluorophenyl) -N-hydroxypicolinamide (Compound 106 ) (0.37 g, 0.95 mmol, 44%) was obtained.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.51 (s, 1H), 9.14 (bs, 1H), 8.77 (s, 1H), 8.28 (t, 1H, J = 5.8 Hz), 8.16 (d, 1H, J = 8.4 Hz), 8.06 (d, 1H, J = 8.4 Hz), 7.73 (t, 1H, J = 8.8 Hz), 7.67 (dd, 1H, J ₁ = 13.6 Hz, J ₂ = 2.4 Hz) , 7.49 (dd, 1H, J ₁ = 8.8 Hz, J ₂ = 2.0 Hz), 4.88-4.68 (m, 1H), 4.19 (t, 1H, J = 9.0 Hz), 3.80 (dd, 1H, J ₁ = 9.2 Hz, J ₂ = 6.4 Hz), 3.44 (t, 2H, J = 5.4 Hz), 1.84 (s, 3H)

LCMS: 389 (M + H ⁺ ) for C ₁₈ H ₁₇ FN ₄ O ₅

Experimental Example 1 Measurement of In Vitro Antimicrobial Activity

In order to determine the antimicrobial activity of the oxazolidinone derivatives synthesized in Examples 1 to 6 in vitro activity test was carried out in the following manner.

In vitro antimicrobial activity of the oxazolidinone derivatives of Examples 1 to 6 of the present invention is 90% inhibition, which is the minimum concentration of antibiotic that can inhibit the growth of bacteria by 90% compared to the drug-untreated control growth by spectroscopic measurements. The concentration (MIC ₉₀ , ug / mL) was evaluated by measuring. MIC ₉₀ is a NCCLS standard [National Committee for Clinical Laboratory Standards. (2000) Methods for Dilution Antimicrobial Susceptibility Test for Bacteria that Grow Aerobically-Fifth Edition: M7-A5. NCCLS, Villanova, PA] was measured by the Broth microdilution method.

1) test strain

Methicillin susceptible Staphylococcus aureus (MSSA), methicillin resistant Staphylococcus aureus (MRSA), vancomycin resistant Enterococci (VRE) Twelve strains were used, including Haemophilus Influenzae and Moraxella. Some results are shown in Table 2.

2) Test substance manufacturing method

The test substance (oxazolidinone derivative compounds 101 to 106 according to the present invention synthesized in Examples 1 to 6) was dissolved in DMSO at a concentration of 10240 ug / mL, and then diluted twice by fold to 20 sterilized with distilled water. Fold diluted. In the antimicrobial experiment, the final concentration was from 128 ug / mL to 0.0625 ug / mL, and the concentration of DMSO used as excipient was 2.5% (V / V). As a control material, the antibacterial activity was compared using the compound of Pharmazolide (Formula B) of Pharmacia & Upzone and the results are shown in Table 1 below.

[Formula B]

TABLE 1

As shown in Table 1, the oxazolidinone derivatives of the present invention are Gram-positive bacteria, such as Staphylococcus aureus and Enterococcus faecalis, which are resistant to conventional antibiotics at much lower concentrations than the control agent linezolid. And gram negative bacteria such as Haemophilus influenza and Moraxella catarrhalis. In particular, it exhibits excellent antibacterial activity against linezolide resistant Enterococcus faecalis.

Therefore, it can be seen that the oxazolidinone derivative of the present invention can be usefully used as an antibiotic.

As described above, the novel oxazolidinone derivatives of the present invention have a broad antibacterial spectrum against resistant bacteria, low toxicity, and Staphylococcus, which is resistant to conventional antibiotics at much lower concentrations than the control line lineolide. It has a strong antibacterial activity against Gram-positive bacteria such as Aureus and Enterococcus faecalis and Gram-negative bacteria such as Haemophilus influenza and Moraxella catarrhalis, and is particularly excellent against lineazlide resistant Enterococcus faecalis. It has antibacterial properties and can be used as an antibiotic. In addition, oxazolidinone derivatives including hydroxamide have higher solubility in water than conventionally known compounds, making it easy to develop oral or injectables.

Claims (5)

A novel oxazolidinone derivative represented by the following formula (1). [Formula 1]

[A in Formula 1 is a heteroaromatic ring substituent of the following structure;

P, Q, R, Y and Z are independently of each other C or N; W is NH, O or S; X is O or NH; Except that P, Q and R are simultaneously C or N.] The method of claim 1, A is an oxazolidinone derivative characterized in that the heteroaromatic ring substituent of the following structure.

The method according to claim 1 or 2, An oxazolidinone derivative characterized in that it is selected from the following compounds.

The method of claim 3, wherein An oxazolidinone derivative characterized in that it is selected from the following compounds.

An pharmaceutical composition for antibiotics comprising an oxazolidinone derivative represented by the following Chemical Formula 2, a hydrate thereof, and a pharmaceutically acceptable salt thereof as an active ingredient. [Formula 2]

[A in Formula 2 is a heteroaromatic ring substituent of the following structure;

P, Q, R, Y and Z are independently of each other C or N; W is NH, O or S; X is O or NH; Provided that P, Q and R are simultaneously C or not N.]