CN101597283A - Triazolyl oxazolidinone compounds and their antibacterial applications - Google Patents

Abstract

The invention discloses triazolyl oxazolidinone compounds and antibacterial application thereof.Triazolyl oxazolidinone compounds, its structural formula be suc as formula shown in (I), and R is aromatic base, replace aminomethyl, the methylol that replaces of heterocyclic substituted methyl, methylol, methylol that fatty acyl group replaces, methylol that aroyl replaces or 4-hetaroylpyrazol.Triazolyl oxazolidinone compounds provided by the invention and at pharmacy acceptable salt has good antibacterial activity, particularly the multidrug resistance bacterium is had good inhibition activity, has a extensive future.

Description

Triazolyl oxazolidinone compounds and their antibacterial applications

technical field

The invention relates to the technical field of medicinal chemistry, in particular to triazolyl oxazolidinone compounds and their use as medicines for treating bacterial infections.

Background technique

Antibiotics and synthetic antibacterial drugs are the first choice for human to treat bacterial infectious diseases. However, due to long-term use and irrational abuse, more and more bacteria are resistant to existing antibacterial drugs, even multidrug resistance. The more common ones are methicillin-resistant Staphylococcus aureus (MRSA) and Staphylococcus epidermidis (MRSE), drug-resistant Streptococcus pneumoniae, etc., which have brought serious problems to the treatment of bacterial infectious diseases, resulting in a delay in the treatment time of patients. Significantly prolonged and increased mortality.

Oxazolidinone antibacterial drugs are a new class of fully synthetic antibacterial drugs with a unique mechanism of action. In 2000, the first oxazolidinone antibacterial drug, Linezolid, was successfully launched on the market. It is effective against a variety of drug-resistant bacteria. Infectious diseases have a significant effect. At present, in-depth structure modification and optimization of oxazolidinone antibacterial drugs are being carried out to develop new drugs with higher antibacterial activity and wider antibacterial spectrum.

Contents of the invention

The object of the present invention is to provide a class of triazolyloxazolidinone compounds with antibacterial activity, especially effective against multi-drug resistant bacteria.

1. The present invention provides the oxazolidinone compound containing substituted 1,2,3-triazole structure as shown in formula (I):

In formula (I), R is aryl, substituted aminomethyl, heterocyclic substituted methyl, hydroxymethyl, fatty acyl substituted hydroxymethyl, aroyl substituted hydroxymethyl or heteroaroyl substituted hydroxymethyl .

The aryl group is phenyl, naphthyl, biphenyl, anthracenyl or phenanthrenyl, among which phenyl is preferred.

"Substituted aminomethyl" means monosubstituted and disubstituted aminomethyl groups substituted by alkyl and aryl groups, among which N,N-dimethylaminomethyl is most preferred.

"Heterocycle" means a five- or six-membered heterocyclic aromatic and non-aromatic group containing 1-4 heteroatoms selected from N, O, and S, including piperidine, tetrahydropyrrole, and phthalimide , Morpholinyl, oxazolidinyl, furyl, thienyl, pyridyl, imidazolyl, thiazolyl, pyrazolyl, oxazolyl, isoxazolyl, isothiazolyl, triazolyl, tetrazolyl , pyrimidinyl, pyridazinyl, etc., among which piperidine, phthalimide, morpholinyl, and oxazolidinone are preferred.

"Alkyl" means a saturated or unsaturated, straight or branched alkane chain of 1 to 6 carbons, including methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl , tert-butyl, allyl, pentyl, isopentyl, neopentyl, tert-pentyl, hexyl, isohexyl, etc.

"Fatty acyl" means 1-6 carbon saturated or unsaturated, linear or branched, and fatty acyl containing halogen substituents, including acetyl, propionyl, isopropionyl, butyryl, isobutyryl , sec-butyryl, tert-butyryl, acryloyl, valeryl, isovaleryl, pivaloyl, tert-valeryl, hexanoyl, isocaproyl and their corresponding halogens (including fluorine, chlorine, bromine, iodine) substituted Acyl and the like, among which acetyl and dichloroacetyl are the best.

"Aroyl" means substituted aryl formyl, substituents include alkyl, aryl, hydroxyl, nitro, fluorine, chlorine, bromine, iodine, amino, etc., wherein methyl, fluorine, chlorine, nitro, Tert-butyl is most preferred.

"Heteroaroyl" means a substituted aromatic heterocyclic formyl group, including furyl, thienyl, pyridyl, imidazolyl, thiazolyl, pyrazolyl, oxazolyl, isoxazolyl, isothiazolyl, Triazolyl, tetrazolyl, pyrimidinyl, pyridazinyl, etc., among which furyl, thienyl, and pyridyl are the best.

"Can be substituted" refers to the above-mentioned "aryl", "aromatic heterocycle", "alkyl", optional halogen atom, alkyl, alkoxy, -OH, -NH ₂ , - NO ₂ and other groups are substituted.

The names of the oxazolidinone compounds 1-16 shown in the above formula (I) are as follows respectively:

Compound 1: (R)-3-[(3-fluoro-4-morpholinyl)phenyl]-5-[(4-phenyl-1-H-1,2,3-triazole)-1 -yl]methyloxazolidin-2-one;

Compound 2: (R)-3-[(3-fluoro-4-morpholinyl)phenyl]-5-[(4-hydroxymethyl-1-H-1,2,3-triazole)- 1-yl]methyloxazolidin-2-one;

Compound 3: (R)-3-[(3-fluoro-4-morpholinyl)phenyl]-5-[(4-aminomethyl-1-H-1,2,3-triazole)- 1-yl]methyloxazolidin-2-one;

Compound 4: (R)-3-[(3-fluoro-4-morpholinyl)phenyl]-5-{[4-(N,N-dimethyl)aminomethyl-1-H-1, 2,3-Triazole]-1-yl}methyloxazolidin-2-one;

Compound 5: (R)-3-[(3-fluoro-4-morpholinyl)phenyl]-5-[(4-morpholinylmethyl-1-H-1,2,3-triazole )-1-yl]methyloxazolidin-2-one;

Compound 6: (R)-3-[(3-fluoro-4-morpholinyl)phenyl]-5-{[4-(2-oxooxazolidin-3-yl)methyl-1-H -1,2,3-Triazole]-1-yl}methyloxazolidin-2-one;

Compound 7: (R)-3-[(3-fluoro-4-morpholinyl)phenyl]-5-[(4-acetoxymethyl-1-H-1,2,3-triazole )-1-yl]methyloxazolidin-2-one;

Compound 8: (R)-3-[(3-fluoro-4-morpholinyl)phenyl]-5-[(4-dichloroacetoxymethyl-1-H-1,2,3-tri Azorazol)-1-yl]methyloxazolidin-2-one;

Compound 9: (R)-3-[(3-fluoro-4-morpholinyl)phenyl]-5-[(4-furan-2-formyloxymethyl-1-H-1,2, 3-triazol)-1-yl]methyloxazolidin-2-one;

Compound 10: (R)-3-[(3-fluoro-4-morpholinyl)phenyl]-5-[(4-thiophene-2-formyloxymethyl-1-H-1,2, 3-triazol)-1-yl]methyloxazolidin-2-one;

Compound 11: (R)-3-[(3-fluoro-4-morpholinyl)phenyl]-5-[(4-pyridine-2-formyloxymethyl-1-H-1,2, 3-triazol)-1-yl]methyloxazolidin-2-one;

Compound 12: (R)-3-[(3-fluoro-4-morpholinyl)phenyl]-5-[(4-p-methylbenzoyloxymethyl-1-H-1,2, 3-triazol)-1-yl]methyloxazolidin-2-one;

Compound 13: (R)-3-[(3-fluoro-4-morpholinyl)phenyl]-5-[(4-p-fluorobenzoyloxymethyl-1-H-1,2,3 -triazol)-1-yl]methyloxazolidin-2-one;

Compound 14: (R)-3-[(3-fluoro-4-morpholinyl)phenyl]-5-[(4-p-chlorobenzoyloxymethyl-1-H-1,2,3 -triazol)-1-yl]methyloxazolidin-2-one;

Compound 15: (R)-3-[(3-fluoro-4-morpholinyl)phenyl]-5-[(4-p-nitrobenzoyloxymethyl-1-H-1,2, 3-triazol)-1-yl]methyloxazolidin-2-one;

Compound 16: (R)-3-[(3-fluoro-4-morpholinyl)phenyl]-5-[(4-p-tert-butylbenzoyloxymethyl-1-H-1,2 , 3-triazole)-1-yl]methyloxazolidin-2-one;

The chemical structural formula of oxazolidinone compounds 1-16 shown in formula (I) is shown in Table 1:

Table 1. Structural formulas of target compounds

2. the present invention also provides the synthetic method of oxazolidinone compound shown in above-mentioned (I) formula, and its synthetic process is as follows:

Using 3,4-difluoronitrobenzene, morpholine and (R)-glycidyl n-butyrate as raw materials, synthesized according to the literature method (Brickner, SJet al J.Med.Chem.1996, 39, 673-679) The intermediate (R)-3-[(3-fluoro-4-morpholinyl)phenyl]-2-oxo-5-oxazolidinemethyl azide compound was obtained. In the presence of a catalyst, the oxazolidinone compound 1-16 represented by the formula (I) is synthesized by a ring closure reaction with a 3-substituted propyne using an organic solvent and a water mixture as a solvent at -10-80°C. The catalyst here is Cu ⁺ salt, such as CuI and the Cu ⁺ salt generated by the reaction of CuSO ₄ with the sodium salt of vitamin C; the organic solvent here includes tetrahydrofuran, dimethylformamide, dimethyl sulfoxide, acetone, methanol, Solvents such as ethanol. The volume ratio of organic solvent to water is 1:1-5.

3. The present invention also provides pharmaceutically acceptable salts of the oxazolidinone compounds represented by the above formula (I). "Pharmaceutically acceptable salt" refers to salts formed with inorganic acids such as hydrochloric acid, sulfuric acid, hydrofluoric acid, hydrobromic acid, phosphoric acid, and nitric acid, and salts formed with formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, Salts with organic acids such as fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, and methanesulfonic acid, and salts with acidic amino acids such as aspartic acid and glutamic acid. The oxazolidinone compounds and their salts of the present invention can be made into various pharmaceutically acceptable carrier preparations or preparations for different administration forms, and the effective weight content thereof is 0.1%-99.9%.

4. The present invention also provides oxazolidinone compounds shown in the above formula (I) and pharmaceutically acceptable salts thereof as the drug for treating infectious diseases, especially infectious diseases caused by multi-drug resistant bacteria. use.

Compared with prior art, the present invention has following advantage:

The triazole-based oxazolidinone compounds and pharmaceutically acceptable salts thereof provided by the invention have good antibacterial activity and good inhibitory activity against multidrug-resistant bacteria, and have broad application prospects.

Detailed ways

Example 1: (R)-3-[(3-fluoro-4-morpholinyl)phenyl]-5-[(4-phenyl-1-H-1,2,3-triazole)- Synthesis of 1-yl]methyloxazolidin-2-one (Compound 1)

(R)-3-[(3-fluoro-4-morpholinyl)phenyl]-2-oxo-5-oxazolidinemethyl azide compound 321mg (1mmol) dissolved in 5ml tetrahydrofuran and 4ml water mixed In the solvent, add 0.5mmol of sodium salt of vitamin C and 0.01mmol of copper sulfate pentahydrate, stir and cool down to about 0°C, add 127.5mg (1.25mmol) of phenylacetylene dropwise, and continue stirring at about 0°C. Track until all the raw materials disappear. After the reaction was completed, 20ml of water was added and stirred, a light yellow solid was produced, filtered, the solid was collected, the filter cake was washed with water, and dried in vacuo to obtain a yellow solid crude product, which was purified by silica gel column chromatography (dichloromethane and ethyl acetate gradient elution ), to obtain 360mg of light yellow solid, yield 85.1%. Melting point: 195.8-197.0°C. ¹ H NMR (400MHz, DMSO-d ₆ ) δ: 8.63(s, 1H), 7.86(d, J=7.2Hz, 1H), 7.46(d, J=7.2Hz, 2H), 7.33-7.40(m, 3H ), 7.16(d, J=8.8Hz, 1H), 7.04(t, J=8.8Hz, 1H), 5.18-5.19(m, 1H), 4.87(d, J=4.4Hz, 2H), 4.25(t , J=8.8Hz, 1H), 3.93(t, J=8.8Hz, 1H), 3.73(s, 4H), 2.95(s, 4H); ¹³ CNMR(100MHz, DMSO-d ₆ )δ: 47.68, 51.12 , 52.61, 66.60, 71.24, 107.20 (d, J=25.9Hz), 114.82, 119.63 (d, J=3.6Hz), 122.84, 125.68, 128.43, 129.39, 130.98, 133.41 (d, J=10.3Hz), 136.16 (d, J=8.9Hz), 146.89, 153.76 (d, J=23.7Hz), 156.18; high-resolution mass spectrum (C ₂₂ H ₂₂ FN ₅ O ₃ +Na ⁺ ): theoretical value 446.1604, observed value 446.1619.

Example 2: (R)-3-[(3-fluoro-4-morpholinyl)phenyl]-5-[(4-hydroxymethyl-1-H-1,2,3-triazole) Synthesis of -1-yl]methyloxazolidin-2-one (compound 2)

The synthesis method was similar to that of compound 1, and 354 mg of a light yellow solid was obtained with a yield of 93.9%. Melting point: 218.6-219.8°C. ¹ HNMR (400MHz, DMSO-d ₆ ) δ: 8.03(s, 1H), 7.47(dd, J=2.4Hz, J'=15.2Hz, 1H), 7.17(dd, J=1.6Hz, J'=8.8 Hz, 1H), 7.06(t, J=9.6Hz, 1H), 5.08-5.15(m, 1H), 4.80(d, J=5.2Hz, 2H), 4.51(s, 2H), 4.21(t, J =9.2Hz, 1H), 3.88(dd, J=6.0Hz, J'=9.2Hz, 1H), 3.73(t, J=4.4Hz, 4H), 2.96(t, J=4.4Hz, 4H); ¹³ CNMR (100MHz, DMSO-d ₆ ) δ: 47.64, 51.12, 52.24, 55.40, 66.60, 71.39, 107.18(d, J=25.9Hz), 114.83, 119.71(d, J=3.7Hz), 124.12, 133.46(d , J=10.5Hz), 136.13(d, J=9.7Hz), 148.64, 153.76(d, J=23.8Hz), 156.18; high resolution mass spectrum (C ₁₇ H ₂₀ FN ₅ O ₄ +Na ⁺ ): theoretical value 400.1397, found 400.1398.

Example 3: (R)-3-[(3-fluoro-4-morpholinyl)phenyl]-5-[(4-aminomethyl-1-H-1,2,3-triazole) Synthesis of -1-yl]methyloxazolidin-2-one (Compound 3)

The synthesis method was similar to that of compound 1, and 321 mg of light yellow solid was obtained with a yield of 85.3%. Melting point: 177.9-180.0°C. ¹ HNMR (400MHz, CDCl ₃ +Methanol-d ₄ ) δ: 7.99(s, 1H), 7.38(dd, J=2.4Hz, J'=14.0Hz, 1H), 7.07(dd, J=1.6Hz, J '=8.4Hz, 1H), 6.95(t, J=8.8Hz, 1H), 5.11-5.14(m, 1H), 4.75-4.90(m, 2H), 4.38(s, 2H), 4.21(t, J =8.8Hz, 1H), 3.97(dd, J=6.0Hz, J'=9.6Hz, 1H), 3.88(t, J=4.4Hz, 4H), 3.06(t, J=4.4Hz, 4H); ¹³ CNMR (100MHz, CDCl ₃ +Methanol-d ₄ ) δ: 30.94, 47.92, 51.19, 52.59, 67.16, 71.14, 107.95 (d, J=26.0Hz), 114.79 (dJ=2.8Hz), 119.23 (d, J= 3.7Hz), 124.47, 132.78 (d, J=10.5Hz), 136.94 (d, J=8.7Hz), 145.94, 154.46, 156.90; high resolution mass spectrum (C ₁₇ H ₂₁ FN ₆ O ₃ +Na ⁺ ): theoretical Value 399.1557, found value 399.1561.

Example 4: (R)-3-[(3-fluoro-4-morpholinyl)phenyl]-5-{[4-(N,N-dimethyl)aminomethyl-1-H-1 , Synthesis of 2,3-triazole]-1-yl}methyloxazolidin-2-one (compound 4)

The synthesis method was similar to that of compound 1, and 312 mg of light yellow solid was obtained with a yield of 77.2%. Melting point: 166.8-168.3°C. ¹ H NMR (400MHz, DMSO-d ₆ ) δ: 8.00(s, 1H), 7.42(d, J=14.8Hz, 1H), 7.12(d, J=8.0Hz, 1H), 7.04(t, J=8.8 Hz, 1H), 5.12(s, 1H), 4.78(s, 2H), 4.20(t, J=8.8Hz, 1H), 3.85(s, 1H), 3.73(s, 4H), 3.47(s, 2H ), 2.95 (s, 4H), 2.09 (s, 6H); ¹³ CNMR (100MHz, DMSO-d ₆ ) δ: 44.92, 47.48, 51.12, 52.31, 53.93, 66.60, 71.16, 107.07 (d, J=26.0Hz ), 114.68, 119.66 (d, J=3.5Hz), 125.08, 133.39 (d, J=10.5Hz), 136.10 (d, J=8.6Hz), 144.35, 153.75 (d, J=18.2Hz), 156.18; High resolution mass spectrum (C ₁₉ H ₂₅ FN ₆ O ₃ +H ⁺ ): theoretical value 405.2050, found value 405.2055.

Example 5: (R)-3-[(3-fluoro-4-morpholinyl)phenyl]-5-[(4-morpholinylmethyl-1-H-1,2,3-triazine Synthesis of azole)-1-yl]methyloxazolidin-2-one (Compound 5)

The synthesis method was similar to that of compound 1, and 332 mg of light yellow solid was obtained with a yield of 77.4%. Melting point: 169.5-171.3°C. ¹ HNMR (400MHz, DMSO-d ₆ ) δ: 8.05(s, 1H), 7.41(d, J=14.8Hz, 1H), 7.11(d, J=8.8Hz, 1H), 7.03(t, J=9.6 Hz, 1H), 5.13(d, J=4.0Hz, 1H), 4.79(s, 2H), 4.20(t, J=9.2Hz, 1H), 3.87(dd, J=5.2Hz, J'=8.8Hz , 1H), 3.73(s, 4H), 3.58(s, 2H), 3.52(s, 4H), 2.95(s, 4H), 2.37(s, 4H); ¹³ CNMR(100MHz, DMSO-d ₆ )δ : 47.42, 51.13, 52.39, 52.98, 66.35, 66.60, 71.08, 107.00 (d, J=26.1Hz), 114.63, 119.63 (d, J=3.7Hz), 125.58, 133.34 (d, J=10.5Hz), 136.09 (d, J=8.7Hz), 143.38, 153.74 (d, J=17.8Hz), 156.17; high-resolution mass spectrum (C ₂₁ H ₂₇ FN ₆ O ₄ +Na ⁺ ): theoretical value 469.1976, measured value 469.1980.

Example 6: (R)-3-[(3-fluoro-4-morpholinyl)phenyl]-5-{[4-(2-oxooxazolidin-3-yl)methyl-1- Synthesis of H-1,2,3-triazole]-1-yl}methyloxazolidin-2-one (Compound 6)

The synthesis method was similar to that of compound 1, and 340 mg of light yellow solid was obtained with a yield of 76.2%. Melting point: 170.4-173.0°C. ¹ HNMR (400MHz, DMSO-d ₆ ) δ: 8.01(s, 1H), 7.43(dd, J=2.4Hz, J'=15.2Hz, 1H), 7.14(dd, J=2.0Hz, J'=8.8 Hz, 1H), 7.04(t, J=8.8Hz, 1H), 5.10-5.16(m, 1H), 4.81(d, J=4.8Hz, 2H), 4.41(s, 2H), 4.18-4.23(m , 3H), 3.88(dd, J=5.6Hz, J'=9.6Hz, 1H), 3.73(t, J=4.4Hz, 4H), 3.39-3.44(m, 2H), 2.96(t, J=4.4 Hz, 4H); ¹³ CNMR (100MHz, DMSO-d ₆ ) δ: 44.24, 47.54, 51.13, 52.49, 62.15, 66.60, 71.17, 75.88, 78.55, 107.06 (d, J=26.1Hz), 114.72, 119.64 (d , J=3.9Hz), 124.92, 133.37 (d, J=10.5Hz), 136.13 (d, J=8.6Hz), 142.69, 153.75 (d, J=18.5Hz), 156.18, 158.15; high-resolution mass spectrum (C ₂₀ H ₂₃ FN ₆ O ₅ +H ⁺ ): theoretical value 447.1792, found value 447.1790.

Example 7: (R)-3-[(3-fluoro-4-morpholinyl)phenyl]-5-[(4-acetoxymethyl-1-H-1,2,3-triazine Synthesis of azole)-1-yl]methyloxazolidin-2-one (Compound 7)

(R)-3-[(3-fluoro-4-morpholinyl)phenyl]-5-[(4-hydroxymethyl-1-H-1,2,3-triazole)-1-yl ]Methyloxazolidin-2-one (Compound 2) 188.5mg (0.5mmol) was dissolved in 5ml of dichloromethane, added 75.75mg (0.75mmol) of triethylamine, stirred and cooled to about 0°C, and acetyl chloride was added dropwise 43.2mg (0.55mmol), after the addition, continue to stir for 2 hours at about 0°C, slowly rise to room temperature, continue to stir for 3 hours, add 20ml of water to the reaction solution, stir, separate the layers, and extract the water layer with dichloromethane Three times, use 10ml dichloromethane each time, combine organic layer, after drying with anhydrous sodium sulfate, filter, get yellow solid crude product after removing solvent, purify with silica gel column chromatography (dichloromethane and ethyl acetate gradient washing off), to obtain 174 mg of a light yellow solid, with a yield of 83.0%. Melting point: 108.5-110.2°C. ¹ HNMR (400MHz, CDCl ₃ ) δ: 7.83(s, 1H), 7.34(dd, J=2.4Hz, J'=14.4Hz, 1H), 7.00(dd, J=2.8Hz, J'=8.8Hz, 1H), 6.90(t, J=8.8Hz, 1H), 5.20(s, 2H), 5.08-5.02(m, 1H), 4.77-4.73(m, 2H), 4.18-4.13(m, 1H), 3.92 -3.89(m, 1H), 3.86(t, J=4.8Hz, 4H), 3.04(t, J=4.8Hz, 4H), 2.07(s, 3H); ¹³ CNMR(100MHz, CDCl ₃ ) δ: 35.77 , 47.42, 50.89(d, J=2.7Hz), 52.23(d, J=9.1), 57.36, 66.91, 70.30, 107.69(d, J=26.1Hz), 114.28(d, J=3.5Hz), 118.80( d, J=3.9Hz), 124.28, 132.10(d, J=10.2Hz), 136.91(d, J=8.8Hz), 145.43, 153.33, 154.15(d, J=245.5Hz), 170.77; high-resolution mass spectrum ( C ₁₉ H ₂₂ FN ₅ O ₅ +Na ⁺ ): theoretical value 442.1503, found value 442.1498.

Example 8: (R)-3-[(3-fluoro-4-morpholinyl)phenyl]-5-[(4-dichloroacetoxymethyl-1-H-1,2,3- Synthesis of Triazol)-1-yl]methyloxazolidin-2-one (Compound 8)

The synthesis method was similar to that of compound 7, and 203 mg of light yellow solid was obtained with a yield of 83.2%. Melting point: 80.4-82.5°C. ¹ HNMR (400MHz, CDCl ₃ ) δ: 7.93(s, 1H), 7.33(dd, J=2.4Hz, J'=14.4Hz, 1H), 7.00(dd, J=1.6Hz, J'=8.8Hz, 1H), 6.91(t, J=8.8Hz, 1H), 5.95(s, 1H), 5.39(s, 2H), 5.05-5.08(m, 1H), 4.72-4.83(m, 2H), 4.11-4.18 (m, 1H), 3.90-3.92(m, 1H), 3.86(t, J=4.4Hz, 4H), 3.04(t, J=4.4Hz, 4H); ¹³ CNMR (100MHz, CDCl ₃ ) δ: 47.41 , 50.90(d, J=2.7Hz), 52.34, 60.00, 63.96, 66.89, 70.26, 107.64(d, J=26.0Hz), 114.25(d, J=3.0Hz), 118.86(d, J=3.8Hz) , 125.79, 132.16(d, J=10.3Hz), 136.81(d, J=8.8Hz), 141.90, 153.31(d, J=245.4Hz), 164.37; high resolution mass spectrum (C ₁₉ H ₂₀ Cl ₂ FN ₅ O ₅ +Na ⁺ ): theoretical value 510.0723, measured value 510.0734.

Example 9: (R)-3-[(3-fluoro-4-morpholinyl)phenyl]-5-[(4-furan-2-formyloxymethyl-1-H-1,2 , 3-triazol)-1-yl] the synthesis of methyl oxazolidin-2-one (compound 9)

The synthesis method was similar to that of compound 7, and 196 mg of light yellow solid was obtained with a yield of 83.2%. Melting point: 153.6-154.4°C. ¹ HNMR (400MHz, CDCl ₃ ) δ: 7.99(s, 1H), 7.58(s, 1H), 7.34(dd, J=1.6Hz, J'=14.4Hz, 1H), 7.19(d, 3.2Hz, 1H ), 6.99(d, J=7.6Hz, 1H), 6.92(t, J=8.8Hz, 1H), 6.50(dd, J=1.6Hz, J'=3.2Hz, 1H), 5.43(s, 2H) , 5.07(s, 1H), 4.77(t, J=16.0Hz, 2H), 4.16(t, J=8.8Hz, 1H), 3.92(t, J=8.8Hz, 1H), 3.86(t, J= 4.4Hz, 4H), 3.04 (t, J = 4.4Hz, 4H); ¹³ CNMR (100MHz, CDCl ₃ ) δ: 47.56, 50.94 (d, J = 2.7Hz), 52.38, 57.67, 66.88, 70.35, 107.63 ( d, J=26.0Hz), 111.99, 112.70, 114.23(d, J=3.0Hz), 118.72, 118.90(d, J=3.7Hz), 121.79, 132.36(d, J=10.3Hz), 136.62(d, J=8.5Hz), 144.04, 146.72, 148.61, 153.38 (d, J=177.5Hz), 158.36; high-resolution mass spectrum (C ₂₂ H ₂₂ FN ₅ O ₆ +Na ⁺ ): theoretical value 494.1452, measured value 494.1455.

Example 10: (R)-3-[(3-fluoro-4-morpholinyl)phenyl]-5-[(4-thiophene-2-formyloxymethyl-1-H-1,2 , 3-triazol)-1-yl] the synthesis of methyl oxazolidin-2-one (compound 10)

The synthesis method was similar to that of compound 7, and 186 mg of light yellow solid was obtained with a yield of 76.4%. Melting point: 83.4-83.5°C. ¹ HNMR (400MHz, CDCl ₃ ) δ: 7.93(s, 1H), 7.80(d, J=3.2Hz, 1H), 7.57(d, J=4.8Hz 1H), 7.33(dd, J=2.4Hz, J '=14.4Hz, 1H), 7.09(t, J=4.8Hz, 1H), 6.99(dd, J=1.6Hz, J'=8.8Hz, 1H), 6.87(t, J=8.8Hz, 1H), 5.43(s, 2H), 5.06(d, J=3.2Hz, 1H), 4.70-4.80(m, 2H), 4.15(t, J=8.8Hz, 1H), 3.92(t, J=8.8Hz, 1H ), 3.86(t, J=4.4Hz, 4H), 3.03(t, J=4.4Hz, 4H); ¹³ CNMR(100MHz, CDCl ₃ )δ: 47.51, 50.93, 52.31, 57.93, 66.93, 70.26, 107.63( d, J=26.1Hz), 114.26, 118.80, 127.85, 128.48, 132.20(d, J=10.3Hz), 132.93(d, J=7.5Hz), 134.01, 135.35, 136.06, 136.84(d, J=9.1Hz ), 153.31, 154.17 (d, J=245.4Hz), 161.95; high-resolution mass spectrum (C ₂₂ H ₂₂ FN ₅ O ₅ S+Na ⁺ ): theoretical value 510.1223, observed value 510.1223.

Example 11: (R)-3-[(3-fluoro-4-morpholinyl)phenyl]-5-[(4-pyridine-2-formyloxymethyl-1-H-1,2 , 3-triazol)-1-yl] the synthesis of methyl oxazolidin-2-one (compound 11)

The synthesis method was similar to that of compound 7, and 187 mg of a light yellow solid was obtained with a yield of 77.6%. Melting point: 78.2-80.5°C. ¹ HNMR (400MHz, CDCl ₃ ) δ: 8.75(d, J=3.6Hz, 1H), 8.13(d, J=7.6Hz, 1H), 7.98(s, 1H), 7.84(d, J=7.6Hz, 1H), 7.49(d, J=4.8Hz 1H), 7.33(dd, J=2.0Hz, J'=14.0Hz, 1H), 6.98(d, J=7.2Hz, 1H), 6.87(t, J= 8.8Hz, 1H), 5.55(s, 2H), 5.04-5.06(m, 1H), 4.69-4.79(m, 2H), 4.12-4.16(m, 1H), 3.90-3.94(m, 1H), 3.86 (t, J=4.4Hz, 4H), 3.03 (t, J=4.4Hz, 4H); ¹³ CNMR (100MHz, CDCl ₃ ) δ: 47.57, 50.93, 52.26, 58.65, 66.97, 70.29, 107.62 (d, J =26.1Hz), 114.24, 118.80(d, J=3.8Hz), 125.46, 125.84, 127.18, 132.22(d, J=10.4Hz), 136.81(d, J=8.7Hz), 137.10, 143.20, 147.49, 149.99 , 153.33, 154.16 (d, J=245.2Hz), 164.93; high-resolution mass spectrum (C ₂₃ H ₂₃ FN ₆ O ₅ +Na ⁺ ): theoretical value 505.1612, found value 505.1610.

Example 12: (R)-3-[(3-fluoro-4-morpholinyl)phenyl]-5-[(4-p-methylbenzoyloxymethyl-1-H-1,2 , 3-triazol)-1-yl] the synthesis of methyl oxazolidin-2-one (compound 12)

The synthesis method was similar to that of compound 7, and 175 mg of a light yellow solid was obtained with a yield of 70.7%. Melting point: 167.5-169.3°C. ¹ HNMR (400MHz, CDCl ₃ ) δ: 7.92(s, 1H), 7.91(d, J=8.0Hz, 2H), 7.32(d, J=2.4Hz, 1H), 7.22(d, J=8.0Hz, 2H), 6.98(dd, J=2.0Hz, J'=8.8Hz, 1H), 6.84(t, J=8.8Hz, 1H), 5.43(s, 2H), 5.02-5.08(m, 1H), 4.69 -4.79(m, 2H), 4.13(t, J=8.8Hz, 1H), 3.90(t, J=8.8Hz, 1H), 3.85(t, J=4.4Hz, 4H), 3.01(t, J= 4.4Hz, 4H), 2.93(s, 3H); ¹³ CNMR (100MHz, CDCl ₃ ) δ: 21.69, 47.51, 50.89, 52.26, 58.68, 66.92, 70.33, 107.59 (d, J=26.0Hz), 114.24, 118.78 (d, J=3.8Hz), 125.43, 126.84, 129.13, 129.78, 132.22(d, J=10.3Hz), 136.79(d, J=8.7Hz), 143.80, 143.99, 153.37, 154.13(d, J=245.6 Hz), 166.38; high resolution mass spectrum (C ₂₅ H ₂₆ FN ₅ O ₅ +Na ⁺ ): theoretical value 518.1816, found value 518.1817.

Example 13: (R)-3-[(3-fluoro-4-morpholinyl)phenyl]-5-[(4-p-fluorobenzoyloxymethyl-1-H-1,2, Synthesis of 3-triazole)-1-yl]methyloxazolidin-2-one (compound 13)

The synthesis method was similar to that of compound 7, and 165 mg of a light yellow solid was obtained with a yield of 66.1%. Melting point: 117.8-118.4°C. ¹ HNMR (400MHz, CDCl ₃ ) δ: 8.05(dd, J=5.6Hz, J'=8.8Hz, 2H), 7.93(s, 1H), 7.31(d, J=2.4Hz, 1H), 7.09(t , J=8.8Hz, 2H), 6.97(dd, J=2.0Hz, J'=8.8Hz, 1H), 6.86(t, J=8.8Hz, 1H), 5.44(s, 2H), 5.03-5.08( m, 1H), 4.71-4.81(m, 2H), 4.14(t, J=8.8Hz, 1H), 3.93(dd, J=6.0Hz, J'=9.2Hz, 1H), 3.86(t, J= 4.8Hz, 4H), 3.03 (t, J=4.8Hz, 4H); ¹³ CNMR (100MHz, CDCl ₃ ) δ: 47.44, 50.89 (d, J=2.8Hz), 52.31, 57.88, 66.90, 70.24, 107.68 ( d, J=26.0Hz), 114.27(d, J=3.1Hz), 115.47(d, J=21.9Hz), 118.81(d, J=3.9Hz), 125.50, 125.83(d, J=2.9Hz), 132.32(d, J=9.4Hz), 136.82(d, J=8.4Hz), 143.60, 153.29, 154.15(d, J=245.2Hz), 164.65, 165.34, 167.17; high-resolution mass spectrum (C ₂₄ H ₂₃ F ₂ N ₅ O ₅ +Na ⁺ ): theoretical value 522.1565, measured value 522.1562.

Example 14: (R)-3-[(3-fluoro-4-morpholinyl)phenyl]-5-[(4-p-chlorobenzoyloxymethyl-1-H-1,2, Synthesis of 3-triazole)-1-yl]methyloxazolidin-2-one (compound 14)

The synthesis method was similar to that of compound 7, and 162 mg of a light yellow solid was obtained with a yield of 62.8%. Melting point: 163.5-164.0°C. ¹ HNMR (400MHz, CDCl ₃ ) δ: 7.96(s, 1H), 7.93(d, J=2.8Hz, 2H), 7.40(d, J=8.4Hz, 2H), 7.30(dd, J=2.4Hz, J'=14.0Hz, 1H), 6.96(dd, J=2.0Hz, J'=8.8Hz, 1H), 6.84(t, J=8.8Hz, 1H), 5.44(s, 2H), 5.03-5.09( m, 1H), 4.71-4.80(m, 2H), 4.14(t, J=8.8Hz, 1H), 3.92(dd, J=6.0Hz, J'=9.2Hz, 1H), 3.86(t, J= 4.4Hz, 4H), 3.02 (t, J=4.4Hz, 4H); ¹³ CNMR (100MHz, CDCl ₃ ) δ: 47.41, 50.88 (d, J=2.8Hz), 52.31, 57.96, 66.92, 70.21, 107.68 ( d, J=26.0Hz), 114.29(d, J=3.0Hz), 118.76(d, J=4.0Hz), 125.51, 128.05, 128.76, 131.16, 132.08(d, J=10.2Hz), 136.88(d, J=8.8Hz), 139.70, 143.49, 153.27, 154.13 (d, J=245.5Hz), 165.44; high-resolution mass spectrum (C ₂₄ H ₂₃ ClFN ₅ O ₅ +Na ⁺ ): theoretical value 538.1269, measured value 538.1278.

Example 15: (R)-3-[(3-fluoro-4-morpholinyl)phenyl]-5-[(4-p-nitrobenzoyloxymethyl-1-H-1,2 , 3-triazol)-1-yl] the synthesis of methyl oxazolidin-2-one (compound 15)

The synthesis method was similar to that of compound 7, and 157 mg of light yellow solid was obtained with a yield of 59.7%. Melting point: 64.0-65.1°C. ¹ HNMR (400MHz, CDCl ₃ ) δ: 8.23-8.25(m, 2H), 8.15-8.17(m, 2H), 8.0(s, 1H), 7.27(d, J=14.0Hz, 1H), 6.94(d , J=8.4Hz, 1H), 6.84(t, J=8.8Hz, 1H), 5.49(s, 2H), 5.06-5.12(m, 1H), 4.75-4.85(m, 2H), 4.16(t, J=9.2Hz, 1H), 3.92(t, J=8.0Hz, 1H), 3.84(s, 4H), 3.01(s, 4H); ¹³ CNMR(100MHz, CDCl ₃ ) δ: 47.37, 50.84(d, J=2.6Hz), 52.40, 58.49, 66.87, 70.32, 107.66(d, J=25.9Hz), 114.33, 118.70(d, J=4.1Hz), 123.52, 125.80, 130.89, 132.04(d, J=10.1Hz ), 134.98, 136.84 (d, J=8.7Hz), 142.89, 150.59, 153.37, 154.02 (d, J=245.4Hz), 164.41; high-resolution mass spectrum (C ₂₄ H ₂₃ FN ₆ O ₇ +Na ⁺ ): theoretical Value 549.1510, found value 549.1514.

Example 16: (R)-3-[(3-fluoro-4-morpholinyl)phenyl]-5-[(4-p-tert-butylbenzoyloxymethyl-1-H-1, Synthesis of 2,3-triazole)-1-yl]methyloxazolidin-2-one (compound 16)

The synthesis method was similar to that of compound 7, and 162 mg of a light yellow solid was obtained with a yield of 60.3%. Melting point: 147.5-148.5°C. ¹ HNMR (400MHz, CDCl ₃ ) δ: 7.96(d, J=8.4Hz, 2H), 7.92(s, 1H), 7.44(d, J=8.4Hz, 2H), 7.33(dd, J=2.4Hz, J'=14.4Hz, 1H), 6.99(dd, J=2.0Hz, J'=8.8Hz, 1H), 6.88(t, J=8.8Hz, 1H), 5.44(s, 2H), 5.02-5.08( m, 1H), 4.69-4.79(m, 2H), 4.16(t, J=8.8Hz, 1H), 3.93(dd, J=6.0Hz, J'=9.2Hz, 1H), 3.85(t, J= 4.8Hz, 4H), 3.02(t, J=4.8Hz, 4H), 1.32(s, 9H); ¹³ CNMR (100MHz, CDCl ₃ )δ: 31.09, 35.11, 47.53, 50.90(d, J=2.7Hz) , 52.24, 57.69, 66.91, 70.30, 107.62 (d, J=26.0Hz), 114.24 (d, J=3.0Hz), 118.80 (d, J=4.1Hz), 125.40, 126.79, 129.64, 132.23 (d, J =10.2Hz), 136.81 (d, J=8.8Hz), 143.88, 153.34, 154.16 (d, J=245.3Hz), 156.97, 166.34; high-resolution mass spectrum (C ₂₈ H ₃₂ FN ₅ O ₅ +Na ⁺ ): The theoretical value is 560.2285, and the measured value is 560.2286.

Example 17: (R)-3-[(3-fluoro-4-morpholinyl)phenyl]-5-[(4-hydroxymethyl-1-H-1,2,3-triazole) Synthesis of Hydrochloride Salt of -1-yl]methyloxazolidin-2-one

(R)-3-[(3-fluoro-4-morpholinyl)phenyl]-5-[(4-hydroxymethyl-1-H-1,2,3-triazole)-1- Base] Methyloxazolidin-2-one (compound 2) 500mg was dissolved in 10ml of methanol, stirred and cooled to 0-5°C, 23.3% methanolic hydrogen chloride solution was added dropwise, adjusted to pH=2-3, and continued to stir for 60 minutes , filtered to obtain a light yellow solid, dried in vacuo to obtain 523mg of its hydrochloride, yield 95.4%, m.p.>230°C, and gradually decomposed.

The above-mentioned oxazolidinone compounds and pharmaceutically acceptable salts thereof are tested for antibacterial activity in vitro, and the determination method is as follows:

1) After the test compound was dissolved in DMSO, it was prepared into 800 μg/ml mother solution for later use.

2) Test method: MB culture was used to determine the minimum inhibitory concentration (MIC) of the compound on the tested strains by the double dilution method based on a 96-well plate. Gradual dilution made the concentration of parallel wells: 128, 64, 32, 16, 8, 4, 2, 1, 0.5, 0.25, 0.125, 0.0625 (μg/ml); placed in a 37°C incubator for 24 hours, and used ( MULTISKAN EX) microplate reader scans the 96-well plate after the test, and in the wells where the ultraviolet absorption shows aseptic growth, the one with the lowest drug concentration is the minimum inhibitory concentration (MIC) of the test drug to the test bacteria.

3) The positive control group is linezolid, ciprofloxacin, penicillin and vancomycin.

4) Experimental strains: E.coli is Escherichia coli ATCC25922; SA is Staphylococcus aureus (staphylococcus aureus) ATCC25923; MRSA ¹ is a clinically isolated subspecies of methicillin-resistant staphylococcus aureus; MRSA ² is the clinical subspecies of methicillin-resistant staphylococcus aureus; SE is staphylococcus epidermidis ATCC12228; EF is enterococcus faecalis ATCC29212

See Table 2 for the minimum inhibitory concentration (MIC) values of the oxazolidinone compounds represented by the above formula (I) and their pharmaceutically acceptable salts.

Table 2. The minimum inhibitory concentration (MIC) of the target compound (in μg/ml)

From the data in Table 2, it can be concluded that all compounds have no inhibitory effect on Escherichia coli, and all compounds except compound 16 have different degrees of inhibitory effects on the positive bacteria tested, wherein compound 2 and compound 7-15 have different inhibitory effects on the positive bacteria tested. It has a strong inhibitory effect on bacteria, especially on methicillin-resistant Staphylococcus aureus.

Claims (10)

1. triazolyl oxazolidinone compound, its structural formula is as shown in formula (I):

In formula (I), R is aryl, substituted aminomethyl, heterocyclic substituted methyl, hydroxymethyl, fatty acyl substituted hydroxymethyl, aroyl substituted hydroxymethyl or heteroaroyl substituted hydroxymethyl . 2. The triazolyl oxazolidinone compound according to claim 1, wherein the aromatic group is phenyl, naphthyl, biphenyl, anthracenyl or phenanthrenyl. 3. triazolyl oxazolidinone compound as claimed in claim 1, is characterized in that described heterocycle is piperidine, tetrahydropyrrole, phthalimide base, morpholinyl, oxazole Alkanonyl, furyl, thienyl, pyridyl, imidazolyl, thiazolyl, pyrazolyl, oxazolyl, isoxazolyl, isothiazolyl, triazolyl, tetrazolyl, pyrimidinyl or pyridazinyl . 4. triazolyl oxazolidinone compound as claimed in claim 1, is characterized in that described fatty acyl is acetyl, propionyl, isopropionyl, butyryl, isobutyryl, sec-butyryl, tert-butyryl Butyryl, acryl, valeryl, isovaleryl, pivaloyl, tert-valeryl, hexanoyl, isohexanoyl or the corresponding acyl groups which contain a halogen substitution. 5. The triazolyl oxazolidinone compound as claimed in claim 1, wherein the aroyl group contains alkyl, aryl, hydroxyl, nitro, fluorine, chlorine, bromine, iodine or amino Substituted aryl formyl. 6. The triazolyl oxazolidinone compound as claimed in claim 1, wherein said heteroaroyl is furyl, thienyl, pyridyl, imidazolyl, thiazolyl, pyrazolyl, oxazole group, isoxazolyl, isothiazolyl, triazolyl, tetrazolyl, pyrimidinyl or pyridazinyl. 7. triazolyl oxazolidinone compound as claimed in claim 1, is characterized in that comprising following compound: Compound 1: (R)-3-[(3-fluoro-4-morpholinyl)phenyl]-5-[(4-phenyl-1-H-1,2,3-triazole)-1 - Base] methyl oxazolidin-2-one, R=-Ph; Compound 2: (R)-3-[(3-fluoro-4-morpholinyl)phenyl]-5-[(4-hydroxymethyl-1-H-1,2,3-triazole)- 1-yl]methyloxazolidin-2-one, R=-CH ₂ OH; Compound 3: (R)-3-[(3-fluoro-4-morpholinyl)phenyl]-5-[(4-aminomethyl-1-H-1,2,3-triazole)- 1-yl]methyloxazolidin-2-one, R=-CH ₂ NH ₂ ; Compound 4: (R)-3-[(3-fluoro-4-morpholinyl)phenyl]-5-{[4-(N,N-dimethyl)aminomethyl-1-H-1, 2,3-Triazole]-1-yl}methyloxazolidin-2-one, R=-CH ₂ NMe ₂ ; Compound 5: (R)-3-[(3-fluoro-4-morpholinyl)phenyl]-5-[(4-morpholinylmethyl-1-H-1,2,3-triazole )-1-yl]methyloxazolidin-2-one,

Compound 6: (R)-3-[(3-fluoro-4-morpholinyl)phenyl]-5-{[4-(2-oxooxazolidin-3-yl)methyl-1-H -1,2,3-triazole]-1-yl}methyloxazolidin-2-one,

Compound 7: (R)-3-[(3-fluoro-4-morpholinyl)phenyl]-5-[(4-acetoxymethyl-1-H-1,2,3-triazole )-1-yl]methyloxazolidin-2-one,

Compound 8: (R)-3-[(3-fluoro-4-morpholinyl)phenyl]-5-[(4-dichloroacetoxymethyl-1-H-1,2,3-tri Azorazol)-1-yl]methyloxazolidin-2-one, Compound 9: (R)-3-[(3-fluoro-4-morpholinyl)phenyl]-5-[(4-furan-2-formyloxymethyl-1-H-1,2, 3-triazol)-1-yl]methyloxazolidin-2-one,

Compound 10: (R)-3-[(3-fluoro-4-morpholinyl)phenyl]-5-[(4-thiophene-2-formyloxymethyl-1-H-1,2, 3-triazol)-1-yl]methyloxazolidin-2-one, Compound 11: (R)-3-[(3-fluoro-4-morpholinyl)phenyl]-5-[(4-pyridine-2-formyloxymethyl-1-H-1,2, 3-triazol)-1-yl]methyloxazolidin-2-one,

Compound 12: (R)-3-[(3-fluoro-4-morpholinyl)phenyl]-5-[(4-p-methylbenzoyloxymethyl-1-H-1,2, 3-triazol)-1-yl]methyloxazolidin-2-one, Compound 13: (R)-3-[(3-fluoro-4-morpholinyl)phenyl]-5-[(4-p-fluorobenzoyloxymethyl-1-H-1,2,3 -triazol)-1-yl]methyloxazolidin-2-one,

Compound 14: (R)-3-[(3-fluoro-4-morpholinyl)phenyl]-5-[(4-p-chlorobenzoyloxymethyl-1-H-1,2,3 -triazol)-1-yl]methyloxazolidin-2-one,

Compound 15: (R)-3-[(3-fluoro-4-morpholinyl)phenyl]-5-[(4-p-nitrobenzoyloxymethyl-1-H-1,2, 3-triazol)-1-yl]methyloxazolidin-2-one,

Compound 16: (R)-3-[(3-fluoro-4-morpholinyl)phenyl]-5-[(4-p-tert-butylbenzoyloxymethyl-1-H-1,2 , 3-triazol)-1-yl] methyl oxazolidin-2-one,

8. The salt formed by the triazolyl oxazolidinone compound and inorganic acid or organic acid according to claim 1. 9. The salt according to claim 8, wherein said inorganic acid is hydrochloric acid, sulfuric acid, hydrofluoric acid, hydrobromic acid, phosphoric acid or nitric acid; said organic acid is formic acid, acetic acid, propionic acid, oxalic acid, propionic acid Diacid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, aspartic acid, or glutamic acid. 10. The application of the triazolyl oxazolidinone compound or the salt thereof according to claim 1 in the treatment of bacterial infection.