Novel oxazolidinone compound and anti-infection application thereof

Abstract

The invention relates to the technical field of chemical synthesis of medicines, and particularly discloses a novel oxazolidinone compound and anti-infection application thereof, and the oxazolidinone compound has a structure as shown in a formula I. The oxazolidinone-containing compound has good biological activity, the preparation method is simple, the oxazolidinone-containing compound can be used for preparing antibiotics, anti-infection drugs and biological probes with good biological inclusiveness, and the application prospect of the oxazolidinone-containing compound containing the triazole structure in the antibacterial and anti-infection aspects is expanded. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical chemical synthesis, and more specifically to a novel oxazolidinone compound and its anti-infection application. Background Art

[0002] Staphylococcus aureus (SA) is the main pathogen causing healthcare-associated infections worldwide. As a typical Gram-positive bacterium, it is extremely common in human suppurative infections and can cause a variety of systemic infections ranging from local suppuration to pneumonia, pseudomembranous colitis, pericarditis, meningitis, sepsis and sepsis. SA infections are divided into hospital-acquired infections and community-acquired infections. The presence of the latter further increases the biohazard and risk of infection outbreaks of this pathogen. Due to the widespread use and even abuse of antibiotics, the problem of bacterial resistance has become increasingly severe, especially the emergence of methicillin-resistant Staphylococcus aureus (MRSA). Therefore, it has become extremely urgent to develop new compounds with novel structures and strong drug resistance.

[0003] In 1978, DuPont discovered for the first time that oxazolidinone compounds had significant antibacterial activity, but the research project was eventually shelved due to their high toxicity. In 1996, Upjohn successfully developed a new generation of oxazolidinone drugs, linezolid, which has a wide range of antibacterial activity against Gram-positive bacteria, covering methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE). However, soon after linezolid was used clinically, drug-resistant strains emerged, prompting researchers to make a lot of improvements to its structure.

[0004] In recent years, oxazolidinone compounds have become the focus of research on synthetic antibacterial drugs. In order to solve the increasingly severe problem of bacterial drug resistance, the present invention provides a novel oxazolidinone compound and its anti-infection application. Summary of the invention

[0005] In order to solve the above technical problems, the present invention provides a novel oxazolidinone compound and its anti-infection application, which has good biological activity against standard strains of Staphylococcus aureus (ATCC 29213, ATCC 43300), methicillin-resistant Staphylococcus aureus (USA300) and intermediate vancomycin-resistant Staphylococcus aureus (Mu50). The results show that the compound has a significant anti-Staphylococcus aureus effect, and its activity is equivalent to that of the positive control drug linezolid (LNZ), and can be used for the preparation of drugs for anti-Staphylococcus aureus infection.

[0006] On the one hand, the present invention provides a novel oxazolidinone compound, which adopts the following technical scheme:

[0007] A novel oxazolidinone compound, wherein the novel oxazolidinone compound has a structure as shown in Formula I:

[0008]

[0009] In the formula I, R is an aliphatic group, an aromatic group, etc.

[0010] Preferably, the aromatic group is Or one of the phenyl groups containing a substituent.

[0011] Preferably, the aliphatic group is a saturated aliphatic group or an unsaturated aliphatic group.

[0012] On the other hand, the present invention provides an application of a novel oxazolidinone compound, using the following technical solution:

[0013] Application of a novel oxazolidinone compound in the preparation of antibiotics.

[0014] Application of a novel oxazolidinone compound in the preparation of anti-infective drugs.

[0015] Application of a novel oxazolidinone compound in the preparation of an anti-Staphylococcus aureus drug.

[0016] A novel oxazolidinone compound is used in the preparation of a drug for resisting Staphylococcus aureus infection.

[0017] Application of a new type of oxazolidinone compound in the preparation of biological probes.

[0018] In summary, the present invention has the following beneficial effects:

[0019] The novel oxazolidinone compounds containing a triazole skeleton of the present invention have good biological activity. Activity test results show that the compounds have significant antibacterial and anti-Staphylococcus aureus infection activities, can be used to prepare antibiotics, anti-infective drugs and biological probes with good biological tolerance, and expand the application prospects of oxazolidinone compounds containing a triazole structure in antibacterial and anti-infective aspects. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] Figure 1 This is the hydrogen nuclear magnetic resonance spectrum of the target compound Ⅰ-1 prepared in Example 1 of the present invention.

[0021] Figure 2 This is the hydrogen nuclear magnetic resonance spectrum of the target compound Ⅰ-2 prepared in Example 2 of the present invention.

[0022] Figure 3 This is the hydrogen nuclear magnetic resonance spectrum of the target compound Ⅰ-3 prepared in Example 3 of the present invention.

[0023] Figure 4 This is the hydrogen nuclear magnetic resonance spectrum of the target compound Ⅰ-4 prepared in Example 4 of the present invention.

[0024] Figure 5 This is the hydrogen nuclear magnetic resonance spectrum of the target compound Ⅰ-5 prepared in Example 5 of the present invention.

[0025] Figure 6 This is the hydrogen nuclear magnetic resonance spectrum of the target compound Ⅰ-6 prepared in Example 6 of the present invention.

[0026] Figure 7 This is the hydrogen nuclear magnetic resonance spectrum of the target compound Ⅰ-7 prepared in Example 7 of the present invention.

[0027] Figure 8 This is the hydrogen nuclear magnetic resonance spectrum of the target compound Ⅰ-8 prepared in Example 8 of the present invention.

[0028] Fig. 9 This is the hydrogen nuclear magnetic resonance spectrum of the target compound Ⅰ-9 prepared in Example 9 of the present invention.

[0029] Fig.10 This is the hydrogen nuclear magnetic resonance spectrum of the target compound Ⅰ-10 prepared in Example 10 of the present invention.

[0030] Fig.11 This is the hydrogen nuclear magnetic resonance spectrum of the target compound Ⅰ-11 prepared in Example 11 of the present invention.

[0031] Fig.12 This is the hydrogen nuclear magnetic resonance spectrum of the target compound Ⅰ-12 prepared in Example 12 of the present invention.

[0032] Fig.13 This is the hydrogen nuclear magnetic resonance spectrum of the target compound Ⅰ-13 prepared in Example 13 of the present invention.

[0033] Fig.14 This is the hydrogen nuclear magnetic resonance spectrum of the target compound Ⅰ-14 prepared in Example 14 of the present invention.

[0034] Fig.15 This is the hydrogen nuclear magnetic resonance spectrum of the target compound Ⅰ-15 prepared in Example 15 of the present invention.

[0035] Fig.16 This is the hydrogen nuclear magnetic resonance spectrum of the target compound Ⅰ-16 prepared in Example 16 of the present invention.

[0036] Fig.17This is the hydrogen nuclear magnetic resonance spectrum of the target compound Ⅰ-17 prepared in Example 17 of the present invention.

[0037] Fig.18 This is the hydrogen nuclear magnetic resonance spectrum of the target compound Ⅰ-18 prepared in Example 18 of the present invention.

[0038] Fig.19 This is the hydrogen nuclear magnetic resonance spectrum of the target compound Ⅰ-19 prepared in Example 19 of the present invention.

[0039] Fig. 20 This is the hydrogen nuclear magnetic resonance spectrum of the target compound Ⅰ-20 prepared in Example 20 of the present invention.

[0040] Fig.21 This is the hydrogen nuclear magnetic resonance spectrum of the target compound Ⅰ-21 prepared in Example 21 of the present invention.

[0041] Fig. 22 This is the hydrogen nuclear magnetic resonance spectrum of the target compound Ⅰ-22 prepared in Example 22 of the present invention.

[0042] Fig.23 This is the hydrogen nuclear magnetic resonance spectrum of the target compound Ⅰ-23 prepared in Example 23 of the present invention.

[0043] Fig.24 This is the hydrogen nuclear magnetic resonance spectrum of the target compound Ⅰ-24 prepared in Example 24 of the present invention. DETAILED DESCRIPTION

[0044] The present invention is further described in detail below with reference to the embodiments.

[0045] Example 1

[0046] Preparation of (R)-2-(4-cyclohexyl-1H-1,2,3-triazol-1-yl)-N-((3-(3-fluoro-4-morpholinophenyl)-2-oxooxazolidin-5-yl)methyl)acetamide (I-1)

[0047]

[0048] As shown in the synthetic route of the target compound Ⅰ-1, 10 g (33.86 mmol, 1.0 eq) of (R)-5-(aminomethyl)-3-(3-fluoro-4-morpholinophenyl)oxazolidin-2-one, 4.11 g (40.36 mmol, 1.2 eq) of azidoacetic acid, and 40 ml of DMF were added to a 100 ml single-necked bottle, cooled to 0°C, and 8.75 g (67.72 mmol, 2.0 eq) of diisopropylethylamine were added, followed by 9.74 g (50.79 mmol, 1.5 eq) of EDCI, and HOBt 6.86g (50.79mmol, 1.5eq), after adding, heat to 50℃ and stir for 3h. After the reaction is completed, the reaction solution is cooled to room temperature and poured into 200ml water. Extract with ethyl acetate three times, combine the organic phases, wash twice with water, dry over anhydrous magnesium sulfate, filter on silica gel, spin-dry the filtrate, add 30ml acetonitrile to the residue and slurry it. Filter the solid to obtain 8.23g of intermediate 1 as a beige solid.

[0049] 1200 mg (0.53 mmol, 1.0 eq) of the intermediate, 57.2 mg (0.53 mmol, 1.0 eq) of cyclohexyl acetylene, 6 ml of tetrahydrofuran, 20.1 mg (0.11 mmol, 0.2 eq) of cuprous iodide and 27.3 mg (0.21 mmol, 0.4 eq) of diisopropylethylamine were added to a 15 ml sealed tube, and stirred overnight at room temperature. The reaction solution was diluted in 15 ml of methanol, filtered through silica gel, and dried by rotation. The residue was slurried with ethyl acetate, filtered, and dried to obtain 34 mg of the target compound of formula I-1 as a white solid.

[0050]

[0051] Example 2

[0052] The preparation method of Example 2 is the same as that of Example 1, except that cyclohexyl acetylene is replaced by 4-fluorophenyl acetylene, and the corresponding target compound I-2 is obtained as 47 mg of a white solid.

[0053] Example 3

[0054] The preparation method of Example 3 is the same as that of Example 1, except that cyclohexyl acetylene is replaced by 1-ethynyl-4-nitrobenzene, and the corresponding target compound I-3 is obtained as a yellow solid (22 mg).

[0055] Example 4

[0056] The preparation method of Example 4 is the same as that of Example 1, except that cyclohexyl acetylene is replaced by 4-propylphenyl acetylene, and the corresponding target compound I-4 is obtained as 32 mg of white solid.

[0057] Example 5

[0058] The preparation method of Example 5 is the same as that of Example 1, except that cyclohexyl acetylene is replaced by 3-ethynylanisole to obtain the corresponding target compound I-5 as a white solid (19 mg).

[0059] Example 6

[0060] The preparation method of Example 6 is the same as that of Example 1, except that cyclohexylacetylene is replaced by phenylacetylene, and the corresponding target compound I-6 is obtained as 47 mg of white solid.

[0061] Example 7

[0062] The preparation method of Example 7 is the same as that of Example 1, except that cyclohexyl acetylene is replaced by cyclopropyl acetylene, and the corresponding target compound I-7 is obtained as a light yellow solid 23 mg.

[0063] Example 8

[0064] The preparation method of Example 8 is the same as that of Example 1, except that cyclohexyl acetylene is replaced by 3-ethynyl pyridine to obtain the corresponding target compound I-8 as a light yellow solid 24 mg.

[0065] Example 9

[0066] The preparation method of Example 9 is the same as that of Example 1, except that cyclohexylacetylene is replaced by 4-ethynyl-α,α,α-trifluorotoluene to obtain the corresponding target compound I-9 as a light yellow solid 24 mg.

[0067] Example 10

[0068] The preparation method of Example 10 is the same as that of Example 1, except that cyclohexyleneacetylene is replaced by ferrocenyleneacetylene, and the corresponding target compound I-10 is obtained as a white solid (29 mg).

[0069] Embodiment 11

[0070] The preparation method of Example 11 is the same as that of Example 1, except that cyclohexyl acetylene is replaced by 1,4-diethynylbenzene to obtain the corresponding target compound I-11 as a white solid (18 mg).

[0071] Example 12

[0072] The preparation method of Example 12 is the same as that of Example 1, except that cyclohexyl acetylene is replaced by 4-ethynylbenzoic acid to obtain the corresponding target compound I-12 as a white solid 27 mg.

[0073] Example 13

[0074] The preparation method of Example 13 is the same as that of Example 1, except that cyclohexyl acetylene is replaced by 3-ethynyl pyridazine to obtain the corresponding target compound I-13 as a yellow solid 25 mg.

[0075] Embodiment 14

[0076] The preparation method of Example 14 is the same as that of Example 1, except that cyclohexyl acetylene is replaced by 4-chlorophenyl acetylene to obtain the corresponding target compound I-14 as a white solid 31 mg.

[0077] Embodiment 15

[0078] The preparation method of Example 15 is the same as that of Example 1, except that cyclohexylacetylene is replaced by 2-ethynylquinoline to obtain the corresponding target compound I-15 as a yellow solid 18 mg.

[0079] Example 16

[0080] The preparation method of Example 16 is the same as that of Example 1, except that cyclohexyl acetylene is replaced by 3-alkynylbenzoic acid to obtain the corresponding target compound I-16 as a white solid 30 mg.

[0081] Embodiment 17

[0082] The preparation method of Example 17 is the same as that of Example 1, except that cyclohexylene is replaced by 2-acetylenebenzoic acid to obtain the corresponding target compound I-17 as a white solid 25 mg.

[0083] Embodiment 18

[0084] The preparation method of Example 18 is the same as that of Example 1, except that cyclohexyl acetylene is replaced by 4-alkynyl-1,2-difluorobenzene to obtain the corresponding target compound I-18 as a light yellow solid 28 mg.

[0085] Embodiment 19

[0086] The preparation method of Example 19 is the same as that of Example 1, except that cyclohexylacetylene is replaced by 2-nitrophenylacetylene to obtain the corresponding target compound I-19 as a yellow solid (19 mg).

[0087] Embodiment 20

[0088] The preparation method of Example 20 is the same as that of Example 1, except that cyclohexylacetylene is replaced by 3-nitrophenylacetylene to obtain the corresponding target compound I-20 as a yellow solid 21 mg.

[0089] Embodiment 21

[0090] The preparation method of Example 21 is the same as that of Example 1, except that cyclohexyl acetylene is replaced by 1-alkynyl-2,4-difluorobenzene to obtain the corresponding target compound I-21 as a light yellow solid 23 mg.

[0091] Embodiment 22

[0092] The preparation method of Example 22 is the same as that of Example 1, except that cyclohexylacetylene is replaced by 3-fluorophenylacetylene to obtain the corresponding target compound I-22 as 35 mg of light yellow solid.

[0093] Embodiment 23

[0094] The preparation method of Example 23 is the same as that of Example 1, except that cyclohexylacetylene is replaced by 2-fluorophenylacetylene to obtain the corresponding target compound I-23 as 30 mg of light yellow solid.

[0095] Embodiment 24

[0096] The preparation method of Example 24 is the same as that of Example 1, except that cyclohexyl acetylene is replaced by 1-ethynyl-3,5-difluorobenzene to obtain the corresponding target compound I-24 as a light yellow solid 32 mg.

[0097] The high-resolution mass spectrometry data and nuclear magnetic resonance hydrogen spectrum data of the novel oxazolidinone compounds prepared in Examples 1-24 are shown in Table 1 below.

[0098] Table 1 High-resolution mass spectrometry data and H NMR data of novel oxazolidinone compounds

[0099]

[0100]

[0101]

[0102] Study on the antibacterial activity of the novel oxazolidinone compounds prepared in Examples 1-24 against Staphylococcus aureus

[0103] Test strains: Methicillin-sensitive Staphylococcus aureus ATCC 29213, Methicillin-resistant Staphylococcus aureus USA300, ATCC 43300, Vancomycin-intermediate-resistant Staphylococcus aureus Mu50

[0104] Positive control drug: linezolid or vancomycin

[0105] Test method: The antibacterial activity test of the novel oxazolidinone compounds prepared in Examples 1-24 was carried out by broth dilution method, as follows:

[0106] According to the guidelines provided by the Clinical and Laboratory Standards Institute (CLSI), first, pick a single colony from the MHA agar plate and transfer it to 5 mL of MHB broth medium. Place the mixture in a 37°C constant temperature shaker and culture it overnight at 200 rpm. The next day, remove the bacterial solution and adjust it to 0.5 McFarland concentration to ensure that the bacterial concentration in the bacterial solution reaches 1.5×10 8 CFU / mL. Then, the bacterial solution was further diluted 100 times to obtain the loading bacterial solution. In the 96-well plate, each row was operated according to the multiple dilution method. Add 200 μL of antibiotics at a concentration of 128 mg / L to each well in the first row, draw 100 μL of liquid from each well in the first row and add it to each well in the second row, and add 100 μL of bacterial solution to mix thoroughly, then draw 100 μL of liquid from each well in the second row and add it to the third row, and so on, perform multiple dilutions continuously to obtain a series of antibiotic solutions with decreasing concentrations, with the bacterial solution as the positive control and the MHB broth medium as the negative control. After the addition of samples, place the 96-well plate in a 37°C constant temperature incubator and incubate for 16 hours. Measure the OD of each well by an enzyme reader 600 Absorbance value. OD 600 The lowest drug concentration with a value lower than 0.1 was taken as the MIC value.

[0107] Table 2 Antibacterial activity results of novel oxazolidinone compounds against Staphylococcus aureus

[0108]

[0109]

[0110] Note: LNZ: linezolid, VAN: vancomycin. All experiments were repeated three times and were independent results.

[0111] From the data shown in Table 2 above, it can be seen that the compounds represented by Formula I-3, Formula I-11 and Formula I-12 generally have good anti-Staphylococcus aureus activity, among which the compound of Formula I-12 has the best antibacterial activity against four strains of Staphylococcus aureus, exceeding or reaching the activity of the control drugs linezolid or vancomycin, and has good application prospects.

[0112] This specific embodiment is merely an explanation of the present invention and is not a limitation of the present invention. After reading this specification, those skilled in the art may make non-creative modifications to the present embodiment as needed. However, as long as they are within the scope of the claims of the present invention, they are protected by the patent law.

Claims

1. A novel oxazolidinone compound, characterized in that: The novel oxazolidinone compound has a structure as shown in Formula I: In the formula I, R is an aliphatic group or an aromatic group.

2. The novel oxazolidinone compound according to claim 1, characterized in that: The aromatic group is Or one of the phenyl groups containing a substituent.

3. The novel oxazolidinone compound according to claim 1, characterized in that: The aliphatic group is a saturated aliphatic group or an unsaturated aliphatic group.

4. Use of the novel oxazolidinone compound according to any one of claims 1 to 3 in the preparation of antibiotics.

5. Use of the novel oxazolidinone compound according to any one of claims 1 to 3 in the preparation of anti-infective drugs.

6. Use of the novel oxazolidinone compound according to any one of claims 1 to 3 in the preparation of an anti-Staphylococcus aureus drug.

7. Use of the novel oxazolidinone compound according to any one of claims 1 to 3 in the preparation of drugs for resisting Staphylococcus aureus infection.

8. Use of the novel oxazolidinone compound according to any one of claims 1 to 3 in the preparation of biological probes.

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