Benzoxazine oxazolidinone compounds for treating bacterial infections

Abstract

The present invention belongs to the field of medical technology, and discloses benzoxazine oxazolidinone compounds for treating bacterial infections. #imgabs0# Specifically, the present invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutical composition thereof in preparing a drug for preventing and / or treating Gram-positive bacterial infections, especially in preparing a drug for preventing and / or treating multidrug-resistant Gram-positive bacterial infections.

Description

Technical Field

[0001] The present invention belongs to the field of medical technology, and in particular, relates to the use of a benzoxazine oxazolidinone compound N-(((3S,3aS)-8-fluoro-1-oxo-7-thiomorpholinyl-3a,4-dihydro-1H,3H-benzo[b]oxazol[3,4-d][1,4]oxazin-3-yl)methyl)acetamide in the preparation of a drug for preventing and / or treating bacterial infection. Background Art

[0002] In 2017, the World Health Organization (WHO) published a list of 12 drug-resistant bacteria or bacterial families that are most in need of antibiotics (WHO publishes a list of bacteria for which new antibiotics are urgently needed. Geneva: WHO, 2017.), and drug-resistant bacterial infections have become a major threat to human health. Therefore, it is urgent to find antibacterial drugs with new structures and mechanisms.

[0003] Oxazolidinone antibiotics exert their antibacterial effects by inhibiting bacterial protein synthesis. Their mechanism of action is different from that of previous antibiotics, so cross-resistance rarely occurs. Linezolid was the first drug of this class to be marketed in 2000 and is used to treat multidrug-resistant G. + Infections caused by bacteria, studies have shown that it also has anti-tuberculosis activity (J. Antimicrob. Chemother., 2009, 64, 388-391), and is used in the form of off-label treatment of drug-resistant tuberculosis. Tedizolid was launched in 2014 for the treatment of acute skin infections (Eur. J. Med. Chem., 2011, 46, 1027-1039). However, long-term use of this type of drug will inhibit mitochondrial protein synthesis and produce bone marrow toxicity; it has an inhibitory effect on monoamine oxidase, thereby causing neurotoxicity (Expert Review of Anti-infective Therapy, 2016, 14, 901–915). At the same time, this type of compound has a short half-life and rapid clearance from the body, resulting in a large dosage. These problems limit the clinical application of oxazolidinone antibiotics. Therefore, it is necessary to develop new antibacterial drugs with stronger activity and lower toxic side effects.

[0004] The applicant disclosed in the previous Chinese patent application CN108727406A a nitrogen-containing heterocyclic substituted benzoxazine oxazolidinone compound and its preparation method and use, wherein compound 4 (compound of formula (I)) (N-(((3S,3aS)-8-fluoro-1-oxo-7-thiomorpholinyl-3a,4-dihydro-1H,3H-benzo[b]oxazol[3,4-d][1,4]oxazin-3-yl)methyl)acetamide), CAS No. 2245791-50-6, molecular formula C 17 H 20 FN3O4S, with a molecular weight of 381.42, has strong anti-Mycobacterium tuberculosis activity and very weak inhibitory activity on mitochondrial protein synthesis (MPS). 50 The concentration of 1 μg / ml of 1 μg / ml was 99.35 μM, indicating that it has a low risk of producing bone marrow toxicity and has higher safety. Currently, there is no report on its therapeutic effect on other non-tuberculous mycobacteria. Summary of the invention

[0005] The object of the present invention is to provide a new use of the compound of formula (I) or a pharmaceutically acceptable salt thereof, namely, use in the preparation of a medicament for preventing and / or treating bacterial infection.

[0006]

[0007] In one aspect, the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for preventing and / or treating a Gram-positive bacterial infection, wherein the Gram-positive bacteria is selected from Staphylococcus epidermidis, Staphylococcus aureus, Staphylococcus saprophyticus, Staphylococcus hominis, Enterococcus faecalis or Enterococcus faecium. The compound of formula (I) or a pharmaceutically acceptable salt thereof can be used as an antibacterial agent to treat infections including, but not limited to, skin infections, soft tissue infections, bacteremia, respiratory tract infections, urinary tract infections, bone infections, eye infections, brain infections and diabetic foot infections.

[0008] On the other hand, the present invention provides a use of a pharmaceutical composition in the preparation of a drug for preventing and / or treating Gram-positive bacterial infection, wherein the pharmaceutical composition comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient. Specifically, the excipient is selected from one or more of a filler, an excipient, a diluent, a binder, a surfactant, an antioxidant, a preservative, a sweetener, a flavoring agent, a flavor, an adsorbent, a lubricant, a disintegrant, a coating agent, a sustained-release agent, a promoter, a propellant, a colorant, a pigment and a dye.

[0009] Beneficial technical effects

[0010] The compound of formula (I) belongs to the benzoxazine oxazolidinone class of compounds, and its structure is shown below:

[0011]

[0012] The comparative document (J. Med. Chem. 2011, 54, 7493-7502) discloses the compound 14 with the following structure. The antibacterial activity of compound 14 was determined by the agar double dilution method. Its MIC against Staphylococcus aureus (Sa) is 4 μg / mL, its MIC against methicillin-resistant Staphylococcus aureus (MRSA) is 4-8 μg / mL, its MIC against methicillin-resistant Staphylococcus epidermidis (MRSE) is 4-8 μg / mL, its MIC against penicillin-resistant Streptococcus pneumoniae (PRSP) is 8-16 μg / mL, and its MIC against Enterococcus faecalis (Ef) is 8-16 μg / mL. Its antibacterial activity is relatively weak, especially against drug-resistant bacteria. In addition, the applicant tested the inhibitory effect of compound 14 on mitochondrial protein synthesis in the previous Chinese patent application CN108727406A. Its IC 50 The value was 35.82 μM, indicating a strong inhibitory effect.

[0013]

[0014] The present invention has confirmed through experiments that the compound of formula (I) has a better antibacterial effect, thereby providing a new and safer drug for the treatment of bacterial infection. DETAILED DESCRIPTION

[0015] The present invention is explained below by means of specific experimental examples, however, these examples do not limit the scope of the present invention.

[0016] the term

[0017] The Gram-positive bacteria mentioned in the present invention include: MSSE: methicillin-sensitive Staphylococcus epidermidis; MRSE: methicillin-resistant Staphylococcus epidermidis; MSSA: methicillin-sensitive Staphylococcus aureus; MRSA: methicillin-resistant Staphylococcus aureus; VISA: vancomycin-intermediate-resistant Staphylococcus aureus; VSE: vancomycin-sensitive Enterococcus faecalis or Enterococcus faecium; and VRE: vancomycin-resistant Enterococcus faecalis or Enterococcus faecium.

[0018] The "pharmaceutical composition" used in the present invention can be prepared according to methods known in the art. Any dosage form suitable for human or animal use can be prepared by combining the compound of the present invention with one or more pharmaceutically acceptable solid or liquid excipients and / or adjuvants.

[0019] The "pharmaceutically acceptable excipient" used in the present invention may refer to any pharmaceutical excipient compatible with the compound of formula (I) or its pharmaceutically acceptable salt of the present application. It includes but is not limited to biocompatible excipients, diluents and carriers. In order to better understand the essence of the present invention, the pharmacological experiments and results of the compound of formula (I) in treating bacterial infections will be used below to illustrate its new use in the pharmaceutical field.

[0020] Experimental Example 1 In vitro antibacterial activity test of the compound of formula (I)

[0021] Experimental method: The minimum inhibitory concentration (MIC) of the compound against the test strain was determined by the agar two-fold dilution method. The test compound was dissolved in DMSO and then diluted to the required concentration with sterile distilled water. The culture medium was added to the culture dish containing the compound and mixed evenly to make the final concentration of the compound in the culture dish: 128, 64, 32, 16, 8, 4, 2, 1, 0.5, 0.25, 0.125 μg / mL. The bacteria were inoculated on the surface of the agar plate containing different concentrations of the compound, and the inoculation amount at each point was about 10 6 CFU / mL, incubate at 37°C for 16 hours and observe the results. The concentration of the compound in the culture medium of the sterile growing plate is the minimum inhibitory concentration (MIC value) of the compound against the bacteria.

[0022] Test strains: All test strains used were standard strains preserved by the Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and collected clinically isolated pathogens, which were re-identified by conventional methods before use, including 4 strains of Staphylococcus epidermidis, 12 strains of Staphylococcus aureus, 1 strain of Staphylococcus saprophyticus, 1 strain of Staphylococcus hominis, 4 strains of Enterococcus faecalis, and 5 strains of Enterococcus faecium.

[0023] The test results are shown in Table 1.

[0024] Table 1 Antibacterial activity of compounds of formula (I)

[0025]

[0026] The results show that the MIC of the compound of formula (I) for sensitive Staphylococcus epidermidis is 1-2 μg / mL, the MIC for resistant Staphylococcus epidermidis is 2 μg / mL, the MIC for sensitive Staphylococcus aureus is 4 μg / mL, the MIC for resistant Staphylococcus aureus is 2-4 μg / mL, the MIC for saprophytic Staphylococcus and Staphylococcus hominis is 4 μg / mL, the MIC for sensitive and resistant Enterococcus faecalis is 4 μg / mL, and the MIC for sensitive and resistant Enterococcus faecium is 4 μg / mL. The results show that the antibacterial activity of the compound of formula (I) is strong, and the antibacterial activity is significantly stronger than that of compound 14 disclosed in the comparative document (document J. Med. Chem. 2011, 54, 7493-7502).

[0027] The above-described aspects are brief statements of the present invention, and those skilled in the art can make modifications, equivalent substitutions and other types of changes to the present invention based on the description. Therefore, the description should be regarded as exemplary.

Claims

1. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for preventing and / or treating bacterial infection, The bacteria are Gram-positive bacteria, and the Gram-positive bacteria are selected from Staphylococcus epidermidis, Staphylococcus aureus, Staphylococcus saprophyticus, Staphylococcus hominis, Enterococcus faecalis or Enterococcus faecium.

2. The use according to claim 1, characterized in that: The infection is selected from the group consisting of skin infection, soft tissue infection, bacteremia, respiratory tract infection, urinary tract infection, bone infection, eye infection, brain infection and diabetic foot infection.

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