2H-chromene derivative and application thereof

Abstract

The invention provides a 2H-chromene derivative and application thereof, and belongs to the technical field of organic compounds and medicines. The 2H-chromene derivative and the pharmaceutically acceptable salt thereof have obvious anti-coronavirus activity, and can be used as a lead compound for further modification and development of anti-coronavirus drugs. The invention solves the problem that the research on the biological activity of 2H-chromene is mainly applied to the anti-inflammatory activity, the antifungal activity and the like, but the research on the anti-coronavirus activity does not exist at present.

Description

Technical Field

[0001] The invention relates to the technical field of organic compounds and medicines, and in particular to a 2H-chromene derivative and application thereof. Background Art

[0002] Coronavirus (CoV) is a type of RNA virus with the longest genome. Its genomic characteristics make it very easy to mutate, which may lead to the emergence of new strains. Highly pathogenic coronaviruses include SARS virus (Severe Acute Respiratory Syndrome), MERS virus (Middle East Respiratory Syndrome) and SARS-CoV-2 (new coronavirus). The existence of coronavirus can be traced back nearly a hundred years, but its early infection usually only causes mild symptoms, so the development of its specific drugs has long been not given enough attention.

[0003] In recent years, several anti-coronavirus drugs have been gradually developed and used in clinical practice. For example, Remdesivir, Lopinavir / Ritonavir combination, Ribavirin, and Paxlovid (an antiviral drug developed by Pfizer). China has also successively released drugs such as Azvudine, Senotegravir / Ritonavir combination packages, and Deuterium Remdesivir Hydrobromide Tablets, providing new options for anti-coronavirus treatment.

[0004] As coronaviruses continue to evolve and pose an increasing threat to human health, the development of specific antiviral drugs for coronaviruses has become a global scientific research issue that needs to be solved urgently. 2H-chromene is an important structural unit of many drugs and natural products with physiological activity. Compounds containing this type of skeleton have shown good activity in anti-inflammatory and antifungal studies, but there is currently no research on anti-coronavirus activity. Therefore, how to provide a 2H-chromene derivative and its application, synthesize 2H-chromene derivatives using chemical synthesis methods, and further explore the anti-coronavirus activity of 2H-chromene derivatives are difficult problems that need to be solved in this field. Further research on 2H-chromene compounds not only provides new possibilities for the development of coronavirus drugs, but also lays the foundation for the development of broad-spectrum antiviral drugs. Summary of the invention

[0005] The purpose of the present invention is to provide a 2H-chromene derivative and an application thereof, so as to fill the research gap in the anti-coronavirus activity of the 2H-chromene derivative.

[0006] In order to achieve the above-mentioned object of the invention, the present invention provides the following technical solutions:

[0007] The present invention provides a 2H-chromene derivative, wherein the 2H-chromene derivative comprises the following structure:

[0008]

[0009] Among them, R 1 and R 2 and R is independently H, a halogen atom, a straight-chain alkyl group, a branched-chain alkyl group, a heteroalkyl group, an aryl group, a heteroaryl group, an alcoholic hydroxyl group, a carbonyl group, a carboxyl group or an alkenyl group.

[0010] Furthermore, the R 1 and R 2 Independently selected from one of the following structures:

[0011]

[0012] Further, the 2H-chromene derivative comprises one of the following structural formulas:

[0013]

[0014] The present invention also provides an application of a 2H-chromene derivative and a pharmaceutically acceptable salt thereof in the preparation of an anti-coronavirus drug.

[0015] Furthermore, the anti-coronavirus drug also contains pharmaceutically acceptable excipients.

[0016] Furthermore, the pharmaceutically acceptable excipients include one or more of diluents, excipients, fillers, binders, wetting agents, disintegrants, absorption enhancers, surfactants, adsorption carriers and lubricants.

[0017] Beneficial effects of the present invention:

[0018] The present invention adopts a chemical synthesis method, using o-bromophenol and its derivatives and 3,6-dimethyl-1,5-diene-3-ol and its derivatives as raw materials and reagents, and undergoes chemical synthesis, structural modification and other steps to prepare the 2H-chromene derivatives of the present invention. This method of obtaining 2H-chromene derivatives by chemical synthesis has the advantages of simplicity, novelty and accuracy compared to plant extraction and separation. The 2H-chromene derivatives of the present invention have obvious anti-coronavirus activity, and can also be used as lead compounds for further modification and development of anti-coronavirus drugs. DETAILED DESCRIPTION

[0019] The present invention provides a 2H-chromene derivative, wherein the 2H-chromene derivative comprises the following structure:

[0020]

[0021] Among them, R 1 and R 2 and R is independently H, a halogen atom, a straight-chain alkyl group, a branched-chain alkyl group, a heteroalkyl group, an aryl group, a heteroaryl group, an alcoholic hydroxyl group, a carbonyl group, a carboxyl group or an alkenyl group.

[0022] In the present invention, the R 1 and R 2 Independently selected from one of the following structures:

[0023]

[0024] In the present invention, the 2H-chromene derivative comprises one of the following structural formulas:

[0025]

[0026] In the present invention, the synthesis path of the 2H-chromene derivative is as follows:

[0027]

[0028] In the present invention, the preparation method of the 2H-chromene derivative is preferably:

[0029] The compound of formula I is dissolved in tetrahydrofuran under a nitrogen atmosphere, vinylmagnesium bromide is added at 0°C, and the reaction is carried out at room temperature to obtain a 3,6-dimethyl-1,5-diene-3-ol derivative of formula III; palladium acetate and potassium carbonate are added to the compound of formula II and the 3,6-dimethyl-1,5-diene-3-ol derivative of formula III under a nitrogen atmosphere, and N,N-dimethylformamide is used as a solvent, and the reaction is carried out at 140°C to obtain a 2H-chromene derivative of formula IV.

[0030] In the present invention, R 1 Select one of the following structures:

[0031]

[0032] In the present invention, the synthesis path of the 3,6-dimethyl-1,5-diene-3-ol derivative is as follows:

[0033]

[0034] The synthetic route of the 3,6-dimethyl-1,5-diene-3-ol derivatives is as follows:

[0035] Acid-Catalyzed Cyclization of Terpenes Under Homogeneous and Heterogeneous Conditions as Probed Through Stereoisotopic Studies:A ConcertedProcess with Competing Preorganized Chair and Boat TransitionStates.Chem.Eur.J.2009,15,11918–11927.

[0036] In the present invention, the synthetic route of the 2H-chromene derivatives is as follows:

[0037] A.Efficient One-Pot Synthesis of 2,2-Dimethyl-2H--chromenes via Pd(II)-Catalyzed Coupling and SiO2-Promoted Condensation of o-Halophenolswith2-Methyl-3-buten-2-ol.Synth.Commun.2015,45,1920-1927.

[0038] The present invention also provides an application of a 2H-chromene derivative and a pharmaceutically acceptable salt thereof in the preparation of an anti-coronavirus drug.

[0039] In the present invention, the anti-coronavirus drug further comprises a pharmaceutically acceptable excipient.

[0040] In the present invention, the pharmaceutically acceptable excipients include one or more of diluents, excipients, fillers, binders, wetting agents, disintegrants, absorption promoters, surfactants, adsorption carriers and lubricants.

[0041] The technical solutions provided by the present invention are described in detail below in conjunction with the embodiments, but they should not be construed as limiting the protection scope of the present invention.

[0042] Example 1

[0043] Synthesis of 2H-chromene derivatives with different substituents at C5-C8

[0044]

[0045] The specific steps are as follows:

[0046] Take compound 3a as an example:

[0047] Under nitrogen atmosphere, 2-bromo-3-fluorophenol (104.2 mg, 0.52 mmol, 1.0 eq.), linalool (160.4 mg, 1.04 mmol, 2.0 eq.), potassium carbonate (215.6 mg, 1.56 mmol, 3.0 eq.) were added to a dry and clean 25 mL reaction tube in sequence, dissolved in 5 mL of N, N-dimethylformamide (DMF) as solvent, stirred evenly, and then palladium acetate (10 mol%) was added to react at 140 ° C. Under nitrogen atmosphere, the reaction was monitored by thin layer chromatography spot plate. After 6 hours of reaction, the reaction was completed. The organic phase was extracted with ethyl acetate (25 mL × 3 times) and collected. The organic phase was dried with anhydrous magnesium sulfate, the solid anhydrous magnesium sulfate was removed by filtration, and after rotary evaporation and concentration, it was purified and separated by silica gel column chromatography to obtain 9.9 mg of compound 3a (yield 7%). The NMR data are as follows:

[0048] 1 H NMR (600MHz, CDCl3) δ6.97–6.92(m,1H),6.54–6.46(m,3H),5.53(d,J=10.1Hz,1H),5.2 3–4.94(m,1H),2.07–2.00(m,2H-),1.67(m,1H),1.59(s,4H),1.50(s,3H),1.33(s,3H).

[0049] Using the above method, a series of 2H-chromene derivatives were synthesized, and the specific products are as follows:

[0050] Compound 3b: (Raw materials: Compounds 3a-3n all used linalool ), the NMR data are as follows:

[0051] 1 H NMR (600 MHz, CDCl3) δ 6.91 (t, J = 7.8 Hz, 1H), 6.59 (d, J = 7.5 Hz, 1H), 6.56 (d, J = 8.1 Hz, 1H), 6.47 (d, J = 10.1 Hz, 1H), 5.53 (d, J = 10.0 Hz, 1H), 5.07–4.99 (m, 1H), 2.21 (s, 3H), 2.12–1.99 (m, 2H-), 1.69–1.62 (m, 1H), 1.59–1.55 (m, 4H), 1.50 (s, 3H), 1.31 (s, 3H), yield 19%.

[0052] Compound 3c: (Raw materials: ), the NMR data are as follows:

[0053] 1 H NMR (600 MHz, CDCl3) δ 6.99–6.93 (m, 1H), 6.85 (d, J = 2.6 Hz, 1H), 6.61 (d, J = 8.6 Hz, 1H), 6.21 (d, J = 9.9 Hz, 1H), 5.53 (d, J = 9.9 Hz, 1H), 5.04–4.97 (m, 1H), 2.07–1.96 (m, 2H-), 1.67–1.62 (m, 1H), 1.59–1.55 (m, 4H), 1.49 (s, 3H), 1.31 (s, 3H), yield 28%.

[0054] Compound 3d: (Raw materials: ), the NMR data are as follows:

[0055] 1 H NMR (600 MHz, CDCl3) δ 6.90 (d, J = 2.2 Hz, 1H), 6.77 (d, J = 2.3 Hz, 1H), 6.67 (d, J = 8.1 Hz, 1H), 6.31 (d, J = 9.8 Hz, 1H), 5.55 (d, J = 9.8 Hz, 1H), 5.11–5.06 (m, 1H), 2.24 (s, 3H), 2.18–2.06 (m, 2H-), 1.75–1.68 (m, 1H), 1.66 (s, 4H), 1.58 (s, 3H), 1.38 (s, 3H), yield: 6%.

[0056] Compound 3e: (Raw materials: ), the NMR data are as follows:

[0057] 1 H NMR (600 MHz, CDCl3) δ 6.85 (d, J = 7.5 Hz, 1H), 6.64 (d, J = 7.6 Hz, 1H), 6.60 (s, 1H), 6.33 (d, J = 9.8 Hz, 1H), 5.50 (d, J = 9.8 Hz, 1H), 5.14–5.08 (m, 1H), 2.27 (s, 3H), 2.17–2.07 (m, 2H-), 1.78–1.71 (m, 1H), 1.67–1.61 (m, 4H), 1.58 (s, 3H), 1.38 (s, 3H), yield: 23%.

[0058] Compound 3f: (Raw materials: ), the NMR data are as follows:

[0059] 1H NMR (600 MHz, CDCl3) δ 6.95–6.83 (m, 1H), 6.58–6.43 (m, 2H-), 6.31 (d, J = 10.0 Hz, 1H), 5.50 (d, J = 9.9 Hz, 1H), 5.14–5.04 (m, 1H), 2.15–2.05 (m, 2H-), 1.77–1.70 (m, 1H), 1.66–1.61 (m, 4H), 1.57 (s, 3H), 1.42–1.35 (m, 3H), yield 13%.

[0060] Compound 3g: (Raw materials: ), the NMR data are as follows:

[0061] 1 H NMR (600 MHz, CDCl3) δ 6.99–6.84 (m, 1H), 6.79–6.66 (m, 2H-), 6.36 (d, J = 1.8 Hz, 1H), 5.62 (d, J = 10.0 Hz, 1H), 5.30–4.98 (m, 1H), 2.27–2.07 (m, 2H-), 1.84–1.77 (m, 1H), 1.71–1.64 (m, 4H), 1.57 (d, J = 7.3 Hz, 3H), 1.44 (s, 3H), yield 15%.

[0062] Compound 3h: (Raw materials: ), the NMR data are as follows:

[0063] 1 H NMR (600 MHz, CDCl3) δ 6.96 (d, J = 7.4 Hz, 1H), 6.81 (d, J = 7.4 Hz, 1H), 6.72 (t, J = 7.3 Hz, 1H), 6.33 (d, J = 9.8 Hz, 1H), 5.54 (d, J = 9.7 Hz, 1H), 5.11 (t, J = 7.4 Hz, 1H), 2.18 (s, 3H), 1.77–1.64 (m, 5H), 1.57 (s, 4H), 1.39 (s, 3H), yield 5%.

[0064] Compound 3i: (Raw materials: ), the NMR data are as follows:

[0065] 1H NMR (600 MHz, CDCl3) δ 6.79–6.75 (m, 1H), 6.64–6.59 (t, 1H), 6.34 (d, J = 9.8 Hz, 1H), 5.61–5.56 (d, 1H), 5.10 (t, J = 7.3, 1.5 Hz, 1H), 2.13 (m, J = 8.0 Hz, 2H-), 1.86–1.77 (m, 1H), 1.65 (s, 4H), 1.56 (s, 3H), 1.45 (s, 3H), yield 16%.

[0066] Compound 3j: (Raw materials: ), the NMR data are as follows:

[0067] 1 H NMR (600MHz, CDCl3) δ7.09(t,J=7.8,3.8Hz,1H),6.95(d,J=7.4,1.7Hz,1H),6.82(t,J=7.4Hz,1H),6.76(d,J=8.1Hz,1H),6.35(d,J=9.9Hz,1H),5.56( d,J=9.9Hz,1H),5.10(t,J=7.3Hz,1H),2.11(m,J=12.4,6.4Hz,2H-),1.74( m,J=13.6,11.1,5.6Hz,1H),1.66(d,4H),1.57(s,3H),1.39(s,3H), the yield is 15%.

[0068] Compound 3k: (Raw materials: ), the NMR data are as follows:

[0069] 1 H NMR (600 MHz, CDCl3) δ 6.70 (d, J = 8.7 Hz, 1H), 6.66 (d, J = 8.7, 3.0 Hz, 1H), 6.54 (d, J = 3.0 Hz, 1H), 6.31 (d, J = 9.9 Hz, 1H), 5.60 (d, J = 9.8 Hz, 1H), 5.09 (t, J = 7.3 Hz, 1H), 2.10 (m, J = 12.4, 6.3 Hz, 2H-), 1.72–1.68 (m, 1H), 1.66 (d, 4H), 1.57 (s, 3H), 1.37 (s, 3H), yield 16%.

[0070] Compound 3l: (Raw materials are ), the NMR data are as follows:

[0071] 1H NMR (600 MHz, CDCl3) δ 6.87 (d, J = 8.2 Hz, 1H), 6.39 (d, J = 8.3, 2.4 Hz, 1H), 6.36 (d, J = 2.5 Hz, 1H), 6.31 (d, J = 9.9 Hz, 1H), 5.42 (d, J = 9.8 Hz, 1H), 5.12–5.07 (t, 1H), 2.11 (m, J = 10.6, 6.9 Hz, 2H-), 1.72 (m, J = 13.7, 6.8, 3.4 Hz, 1H), 1.66 (d, 4H), 1.58 (s, 3H), 1.38 (s, 3H), yield 11%.

[0072] Compound 3m: (Raw materials are ), the NMR data are as follows:

[0073] 1 H NMR (600 MHz, CDCl3) δ7.09 (t, 1H), 6.98–6.94 (m, 1H), 6.82 (t, J=7.4 Hz, 1H), 6.77 (d, J=8.1 Hz, 1H), 6.36 (d, J=9.8 Hz, 1H), 5.56 (d, J=9.9 Hz, 1H), 5.14–5.07 (m, 1H), 2.21–2.04 (m, 2H-), 1.81–1.71 (m, 1H), 1.66 (s, 4H), 1.58 (s, 3H), 1.40 (s, 3H), yield: 26%.

[0074] Example 2

[0075] Synthesis of 2H-chromene derivatives with different substituents at C-2 position

[0076]

[0077] The specific steps are as follows:

[0078] Take compound 3n as an example:

[0079] Under nitrogen atmosphere, add 6,10,14-trimethylpentadeca-5,9,13-triene-2-one (1.3 g, 5.0 mmol, 1.0 eq.) to a dry and clean 50 mL reaction tube, dissolve it in 15 mL of ultra-dry tetrahydrofuran (THF), stir evenly, slowly add vinylmagnesium bromide (5 mL, 9.9 mmol, 2.0 eq.) at 0 ° C, and react at room temperature. Under nitrogen atmosphere, the reaction is monitored by thin layer chromatography spot plate. After about 3 hours of reaction, the reaction is completed. The reaction solution is slowly poured into water to quench, extracted with ethyl acetate (25 mL × 3 times) and the organic phase is collected. The organic phase is dried with anhydrous magnesium sulfate, the solid anhydrous magnesium sulfate is filtered off, and after rotary evaporation and concentration, it is purified and separated by silica gel column chromatography to obtain the product 3,7,11-trimethyltwelve carbon-1,6,10-triene-3-ol. In a dry and clean 25mL reaction tube, add 3,7,11-trimethyl dodeca-1,6,10-triene-3-ol (290.2mg, 1.0mmol, 2.0eq.), o-bromophenol (86.5mg, 0.5mmol, 1.0eq.), potassium carbonate (207.3mg, 1.5mmo, 3.0eq.) in sequence, dissolve in 5mL of N,N-dimethylformamide (DMF), stir evenly, and finally add palladium acetate (12mg, 10mol%), and react at 140℃. Under nitrogen atmosphere, the reaction is monitored by thin layer chromatography spot plate. After about 6 hours of reaction, the reaction is completed. Ethyl acetate (25mL×3 times) is extracted and the organic phase is collected, and the organic phase is dried with anhydrous magnesium sulfate. The solid anhydrous magnesium sulfate is filtered out, and after rotary evaporation and concentration, it is purified and separated by silica gel column chromatography to obtain 22.7mg compound 3n (yield is 18%). The NMR data are as follows:

[0080] 1 H NMR (600MHz, CDCl3) δ7.09 (m, J=7.7, 1.7Hz, 1H), 6.95 (m, J=7.5, 1.7Hz, 1H), 6.82 (t, J=7 .4Hz,1H),6.76(d,J=8.1Hz,1H),6.35(d,J=9.9Hz,1H),5.56(d,J=9.9Hz,1H),5.10(m,J= 13.5,7.1Hz,3H),2.14(m,J=12.4,6.2Hz,1H),2.05(q,J=7.5Hz,4H),1.96(t,J=7.7Hz,4H ),1.75(m,J=13.9,11.1,5.7Hz,1H),1.70–1.64(m,4H),1.61–1.55(m,10H),1.39(s,3H).

[0081] Experimental Example 1

[0082] Anti-coronavirus activity of 2H-chromene derivatives:

[0083] Evaluation of drug efficacy against multiple coronaviruses: Coronavirus OC43-VR-1558 / HRT-18, using the HCoV-OC43 / HRT-18 cell model, with remdesivir as a positive control, the MTT method was used to detect the cytotoxicity of candidate drugs on HRT-18 cells, and the drug half-toxic concentration (CC 50 ) and the median effective concentration (EC 50 ).

[0084] 1. Experimental Materials

[0085] Instruments and reagents: CO2 incubator (Thermofisher_3111), microplate reader (Molecular Devices_SpectraMax), inverted microscope (OLYMPUS_CKX41), MTT (Sigma Aldrich), DMEM medium (Gibco), human colorectal cancer cells (HRT-18), also known as HCT-8, fetal bovine serum (Gibco), dimethyl sulfoxide DMSO (AlfaAesar), trypsin (MP Biomedicals).

[0086] Test sample: The compound obtained in Example 1, with a purity of more than 95%; at the same time, remdesivir was selected as the positive control drug, and each compound was dissolved in DMSO and then diluted.

[0087] 2. Cytotoxicity experiment:

[0088] 1) Human colorectal cancer cells (HRT-18) were seeded in 96-well plates, 8,000 cells / well, and cultured at 37°C, 5% CO2 for 24 hours; the cells were divided into the following 2 groups:

[0089] ① Cell control group: only human colorectal cancer cells (HRT-18);

[0090] ② Drug group: Compound 3b, compound 3f, compound 3g, compound 3i, compound 3j and compound 3m were added to HRT-18 cells respectively;

[0091] 2) Compound 3b, compound 3f, compound 3g, compound 3i, compound 3j and compound 3m prepared in Example 1 were added to HRT-18 cells in the drug group, and the concentration gradient of each compound was set to 0, 1.5625, 3.125, 6.25, 12.5, 25, 50, 100 μM;

[0092] 3) Continue to culture at 37°C, 5% CO2 for 120 h, then add Reagents;

[0093] 4) Use Molecular Devices_SpectraMax multi-function microplate reader to detect absorbance;

[0094] 5) The cytotoxicity of the compound to HRT-18 cells was calculated by the following formula:

[0095] Cytotoxicity (%) = (cell control group - drug group) / (cell control group) × 100;

[0096] The cell control group and drug group are the corresponding absorbance values, the same below.

[0097] CC was calculated using IBM SPSS Statistics 20 software 50 (drug concentration at which 50% of cells die).

[0098] Anti-coronavirus activity:

[0099] 1) HRT-18 cells were seeded in 96-well plates, 1×10 4 The cells were cultured at 37°C and 5% CO2 for 24 hours and then divided into the following 3 groups:

[0100] ① Cell control group: only human colorectal cancer cells (HRT-18);

[0101] ② Virus control group: only virus was added to HRT-18 cells;

[0102] ③ Drug and virus group (with remdesivir as positive control): Compound 3b, Compound 3f, Compound 3g, Compound 3i, Compound 3j and Compound 3m prepared in Example 1, remdesivir and the same virus as the virus control group in HRT-18 cells;

[0103] 2) administration in three modes of action, wherein the concentration gradients of compound 3b, compound 3f, compound 3g, compound 3i, compound 3j, compound 3m and remdesivir prepared in Example 1 for treating cells were 0, 1.5625, 3.125, 6.25, 12.5, 25, 50, and 100 μM, respectively, and the virus was the coronavirus HCoV-OC43 virus (OC43-VR-1558) with a multiplicity of infection (MOI) of 1;

[0104] Mode 1: Administration before infection (preventive administration) Compound 3b, compound 3f, compound 3g, compound 3i, compound 3j, compound 3m and remdesivir prepared in Example 1 were first added to treat the cells respectively, incubated at 37°C for 2 hours, and then aspirated, and then the coronavirus HCoV-OC43 virus with an infection multiplicity (MOI) of 1 was added, and the virus solution was discarded after incubation for 2 hours.

[0105] Mode 2: The coronavirus HCoV-OC43 virus with a multiplicity of infection (MOI) of 1 was added and the compounds 3b, 3f, 3g, 3i, 3j, 3m and remdesivir prepared in Example 1 were treated with the cells respectively (drugs and viruses were added at the same time).

[0106] Mode 3: After adding the coronavirus HCoV-OC43 virus with a multiplicity of infection (MOI) of 1 for 2 hours, the virus solution was discarded, and then the compounds 3b, 3f, 3g, 3i, 3j, 3m and remdesivir prepared in Example 1 were added for treatment respectively.

[0107] 3) Continue to culture at 37°C, 5% CO2 for 120 h, then add Reagents;

[0108] 4) Use Molecular Devices_SpectraMax multi-function microplate reader to detect absorbance;

[0109] 5) The protective effect of the compound on influenza virus infected cells was calculated by the following formula:

[0110] Cell protection rate (%) = (drug and virus group - virus control group) / (cell control group - virus control group) × 100;

[0111] The drug, virus group and virus control group referred to herein are all corresponding absorbance values, the same below.

[0112] EC was calculated using IBM SPSS Statistics 20 software 50 (Concentration required to protect 50% of HRT-8 cells from influenza virus killing).

[0113] Experimental Results

[0114] The cytotoxicity of the 2H-chromene derivatives 3b, 3f, 3g, 3i, 3j and 3m prepared in Example 1 to HRT-8 cells was 5 to 50 μM;

[0115] Example 1 The cytotoxicity of the 2H-chromene derivatives 3b, 3f, 3g, 3i, 3j and 3m prepared in Example 1 to HRT-8 and the inhibitory activity to the coronavirus HCoV-OC43 virus are shown in Table 1:

[0116] Table 12 In vitro anti-coronavirus HCoV-OC43 activity of H-chromene compounds 3b, 3f, 3g, 3i, 3j and 3m

[0117] Compound <![CDATA[EC 50 (μM)]]> <![CDATA[CC 50 (μM)]]> YES 3b 16.41±2.33 >50 3.05 3f 17.63±5.59 >50 2.84 3g 3.35±0.44 >25 7.46 3i 11.70±3.1 >50 4.27 3j 21.89±2.67 >50 2.28 3m 7.61±1.29 >50 6.57 Remdesivir 0.11±0.03 15.8 143.6

[0118] Coronavirus: OC43-VR-1558, Cells: HRT-18 / HCT-8

[0119] As can be seen from Table 1, compound 3g has the best anti-coronavirus activity (EC 50 =3.35μM), but has certain toxicity (CC 50 >25μM), SI=7.46; compound 3m had the second highest anti-coronavirus activity (EC 50 =7.61μM) and less toxic (CC 50 >50μM), SI=6.57; IC of positive drug Remdesivir against coronavirus 50 0.11 μM, but there is obvious cytotoxicity, CC 50 =15.8 μM. In comparison, although compound 3g has certain toxicity, its selectivity index is better than that of compound 3m, and it has the prospect of becoming an anti-coronavirus drug.

[0120] As can be seen from the above embodiments, the present invention provides a 2H-chromene derivative and its application. The 2H-chromene derivative of the present invention has obvious anti-coronavirus activity, and can also be used as a lead compound for further modification and development of anti-coronavirus drugs. The problem that the current research on the biological activity of 2H-chromene is mainly on anti-inflammatory and antifungal activities, but there is no research on anti-coronavirus activity is solved.

[0121] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. A 2H-chromene derivative, characterized in that The 2H-chromene derivatives include the following structures: Among them, R 1 and R 2 and R is independently H, a halogen atom, a straight-chain alkyl group, a branched-chain alkyl group, a heteroalkyl group, an aryl group, a heteroaryl group, an alcoholic hydroxyl group, a carbonyl group, a carboxyl group or an alkenyl group.

2. The 2H-chromene derivative according to claim 1, characterized in that The R 1 and R 2 Independently selected from one of the following structures:

3. The 2H-chromene derivative according to claim 1 or 2, characterized in that The 2H-chromene derivative comprises one of the following structural formulas:

4. Use of the 2H-chromene derivative and a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3 in the preparation of anti-coronavirus drugs.

5. The use according to claim 4, characterized in that: The anti-coronavirus drug also contains pharmaceutically acceptable excipients.

6. The use according to claim 5, characterized in that: The pharmaceutically acceptable excipients include one or more of diluents, excipients, fillers, binders, wetting agents, disintegrants, absorption promoters, surfactants, adsorption carriers and lubricants.

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