Sesquiterpenoid derivatives and their use in the manufacture of broad-spectrum antiviral drugs - Patents.com

Abstract

The present invention provides sesquiterpenoid derivatives and their application in the preparation of broad-spectrum antiviral drugs. [Solution] The present invention discloses sesquiterpenoid derivatives and their application in the preparation of broad-spectrum antiviral drugs, which stimulate heterogeneous nuclear ribonucleoprotein A2 / B1, activate the TANK-binding kinase 1-interferon regulatory factor 3 cell signal pathway, increase the secretion of endogenous type I interferon, and have inhibitory effects on various viruses. As a broad-spectrum antiviral drug, it can prevent or treat infectious diseases and illnesses caused by various viruses, including new coronavirus, vesicular stomatitis virus VSV-G, human immunodeficiency virus, hepatitis C virus, Japanese encephalitis virus, influenza virus, poliovirus, coxsackievirus, dengue virus, rotavirus, tobacco mosaic virus, measles virus, mumps virus, Ebola virus, Marburg virus, herpes virus and adenovirus. The sesquiterpenoid derivatives can be used as raw materials to prepare oral dosage forms such as tablets, capsules, drip pills, or clinically acceptable pharmaceutical preparations such as inhalants and injections.

Description

[Technical field]

[0001] The present invention relates to the field of pharmaceutical technology, and in particular to sesquiterpenoid derivatives and their uses which are beneficial in the treatment of a wide range of viral infectious diseases and conditions. [Background technology]

[0002] Viral infections are a constant threat to human life and health. Although specific vaccines and antiviral drugs have shown therapeutic effects, there are still problems such as toxicity, drug resistance, or vaccines that can only prevent and not cure. In addition, there is a lack of broad-spectrum antiviral drugs to combat the outbreak of some acute viral infections, such as pneumonia caused by the new coronavirus, which seriously harms human health and poses a serious threat to the public health and safety of society. At present, during acute viral outbreaks, interferon and hormone therapy have achieved certain therapeutic effects, but there are still problems with off-target effects and side effects. Therefore, discovering broad-spectrum antiviral drugs is important to solve the problems of side effects, drug resistance, and acute viral outbreaks.

[0003] Modulation of host immunity is a research strategy for broad-spectrum antiviral drugs. Immune response dysfunction is considered to be the main cause of persistent viral infection. Therefore, restoring or enhancing innate immunity and inducing adaptive immune responses against viruses may contribute to the elimination of viruses. To date, attempts based on immune strategies have not been ideal and have risks such as off-target effects and significant side effects. Therefore, combining effective antiviral drugs with immunotherapy is a new strategy for broad-spectrum antiviral drugs. Summary of the Invention [Problem to be solved by the invention]

[0004] The object of the present invention is to provide a sesquiterpenoid derivative and its use in the preparation of a broad-spectrum antiviral drug in response to the shortcomings of the prior art. The present invention is an effective broad-spectrum antiviral drug with a new target, which can significantly inhibit RNA and DNA viruses such as the new coronavirus (SARS-CoV-2), vesicular stomatitis virus VSV-G, human immunodeficiency virus, hepatitis C virus, Japanese encephalitis virus, influenza virus, poliovirus, coxsackievirus, dengue virus, rotavirus, tobacco mosaic virus, measles virus, mumps virus, Ebola virus, Marburg virus, herpes virus and adenovirus. [Means for solving the problem]

[0005] In order to achieve the above object of the present invention, the present invention provides the following technical solutions: A sesquiterpenoid derivative having a structure represented by the following structural formula I, II, III or IV. [ka] Here, in structural formulas I to IV, R1 is independently selected from the group consisting of hydrogen, a benzoyl group, a p-hydroxybenzoyl group, a polyhydroxybenzoyl group, a p-methoxybenzoyl group, a polymethoxybenzoyl group, and a benzoyl group substituted with fluorine, chlorine, or bromine.

[0006] Furthermore, it is preferable that the compound has a structure represented by Formula I, and R1 is preferably a benzoyl group or a p-hydroxybenzoyl group.

[0007] The present invention further provides the use of the above sesquiterpenoid derivatives in the manufacture of a medicament for treating a viral infection.

[0008] Furthermore, the viral infection is a viral infection caused by the novel coronavirus (SARS-CoV-2), vesicular stomatitis virus (VSV-G), human immunodeficiency virus, hepatitis C virus, Japanese encephalitis virus, influenza virus, poliovirus, coxsackievirus, dengue virus, rotavirus, tobacco mosaic virus, measles virus, mumps virus, Ebola virus, Marburg virus, herpes virus, and adenovirus.

[0009] Additionally, the sesquiterpenoid derivatives may be combined with a pharmaceutical and / or edible carrier.

[0010] Further, the sesquiterpenoid derivative is included in the pharmaceutical agent in a therapeutically effective amount.

[0011] Moreover, the therapeutically effective amount is sufficient to stimulate hnRNPA2B1 and activate the TANK-binding kinase 1-interferon regulatory factor 3 (TBK1-IRF3) pathway, thereby resulting in the production of endogenous type I interferon.

[0012] Further, the pharmaceutical product includes oral administration formulations including tablets, pills, capsules, granules, microcapsule tablets, suspensions, drops, or oral liquids, or parenteral administration formulations including injections, aerosols, suppositories, or subcutaneous administration. Effect of the Invention

[0013] The present invention has an excellent technical effect of stimulating hnRNPA2B1, forming homodimers, activating the TANK-binding kinase 1-interferon regulatory factor 3 (TBK1-IRF3) pathway, causing the production of endogenous type I interferon, and exhibiting significant viral activity. Compared with current pharmaceuticals for treating viral infections, the present invention has a completely new target, can improve / improve toxicological safety (i.e., reduced toxicity), and can improve / improve metabolic stability, and the present invention has a longer half-life and / or smaller side effects while at the same time producing similar or improved biological activity (drug efficacy). The present invention can be used for the prevention or treatment of viral infections and diseases, and as a protective agent for visceral damage, such as liver damage caused by hepatitis B virus. It can also be used to investigate chemical tools and drugs related to viral infections involving hnRNPA2B1.

[0014] The present invention relates to a method for preventing and treating the novel coronavirus (SARS-CoV-2) (median effective dose IC 50 485nM), vesicular stomatitis virus (IC 50 1.72 μM), human immunodeficiency virus (IC 50 1.70 μM), Hepatitis C virus (IC 50 551nM), Japanese encephalitis virus (IC 50 1.31 μM), influenza virus (IC 50 720nM), poliovirus (IC 50 2.75 μM), Coxsackievirus (IC 50 720nM), dengue virus (IC 50 314nM), rotavirus (IC 50 541nM), tobacco mosaic virus (IC 50 1.45μM), measles virus (IC 50 1.62 μM), mumps virus (IC 50 1.81μM)(IC 50 1.37 μM), Ebola virus (IC 50 1.41 μM), Marburg virus (IC 50 1.38 μM), herpes virus (IC 50 1.79 μM) and adenovirus (IC 501.48μM), which is far superior to the positive control, and does not show cytotoxicity at a high concentration of 500M. Further investigation showed that the median effective dose in mice was 20mg / kg, and the maximum daily dose in mice was 2000mg / kg. No toxic reactions occurred after 7 days of continuous observation. This shows that the drug can inhibit multiple viruses with high efficiency and low toxicity, and can be used as a broad-spectrum antiviral drug. [Brief description of the drawings]

[0015] [Figure 1] Schematic diagram of the viral inhibitory activity of Phyllanthus pentanamide PA-X1 in a cell model, where (a) is a schematic diagram of the inhibitory activity against the novel coronavirus (SARS-COV-2), and (b) is a schematic diagram of the inhibitory activity against vesicular stomatitis virus. [Diagram 2] Schematic diagram showing that Amedema japonica pentanamide PA-X1 upregulates endogenous type I interferon IFN-β. [Diagram 3] FIG. 1 shows the binding pattern of Amedema nigra pentanamide PA-X1 and hnRNPA2B1. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0016] Research has found that stimulating hnRNPA2B1 and activating the TANK-binding kinase 1-interferon regulatory factor 3 (TBK1-IRF3) pathway results in the production of endogenous type I interferon with significant inhibitory activity against many viruses. Therefore, individuals suffering from this disease can receive a composition containing Phyllanthus pentyl ester or Phyllanthus pentanamide (or one of the analogs and congeners structurally related to Phyllanthus pentyl ester or Phyllanthus pentanamide, which is one of the main active ingredients) according to the present invention.

[0017] In addition, the study of hnRNPA2B1 is an important means for investigating the pathogenesis of viral infections, such as the novel coronavirus (SARS-COV-2), vesicular stomatitis virus, hepatitis B virus, hepatitis C virus, and viral visceral damage. The amplexicaule ester or amplexicaule pentanamide of the present invention can significantly upregulate endogenous type I interferon IFN-β. Therefore, the amplexicaule ester or amplexicaule pentanamide of the present invention (or one of the analogs and congeners structurally related to amplexicaule ester or amplexicaule pentanamide, which is one of the main active ingredients) can be used in research to investigate the pathogenesis of viral infections.

[0018] Since the oleander esters or oleander pentanamides of the present invention have eight chiral stereocenters, the oleander esters or oleander pentanamides prove to have better biological activity as racemic (or diastereomeric) mixtures, R and S enantiomeric (or diastereomeric) mixtures, or pure enantiomers (R or S) (or diastereomers). When the pure enantiomers show better biological activity, they are called eutomers, and the enantiomers with less biological activity are called distomers.

[0019] Since the Amplexicaule esters or Amplexicaule pentanamides of the present invention have three free hydroxyl groups, the Amplexicaule esters or Amplexicaule pentanamides, as salts and / or esters, are proven to have better biological activity and / or better metabolic parameters.

[0020] The effective pharmaceutical formulations and compositions of the present invention can be used to treat a variety of viral infections and diseases, such as, for example, novel coronavirus (SARS-CoV-2), vesicular stomatitis virus VSV-G, human immunodeficiency virus, hepatitis C virus, Japanese encephalitis virus, influenza virus, poliovirus, coxsackievirus, dengue virus, rotavirus, tobacco mosaic virus, measles virus, mumps virus, Ebola virus, Marburg virus, herpes virus, and adenovirus. These pharmaceutical preparations are typically used to treat human patients, but may also be used to treat similar or identical diseases in other animals, such as primates, poultry (e.g., chickens, ducks, geese), farm animals (e.g., pigs, cows), sport animals (e.g., racing horses), and pets (e.g., dogs and cats).

[0021] Pharmaceutically acceptable carriers according to the present invention include, but are not limited to, calcium carbonate, calcium phosphate, calcium sulfate, sucrose, glucose, lactose, fructose, xylitol, sorbitol, starch, starch paste, cellulose derivatives, gelatin, polyvinylpyrrolidone, sodium chloride, dextrin, stearic acid, magnesium stearate, calcium stearate, vegetable oils, polyethylene glycol, sterile phosphate buffered saline, saline, Ringer's solution, and combinations thereof.

[0022] Pharmaceutically acceptable salts according to the invention include the sodium, potassium, lithium, zinc, aluminium, calcium and magnesium salts.

[0023] The dosage form of the oral administration agent according to the present invention includes, but is not limited to, a solid oral dosage form (e.g., enteric-coated tablets, drop pills, oral tablets, chewable tablets, granules, powders or capsules) or a liquid oral dosage form (e.g., syrup or tincture). In addition, the ambrosia ester or ambrosia pentanamide and its derivative or composition of the present invention can be added to food and beverages and orally administered. In addition, the ambrosia ester or ambrosia pentanamide and its derivative or composition of the present invention can be incorporated into chewing gum to facilitate oral administration and absorption.

[0024] Parenteral administration according to the present invention includes, but is not limited to, administration by injection or other systemic routes, such as transdermal or transmucosal administration (e.g., nasal, sublingual, buccal, vaginal or rectal administration, via suppositories). Other routes of administration (e.g., that may be used in veterinary applications) include enteral and parenteral administration, including intramuscular, subcutaneous and / or intramedullary injections, and intrathecal, direct ventricular, intravenous, intraperitoneal, intranasal or intraocular injections.

[0025] The Amplexicaule esters or Amplexicaule pentanamides and derivatives or combinations thereof according to the present invention may be combined with other active pharmaceutical ingredients to prepare other new pharmaceutical compositions.

[0026] The Amplexicaule ester or Amplexicaule pentanamide or any derivative or combination thereof of the present invention is used to alleviate the above conditions with demonstrable therapeutic and therapeutically relevant activity.

[0027] The above-mentioned Amplexicaule ester or Amplexicaule pentanamide or any derivative or combination thereof of the present invention have good therapeutic effect, good pharmaceutical metabolism parameters and generally no toxicity, making the compounds of the present invention ideal pharmaceuticals for treating the above-mentioned diseases.

[0028] The structural formula of the sesquiterpenoid derivative of the present invention is as follows: [ka]

[0029] The preparation of said sesquiterpenoid derivatives comprises the following steps:

[0030] 1. 10 kg of Phyllanthus acidus rhizomes were extracted with methanol three times under reflux to obtain 429 g of extract. The crude extract was dispersed in 5.5 L of H2O, extracted five times with equal volumes of ethyl acetate and n-butanol, respectively, concentrated to dryness, dissolved in methanol, and eluted with CH3OH / H2O (0-100) (V / V%) using macroporous resin column Diaion HP20SS column chromatography to obtain five fractions. Fractions 2 and 3 were combined and purified by Sephadex LH20 (CH3OH 0-100%) column chromatography to obtain five fractions. The previous two fractions (41.0 g) were combined, and then column chromatography was repeated using normal phase silica gel column chromatography (CHCl3-CH3OH-H2O, 9:1:0-7:3:0.5), reverse phase RP-8 (CH3OH 30%-80%) and gel resin column Toyopearl HW 40C (CH3OH 0-30%), followed by preparative high performance liquid chromatography (CH3CN 15-30%) to give phyllanthacidoid A (10 g) and phyllanthacidoid B (1 g).

[0031] 2. Philanthasidoid A and B (1.27*10 -5 mol) were dissolved in 1 ml of 0.72 M aqueous potassium carbonate solution and hydrolyzed at 60°C for 2 hours to produce phyllanthacidoid aglycones A and B.

[0032] 3. Philanthasidoid aglycone A is dissolved in an organic solvent and reacted with 20 molar equivalents of n-pentylamine at room temperature for 12 hours to produce compound PA-X1.

[0033] 4. Philanthasidoid aglycone B is dissolved in an organic solvent and reacted with 20 molar equivalents of n-pentylamine at room temperature for 12 hours to produce compound PA-X2.

[0034] 5. Philanthasidoid aglycone A is dissolved in an organic solvent and reacted with 367 molar equivalents of n-pentanol at room temperature for 12 hours to produce compound PA-X3.

[0035] 6. Philanthasidoid aglycone B is dissolved in an organic solvent and reacted with 367 molar equivalents of n-pentanol at room temperature for 12 hours to produce compound PA-X4.

[0036] 7. Philanthasidoid aglycone A is dissolved in an organic solvent and reacted with 20 molar equivalents of butylamine at room temperature for 12 hours to produce compound PA-X5.

[0037] 8. Philanthasidoid aglycone B is dissolved in an organic solvent and reacted with 20 molar equivalents of n-butylamine at room temperature for 12 hours to produce compound PA-X6.

[0038] 9. Philanthasidoid aglycone A is dissolved in an organic solvent and reacted with 367 molar equivalents of n-butanol at room temperature for 12 hours to produce compound PA-X7.

[0039] 10. Philanthasidoid aglycone B was dissolved in an organic solvent and reacted with 367 molar equivalents of n-butanol at room temperature for 12 hours to produce compound PA-X8.

[0040] In the above steps, unless otherwise specified, all the ratios are molar ratios.

[0041] The following examples of the present invention will further illustrate the essential contents of the present invention, but do not limit the present invention in any manner, and any conversion or replacement made based on the present invention falls within the scope of protection of the present invention.

[0042] Example 1: Synthesis of PA-X1 (PAC5) Step (1): Approximately 10 mg of phyllanthacidoid A (PA) was placed in a reaction tube, and 1 ml of 0.72 M potassium carbonate solution was added. After dissolution, the mixture was placed in a 60 °C oil bath and magnetically stirred for 2 hours, and reacted until the raw material was consumed. The solution was neutralized to acidity with 1 M hydrochloric acid, and the pH value was about 2. A certain amount of saline was added to the solution until the volume was about 4.5 ml, and the solution was extracted with 4.5 x 3 ml ethyl acetate. The organic phases were combined, and the solvent was removed by distillation under reduced pressure to obtain the product. Step (2): 10 mg of the product obtained in step (1) was dissolved in 1 ml of DMF dried with 3A molecular sieves, placed in a reaction tube, and 20 molar equivalents of n-pentylamine were added. Then, 10 molar equivalents of HOSU, EDCI, and 2 molar equivalents of DMAP were added, and the mixture was reacted at room temperature overnight. The reaction status of the raw material was monitored by TLC, and the reaction was usually completed after 12 hours. After the reaction was completed, 10% citric acid was added to the reaction solution up to 4-5ml, and extracted with 5 x 3ml ethyl acetate. The organic phases were combined and concentrated, and then dissolved in about 7ml of dichloromethane. If a precipitate was present, a small amount of methanol was added to promote dissolution (methanol content was less than 5%), and the precipitate was separated and purified with amino silica gel to obtain PA-X1, with a yield of about 51%. Spectral data for PA-X1: ESI-MS: m / z 508 [M+H] + ; 11H NMR (600 MHz, MeOD) δ 7.86 (ddd, J = 8.8, 2.7, 2.0 Hz, 2H, H-16, H-20), 6.73 (ddd, J = 8.8, 2.7, 2.0 Hz, 2H, H-17, H-19), 5.12 (brd, J = 2.6 Hz, 1H, H-10), 4.01 (t, J = 3.2 Hz, 1H, H-5), 3.93 (t, J = 11.4 Hz, 1H, H-12a), 3.79 (dd, J = 10.5, 5.6 Hz, 1H, H-1), 3.65 (s, 1H, H-7), 3.49 (dd, J = 11.1, 4.5 Hz, 1H, H-12b), 3.01 - 2.92 (m, 2H, H-1’), 2.33 (ddd, J = 15.1, 11.3, 5.6 Hz, 1H, H-3), 2.10 - 2.03 (m, 1H, H-9a), 2.02 - 1.95 (m, 2H, H-11, H-9b), 1.88 (ddd, J = 14.6, 11.7, 3.2 Hz, 1H, H-2a), 1.69 (dt, J = 14.0, 5.7 Hz, 1H, H-4a), 1.59 (ddd, J = 14.4, 5.3, 3.5 Hz, 1H, H-4b), 1.46 (dt, J = 13.9, 9.8 Hz, 1H, H-2b), 1.31 (dt, J = 14.8, 7.2 Hz, 2H, H-2’), 1.25 - 1.17 (m, 2H, H-3’), 1.16 - 1.09 (m, 2H, H-4’), 0.79 (t, J = 7.3 Hz, 3H, H-5’), 0.78 (d, J = 6.9 Hz, 3H, H-13).

[0043] Example 2: Synthesis of PA-X2 Step (1): 10 mg of phyllanthacidoid B (PB) was placed in a reaction tube, and 1 ml of 0.72 M potassium carbonate solution was added. After dissolution, the mixture was heated and stirred at 60 ° C for 2 hours, and reacted until the raw material was consumed. The solution was neutralized to acidity with 1 M hydrochloric acid, and the pH value was about 2. A certain amount of saline was added to the solution until the volume was about 4.5 ml, and the solution was extracted with 4.5 × 3 ml ethyl acetate. The organic phases were combined, and the solvent was removed by distillation under reduced pressure to obtain the product. Step (2): 10 mg of the product obtained in step (1) was dissolved in 1 ml of DMF dried with 3A molecular sieves, placed in a reaction tube, and 20 molar equivalents of n-pentylamine were added. Then, 10 molar equivalents of HOSU, EDCI, and 2 molar equivalents of DMAP were added, and the mixture was reacted at room temperature overnight. The reaction status of the raw materials was monitored by TLC, and the reaction was usually completed after 12 hours. After the reaction was completed, 10% citric acid was added to the reaction solution up to 4-5ml, and extracted with 5 x 3ml ethyl acetate. The organic phases were combined and concentrated, and then dissolved in about 7ml of dichloromethane. If a precipitate was present, a small amount of methanol was added to promote dissolution (methanol content was less than 5%), and the precipitate was separated and purified with amino silica gel to obtain PA-X2, with a yield of about 44%. Spectral data for PA-X2: ESI-MS: m / z 514 [M+Na] + ; 11H NMR (600 MHz, MeOD) δ 8.00 (brdd, J = 8.3, 1.3 Hz, 2H, H-16, H-20), 7.49 (brt, J = 7.4 Hz, 1H, H-18), 7.37 (brt, J = 7.8 Hz, 2H, H-17, H-19), 5.18 (brd, J = 2.6 Hz, 1H, H-10), 4.02 (t, J = 3.3 Hz, 1H, H-5), 3.95 (t, J = 11.4 Hz, 1H, H-12a), 3.79 (dd, J = 10.5, 5.5 Hz, 1H, H-1), 3.65 (s, 1H, H-7), 3.51 (dd, J = 11.1, 4.4 Hz, 1H, H-12b), 3.00 - 2.89 (m, 2H, H-1’), 2.33 (ddd, J = 15.1, 11.3, 5.6 Hz, 1H, H-3), 2.09 (dd, J = 14.8, 3.2 Hz, 1H, H-9a), 2.05 - 1.97 (m, 2H, H-11, H-9b), 1.89 (ddd, J = 14.7, 11.6, 3.3 Hz, 1H, H-2a), 1.68 (dt, J = 14.0, 5.6 Hz, 1H, H-4a), 1.58 (ddd, J = 14.4, 5.4, 3.6 Hz, 1H, H-4b), 1.47 (dt, J = 14.0, 9.9 Hz, 1H, H-2b), 1.30 (dt, J = 14.4, 7.2 Hz, 2H, H-2’), 1.24 - 1.17 (m, 2H, H-3’), 1.12 (tdd, J = 9.6, 7.0, 3.7 Hz, 2H, H-4’), 0.80 (t, J = 7.2 Hz, 3H, H-5’), 0.79 (d, J = 7.2 Hz, 3H, H-13).

[0044] Example 3: Synthesis of PA-X5 Step (1): Approximately 10 mg of phyllanthacidoid A (PA) was placed in a reaction tube, and 1 ml of 0.72 M potassium carbonate solution was added. After dissolution, the mixture was placed in a 60 °C oil bath and magnetically stirred for 2 hours, and reacted until the raw material was consumed. The solution was neutralized to acidity with 1 M hydrochloric acid, and the pH value was about 2. A certain amount of saline was added to the solution until the volume was about 4.5 ml, and the solution was extracted with 4.5 × 3 ml ethyl acetate. The organic phases were combined, and the solvent was removed by distillation under reduced pressure to obtain the product. Step (2): 10 mg of the product obtained in step (1) was dissolved in 1 ml of DMF dried with 3A molecular sieves, placed in a reaction tube, and 20 molar equivalents of n-butylamine were added. Then, 10 molar equivalents of HOSU, EDCI, and 2 molar equivalents of DMAP were added, and the mixture was reacted at room temperature overnight. The reaction status of the raw material was monitored by TLC, and the reaction was usually completed after 12 hours. After the reaction was completed, 10% citric acid was added to the reaction solution up to 4-5ml, and extracted with 5 x 3ml ethyl acetate. The organic phases were combined and concentrated, and then dissolved in about 7ml of dichloromethane. If a precipitate was present, a small amount of methanol was added to promote dissolution (methanol content was less than 5%), and the precipitate was separated and purified with amino silica gel to obtain PA-X5, with a yield of about 49%. Spectral data for PA-X5: ESI-MS: m / z 516 [M+Na] + ; 1H NMR (600 MHz, MeOD) δ 7.97(ddd, J = 8.82, 2.64, 2.04 Hz, 2H, H-17, H-21), 6.84 (ddd, J = 8.82, 2.70, 1.98 Hz, 2H, H-18, H-20), 5.24 (br d, J = 2.5 Hz, 1H, H10), 4.12 (t, J = 3.2 Hz, 1H, H-5), 4.05 (t, J = 11.4 Hz, 1H, H-12), 3.91 (dd, J = 10.5, 5.6 Hz, 1H, H-1), 3.76 (s, 1H, H-7), 3.61 (dd, J = 11.0, 4.4 Hz, 1H, H-12), 3.09 (br ddd, J = 13.3, 7.1, Hz, 2H, H-1'), 2.44 (ddd, J = 15.0, 11.3, 5.6 Hz, 1H, H-3), 2.21-2.04 (m, 3H, H-11 H-9), 2.00 (ddd, J = 14.7, 9.4, 3.2 Hz, 1H, H-2), 1.81 (dt, J = 14.0, 5.7 Hz, 1H, H-4), 1.70 (ddd, J = 14.4, 5.3, 3.5 Hz, 1H, H-4), 1.58 (dt, J = 14.0, 9.8 Hz, 1H, H-2), 1.43-1.36 (m, 2H, H-2'), 1.33-1.25 (m, 2H, H-3'), 0.92 (t, J = 7.4 Hz, 3H, H-4'), 0.90 (d, J = 6.9 Hz, 3H, H-13).

[0045] Example 4: Synthesis of PA-X7 The product obtained in step (1) in Example 1 (the amount of raw PA used is about 10 mg) is dissolved in 0.5 ml of DMF dried with 3A molecular sieves and placed in a reaction tube, 367 molar equivalents of n-butanol are added, and after stirring and mixing, 10 molar equivalents of EDCI and 2 molar equivalents of DMAP are added, and the reaction is carried out at room temperature overnight, and the reaction status of the raw materials is monitored by TLC, and the reaction is usually completed after 12 hours. After the reaction is completed, 10% citric acid is added to the reaction solution up to 4-5 ml, and extracted with 5 x 3 ml ethyl acetate, and the organic phase is combined and concentrated, and further dissolved in about 7 ml of dichloromethane. If there is a precipitate, a small amount of methanol is added to promote dissolution (methanol content is less than 5%), and the product is separated and purified with amino silica gel to obtain the product, the yield is about 60%, and the reaction is monitored by thin layer chromatography, and the reaction is usually completed after 12 hours. After the reaction is completed, EtOAc is added to the reaction mixture. The pure target product was obtained by separation and purification using amino silica gel in a yield of about 49%. Spectral data for PA-X7: ESI-MS: m / z 517[M+Na] +;PA-X7 spectral data: ESI-MS: m / z 517 [M+Na]+;1H NMR (600 MHz, MeOD) δ 7.97 (br d, J = 8.7 Hz, 2H, H-17, H-21), 6.83 (br d, J = 8.7 Hz, 2H, H-18, H-20), 5.22 (br d, J = 2.5 Hz, 1H, H-10), 4.11-3.97 (m, 4H, H-5, H-12,H-1'), 3.81 (dd, J = 11.0, 4.5 Hz, 1H, H-1), 3.81 (s, 7-H), 3.62 (dd, J = 11.1, 4.6Hz, 1H, H-12), 2.54 (qd, J = 11.3, 5.7 Hz, 1H, H-3), 2.17-2.07 (m, 3H, H11, H-9), 2.01-1.91 (m, 2H, H-2, H-4), 1.86 (ddd, J = 14.5, 11.5, 3.1 Hz, 1H,H-4), 1.60-1.55 (m, 3H, H-2,H-2'), 1.39-1.32 (m, 2H,H-3'), 0.95 (t, J = 7.41 Hz, 3H, H-4'), 0.91 (t, J = 6.93 Hz, 3H, H-13).

[0046] Example 5: In vitro activity test against novel coronavirus (SARS-CoV-2) and vesicular stomatitis virus (VSV) 293T / ACE2 or Huh-7 cells were seeded into 24-well plates at a density of 10 per well. 4After overnight incubation, appropriate amounts of the novel coronavirus SARS-CoV-2 or vesicular stomatitis virus VSV-G were added, respectively, and the culture medium was replaced with a new culture medium containing different concentrations of the test sample after 12 hours of infection. After subculture for 3 days, the cells were lysed with 50 μL of lysis reagent (Promega) for 15 minutes. Then, the fluorescent enzyme activity was quantified by measuring the luminescence when adding the fluorescent enzyme measurement substrate (Promega, USA) using Kyodo HTX (Bio Tek, USA), and the half inhibitory concentration of the test sample was calculated, which was the novel coronavirus (SARS-CoV-2) (half effective dose IC50 485 nM, as shown in (a) of Figure 1) and vesicular stomatitis virus (IC50 1.72 μM, as shown in (b) of Figure 1), respectively.

[0047] Example 6: Study of the mechanism of action of endogenous type I interferon IFN-β to upregulate antiviral activity Our study found that PAC5 binds to a pocket near Asp49 in the RNA recognition motif 1 (RRM1) of hnRNPA2B1 (Fig. 2), activates hnRNPA2B1 protein, and enhances the phosphorylation of TBK1 and IRF3, thereby initiating the TBK1-IRF3 pathway, activating the type I IFN signaling pathway, and significantly increasing the production of IFN-β in virus-infected mice (Fig. 3).

[0048] Example 7: Preparation of PA-X1 tablets Mix 1000g of PA-X1 and 100g of pharmaceutical starch evenly, granulate with an appropriate amount of ethanol as a binder, dry, granulate with a granulator, and compress into tablets. 0.30g / tablet, orally administered, 1-2 tablets each time, twice a day.

[0049] Example 8: Preparation of PA-X1 Capsules Mix 1000g of PA-X1 and 100g of pharmaceutical starch evenly, granulate with an appropriate amount of ethanol as a binder, dry, granulate with a granulator, and put into 0# capsules. 0.30g / granule, orally administered, 1-2 capsules each time, twice a day.

[0050] Example 9: Preparation of PA-X1 Granules PA-X1 is granulated by a granulator and dispensed. It is orally administered, 5g each time, twice a day.

[0051] Example 10: Preparation of PA-X1 beverage PA-X1 100g, edible purified water 1000mL, sugar powder 500g, appropriate amount of stabilizer and flavoring agent are mixed uniformly and dispensed to obtain the product. Oral administration is 10mL each time, twice a day.

[0052] Example 11: Preparation of PA-X2 tablets Mix 1000g of PA-X2 and 100g of pharmaceutical starch evenly, granulate with an appropriate amount of ethanol as a binder, dry, granulate with a granulator, and compress into tablets. 0.30g / tablet, orally administered, 1-2 tablets each time, twice a day.

[0053] Example 12: Preparation of PA-X2 Capsules Mix 1000g of PA-X2 and 100g of pharmaceutical starch evenly, granulate with an appropriate amount of ethanol as a binder, dry, granulate with a granulator, and put into 0# capsules. 0.30g / granule, orally administered, 1-2 capsules each time, twice a day.

[0054] Example 13: Preparation of PA-X2 Granules PA-X2 is granulated by a granulator and dispensed. It is orally administered, 5g each time, twice a day.

[0055] Example 14: Preparation of PA-X2 beverage Mix 100g of PA-X2, 1000mL of purified water, 500g of sugar powder, and an appropriate amount of stabilizer and flavoring agent evenly and dispense to obtain the product. Oral administration: 10mL each time, twice a day.

Claims

1. A sesquiterpenoid derivative having a structure represented by the following structural formula I, II, III or IV: 【Chemistry 1】 (In Structural Formulas I to IV, each R1 is independently selected from the group consisting of hydrogen, benzoyl, p-hydroxybenzoyl, polyhydroxybenzoyl, p-methoxybenzoyl, polymethoxybenzoyl, and benzoyl substituted with fluorine, chlorine, or bromine.)

2. The sesquiterpenoid derivative according to claim 1, characterized in that it has a structure represented by structural formula I (wherein R1 is preferably a benzoyl group or a p-hydroxybenzoyl group).

3. 13. Use of the sesquiterpenoid derivative of claim 1 in the manufacture of a medicament for treating a viral infection.

4. The use according to claim 3, characterized in that the virus comprises a novel coronavirus, vesicular stomatitis virus (VSV-G), human immunodeficiency virus, hepatitis C virus, Japanese encephalitis virus, influenza virus, poliovirus, coxsackievirus, dengue virus, rotavirus, tobacco mosaic virus, measles virus, mumps virus, Ebola virus, Marburg virus, herpes virus, or adenovirus.

5. 4. The use according to claim 3, characterized in that the sesquiterpenoid derivative may be combined with a pharmaceutical carrier and / or an edible carrier.

6. The use according to claim 5, characterized in that the sesquiterpenoid derivative is contained in the pharmaceutical in a therapeutically effective amount.

7. The use according to claim 6, characterized in that the therapeutically effective amount is the amount of the sesquiterpenoid derivative capable of activating heterogeneous nuclear ribonucleoprotein A2 / B1 and upregulating endogenous type I interferon.

8. The pharmaceutical product is Oral dosage forms, including tablets, pills, capsules, granules, microcapsule tablets, suspensions, drop pills, or oral liquids; or 6. The use according to claim 5, characterized in that it is a parenteral administration preparation, including an injection, an aerosol, a suppository, or a subcutaneous administration preparation.

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