WO2021208711A1 - Application of tylophora alkaloid or salt thereof in resisting coronavirus - Google Patents

Abstract

The present invention relates to the field of pharmacy, and in particular, to application of tylophora alkaloid or salt thereof in resisting coronavirus. The tylophora alkaloid has the structure as shown in formula (1). The tylophora alkaloid or the salt thereof provided has an excellent coronavirus inhibition effect, and particularly shows high inhibition activity in the novel coronavirus 2019-nCoV inhibition test result.

Description

Application of waerten alkaloids or their salts in anti-coronavirus

Cross-references to related applications

This application claims the rights and interests of the Chinese patent application 202010304623.3 filed on April 17, 2020, the content of which is incorporated herein by reference.

Technical field

The invention relates to the field of pharmacy, in particular to the application of waertine alkaloids or their salts in anti-coronavirus.

Background technique

Coronavirus is a large virus family, known to cause colds and more serious diseases such as Middle East Respiratory Syndrome (MERS) and Severe Acute Respiratory Syndrome (SARS). The new coronavirus is a new strain of coronavirus that has never been found in the human body before. It was named 2019 new coronavirus (2019-nCoV) by the World Health Organization on January 12, 2020.

At present, there is no drug that can effectively prevent and treat the new coronavirus.

Summary of the invention

The purpose of the present invention is to provide a drug with high inhibitory activity of coronavirus, especially novel coronavirus.

In order to achieve the above-mentioned object, the present invention provides an application of a wolterine alkaloid or a salt thereof in the preparation of a drug for inhibiting the 2019-nCoV coronavirus, the wolterine alkaloid having a structure represented by formula (1);

Wherein, R ₁ -R ₈ are each independently selected from H, hydroxyl, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl and -COOR ₉ , and R ₉ is C1- C6 alkyl.

The valerian alkaloid or its salt provided by the present invention has an excellent coronavirus inhibitory effect, and the results of the new coronavirus 2019-nCoV inhibitory test show a higher inhibitory activity than the currently popular high-activity drug remdesivir.

Description of the drawings

Figure 1 shows the results of the novel coronavirus 2019-nCoV inhibition test.

Detailed ways

The endpoints and any values of the ranges disclosed herein are not limited to the precise range or value, and these ranges or values should be understood to include values close to these ranges or values. For numerical ranges, between the end values of each range, between the end values of each range and individual point values, and between individual point values can be combined with each other to obtain one or more new numerical ranges. These values The scope should be considered as specifically disclosed herein.

The present invention provides an application of a wolterine alkaloid or a salt thereof in the preparation of a drug for inhibiting the 2019-nCoV coronavirus, wherein the wolterine alkaloid has a structure represented by formula (1);

Wherein, R ₁ -R ₈ are each independently selected from H, hydroxyl, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl and -COOR ₉ , and R ₉ is C1- C6 alkyl.

In the present invention, the waertine alkaloid or its salt has been disclosed in the patent application before the present invention, but it is only used as a plant virus control agent (CN101875657A), a plant fungicide (CN105394058B), an anticancer agent ( CN102002041A) and anti-inflammatory drugs (CN101948470A). At the time of the new coronavirus epidemic, the inventor of the present invention unexpectedly found that the gorgon alkaloids or their salts also have good activity in inhibiting coronaviruses, and can be used as Coronavirus treatment drugs. For this reason, the dolvine alkaloid or salt thereof of the present invention can be prepared according to the method described in the above-mentioned published patent application. And related preparation methods are incorporated into the present invention, and the preparation methods of waerten alkaloids or their salts will not be repeated in the present invention.

According to the present invention, the wolteren alkaloids have an optically active center, that is, a chiral carbon site marked as "*". For this reason, the wolteren alkaloids or their salts of the present invention may have a single optical structure. The type may also be a combination of compounds with multiple optical configurations, and is preferably a compound with a single optical configuration. For this reason, preferably, the waertine alkaloid or salt thereof has an R-optical isomer structure represented by formula (1) or an S-optical isomer structure represented by formula (1).

According to the present invention, in order to obtain a drug having a more excellent inhibitory effect on the coronavirus, preferably, R ₁ -R ₈ are each independently selected from H, hydroxyl, halogen, C1-C4 alkyl, C1-C4 alkoxy , C1-C4 hydroxyalkyl and -COOR ₉ , R ₉ is C1-C4 alkyl.

More preferably, R ₁ -R ₈ are each independently selected from H, hydroxyl, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, n-butyl, methoxy, ethoxy Group, n-propoxy, isopropoxy, n-butoxy, hydroxymethyl, hydroxyethyl, 3-hydroxypropyl, 4-hydroxybutyl, -COOCH ₃ , -COOCH ₂ CH ₃ , -COOCH ₂ CH ₂ CH ₃ and -COOCH ₂ CH ₂ CH ₂ CH ₃ .

More preferably, R ₁ , R ₄ , R ₅ and R ₈ are H, and R ₂ -R ₃ and R ₆ -R ₇ are each independently selected from methyl, ethyl, n-propyl, isopropyl, n-propyl Butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, hydroxymethyl, hydroxyethyl, 3-hydroxypropyl, 4-hydroxybutyl, -COOCH ₃ , -COOCH ₂ CH ₃ , -COOCH ₂ CH ₂ CH ₃ and -COOCH ₂ CH ₂ CH ₂ CH ₃ .

According to the present invention, although the salt of the wolteren alkaloid of the present invention can have various salt forms in the art, it may be a salt formed by an organic acid and a wolterine alkaloid, or an inorganic acid and a wolterine alkaloid. Salts formed by bases.

Preferably, the salt of the valerian alkaloid is a compound represented by formula (2);

Among them, HX is halogen acid, organic carboxylic acid or organic sulfonic acid.

More preferably, the HX is HF, HCl, HBr, n-propionic acid, n-butyric acid, malonic acid, oxalic acid, adipic acid, camphorsulfonic acid, trans-ferulic acid, salicylic acid, malic acid, amber Acid, p-hydroxybenzoic acid, lactic acid, caffeic acid, chlorogenic acid, p-aminobenzenesulfonic acid, 5-sulfosalicylic acid, fumaric acid, gluconic acid, itaconic acid or sorbic acid, more preferably malic acid. The HX may also have optical activity, and for this reason, the salt of the wolterine alkaloid may have a variety of configurations:

For example, when the waerten alkaloid is in the R-configuration, HX is in the R-configuration, forming an R, R-optical isomer with the salt of the waerten alkaloid;

When the waerten alkaloid is in the R-configuration, HX is in the S-configuration, forming an R, S-optical isomer with the salt of the waerten alkaloid;

When the waerten alkaloid is in the S-configuration, HX is in the R-configuration, forming an S,R-optical isomer with the salt of the waerten alkaloid;

When the waerten alkaloid is in the S-configuration, HX is in the S-configuration, forming an S, S-optical isomer having the salt of the waerten alkaloid.

The valerian alkaloid salt may be a mixture of the above-mentioned optical isomers, or a single optical isomer, preferably an optical isomer with a certain optical purity.

In a preferred embodiment of the present invention, the valerian alkaloid or salt thereof is selected from one or more of the compounds shown in the following formula;

The waertine alkaloids or salts thereof of the present invention have high inhibitory activity against coronavirus 2019-nCoV and possible 2019-nCoV coronavirus variants in the future.

When the valerian alkaloid or its salt of the present invention is used as a 2019-nCoV coronavirus inhibitory drug, it can be provided as a pure compound, can also be compounded with other antiviral drugs, or prepared into pills, capsules, tablets or injections, etc. Dosage form. In this regard, the present invention is not particularly limited.

Hereinafter, the present invention will be described in detail through examples.

Preparation Example 1

This preparation example is used to illustrate the preparation of the compound represented by formula (S, R-2-1).

The compound represented by formula (S, R-2-1) is prepared according to the above reaction process.

(1) Preparation of compound 2

Under the protection of N _{2 , add 1.14 g (0.03 mol) NaBH 4 in} batches to 150 mL of freshly evaporated anhydrous THF at room temperature, add 6.84 g (0.02 mol) of raw material 1 (purchased from Bailingwei Technology Co., Ltd.) under stirring, and stir for 10 Min, 6.99 g (0.03 mol) of zirconium tetrachloride was slowly added, and the mixture was stirred at room temperature for 10 hours. TLC detected that the raw material had reacted completely. Under ice-water bath cooling, add dropwise 10mL water and 10mL dilute hydrochloric acid to fully decompose the excess NaBH ₄ , after desolventization, _{dilute with 250mL CH 2} Cl ₂ and 50mL water, stir and separate the liquid, wash the organic phase with water, wash with saturated brine, and anhydrous MgSO ₄ After drying and desolventizing, 6.46 g of a white solid product was obtained, namely compound 2, with a yield of 95%. Melting point: 181-183°C; ¹ H NMR (CDCl ₃ , 400MHz) δ 7.81 (s, 1H), 7.75 (s, 1H), 7.56 (s, 1H), 7.54 (s, 1H), 7.18 (s, 1H) ), 5.11(s, 2H), 4.13(s, 3H), 4.12(s, 3H), 4.06(s, 3H), 4.02(s, 3H).

(2) Preparation of compound 3

Compound 2 (14.1g, 43.0mmol) and dry CH ₂ Cl ₂ (300mL) were mixed, and PBr ₃ (6.1mL, 17.5g, 64.6mmol) of CH ₂ Cl ₂ (60mL) was slowly added dropwise at 0°C ) The solution was naturally warmed to room temperature and reacted for 6 hours. Under cooling in an ice water bath, ice water (100 mL) was slowly added dropwise to separate the liquids. The aqueous phase was extracted with CH ₂ Cl ₂ (3×50 mL), and the organic phases were combined. The organic phase was washed successively with water and saturated brine, dried over anhydrous Na ₂ SO ₄ and dissolved under reduced pressure to obtain a white solid 2,3,6,7-tetramethoxy-9-phenanthrenemethyl bromide, which was directly used in the next reaction .

Mix 2,3,6,7-tetramethoxy-9-phenanthrenemethyl bromide, L-glutamate dimethyl hydrochloride solid (BMPAC, 13.66g, 64.5mmol) and treated DMF (450mL) After stirring and dissolving, add finely ground anhydrous K ₂ CO ₃ powder (8.91 g, 64.5 mmol) at one time, and the mixture is stirred overnight at room temperature. DMF was distilled off under reduced pressure, CH ₂ Cl ₂ and H ₂ O were added to separate the liquids, the organic phase was dried with anhydrous Na ₂ SO ₄ , and the N-alkylated product obtained by desolvation was directly used for the next reaction without purification.

The product obtained in the previous step was dissolved in CH ₃ OH (300 mL) and AcOH (180 mL), and reacted overnight at room temperature. After removing most of the solvent under reduced pressure _{, 200 mL of CH 2} Cl ₂ and H ₂ O were added to dilute, and the liquids were separated, and the organic phase was dried over anhydrous Na ₂ SO ₄ . After filtering and removing the solvent, the ring-closure product compound 3 is obtained. The three-step yield is 57%. Melting point: 236-238°C; ¹ H NMR (CDCl ₃ , 400MHz) δ 7.80 (s, 1H), 7.77 (s, 1H), 7.62 (s, 1H), 7.41 (s, 1H), 7.17 (s, 1H) ), 5.50(d, ² J _HH = 14.4Hz, 1H), 4.40(d, ² J _HH = 14.4Hz, 1H), 4.12(s, 6H), 4.03(s, 6H), 3.84-3.87(m, 1H), 3.58 (s, 3H), 2.53-2.66 (m, 1H), 2.33-2.46 (m, 1H), 1.92-2.19 (m, 2H); HRMS (ESI) m/z calcd.for C ₂₅ H ₂₇ NO ₇ Na(M+Na) ⁺ 476.1680, found 476.1680.

(3) Preparation of compound 4

1.81 g (4.0 mmol) of compound 3, 50 mL of dioxane, 40 mL of methanol and 30 mL of 2N KOH aqueous solution were sequentially added at room temperature, and the mixture was stirred and reacted at room temperature for 3 hours. Desolubilize, dilute with 100mL of water, separate the liquids, extract the aqueous phase with ether (3×30mL), acidify the aqueous phase with dilute hydrochloric acid under cooling and stirring to pH≈1, precipitate a large amount of white solid, collect the solid product compound 4 by filtration, the yield is 97 %. Melting point is greater than 300°C; ¹ H NMR (400MHz, DMSO-d ₆ ) δ 7.99 (s, 1H), 7.95 (s, 1H), 7.45 (s, 1H), 7.42 (s, 1H), 7.33 (s, 1H), 5.38(d, J=14.8Hz, 1H), 4.16(d, J=14.8Hz, 1H), 3.98(s, 6H), 3.86(s, 3H), 3.82(s, 3H), 3.64( dd, J ₁ =9.6Hz, J ₂ =3.2Hz, 1H), 2.39-2.30 (m, 2H), 2.16-2.07 (m, 1H), 1.89-1.84 (m, 1H); ¹³ C NMR (100MHz, DMSO-d ₆ )δ174.2, 173.2, 149.3, 148.9, 148.7, 148.6, 126.9, 125.7, 125.2, 124.6, 124.3, 124.1, 108.4, 104.8, 104.2, 103.7, 57.9, 55.9, 55.8, 55.4, 55.4, 43.6 , 29.2, 22.3.

(4) Preparation of compound 5

Add 0.27 g (0.9 mmol) of solid phosgene (BTC), 20 mL of anhydrous CH ₂ Cl ₂ (DCM) in a N ₂ atmosphere, and slowly drop 1.1 g (2.5 mmol) of the compound 4 obtained above and 0.28 g (2.8 mmol) in 100mL of anhydrous CH ₂ Cl ₂ solution, the mixture was stirred at room temperature for 2 hours and heated at reflux for 8h, and slowly added dropwise under reflux 1.25mL (5.2 mmol) of anhydrous SnCl 20mL CH ₂ Cl ₂ solution of ₄ dropwise. , Continue the reflux reaction for 6h. Cool, slowly add 15 mL of 1N hydrochloric acid, stir, and separate the layers. The organic phase is washed with water and saturated brine, dried with anhydrous Na ₂ SO ₄ , desolvated and subjected to rapid decompression column chromatography to obtain a bright yellow solid, namely compound 5. , Yield 96%, melting point 224-227°C; ¹ H NMR (400MHz, CDCl ₃ ) δ 9.09 (s, 1H), 7.77 (s, 1H), 7.75 (s, 1H), 7.27 (s, 1H) , 5.71(d, J=18.0 Hz, 1H), 4.68(d, J=18.0Hz, 1H), 4.44-4.40(m, 1H), 4.16(s, 3H), 4.12(s, 3H), 4.09( s, 3H), 4.08 (s, 3H), 2.64-2.56 (m, 4H); ¹³ C NMR (100MHz, CDCl ₃ ) δ 195.6, 174.0, 151.8, 149.8, 149.2, 149.0, 137.2, 127.9, 124.5, 123.2, 121.8, 121.5, 107.6, 104.1, 102.9, 102.4, 61.0, 56.1, 56.0, 55.9, 55.8, 40.7, 30.1, 20.8.

(5) Preparation of compound 6

Compound 5 (1.78 g, 4.23 mmol) was dissolved in absolute ethanol (100 mL), NaBH ₄ (0.32 g, 8.45 mmol) was added, and the mixture was stirred at room temperature for 4 hours. TLC detected the complete disappearance of the raw material reaction. After partial desolvation, H ₂ O (50 mL) and CH ₂ Cl ₂ (100 mL) were added to dilute, and the reaction was quenched with ice water under stirring and ice bath, and the liquids were separated. The aqueous phase was washed with water and saturated brine successively, and anhydrous The solid product obtained by drying with Na ₂ SO ₄ and desolving under reduced pressure is directly used in the next reaction without purification.

The product obtained in the previous step was dissolved in CH ₂ Cl ₂ (40 mL), and trifluoroacetic acid (20 mL) and triethylsilane (4 mL) were sequentially added with stirring. The mixture was heated and refluxed for 1 h, and the plate reaction was complete. Add CH ₂ Cl ₂ (80 mL) and water (50 mL) to dilute, stir and separate the liquids, and then wash the organic phase with water and saturated brine, dry with anhydrous Na ₂ SO ₄ , and desolvate under reduced pressure to obtain a pale yellow solid product, that is Compound 6 (1.71g, yield 95%); melting point: 238-240°C; ¹ H NMR (400MHz CDCl ₃ ), δ 7.84 (s, 1H), 7.83 (s, 1H), 7.27 (s, 1H) , 7.14(s, 1H), 5.32(d, J=18.0Hz, 1H), 4.59(d, J=18.0Hz, 1H), 4.14(s, 3H), 4.13(s, 3H), 4.07(s, 3H), 4.05 (s, 3H), 4.00-3.96 (m, 1H), 3.51 (dd, J ₁ = 16.0 Hz, J ₂ = 4.0 Hz, 1H), 2.91-2.84 (m, 1H), 2.71-2.67 (m, 2H), 2.63-2.54 (m, 1H), 2.09-1.96 (m, 1H); ¹³ C NMR (100MHz, CDCl ₃ ) δ 174.1, 148.0, 147.84, 147.81, 123.8, 123.1, 122.9, 122.44, 122.32, 121.1, 102.7, 102.42, 102.31, 101.6, 55.05, 55.00, 54.95, 54.88, 52.6, 40.3, 32.3, 29.1, 24.2.

(6) Preparation of compound 7

Add 0.08 g (2 mmol) of NaBH ₄ and 0.41 g (1 mmol) of compound 6 to 50 mL of anhydrous THF at room temperature under N ₂ protection. The mixture is stirred for 10 min, and 0.23 g (1 mmol) of zirconium tetrachloride is slowly added. The reaction is stirred at room temperature for 24 h. TLC detects that the raw material reaction is complete. Cool with ice water, decompose with 20 mL of water, add 50 mL of CH ₂ Cl _{2 and} stir, filter with diatomaceous earth, _{wash with CH 2} Cl ₂ and separate. The organic phase is washed with saturated brine, dried with anhydrous Na ₂ SO ₄ , and removed. A light yellow solid product compound 7 was dissolved with a yield of 93% and an ee value of 99% as tested by chiral HPLC (test conditions: AD-H column, mobile phase ratio: n-hexane: isopropanol = 75: 25, plus 0.1% Et ₃ N, UV absorption wavelength 254nm, flow rate: 1.0mL/min); melting point 272°C dec; ¹ H NMR (300MHz, CDCl ₃ ) δ 7.83(s, 1H), 7.82(s, 1H), 7.31(s , 1H), 7.15 (s, 1H), 4.63 (d, J = 14.4 Hz, 1H), 4.12 (s, 6H), 4.06 (s, 3H), 4.05 (s, 3H), 3.67 (d, J = 14.4Hz, 1H), 3.50-3.46(m, 1H), 3.39-3.34(m, 1H), 2.94-2.89(m, 1H), 2.52-2.46(m, 2H), 2.29-2.21(m, 1H) , 2.08-2.01 (m, 1H), 1.95-1.90 (m, 1H), 1.81-1.74 (m, 1H); ¹³ C NMR (100MHz, CDCl ₃ ) δ 148.7, 148.5, 148.4, 126.3, 125.9, 124.4 , 123.6, 123.4, 104.0, 103.5, 103.3, 103.1, 60.2, 56.1, 55.93, 55.89, 55.2, 54.0, 33.8, 31.3, 21.7.

(7) Compound represented by formula (S, R-2-1)

_{Add 50 mL CH 2} Cl ₂ and 50 mL CH ₃ OH to 1.0 mmol D-malic acid respectively. At room temperature, slowly add 1.0 mmol compound 7 in 50 mL CH ₂ Cl ₂ solution, after dripping, continue to stir and react for 8 hours, and filter to obtain the compound Compound represented by formula (S, R-2-1), yield 97%; melting point: 245-247°C; ¹ H NMR (400MHz, DMSO-d ₆ ) 8.10 (s, 2H), 7.41 (s, 1H) , 7.26 (s, 1H), 4.85 (d, J = 14.8 Hz, 1H), 4.20-4.16 (m, 1H), 4.10 (s, 6H), 4.00 (s, 6H), 3.59-3.55 (m, 2H) ), 3.03-2.60 (m, 5H), 2.48-2.43 (m, 1H), 2.39-2.33 (m, 1H), 2.06-1.99 (m, 2H), 1.86-1.78 (m, 1H).

Example 1

In the following, the inhibitory effect of the compound represented by formula (S, R-2-1) on the new coronavirus 2019-nCoV will be evaluated through multiple concentration gradient experiments at the cellular level.

(1) Dilute the new coronavirus 2019-nCoV (from virus isolation) with DMEM so that the titer of the new coronavirus 2019-nCoV is 100TCID ₅₀ /100μL maintenance solution. DMEM (Gibco) medium was added with 2% serum (Gibco) and double antibodies (penicillin and streptomycin) to prepare a maintenance solution.

(2) Dilute the compound represented by formula (S, R-2-1) (10mM) with a 10-fold gradient to different concentrations (5μM, 0.5μM, 0.05μM, 0.005μM, 0.0005μM, 0.00005μM) with maintenance solution The solution to be tested, each concentration volume is 900μL; Remedsivir (Remedsivir, purchased from Gilead Sciences) is gradually diluted to different concentrations (100μM, 20μM, 4μM, 0.8μM, 0.16μM, 0.032μM) solution to be tested, each concentration volume is 800μL; at the same time, 0μM compound represented by formula (S, R-2-1) is set as the negative control group, and the blank control of the no-drug group.

(3) Inoculate Vero cells (ATCC, CCL81) in a 96-well plate and _{incubate overnight in a 37°C, 5% CO 2} incubator. When it grows to 90%-100% density, discard the culture supernatant. Wash with PBS twice.

(4) Take the 96-well plate of step (3), add the system configured in step (1) to the well, place it in a 37°C, 5% CO ₂ incubator and incubate for 2 hours, wash it with DMEM once, discard it, and Step (2) The configured system is added to the well, and it is placed in a 37°C, 5% CO ₂ incubator and incubated for 48 hours.

(5) Take the 96-well plate of step (4), draw 100 μL/well of the culture supernatant, and transfer it to the matching extraction plate of the automatic nucleic acid extractor of Tianlong Biotechnology Co., Ltd., and perform nucleic acid extraction according to the kit instructions. Take 5 μL of nucleic acid for RT-PCR system preparation (TaKaRa) and qRT-PCR experiment (target is ORF1ab, Roche 480).

(6) The data is processed with graphpad, and the EC ₅₀ (half of the maximum effect concentration, that is, the concentration of the test substance at which 50% of the maximum effect can be caused in the efficacy experiment) of the inhibitor is calculated, and the results are shown in Figure 1 and Table 1.

Table 1

Inhibitor	EC 50 /μM
Formula (S, R-2-1)	0.03
Remdesivir	0.75

It can be seen that the wolteren alkaloid or its salt of the present invention has an excellent 2019-nCoV coronavirus inhibitory effect. In the new coronavirus 2019-nCoV inhibition test, the wolteren alkaloid or its salt of the present invention has the largest half The effect concentration EC ₅₀ is only 4% of Radixivir, and the activity is more than 20 times higher than Radixivir.

The preferred embodiments of the present invention are described in detail above, but the present invention is not limited thereto. Within the scope of the technical concept of the present invention, a variety of simple modifications can be made to the technical solution of the present invention, including the combination of various technical features in any other suitable manner. These simple modifications and combinations should also be regarded as the disclosed content of the present invention. All belong to the protection scope of the present invention.

Claims (9)

1. An application of a waerten alkaloid or a salt thereof in the preparation of a drug for inhibiting coronavirus 2019-nCoV, the waerten alkaloid having a structure represented by formula (1);

   

   Wherein, R ₁ -R ₈ are each independently selected from H, hydroxyl, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl and -COOR ₉ , and R ₉ is C1- C6 alkyl.
2. The application according to claim 1, wherein R _1- R ₈ are each independently selected from H, hydroxyl, halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 hydroxyalkyl and -COOR ₉ , R ₉ is a C1-C4 alkyl group.
3. The application according to claim 2, wherein R ₁ -R ₈ are each independently selected from H, hydroxyl, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, n-butyl , Methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, hydroxymethyl, hydroxyethyl, 3-hydroxypropyl, 4-hydroxybutyl, -COOCH ₃ , -COOCH ₂ CH ₃ , -COOCH ₂ CH ₂ CH ₃ and -COOCH ₂ CH ₂ CH ₂ CH ₃ .
4. The application according to claim 3, wherein R ₁ , R ₄ , R ₅ and R ₈ are H, and R ₂ -R ₃ and R ₆ -R ₇ are each independently selected from methyl, ethyl, n-propyl , Isopropyl, n-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, hydroxymethyl, hydroxyethyl, 3-hydroxypropyl, 4-hydroxybutan Groups, -COOCH ₃ , -COOCH ₂ CH ₃ , -COOCH ₂ CH ₂ CH ₃ and -COOCH ₂ CH ₂ CH ₂ CH ₃ .
5. The use according to any one of claims 1-4, wherein the salt of the waertine alkaloid is a compound represented by formula (2);

   

   Among them, HX is halogen acid, organic carboxylic acid or organic sulfonic acid.
6. The application according to claim 5, wherein HX is HF, HCl, HBr, n-propionic acid, n-butyric acid, malonic acid, oxalic acid, adipic acid, camphorsulfonic acid, trans ferulic acid, salicylic acid , Malic acid, succinic acid, p-hydroxybenzoic acid, lactic acid, caffeic acid, chlorogenic acid, p-aminobenzenesulfonic acid, 5-sulfosalicylic acid, fumaric acid, gluconic acid, itaconic acid or sorbic acid.
7. The use according to claim 6, wherein HX is malic acid.
8. The application according to any one of claims 1 to 4, wherein the waertine alkaloid or its salt has an R-optical isomer structure represented by formula (1) or a structure represented by formula (1) S-optical isomer structure.
9. The use according to any one of claims 1-8, wherein the waertine alkaloid or salt thereof is selected from one or more of the compounds shown in the following formula;

   

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