Application of glycosyl polyether compound in prevention and / or treatment of porcine reproductive and respiratory syndrome virus

Abstract

The invention provides medical application of a glycosyl polyether compound or a tautomer, a meracemate, a raceme, an enantiomer, a diastereoisomer or a mixture form of the glycosyl polyether compound, a deuterated isotope derivative, a pharmaceutically acceptable hydrate, a solvate, a salt or a co-crystal of the glycosyl polyether compound in prevention and treatment of porcine reproductive and respiratory syndrome.

Description

Technical Field

[0001] The present invention relates to the fields of virology, oncology and molecular biology, and particularly relates to glycosyl polyether compounds targeting actin and their application in the preparation of drugs for preventing and / or treating African swine fever virus. Background Art

[0002] African swine fever (ASF) is an acute and highly contagious disease caused by African swine fever virus (ASFV), with a fatality rate of up to 100%. It is a complex virus with high variability, and its structure consists of a nucleic acid core and multiple proteins, including enzymes required for virus replication.

[0003] Currently, there are mainly two methods for treating African swine fever virus clinically: traditional Chinese medicine and Western medicine. Traditional Chinese medicine mainly uses prescriptions such as clearing heat and detoxifying, cooling blood and stopping bleeding, etc., to improve the body's immunity by adjusting the internal environment of the body, thereby fighting the virus. Western medicine mainly uses antibiotics, antipyretics and analgesics, etc., to relieve symptoms, reduce the illness and lower the mortality rate. However, these drugs can only relieve the illness to a certain extent and cannot solve the fundamental problem. Currently, the vaccines against African swine fever virus on the market mainly include inactivated vaccines and gene vaccines. Research shows that the significance of these two vaccines in preventing and controlling the spread of African swine fever virus is not great. Currently, the main prevention and control measures are still comprehensive prevention and control measures mainly based on prevention. Once infected, pigs will be immediately blocked, isolated and culled, which not only causes heavy economic losses to farmers and even the entire pig industry, but also cannot meet the large-scale development of China's pig industry and threatens China's pork supply.

[0004] In the breeding industry, pigs infected with African swine fever virus may be simultaneously infected with porcine reproductive and respiratory syndrome (PRRS), which is an infectious disease caused by porcine reproductive and respiratory syndrome virus (PRRSV), and can cause symptoms such as fever, anorexia in pigs, and late abortion, premature birth, stillbirth, weak fetus and mummified fetus in pregnant sows. In addition, porcine reproductive and respiratory syndrome virus mainly exists in the noses and eyes of diseased pigs. Its transmission mainly occurs through the environment contaminated by the droplets and feces and urine of diseased pigs. It can also be transmitted through contact between pigs, and even through the air. Due to the wide range of transmission routes of porcine reproductive and respiratory syndrome virus and the large differences in antigenicity and pathogenicity of its variant strains, it is difficult to prevent and control porcine reproductive and respiratory syndrome, and drugs against porcine reproductive and respiratory syndrome virus need to be developed. Summary of the Invention

[0005] To solve the above problems, the present invention provides the use of polyether compounds in the preparation of drugs for preventing and / or treating porcine reproductive and respiratory syndrome (PRRS). Through experiments, the present invention has found that polyether compounds have good efficacy and a high safety concentration, and can inhibit the replication of PRRS virus genes, protein expression, and the production of virus particles.

[0006] Specifically, the present invention provides the use of a glycosyl polyether compound or its tautomer, mesomer, racemate, enantiomer, diastereomer, or a mixture thereof, isotope derivative, pharmaceutically acceptable hydrate, solvate, salt, or cocrystal in the preparation of drugs for preventing and / or treating PRRS virus. The glycosyl polyether compound has the structure shown by the following formula:

[0007]

[0008] Wherein,

[0009] R 11 、R 12 、R 13 、R 14 、R 16 、R 17 、R 18 、R 19 are each independently selected from hydrogen, -OH, C 1-3 alkyl, C 1-3 alkoxy, -O-C(O)-CH2-R,

[0010] R 15 is selected from C 1-3 alkyl or -CHR’-C(O)OH;

[0011] R 16a is selected from C 1-3 alkyl or C 1-3 alkoxy;

[0012] R 16b 、R 16c are each independently selected from hydrogen, C 1-3 alkyl, C 1-3 alkoxy,

[0013] R 12a 、R 12b 、R 14a 、R 14b 、R 17a 、R 18a 、R L are each independently selected from hydrogen or C 1-3 alkyl;

[0014] R 20 is selected from C1-3 An alkyl- or hydroxy-substituted C 1-3 alkyl;

[0015] R is selected from amino, C 1-3 alkyl, C 3-6 cycloalkyl, halogen, azido or C 5-6 aryl, said C 1-3 alkyl, C 3-6 cycloalkyl is optionally substituted by 1-4 halogen atoms, and said C 5-6 aryl is optionally substituted by 1-4 halogen atoms or C 1-3 alkyl;

[0016] R' is selected from hydrogen or C 1-3 alkyl;

[0017] R 21 、R 22 、R 23 、R 24 、R 25 、R 25a 、R 25b 、R 26 、R 27 each independently is selected from hydrogen, C 1-3 alkyl, halo C 1-3 alkyl, -OH, -C 1-3 alkyl-OH,

[0018] Y is selected from

[0019] R 30a is selected from hydrogen, C 1-3 alkyl or -CR 31 R 32 ;

[0020] R 28 、R 29 、R 30 、R 31 、R 32 、R 33 、R 34 、R 35 、R 36 each independently is selected from hydrogen, C 1-3 alkyl, C 1-3 alkoxy, halo C 1-3 alkyl, -OH, -C 1-3 alkyl-OH,

[0021] In one example, R 11 is selected from hydrogen, -OH, C 1-3 alkyl, C 1-3Alkoxy, -O-C(O)-CH2-R,

[0022] In one instance, R 11 is selected from -OH, C 1-3 The alkoxy -O-C(O)-CH2-R can further be -OH, methoxy or -O-C(O)-CH2-N3.

[0023] In one instance, R 12 is selected from hydrogen, -OH, C 1-3 alkyl, C 1-3 alkoxy, -O-C(O)-CH2-R,

[0024] In one instance, when the " 12 " between R 12b and R is a single bond, R 12 is selected from -OH, C 1-3 alkoxy or -O-C(O)-CH2-R, and can further be -OH, methoxy or -O-C(O)-CH2-Cl.

[0025] In one instance, when the " 12 " between R 12b and R is a double bond, both R 12 and R 12b are hydrogen.

[0026] In one instance, R 13 is selected from hydrogen, -OH, C 1-3 alkyl, C 1-3 alkoxy, -O-C(O)-CH2-R,

[0027] In one instance, R 13 is selected from -OH, C 1-3 alkoxy or -O-C(O)-CH2-R, and can further be -OH, methoxy or -O-C(O)-CH2-N3.

[0028] In one instance, R 14 is selected from hydrogen, -OH, C 1-3 alkyl, C 1-3 alkoxy, -O-C(O)-CH2-R,

[0029] In one instance, R 14 is selected from hydrogen, C1-3 an alkoxy group or may further be further selected from hydrogen, a methoxy group or

[0030] In one instance, R 16 is selected from hydrogen, -OH, C 1-3 alkyl, C 1-3 alkoxy, -O-C(O)-CH2-R,

[0031] In one instance, R 16 is selected from hydrogen, -OH, C 1-3 alkoxy, and is further selected from hydrogen, -OH, a methoxy group,

[0032] In one instance, R 17 is selected from hydrogen, -OH, C 1-3 alkyl, C 1-3 alkoxy, -O-C(O)-CH2-R, and is further selected from hydrogen or

[0033] In one instance, R 18 is selected from hydrogen, -OH, C 1-3 alkyl, C 1-3 alkoxy, -O-C(O)-CH2-R, and is further selected from hydrogen,

[0034] In one instance, R 19 is selected from hydrogen, -OH, C 1-3 alkyl, C 1-3 alkoxy, -O-C(O)-CH2-R,

[0035] In one instance, R 19 is selected from hydrogen, C 1-3 alkoxy, and is further selected from hydrogen, a methoxy group,

[0036] In one instance, R 11 , R 12 , R 13 , R 14 , R 16 , R 17, R 18 , R 19 At least 1, 2, or 3 of them are selected from

[0037] In one instance, R 11 , R 12 , R 13 are not simultaneously -OH. Preferably, at most 2 of R 11 , R 12 , R 13 are -OH; preferably, exactly 2 of R 11 , R 12 , R 13 are -OH.

[0038] In one instance, R is selected from amino, methyl, cyclopropyl, chlorine, azide, phenyl, or tolyl.

[0039] In one instance, R 11 , R 12 , R 13 , R 14 , R 16 , R 17 , R 18 , R 19 are each independently selected from hydrogen, -OH, methyl, methoxy, -O-C(O)-CH2-N3,

[0040] In one instance, R 12a , R 12b , R 14a , R 14b , R 17a , R 18a , R L are each independently selected from hydrogen or methyl.

[0041] In one instance, R 15 is selected from methyl, -CH-C(O)OH, or -CH(CH3)-C(O)OH.

[0042] In one instance, R 16a is selected from methyl or ethoxy.

[0043] In one instance, R 16b , R 16c are each independently selected from hydrogen, methyl, methoxy, and are further selected from hydrogen, methyl, methoxy, or

[0044] In one instance, R 16cSelected from hydrogen, methyl, methoxy,

[0045] In one instance, R 16b Selected from hydrogen, methyl, methoxy,

[0046] In one instance, R 20 Selected from methyl or -CH2-OH.

[0047] In one instance, is

[0048] In one instance, is

[0049] In one instance, is

[0050] In one instance, is

[0051] The present disclosure also provides the use of a glycosyl polyether compound or its tautomer, mesomer, racemate, enantiomer, diastereomer or a mixture thereof, isotope derivative, pharmaceutically acceptable hydrate, solvate, salt or co-crystal in the preparation of a drug for preventing and / or treating porcine reproductive and respiratory syndrome, wherein the glycosyl polyether compound has the structure shown by the following formula:

[0052]

[0053] Wherein, R 11 , R 12 , R 13 are selected from hydrogen or -C(O)-CH2-R;

[0054] R is selected from amino, C 1-3 alkyl, C 3-6 cycloalkyl, halogen, azide or C 5-6 aryl, the C 1-3 alkyl, C 3-6 cycloalkyl is optionally substituted with 1-4 halogen atoms, and the C 5-6 aryl is optionally substituted with 1-4 halogen atoms or C 1-3 alkyl.

[0055] In one instance, in the aforementioned formula (I), R is selected from amino, methyl, cyclopropyl, chlorine, azide, phenyl or tolyl.

[0056] In one instance, in the aforementioned formula (I), R11 and R 12 and R 13 are not simultaneously hydrogen.

[0057] In one instance, in the aforementioned formula (I), R 11 and R 12 and R 13 at most 2 are hydrogen.

[0058] In one instance, in the aforementioned formula (I), R 11 and R 12 and R 13 there are exactly 2 hydrogens.

[0059] The present invention also provides the use of a glycosyl polyether compound or its tautomer, mesomer, racemate, enantiomer, diastereomer or a mixture thereof, isotope derivative, pharmaceutically acceptable hydrate, solvate, salt or co-crystal in the preparation of a drug for preventing and / or treating porcine reproductive and respiratory syndrome (PRRS), wherein the glycosyl polyether compound has the structure shown by the following formula:

[0060]

[0061] Wherein,

[0062] R 21 and R 22 and R 23 and R 24 and R 25 and R 26 and R 27 are selected from hydrogen, C 1-3 alkyl, halogenated C 1-3 alkyl, -OH, -C 1-3 alkyl-OH,

[0063]

[0064] In one instance, in the aforementioned formula (II) or formula (II-1), R 21 and R 22 and R 23 and R 24 and R 25 and R 26 and R 27 are selected from hydrogen, methyl, -OH,

[0065] In one instance, in the aforementioned formula (II) or formula (II-1), R 21 and R 23 are each independently selected from hydrogen or methyl.

[0066] In one instance, in the foregoing formula (II) or formula (II-1), R 21 and R 23 are each independently selected from hydrogen or methyl and R 21 and R 23 are not both methyl at the same time.

[0067] In one instance, in the foregoing formula (II) or formula (II-1), R 21 and R 23 are each independently selected from hydrogen or methyl and one of R 21 and R 23 is methyl and the other is not.

[0068] In one instance, in the foregoing formula (II) or formula (II-1), R 22 is selected from hydroxy,

[0069] In one instance, in the foregoing formula (II) or formula (II-1), R 22 is selected from hydroxy,

[0070] In one instance, in the foregoing formula (II) or formula (II-1), R 24 is selected from hydroxy,

[0071] In one instance, in the foregoing formula (II) or formula (II-1), R 24 is selected from hydrogen, hydroxy,

[0072] In one instance, in the foregoing formula (II) or formula (II-1), R 25 and R 26 are each independently selected from hydrogen,

[0073] In one instance, in the foregoing formula (II) or formula (II-1), R 25 and R 26 are each independently selected from hydrogen,

[0074] In one instance, in the foregoing formula (II) or formula (II-1), R 25 and R 26 are each independently selected from hydrogen, and R 25 and R 26 are not both

[0075] In one instance, in the foregoing formula (II), R25a , R 25b are each independently selected from hydrogen or methyl.

[0076] In one example, in the foregoing formula (II) or formula (II-1), R 27 is selected from -C 1-3 alkyl or -C 1-3 alkyl-OH.

[0077] In one example, in the foregoing formula (II) or formula (II-1), R 27 is selected from methyl or -CH2-OH.

[0078] The present invention also provides an application of a glycosyl polyether compound or a tautomer, mesomer, racemate, enantiomer, diastereomer or a mixture thereof, an isotope derivative, a pharmaceutically acceptable hydrate, solvate, salt or co-crystal thereof in the preparation of a drug for preventing and / or treating porcine reproductive and respiratory syndrome. The glycosyl polyether compound has a structure represented by the following formula:

[0079]

[0080] Wherein,

[0081] Y is selected from

[0082] R 28 , R 29 , R 30 , R 31 , R 32 , R 33 , R 34 , R 35 , R 36 are each independently selected from hydrogen, C 1-3 alkyl, C 1-3 alkoxy, halo C 1-3 alkyl, -OH, -C 1-3 alkyl-OH,

[0083] In one example, in the foregoing formula (III) or formula (III-1), R 28 is selected from hydrogen, C 1-3 alkyl, C 1-3 alkoxy, halo C 1-3 alkyl, -OH, -C 1-3 alkyl-OH, is further selected from hydrogen, C 1-3 alkoxy or

[0084] In one example, in the foregoing formula (III) or formula (III-1), R 29Selected from hydrogen, C 1-3 alkyl, C 1-3 alkoxy, halo C 1-3 alkyl, -OH, -C 1-3 alkyl-OH, further selected from -OH or C 1-3 alkoxy, and even further selected from -OH or methoxy.

[0085] In one instance, in the foregoing formula (III) or formula (III-1), R 30 is selected from hydrogen, C 1-3 alkyl, C 1-3 alkoxy, halo C 1-3 alkyl, -OH, -C 1-3 alkyl-OH, further selected from hydrogen, C 1-3 alkyl or even further selected from hydrogen, methyl or

[0086] In one instance, in the foregoing formula (III) or formula (III-1), R 31 is selected from hydrogen, C 1-3 alkyl, C 1-3 alkoxy, halo C 1-3 alkyl, -OH, -C 1-3 alkyl-OH,

[0087] In one instance, in the foregoing formula (III) or formula (III-1), R 32 is selected from hydrogen, C 1-3 alkyl, C 1-3 alkoxy, halo C 1-3 alkyl, -OH, -C 1-3 alkyl-OH,

[0088] In one instance, in the foregoing formula (III) or formula (III-1), R 30a is selected from hydrogen, methyl, ethyl, propyl or

[0089] In one instance, is

[0090] In one instance, in the foregoing formula (III) or formula (III-1), R 33 , R 34 is selected from -OH, C 1-3 alkyl, -C 1-3 alkyl-OH or further selected from -OH, -CH2-OH or

[0091] In one instance, in the foregoing formula (III) or formula (III-1), R 35 is selected from hydrogen or C 1-3 alkyl

[0092] In one instance, in the foregoing formula (III) or formula (III-1), R 36 is selected from hydrogen or C 1-3 alkyl

[0093] In one instance, is

[0094] In one instance, is

[0095] In one instance, in the foregoing formula (III) or formula (III-1), Y is selected from

[0096] In one instance, the compound of formula (III-1) includes the following structure:

[0097] In one instance, the formula (I) includes the following structure:

[0098]

[0099]

[0100]

[0101] In one instance, the compound of formula (II) includes the following structure:

[0102]

[0103]

[0104] In one instance, the compound of formula (III) includes the following structure:

[0105]

[0106] In one instance, the drug of the present invention further includes a pharmaceutically acceptable excipient.

[0107] In one instance, the drug of the present invention can inhibit the gene replication of porcine reproductive and respiratory syndrome virus.

[0108] In one example, the drug of the present invention can inhibit the expression of porcine reproductive and respiratory syndrome virus (PRRSV) proteins.

[0109] In one example, the drug of the present invention can inhibit the production of PRRSV virions. BRIEF DESCRIPTION OF THE DRAWINGS

[0110] Figure 1 It is the inhibition results of different concentrations of Endusamycin on PRRSV observed under a microscope in Example 1.

[0111] Figure 2 It is the inhibition results of different concentrations of Maduramycin on PRRSV observed under a microscope in Example 2. DETAILED DESCRIPTION

[0112] I. Definitions

[0113] In this disclosure, unless otherwise specified, scientific and technical terms used herein have the meanings commonly understood by those skilled in the art. At the same time, to better understand this disclosure, the following provides definitions and explanations of relevant terms.

[0114] For the purpose of clear and concise description, features are described herein as part of the same or separate embodiments. However, it is to be understood that the scope of this disclosure may include some embodiments having combinations of all or some of the described features.

[0115] As used herein, the "glycosyl polyether compound" refers to a polyether compound with glycosyl modification.

[0116] As used herein, the "C 1-3 alkyl" refers to a straight-chain or branched-chain alkyl having 1 to 3 carbon atoms. Specific examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, and isopropyl.

[0117] As used herein, the "alkoxy" refers to a group having an -O-alkyl structure, where the alkyl is defined as above.

[0118] As used herein, the "halogen" refers to fluorine, chlorine, bromine, and iodine.

[0119] As used herein, the term "substituted" or "substitution" means that any one or more hydrogen atoms on a specific atom are replaced by a substituent.

[0120] In this document, " " represents the chemical bond connection.

[0121] The medicament or pharmaceutical composition of the present disclosure can be administered orally, topically, parenterally or mucosally (e.g., sublingually, by inhalation or rectally) in dosage unit formulations comprising conventional non-toxic pharmaceutically acceptable carriers.

[0122] For oral administration in the form of tablets or capsules, the active pharmaceutical ingredient can be combined with non-toxic, pharmaceutically acceptable excipients such as binders (e.g., pregelatinized corn starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g., lactose, sucrose, glucose, mannitol, sorbitol and other reducing and non-reducing sugars, microcrystalline cellulose, calcium sulfate or calcium hydrogen phosphate); lubricants (e.g., magnesium stearate, talc or silica, stearic acid, sodium stearyl fumarate, behenin, calcium stearate, etc.); disintegrants (e.g., potato starch or sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulfate), coloring agents and flavoring agents, gelatin, sweeteners, natural and synthetic gums (such as gum arabic, tragacanth or alginate), buffer salts, carboxymethylcellulose, polyethylene glycol, waxes, etc. For oral administration in liquid form, the pharmaceutical ingredient can be combined with non-toxic, pharmaceutically acceptable inert carriers (e.g., ethanol, glycerol, water), anti-settling agents (e.g., sorbitol syrup, cellulose derivatives or hydrogenated edible fats), emulsifiers (e.g., lecithin or gum arabic), non-aqueous carriers (e.g., almond oil, esters of fatty acids, ethanol or fractionated vegetable oils), preservatives (e.g., methyl p-hydroxybenzoate or propyl p-hydroxybenzoate or sorbic acid), etc. Stabilizers such as antioxidants (BHA, BHT, propyl gallate, sodium ascorbate, citric acid) can also be added to stabilize the dosage form.

[0123] Tablets containing the active compound can be coated by methods well known in the art. The compositions of the present disclosure containing a compound of formula I as the active compound can also be incorporated into beads, microspheres or microcapsules, for example constructed from polyglycolic acid / lactic acid (PGLA). Preparations for oral administration in liquid form can take, for example, the form of solutions, syrups, emulsions or suspensions or they can be presented as dry products to be reconstituted with water or other suitable excipients before use. Preparations for oral administration can be suitably formulated to provide controlled or delayed release of the active compound.

[0124] The medicaments or pharmaceutical compositions of the present disclosure can be delivered parenterally, i.e., by intravenous (i.v.), intracerebroventricular (i.c.v.), subcutaneous (s.c.), intraperitoneal (i.p.), intramuscular (i.m.), subdermal (s.d.) or intradermal (i.d.) administration, by direct injection, for example by rapid bolus injection or continuous infusion. Formulations for injection can be presented in unit dosage forms, for example in ampoules or multi-dose containers with added preservatives. The compositions can be in the form of excipients, suspensions, solutions or emulsions in oily or aqueous carriers, and can contain formulating agents such as anti-settling agents, stabilizers and / or dispersing agents. Alternatively, the active ingredient can be in powder form and reconstituted with a suitable carrier (such as sterile pyrogen-free water) before use.

[0125] The medicaments or pharmaceutical compositions of the present disclosure can also be formulated for rectal administration, for example in the form of suppositories or retention enemas (for example, containing conventional suppository bases such as cocoa butter or other glycerides).

[0126] The term "treatment" includes inhibiting, alleviating, preventing or eliminating one or more symptoms or side effects associated with the disease, disorder or condition being treated. The term "effective amount" or "therapeutically effective amount" means a dose sufficient to treat, inhibit or alleviate one or more symptoms of the disease state being treated or otherwise provide the desired pharmacological and / or physiological effect. The exact dose will vary depending on a variety of factors, such as subject-dependent variables (e.g., age, immune system health, etc.), the disease or disorder, and the treatment being administered. The effect of the effective amount can be relative to a control. Such controls are known in the art and are discussed herein, and can be, for example, the condition of the subject before or without administration of the medicament or pharmaceutical combination, or in the case of a pharmaceutical combination, the combined effect can be compared with the effect of administering only one of the drugs.

[0127] The term "pharmaceutical composition" means a composition comprising a compound or a pharmaceutically acceptable salt thereof as described in the present disclosure, and at least one pharmaceutically acceptable ingredient selected from the following, depending on the mode of administration and the nature of the dosage form, including but not limited to: carriers, diluents, adjuvants, excipients, preservatives, fillers, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, fragrances, antibacterial agents, antifungal agents, lubricants, dispersing agents, temperature-sensitive materials, temperature regulators, adhesives, stabilizers, suspending aids, etc.

[0128] According to the above content of the present disclosure, and in accordance with the common general knowledge and customary means in the art, without departing from the above basic technical idea of the present disclosure, various other forms of modifications, substitutions or changes can also be made.

[0129] II. Examples

[0130] The technical solutions provided by the present invention will be described in detail below in conjunction with embodiments, but they should not be construed as limiting the protection scope of the present invention.

[0131] Unless otherwise specified, the reagents used in the experiments are all common commercially available reagents; the operation methods in the experiments are all operation methods known in the art unless otherwise specified. Unless otherwise specified, the polyether compounds of the present invention can be synthesized by the preparation methods described in Chinese Patent Applications CN202310856216.7 and CN202210665221.5, which are commonly used in the art.

[0132] In the following examples, the PRRSV NADC-30 strain is used, but not limited to the NADC-30 strain.

[0133] Example 1: Inhibitory effect of different concentrations of Endusamycin on Porcine Reproductive and Respiratory Syndrome Virus (PRRSV)

[0134] After counting PAM cells, they were diluted to an appropriate density with DMEM nutrient solution containing 8% fetal bovine serum (FBS) and added to a 6-well plate containing glass slides at a concentration of 2×10 6 / well. The plate was placed in an incubator at 37°C and 5% CO2 for culture. After the cells adhered to form a monolayer density (about 12 hours), DMSO control (DMEM) and different concentrations of Endusamycin (1 μM, 3 μM) were used to treat PAM cells at 37°C for 2 hours, and then inoculated with a fluorescently labeled PRRSV NADC-30 strain (MOI = 0.1) for infection. After co-culturing in an incubator at 37°C and 5% CO2 for 36 hours, the replication of the virus in PAM cells was observed under a fluorescence microscope.

[0135] Effect of Endusamycin on PRRSV in PAM cells after treatment ( Figure 1 ) indicates that Endusamycin can significantly inhibit the infection of PRRSV at a relatively low concentration and shows an obvious dose-dependence. The polyether compounds of the present invention can inhibit the gene replication of PRRSV, inhibit the protein expression of PRRSV, and / or the production of its particles.

[0136] Example 2: Inhibitory effect of different concentrations of Maduramycin on Porcine Reproductive and Respiratory Syndrome Virus (PRRSV)

[0137] After counting PAM cells, they were diluted to an appropriate density with DMEM nutrient solution containing 8% fetal bovine serum (FBS) and added to a 6-well plate at a concentration of 2×10 6The concentration of the / hole was added to a 6-well plate containing glass slides and cultured in an incubator at 37 °C with 5% CO2. After the cells adhered to form a monolayer density (about 12 hours), the DMSO control (DMEM) and different concentrations of Maduramycin (1 μM, 3 μM) were pre-treated with PAM cells at 37 °C for 2 hours, and then inoculated with the fluorescently labeled Porcine reproductive and respiratory syndrome virus (PRRSV) NADC-30 strain (MOI = 0.1) for infection. After co-culturing in an incubator at 37 °C with 5% CO2 for 36 hours, the replication of the virus in PAM cells was observed under a fluorescence microscope.

[0138] Effect of Porcine reproductive and respiratory syndrome virus in PAM cells after Maduramycin treatment ( Figure 2 ), indicating that Maduramycin can significantly inhibit the infection of Porcine reproductive and respiratory syndrome virus at a relatively low concentration and shows an obvious dose-dependence. The polyether compound of the present invention can inhibit the gene replication of Porcine reproductive and respiratory syndrome virus, inhibit the protein expression of Porcine reproductive and respiratory syndrome virus and / or the production of its particles.

[0139] Example 3: Inhibitory effects of nanchangmycin, A-130-A and CP-80,219 compounds on Porcine reproductive and respiratory syndrome virus

[0140] After counting PAM cells, they were diluted to an appropriate density with DMEM nutrient solution containing 8% fetal bovine serum (FBS) and added to a 6-well plate containing glass slides at a concentration of 2×10 6 / hole and cultured in an incubator at 37 °C with 5% CO2. After the cells adhered to form a monolayer density (about 12 hours), the DMSO control (DMEM) and different concentrations of nanchangmycin, A-130-A and CP-80,219 (0.1 μM, 1 μM) were treated with PAM cells at 37 °C. At the same time, they were inoculated with the fluorescently labeled Porcine reproductive and respiratory syndrome virus NADC-30 strain (MOI = 0.1) for infection. After co-culturing in an incubator at 37 °C with 5% CO2 for 36 hours, the cells were collected, lysed, and a Real-time PCR assay was performed to detect the relative expression changes of the PRRSV NSP-9 gene in the drug treatment group and the virus control group, and then the inhibition rate of the compound on PRRSV was calculated.

[0141] Upstream and downstream primer sequences of NSP-9 and GAPDH genes:

[0142] NSP9-F: 5'-CTAAGAGAGGTGGCCTGTCG-3' (SEQ ID NO: 1);

[0143] NSP9-R: 5'-GAGACTCGGCATACAGCACA-3' (SEQ ID NO: 2);

[0144] GAPDH-F: 5'-GCAAAGACTGAACCCACTAATTT-3' (SEQ ID NO:3);

[0145] GAPDH-R: 5'-TTGCCTCTGTTGTTACTTGGAGAT-3 (SEQ ID NO:4).

[0146] The experimental results are shown in Table 1 below.

[0147] Table 1 Inhibition rates of nanchangmycin, A-130-A, and CP-80,219 against porcine reproductive and respiratory syndrome virus

[0148]

[0149] Example 4: Inhibitory effect of Len series compounds on PRRSV virus

[0150] After counting PAM cells, they were diluted to an appropriate density with DMEM nutrient solution containing 8% fetal bovine serum (FBS) and added to a 6-well plate containing glass slides at a concentration of 2×10 6 / well. They were cultured in an incubator at 37°C and 5% CO2. After the cells adhered to form a monolayer density (about 12 hours), DMSO control (DMEM) and different concentrations of Len-10 or Len-11 (0.1 μM, 1 μM) were used to treat PAM cells at 37°C. At the same time, they were then inoculated with a fluorescently labeled porcine reproductive and respiratory syndrome virus NADC-30 strain (MOI = 0.1) for infection. After co-culturing in an incubator at 37°C and 5% CO2 for 36 hours, the cells were collected, lysed, and a Real-time PCR test was performed to detect the changes in the relative expression levels of the PRRSV NSP-9 gene in the drug treatment group and the virus control group, and then the inhibition rate of the compound against PRRSV was calculated. The upstream and downstream primer sequences of NSP-9 and GAPDH genes were the same as those in Example 3.

[0151] The experimental results are shown in Table 2 below.

[0152] Table 2 Inhibition rates of Len series compounds against porcine reproductive and respiratory syndrome virus

[0153]

[0154] Example 5: Inhibitory effect of Mad series compounds on PRRSV virus

[0155] After counting PAM cells, they were diluted to an appropriate density with DMEM nutrient solution containing 8% fetal bovine serum (FBS) and added to a 6-well plate containing glass slides at a concentration of 2×10 6The concentration of the compound was added to a 6-well plate containing glass slides and cultured in an incubator at 37°C with 5% CO2. After the cells adhered to form a monolayer density (about 12 hours), DMSO control (DMEM) and different concentrations of Mad series compounds (0.1 μM, 1 μM) were used to treat PAM cells at 37°C. At the same time, the PAM cells were inoculated with a fluorescently labeled Porcine reproductive and respiratory syndrome virus (PRRSV) NADC-30 strain (MOI = 0.1) and infected. They were co-cultured in an incubator at 37°C with 5% CO2 for 36 hours. Then the cells were collected, lysed, and subjected to Real-time PCR to detect the relative expression changes of the PRRSV NSP-9 gene in the drug treatment group and the virus control group. Then the inhibition rate of the compound against PRRSV was calculated. The upstream and downstream primer sequences of NSP-9 and GAPDH genes were the same as those in Example 3.

[0156] The experimental results are shown in Table 3 below.

[0157] Table 3 Inhibition rate of Mad series compounds against Porcine reproductive and respiratory syndrome virus (PRRSV)

[0158]

[0159]

[0160] Example 6: Inhibitory effect of End series compounds on Porcine reproductive and respiratory syndrome virus (PRRSV)

[0161] After counting the PAM cells, they were diluted to an appropriate density with DMEM nutrient solution containing 8% fetal bovine serum (FBS) and added to a 6-well plate containing glass slides at a concentration of 2×10 6 / well and cultured in an incubator at 37°C with 5% CO2. After the cells adhered to form a monolayer density (about 12 hours), DMSO control (DMEM) and different concentrations of End series compounds (0.1 μM, 1 μM) were used to treat PAM cells at 37°C. At the same time, the PAM cells were inoculated with a fluorescently labeled Porcine reproductive and respiratory syndrome virus (PRRSV) NADC-30 strain (MOI = 0.1) and infected. They were co-cultured in an incubator at 37°C with 5% CO2 for 36 hours. Then the cells were collected, lysed, and subjected to Real-time PCR to detect the relative expression changes of the PRRSV NSP-9 gene in the drug treatment group and the virus control group. Then the inhibition rate of the compound against PRRSV was calculated. The upstream and downstream primer sequences of NSP-9 and GAPDH genes were the same as those in Example 3.

[0162] The experimental results are shown in Table 4 below.

[0163] Table 4 Inhibition rate of End series compounds against Porcine reproductive and respiratory syndrome virus (PRRSV)

[0164]

[0165]

[0166] Example 7: Inhibitory Effect of CP Series Compounds on PRRSV Virus

[0167] After counting PAM cells, they were diluted to an appropriate density with DMEM nutrient solution containing 8% fetal bovine serum (FBS) and added to a 6-well plate containing glass slides at a concentration of 2×10 6 / well. The plate was placed in an incubator at 37°C and 5% CO2 for culture. After the cells adhered to form a monolayer density (about 12 hours), DMSO control (DMEM) and CP series compounds at different concentrations (0.1 μM, 1 μM) were used to treat PAM cells at 37°C. At the same time, the cells were inoculated with the fluorescently labeled Porcine Reproductive and Respiratory Syndrome Virus (PRRSV) NADC-30 strain (MOI = 0.1) for infection. After co-culturing in an incubator at 37°C and 5% CO2 for 36 hours, the cells were collected, lysed, and subjected to Real-time PCR to detect the relative expression changes of the PRRSV NSP-9 gene in the drug treatment group and the virus control group. Then, the inhibition rate of the compound on PRRSV was calculated. The upstream and downstream primer sequences of NSP-9 and GAPDH genes were the same as those in Example 3.

[0168] The experimental results are shown in Table 5 below.

[0169] Table 5 Inhibition Rate of CP Series Compounds on Porcine Reproductive and Respiratory Syndrome Virus

[0170]

[0171] The foregoing description of specific exemplary embodiments of the present invention is for purposes of illustration and exemplification. These descriptions are not intended to limit the invention to the precise forms disclosed, and it is apparent that many changes and variations are possible in light of the above teachings. The purpose of selecting and describing the exemplary embodiments is to explain the specific principles of the invention and its practical applications, so that those skilled in the art can implement and utilize various different exemplary embodiments of the invention, as well as various different selections and changes. The scope of the invention is intended to be defined by the claims and their equivalents.

Claims

1. Use of a glycosyl polyether compound or its tautomer, meso form, racemate, enantiomer, diastereomer or a mixture thereof, isotope derivative, pharmaceutically acceptable hydrate, solvate, salt or co-crystal in the preparation of a medicament for preventing and / or treating porcine reproductive and respiratory syndrome virus (PRRSV), wherein the glycosyl polyether compound has the structure shown by the following formula: Wherein, R 11 、R 12 、R 13 、R 14 、R 16 、R 17 、R 18 、R 19 each independently selected from hydrogen, -OH, C 1-3 alkyl, C 1-3 alkoxy, -O-C(O)-CH2-R, R 15 selected from C 1-3 alkyl or -CHR'-C(O)OH; R 16a selected from C 1-3 alkyl or C 1-3 alkoxy; R 16b 、R 16c each independently selected from hydrogen, C 1-3 alkyl, C 1-3 alkoxy, R 12a 、R 12b 、R 14a 、R 14b 、R 17a 、R 18a 、R L are each independently selected from hydrogen or C 1-3 alkyl; R 20 selected from C 1-3 alkyl or hydroxy-substituted C 1-3 alkyl; R is selected from amino, C 1-3 alkyl, C 3-6 cycloalkyl, halogen, azide or C 5-6 aryl, wherein the C 1-3 alkyl and C 3-6 cycloalkyl are optionally substituted with 1-4 halogen atoms, and the C 5-6 aryl is optionally substituted with 1-4 halogen atoms or C 1-3 alkyl; R’ is selected from hydrogen or C 1-3 alkyl; R 21 、R 22 、R 23 、R 24 、R 25 、R 25a 、R 25b 、R 26 、R 27 each independently selected from hydrogen, C 1-3 alkyl, halo C 1-3 alkyl, -OH, -C 1-3 alkyl-OH, Y is selected from R 30a selected from hydrogen, C 1-3 alkyl or -CR 31 R 32 ; R 28 、R 29 、R 30 、R 31 、R 32 、R 33 、R 34 、R 35 、R 36 each independently selected from hydrogen, C 1-3 alkyl, C 1-3 alkoxy, halo-C 1-3 alkyl, -OH, -C 1-3 alkyl-OH, 2. The application according to claim 1, wherein R 11 、R 12 、R 13 are not simultaneously -OH. Preferably, at most 2 of R 11 、R 12 、R 13 are -OH; preferably, exactly 2 of R 11 、R 12 、R 13 are -OH.

3. The application according to claim 1 or 2, wherein R is selected from amino, methyl, cyclopropyl, chlorine, azide, phenyl or tolyl.

4. The application according to any one of claims 1-3, wherein, R 11 、R 12 、R 13 、R 14 、R 16 、R 17 、R 18 、R 19 are each independently selected from hydrogen, -OH, methyl, methoxy, -O-C(O)-CH2-N3, Preferably, R 11 , R 12 , R 13 , R 14 , R 16 , R 17 , R 18 , R 19 at least 1, 2 or 3 of which are selected from 5. The application according to any one of claims 1-4, wherein R 12a 、R 12b 、R 14a 、R 14b 、R 17a 、R 18a 、R L Each independently selected from hydrogen or methyl.

6. The application according to any one of claims 1-5, wherein, R 15 selected from methyl, -CH-C(O)OH or -CH(CH3)-C(O)OH; Preferably, R 16a is selected from methyl or ethoxy; Preferably, R 16c , R 16d are each independently selected from hydrogen, methyl, methoxy, 7. The application according to claim 1, wherein, R 21 、R 22 、R 23 、R 24 、R 25 、R 25a 、R 25b 、R 26 、R 27 selected from hydrogen, methyl, -OH, Preferably, R 21 and R 23 are each independently selected from hydrogen or methyl; Preferably, R 21 , R 23 are each independently selected from hydrogen or methyl and R 21 , R 23 are not both methyl at the same time; Preferably, R 21 , R 23 are each independently selected from hydrogen or methyl and one of R 21 , R 23 is methyl; Preferably, R 22 is selected from hydroxyl, Preferably, R 24 is selected from hydrogen, hydroxyl, Preferably, R 25 , R 26 are each independently selected from hydrogen, Preferably, R 25 and R 26 are each independently selected from hydrogen, and R 25 and R 26 are not simultaneously Preferably, R 27 is selected from -C 1-3 alkyl or -C 1-3 alkyl-OH; Preferably, R 27 is selected from methyl or -CH2-OH.

8. The application according to claim 1, wherein, Y is selected from 9. Use of the following glycosyl polyether compound, or its tautomer, meso form, racemate, enantiomer, diastereomer or a mixture thereof, isotope derivative, pharmaceutically acceptable hydrate, solvate, salt or co-crystal in the preparation of a medicament for preventing and / or treating porcine reproductive and respiratory syndrome virus (PRRSV):

10. The application according to any one of 1-9, wherein, The medicament can inhibit PRRSV gene replication, inhibit PRRSV protein expression and / or inhibit PRRSV particle production.

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