Compound medicine composition and application thereof

Abstract

The invention relates to the field of pharmaceutical compositions, and particularly discloses a compound pharmaceutical composition with an anti-coronavirus effect and application of the compound pharmaceutical composition. Effective / active ingredients of the compound medicine composition comprise an Mpro inhibitor Y62222 and an RdRp inhibitor ATV014, wherein the Mpro inhibitor Y62222 is an Mpro inhibitor Y62222; the two components have a synergistic effect on treatment of virus infection diseases in a certain proportion, have a remarkable effect on treatment of the virus infection diseases, can be used as an anti-coronavirus drug, are beneficial to improvement of the antiviral effect and reduction of adverse reaction and drug resistance of the drug, have a good clinical medication development prospect, and are worthy of popularization and application. And a new medicinal application is provided for clinic.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical compositions, and in particular relates to a compound pharmaceutical composition and its use. Background Art

[0002] The new coronavirus (SARS-CoV-2) is a virus that poses a serious threat to global public health security and has caused the COVID-19 pandemic. Although there are treatments including vaccinations and antiviral drugs, the emergence of mutant strains has caused repeated outbreaks, so the development of new, safe and effective antiviral drugs is of great significance to curbing the epidemic.

[0003] The main protease (Mpro / 3CLpro) and RNA polymerase (RdRp) are two important proteases produced by the new coronavirus. After the SARS-CoV-2 virus enters the cell, the nucleocapsid and the virus's own positive-strand RNA are released into the cytoplasm. The open reading frames ORF1a and ORF1b of the positive-strand RNA are translated to produce non-structural proteins, which are cleaved by PLpro and Mpro / 3CLpro, and finally produce 16 non-structural proteins including helicase and RNA-dependent RNA polymerase (RdRp), which participate in the viral transcription and replication process. Therefore, inhibiting Rdrp and Mpro / 3CLpro can effectively inhibit the infection and replication of the virus, and is a key target for the development of antiviral drugs.

[0004] Currently, several drugs targeting SARS-CoV-2 have been approved for use, such as the RdRp inhibitor Remdesivir and the Mpro inhibitor Paxlovid. However, single-drug treatment may have problems such as insufficient efficacy and increased drug resistance. Therefore, there is still an urgent need for a drug that is effective and resistant to drug resistance to inhibit coronavirus. Summary of the invention

[0005] In order to solve the above technical problems, the present invention provides the following technical solutions.

[0006] In a first aspect, the present invention provides a use of an Mpro inhibitor in combination with an RdRp inhibitor in the preparation of a medicament for alleviating or treating coronavirus infection.

[0007] The present invention provides use of an Mpro inhibitor in combination with an RdRp inhibitor in the preparation of a medicament for alleviating or treating coronavirus infection, wherein the Mpro inhibitor and the RdRp inhibitor are triazine compounds and nucleoside compounds, respectively.

[0008] The coronavirus infection described in the present invention is selected from MHV-A59 (mouse hepatitis virus A59 strain), HCoV-229E (human coronavirus 229E), HCoV-OC43 (human coronavirus OC43), HCoV-NL63 (human coronavirus NL63), HCoV-HKU1 (human coronavirus HKU1), SARS-CoV (SARS coronavirus), MERS-CoV (Middle East respiratory syndrome coronavirus), new coronavirus, mouse hepatitis virus, feline coronavirus, canine coronavirus, bovine coronavirus, avian infectious bronchitis virus or porcine coronavirus.

[0009] In some embodiments, the novel coronavirus infection is a novel coronavirus infection caused by the common type of the novel coronavirus and its variants, and the novel coronavirus and its variants include Alpha variants, Beta variants, Gamma variants, Delta variants, Lambda variants and / or Omicron variants.

[0010] In some embodiments, the infection is caused by a coronavirus and includes fever, headache, cough, sore throat, muscle aches, pneumonia, acute respiratory tract infection, severe acute respiratory tract infection, hypoxic respiratory failure and acute respiratory distress syndrome, sepsis or septic shock.

[0011] In a second aspect, the present invention provides a compound pharmaceutical composition.

[0012] The present invention provides a compound pharmaceutical composition comprising:

[0013] (a) one or more Mpro inhibitors,

[0014] (b) one or more RdRp inhibitors;

[0015] The Mpro inhibitor is selected from compound Y62222 or a pharmaceutically acceptable salt, cocrystal, isomer, metabolite, prodrug, solvate or hydrate thereof, or a combination thereof,

[0016]

[0017] The Rdrp inhibitor is selected from compound ATV014 or a pharmaceutically acceptable salt, cocrystal, isomer, metabolite, prodrug, solvate or hydrate thereof, or a combination thereof, and the molar ratio of the Mpro inhibitor to the Rdrp inhibitor is 50:1 to 1:50,

[0018]

[0019] In some embodiments, the compound Y62222 has the following tautomeric formula Y62222a,

[0020]

[0021] In some embodiments, the triazine compound in the compound pharmaceutical composition may exist in the form of compound Y62222, or in the form of tautomer Y62222a, or in the form of compound Y62222 and tautomer Y62222a at the same time.

[0022] In some embodiments, the co-crystal of Y62222 is a binary co-crystal formed by compound Y62222 and an organic acid or a ternary co-crystal formed by compound Y62222, nicotinamide and an organic acid.

[0023] In some embodiments, the co-crystal of the compound ATV014 is a binary co-crystal formed by ATV014 and an organic acid or a ternary co-crystal formed by ATV014, nicotinamide and an organic acid.

[0024] In some embodiments, the organic acid in the organic acid of the compound Y62222 and the organic acid in the organic acid of the compound ATV014 respectively and independently include acetic acid, benzoic acid, mandelic acid, maleic acid, fumaric acid, malic acid or citric acid.

[0025] In some embodiments, the pharmaceutically acceptable salt among the pharmaceutically acceptable salts of the compound ATV014 and the pharmaceutically acceptable salt among the pharmaceutically acceptable salts of the compound ATV014 are independently selected from hydrochloride, hydrobromide, sulfate, phosphate, benzenesulfonate, p-toluenesulfonate, methanesulfonate, tartrate, camphorsulfonate, lithium salt, sodium salt, potassium salt, calcium salt, magnesium salt, aluminum salt, ammonium salt, ethylenediamine salt or triethylamine salt.

[0026] In some embodiments, the molar ratio of the Mpro inhibitor to the RdRp inhibitor is about 40:1 to 1:40.

[0027] In some embodiments, the molar ratio of the Mpro inhibitor to the RdRp inhibitor is about 30:1 to 1:30.

[0028] In some embodiments, the molar ratio of the Mpro inhibitor to the RdRp inhibitor is about 20:1 to 1:20.

[0029] In some embodiments, the molar ratio of the Mpro inhibitor to the RdRp inhibitor is about 10:1 to 1:10.

[0030] In some embodiments, the molar ratio of the Mpro inhibitor to the RdRp inhibitor is about 50:1, 40:1, 30:1, 20:1, 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 3:1, 2:1, 1.5:1, 1:1, 1:1.5, 1:2, 1:3, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:20, 1:30, 1:40 or 1:50.

[0031] In some embodiments, the molar ratio of the Mpro inhibitor to the RdRp inhibitor is 5:1 to 1:10.

[0032] In some embodiments, the compound pharmaceutical composition of the present invention can be prepared according to the disclosed content using any method known to those skilled in the art, such as conventional mixing, dissolving, granulating, emulsifying, grinding, encapsulating, embedding or lyophilizing processes.

[0033] In a third aspect, the present invention provides a preparation.

[0034] In another aspect, the present invention provides a preparation comprising the aforementioned compound pharmaceutical composition and a pharmaceutically acceptable carrier.

[0035] In some embodiments, the pharmaceutically acceptable carrier is selected from any one or more of a filler, a binder, a disintegrant, a glidant, a lubricant or a flavoring agent.

[0036] In some embodiments, the preparation is an oral preparation, which can be a powder, granules, pills, capsules, tablets, lozenges or oral liquids.

[0037] In some embodiments, the total mass of the Mpro inhibitor and the RdRp inhibitor in a single dose of the preparation is 2 mg-2000 mg. In some embodiments, the total mass of the Mpro inhibitor and the RdRp inhibitor in a single dose of the formulation is 2.0 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, 5 mg, 5.5 mg, 6.0 mg, 6.5 mg, 7.0 mg, 7.5 mg, 8.0 mg, 8.5 mg, 9.0 mg, 9.5 mg, 10 mg, 10.5 mg, 11 mg, 11.5 mg, 12 mg, 12.5 mg, 13 mg, 13.5 mg, 14 mg, 14.5 mg, 15 mg, 15.5 mg, 16 mg, 16.5 mg, 17 mg, 17.5 mg, 18 mg, 18.5 mg, 19 mg, 19.5 mg, 20 mg, 22.5 mg, 25 mg, 27.5 mg, 30 mg, 32.5 mg, 35 mg, 37.5 mg, 40 mg g, 42.5mg, 45mg, 47.5mg, 50mg, 52.5mg, 55mg, 60mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 9 5mg, 100mg, 150mg, 200mg, 250mg, 300mg, 350mg, 400mg, 450mg, 500mg, 550mg, 600mg, 650mg , 700mg, 750mg, 800mg, 850mg, 900mg, 950mg, 1000mg, 1050mg, 1100mg, 1150mg, 1200mg, 1250mg, 1300mg, 1350mg, 1400mg, 1450mg, 1500mg, 1600mg, 1700mg, 1800mg, 1900mg or 2000mg.

[0038] In some embodiments, the pharmaceutically acceptable carrier (pharmaceutical excipient) may be those excipients widely used in the field of drug production. Excipients are mainly used to provide a safe, stable and functional pharmaceutical composition, and can also provide a method to dissolve the active ingredient at a desired rate after the subject receives the administration, or promote the effective absorption of the active ingredient after the subject receives the composition. In some embodiments, the pharmaceutical excipient may be an inert filler, or provide a certain function, such as stabilizing the overall pH value of the composition or preventing the degradation of the active ingredient of the composition. In some embodiments, the pharmaceutical excipient may include one or more of the following excipients: adhesives, suspending agents, emulsifiers, diluents, fillers, granulating agents, adhesives, disintegrants, lubricants, anti-adhesive agents, glidants, wetting agents, gelling agents, absorption delay agents, dissolution inhibitors, enhancers, adsorbents, buffers, chelating agents, preservatives, colorants, flavoring agents and sweeteners.

[0039] In some embodiments, the filler is selected from any one of calcium carbonate, magnesium carbonate, calcium phosphate, calcium sulfate, magnesium oxide, carboxymethylcellulose calcium, carboxymethylcellulose sodium, sucrose, lactose, fructose, xylitol, mannitol, starch or its derivatives, dextrin or microcrystalline cellulose, or a mixture of two or more thereof in any proportion.

[0040] In some embodiments, the binder is selected from any one of gum arabic, gelatin, tragacanth, dextrin, polyvinyl pyrrolidone, starch and its derivatives, sodium alginate, sorbitol, syrup, hydroxypropyl methylcellulose, methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, ethyl cellulose, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, glucose or polymethacrylate, or a mixture of two or more thereof in any proportion.

[0041] In some embodiments, the disintegrant is selected from any one of starch, alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium, cross-linked carboxymethylcellulose sodium, cross-linked polyvinyl pyrrolidone, low-substituted hydroxypropyl methylcellulose, microcrystalline cellulose or methylcellulose, or a mixture of two or more thereof in any proportion.

[0042] The glidant is selected from any one of colloidal silicon dioxide, powdered cellulose, magnesium trisilicate, silicon dioxide, talc, etc., or a mixture of two or more of them in any proportion.

[0043] In some embodiments, the lubricant is selected from any one of calcium stearate, glyceryl monostearate, glyceryl palmitostearate, magnesium stearate, microcrystalline cellulose, sodium benzoate, sodium chloride, sodium lauryl sulfate, magnesium stearate, sodium stearyl fumarate, talc, zinc stearate and polyethylene glycol, or a mixture of two or more thereof in any proportion.

[0044] In some embodiments, the flavoring agent is selected from any one of stevioside, aspartame and other commonly used flavors and sweeteners in the art, or a mixture of two or more of them in any proportion.

[0045] In a fourth aspect, the present invention provides a medicine kit product.

[0046] A medicine kit product, comprising a first preparation unit and a second preparation unit, wherein the first preparation unit and the second preparation unit are both independently present in the medicine kit product;

[0047] The first formulation unit comprises an active ingredient A, which is an Mpro inhibitor, which is a triazine compound selected from compound Y62222 or a pharmaceutically acceptable salt, cocrystal, isomer, metabolite, prodrug, solvate or hydrate thereof, or a combination thereof;

[0048] The second formulation unit includes an active ingredient B, which is an RdRp inhibitor, which is a nucleoside analogue selected from the compound ATV014 or a pharmaceutically acceptable salt, cocrystal, isomer, metabolite, prodrug, solvate or hydrate thereof, or a combination thereof;

[0049] The molar ratio of the single-dose strength of the first preparation unit to the single-dose strength of the second preparation unit is 50:1 to 1:50,

[0050]

[0051] In some embodiments, the co-crystal of compound Y62222 is a binary co-crystal formed by Y62222 and an organic acid or a ternary co-crystal formed by Y62222, nicotinamide and an organic acid.

[0052] In some embodiments, the co-crystal of the compound ATV014 is a binary co-crystal formed by ATV014 and an organic acid or a ternary co-crystal formed by ATV014, nicotinamide and an organic acid.

[0053] In some embodiments, the organic acid in the organic acid of the compound Y62222 and the organic acid in the organic acid of the compound ATV014 respectively and independently include acetic acid, benzoic acid, mandelic acid, maleic acid, fumaric acid, malic acid or citric acid.

[0054] In some embodiments, the pharmaceutically acceptable salt among the pharmaceutically acceptable salts of the compound Y62222 and the pharmaceutically acceptable salt among the pharmaceutically acceptable salts of the compound ATV014 are independently selected from hydrochloride, hydrobromide, sulfate, phosphate, benzenesulfonate, p-toluenesulfonate, methanesulfonate, tartrate, camphorsulfonate, lithium salt, sodium salt, potassium salt, calcium salt, magnesium salt, aluminum salt, ammonium salt, ethylenediamine salt or triethylamine salt.

[0055] In some embodiments, the molar ratio of the single-dose strength of the first formulation unit to the single-dose strength of the second formulation unit is 40:1 to 1:40.

[0056] In some embodiments, the molar ratio of the single-dose strength of the first formulation unit to the single-dose strength of the second formulation unit is 30:1 to 1:30.

[0057] In some embodiments, the molar ratio of the single-dose strength of the first formulation unit to the single-dose strength of the second formulation unit is 20:1 to 1:20.

[0058] In some embodiments, the molar ratio of the single-dose strength of the first formulation unit to the single-dose strength of the second formulation unit is 10:1 to 1:10.

[0059] In some embodiments, the molar ratio of the single dose strength of the first formulation unit to the single dose strength of the second formulation unit is 50:1, 40:1, 30:1, 20:1, 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 3:1, 2:1, 1.5:1, 1:1, 1:1.5, 1:2, 1:3, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:20, 1:30, 1:40 or 1:50.

[0060] In some embodiments, the molar ratio of the single-dose strength of the first formulation unit to the single-dose strength of the second formulation unit is 5:1 to 1:10.

[0061] In some embodiments, the single dose strength of the first dosage unit is 1 mg-1500 mg. In some embodiments, the single dose strength of the first dosage unit is 1 mg, 1.5 mg, 2.0 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, 5 mg, 5.5 mg, 6.0 mg, 6.5 mg, 7.0 mg, 7.5 mg, 8.0 mg, 8.5 mg, 9.0 mg, 9.5 mg, 10 mg, 10.5 mg, 11 mg, 11.5 mg, 12 mg, 12.5 mg, 13 mg, 13.5 mg, 14 mg, 14.5 mg, 15 mg, 15.5 mg, 16 mg, 16.5 mg, 17 mg, 17.5 mg, 18 mg, 18.5 mg, 19 mg, 19.5 mg, 20 mg, 22.5 mg, 25 mg, 27.5 mg, 30 mg, 32.5 mg , 35mg, 37.5mg, 40mg, 42.5mg, 45mg, 47.5mg, 50mg, 52.5mg, 55mg, 60mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 150mg, 200mg, 250mg, 300mg, 350mg, 400mg, 450 mg, 500mg, 550mg, 600mg, 650mg, 700mg, 750mg, 800mg, 850mg, 900mg, 950mg, 1000mg, 1050mg, 1100mg, 1150mg, 1200mg, 1250mg, 1300mg, 1350mg, 1400mg, 1450mg, 1500mg.

[0062] In some embodiments, the single dose strength of the second dosage unit is 1 mg-1500 mg. In some embodiments, the single dose strength of the second dosage unit is 1 mg, 1.5 mg, 2.0 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, 5 mg, 5.5 mg, 6.0 mg, 6.5 mg, 7.0 mg, 7.5 mg, 8.0 mg, 8.5 mg, 9.0 mg, 9.5 mg, 10 mg, 10.5 mg, 11 mg, 11.5 mg, 12 mg, 12.5 mg, 13 mg, 13.5 mg, 14 mg, 14.5 mg, 15 mg, 15.5 mg, 16 mg, 16.5 mg, 17 mg, 17.5 mg, 18 mg, 18.5 mg, 19 mg, 19.5 mg, 20 mg, 22.5 mg, 25 mg, 27.5 mg, 30 mg, 32.5 mg , 35mg, 37.5mg, 40mg, 42.5mg, 45mg, 47.5mg, 50mg, 52.5mg, 55mg, 60mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 150mg, 200mg, 250mg, 300mg, 350mg, 400mg, 450 mg, 500mg, 550mg, 600mg, 650mg, 700mg, 750mg, 800mg, 850mg, 900mg, 950mg, 1000mg, 1050mg, 1100mg, 1150mg, 1200mg, 1250mg, 1300mg, 1350mg, 1400mg, 1450mg, 1500mg.

[0063] In some embodiments, the first formulation unit further comprises a pharmaceutically acceptable carrier; and the second formulation unit further comprises a pharmaceutically acceptable carrier.

[0064] In some embodiments, the pharmaceutically acceptable carrier in the first formulation unit and the pharmaceutically acceptable carrier in the second formulation unit are independently selected from any one or more of a filler, a binder, a disintegrant, a glidant, a lubricant or a flavoring agent.

[0065] In some embodiments, the first dosage unit and the second dosage unit are each independently an oral dosage form selected from powders, granules, pills, capsules, tablets, lozenges or oral liquids.

[0066] In a fifth aspect, the present invention provides a method or use for alleviating or treating coronavirus infection.

[0067] The present invention also provides a method for alleviating or treating coronavirus infection, comprising administering an effective dose of a combination of the following compounds:

[0068] (a) one or more Mpro inhibitors;

[0069] (b) one or more RdRp inhibitors.

[0070] In some embodiments, the compound pharmaceutical composition described in the second aspect, the preparation described in the third aspect, or the medicine kit product described in the fourth aspect is used in the preparation of a drug for alleviating or treating coronavirus infection.

[0071] In some embodiments, the coronavirus infection is selected from MHV-A59, HCoV-229E, HCoV-OC43, HCoV-NL63, HCoV-HKU1, SARS-CoV, MERS-CoV, new coronavirus, mouse hepatitis virus, feline coronavirus, canine coronavirus, bovine coronavirus, avian infectious bronchitis virus or porcine coronavirus.

[0072] In some embodiments, the novel coronavirus infection is a novel coronavirus infection caused by the common type of the novel coronavirus and its variants, and the novel coronavirus and its variants include Alpha variants, Beta variants, Gamma variants, Delta variants, Lambda variants and / or Omicron variants.

[0073] In some embodiments, the infection is caused by a coronavirus and includes fever, headache, cough, sore throat, muscle aches, pneumonia, acute respiratory tract infection, severe acute respiratory tract infection, hypoxic respiratory failure and acute respiratory distress syndrome, sepsis or septic shock.

[0074] In a further preferred embodiment of the present invention, the single administration dose of the Mpro inhibitor combined with the RdRp inhibitor, the single administration dose of the RdRp inhibitor, or the single administration total dose of the Mpro inhibitor and the RdRp inhibitor are independently selected from 1 mg to 1500 mg. In some embodiments, the single dose of the Mpro inhibitor in combination with the RdRp inhibitor, the single dose of the RdRp inhibitor, or the total single dose of the Mpro inhibitor and the RdRp inhibitor is independently selected from 1 mg, 1.5 mg, 2.0 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, 5 mg, 5.5 mg, 6.0 mg, 6.5 mg, 7.0 mg, 7.5 mg, 8.0 mg, 8.5 mg, 9.0 mg, 9.5 mg, 10 mg, 10.5 mg, 11 mg, 11.5 mg, 12 mg, 12.5 mg, 13 mg, 13.5 mg, 14 mg, 14.5 mg, 15 mg, 15.5 mg, 16 mg, 16.5 mg, 17 mg, 17.5 mg, 18 mg, 18.5 mg, 19 mg, 19.5 mg, 20 mg, 22.5mg, 25mg, 27.5mg, 30mg, 32.5mg, 35mg, 37.5mg, 40mg, 42.5mg, 45mg, 47.5mg, 50mg, 52.5m g, 55mg, 60mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 150mg, 200mg, 250mg, 300mg, 350mg, 400mg, 450mg, 500mg, 550mg, 600mg, 650mg, 700mg, 750mg, 800mg, 850mg, 900mg, 950mg , 1000mg, 1050mg, 1100mg, 1150mg, 1200mg, 1250mg, 1300mg, 1350mg, 1400mg, 1450mg, 1500mg.

[0075] In a further preferred embodiment of the present invention, the administration frequency of the Mpro inhibitor combined with the RdRp inhibitor is selected from once a day, twice a day or three times a day.

[0076] In a preferred embodiment of the present invention, the single administration dose of the Mpro inhibitor combined with the RdRp inhibitor, the single administration dose of the RdRp inhibitor, or the single administration total dose of the Mpro inhibitor and the RdRp inhibitor are independently selected from 1 mg-1500 mg. In some embodiments, the single dose of the Mpro inhibitor in combination with the RdRp inhibitor, the single dose of the RdRp inhibitor, or the total single dose of the Mpro inhibitor and the RdRp inhibitor is independently selected from 1 mg, 1.5 mg, 2.0 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, 5 mg, 5.5 mg, 6.0 mg, 6.5 mg, 7.0 mg, 7.5 mg, 8.0 mg, 8.5 mg, 9.0 mg, 9.5 mg, 10 mg, 10.5 mg, 11 mg, 11.5 mg, 12 mg, 12.5 mg, 13 mg, 13.5 mg, 14 mg, 14.5 mg, 15 mg, 15.5 mg, 16 mg, 16.5 mg, 17 mg, 17.5 mg, 18 mg, 18.5 mg, 19 mg, 19.5 mg, 20 mg, 22.5mg, 25mg, 27.5mg, 30mg, 32.5mg, 35mg, 37.5mg, 40mg, 42.5mg, 45mg, 47.5mg, 50mg, 52.5m g, 55mg, 60mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 150mg, 200mg, 250mg, 300mg, 350mg, 400mg, 450mg, 500mg, 550mg, 600mg, 650mg, 700mg, 750mg, 800mg, 850mg, 900mg, 950mg , 1000mg, 1050mg, 1100mg, 1150mg, 1200mg, 1250mg, 1300mg, 1350mg, 1400mg, 1450mg, 1500mgo

[0077] In a further preferred embodiment of the present invention, the frequency of administration of the Mpro inhibitor combined with the RdRp inhibitor is once a day, and the single dose of the Mpro inhibitor combined with the RdRp inhibitor, the single dose of the RdRp inhibitor, or the total single dose of the Mpro inhibitor and the RdRp inhibitor are independently selected from 1 mg to 1500 mg. In some embodiments, the frequency of administration of the Mpro inhibitor combined with the RdRp inhibitor is once a day, and the single dose of the Mpro inhibitor combined with the RdRp inhibitor, the single dose of the RdRp inhibitor, or the total single dose of the Mpro inhibitor and the RdRp inhibitor are independently selected from 1 mg, 1.5 mg, 2.0 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, 5 mg, 5.5 mg, 6.0 mg, 6.5 mg, 7.0 mg, 7.5 mg, 8.0 mg, 8.5 mg, 9.0 mg, 9.5 mg, 10 mg, 10.5 mg, 11 mg, 11.5 mg, 12 mg, 12.5 mg, 13 mg, 13.5 mg, 14 mg, 14.5 mg, 15 mg, 15.5 mg, 16 mg, 16.5 mg, 17 mg, 17.5 mg, 18 mg, 18.5 mg, 19 mg, g, 19.5mg, 20mg, 22.5mg, 25mg, 27.5mg, 30mg, 32.5mg, 35mg, 37.5mg, 40mg, 42.5mg, 45mg, 47.5mg , 50mg, 52.5mg, 55mg, 60mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 150mg, 200mg, 250mg , 300mg, 350mg, 400mg, 450mg, 500mg, 550mg, 600mg, 650mg, 700mg, 750mg, 800mg, 850mg, 900mg, 95 0mg, 1000mg, 1050mg, 1100mg, 1150mg, 1200mg, 1250mg, 1300mg, 1350mg, 1400mg, 1450mg, 1500mg.

[0078] In some embodiments, an Mpro inhibitor and a Rdrp inhibitor are applied simultaneously, concurrently, independently or sequentially.

[0079] In some embodiments, the Mpro inhibitor and the RdRp inhibitor are formulated to be administered once daily, twice daily, or three times daily on the same day.

[0080] In some embodiments, the Mpro inhibitor and the RdRp inhibitor are formulated to be co-delivered in a common oral dosage unit.

[0081] In some embodiments, the Mpro inhibitor and the RdRp inhibitor are formulated to be administered in separate oral dosage units.

[0082] Beneficial Effects

[0083] Compared with the prior art, the present invention has the following outstanding advantages and beneficial effects:

[0084] Advantages of the present invention:

[0085] 1. The present invention provides a compound pharmaceutical composition, preparation, and kit product, which consists of an Mpro inhibitor and an RdRp inhibitor, and contains a first active ingredient, an Mpro inhibitor (Y62222), and a second active ingredient, an RdRp inhibitor (ATV014), in a molar ratio within a specific range. The compound pharmaceutical composition, preparation, and kit product has a synergistic effect and is considered to have good drug development prospects after comprehensive evaluation.

[0086] 2. The compound pharmaceutical composition, preparation, and medicine kit products provided by the present invention can flexibly select dosage ratios, and combined use can improve the antiviral efficacy and reduce the drug resistance problem that may be caused by the use of a single drug.

[0087] 3. The compound pharmaceutical composition, preparation and medicine kit products provided by the present invention have lower side effects and reduce the burden on the patient's body.

[0088] 4. The preparation methods of the compound pharmaceutical composition, preparation and medicine kit products provided by the present invention are simple and easy to implement for large-scale production.

[0089] 5. The preparation method of the compound pharmaceutical composition, preparation, and medicine kit product provided by the present invention takes into account the selection of pharmaceutically acceptable carriers and excipients, which helps to improve the stability and bioavailability of the compound pharmaceutical composition preparation.

[0090] 6. By using different excipients, the compound pharmaceutical composition, preparation, and medicine kit products provided by the present invention can meet the needs of different patients and improve patient compliance.

[0091] 7. Provided is a pharmaceutical use, wherein the pharmaceutical use of the compound pharmaceutical composition, preparation, and medicine kit product utilizes the synergistic effect between drugs to achieve better therapeutic effects.

[0092] 8. IC of Y62222 50 =0.0622μM, IC of ATV014 50 =0.1814μM, when the molar ratio of Y62222 to ATV014 is 1:1, IC 50=0.04987μM. Y62222 and ATV014 have a synergistic effect when combined; especially when the molar ratio of the two is 5:1~1:

[0093] The synergistic effect is strongest at 10 o'clock.

[0094] The contribution of the present invention lies in the discovery that drugs within a specific range have synergistic effects. Therefore, those skilled in the art can understand that when the types and proportions of active ingredients in a unit dosing unit are within the scope described in the present invention, it can be considered that the technical scheme protected by the present invention is used; specifically, the aforementioned unit dosing unit or single-dose administration or single-dose specification refers to the smallest unit for clinical use, such as: a unit tablet, a unit capsule, a unit bottle of oral liquid, a unit package of granules, etc.

[0095] Definitions and general terms

[0096] Certain embodiments of the present invention are now described in detail, examples of which are illustrated by the accompanying structural formulas and chemical formulae. The present invention is intended to cover all alternatives, modifications, and equivalent technical solutions, which are all included within the scope of the present invention as defined in the claims. It should be recognized by those skilled in the art that many methods and materials similar or equivalent to those described herein can be used to practice the present invention. The present invention is in no way limited to the methods and materials described herein. In the event that one or more of the combined documents, patents, and similar materials differ from or contradict the present application (including but not limited to defined terms, term uses, described techniques, etc.), the present application shall prevail.

[0097] It should be further appreciated that certain features of the invention, which for clarity are described in multiple separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which for brevity are described in a single embodiment, may also be provided separately or in any suitable sub-combination.

[0098] The term "comprising" is an open expression, that is, including the contents specified in the present invention but not excluding other contents.

[0099] The term "pharmaceutically acceptable" means that salts, solvents, excipients, etc. are generally non-toxic, safe, and suitable for use by patients. The "patient" is preferably a mammal, more preferably a human.

[0100] The term "single dose" refers to the dosage unit or each dosage unit in the pharmaceutical preparation (such as each tablet, each capsule, each packet of powder, each packet of granules, each pill, each lozenge or each bottle of oral liquid).

[0101] The term "single dose strength" refers to the mass or molar amount of the active ingredient in the dosage unit or per dosage unit in the pharmaceutical preparation (e.g., per tablet, per capsule, per packet of powder, per packet of granules, per pill, per lozenge or per bottle of oral liquid).

[0102] The "pharmaceutically acceptable salt" used in the present invention refers to the organic salt and inorganic salt of the compound of the present invention. Pharmaceutically acceptable salts are well known in the art, as described in the literature: SM Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66: 1-19. Pharmaceutically acceptable salts formed by non-toxic acids include, but are not limited to, inorganic acid salts formed by reaction with amino groups: hydrochlorides, hydrobromides, phosphates, sulfates, perchlorates, and organic acid salts such as acetates, oxalates, maleates, tartrates, citrates, succinates, malonates, or other methods described in books and literature, such as ion exchange methods, to obtain these salts. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, cyclopentylpropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, stearate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C 1-4 The present invention also contemplates quaternary ammonium salts formed by compounds of any N group. Water-soluble or oil-soluble or dispersible products can be obtained by quaternization. Alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Pharmaceutically acceptable salts further include appropriate, non-toxic ammonium, quaternary ammonium salts and amine cations formed by counter-balancing ions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, Ci-s sulfonates and aromatic sulfonates.

[0103] The "solvate" of the present invention refers to an association formed by one or more solvent molecules and the compound of the present invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid and aminoethanol. The term "hydrate" refers to an association formed by a solvent molecule that is water.

[0104] "Combination" means a fixed combination in a single dosage unit form or a kit of parts for combined administration, wherein the compounds disclosed herein and the combination partner can be administered independently at the same time or can be administered separately at certain time intervals, especially so that the combination partner exhibits a cooperative, such as synergistic effect. The terms "pharmaceutical composition" or "combined administration" and the like as used herein are intended to encompass administration of the selected combination partners to a single individual (e.g., patient) in need thereof, and are intended to include treatment regimens in which the substances are not necessarily administered by the same route of administration or at the same time.

[0105] The term "treat" refers to therapeutic treatment. When referring to a specific condition, treatment means: (1) ameliorating the disease or one or more biological manifestations of the condition, (2) interfering with (a) one or more points in the biological cascade leading to or causing the condition or (b) one or more biological manifestations of the condition, (3) ameliorating one or more symptoms, effects, or side effects associated with the condition or one or more symptoms, effects, or side effects associated with the condition or its treatment, or (4) slowing the progression of the condition or one or more biological manifestations of the condition.

[0106] The term "therapeutically effective amount" refers to an amount of a compound that is effective in treating a disease or condition described herein when administered to a patient."Therapeutically effective amount" will vary depending on the compound, the condition and its severity, and the age of the patient to be treated, and can be adjusted as needed by those skilled in the art. BRIEF DESCRIPTION OF THE DRAWINGS

[0107] Figure 1 The figure shows a bar graph of the virus inhibition rate of Y62222 in Example 1 of the present invention when used in combination with ATV014 at different concentrations.

[0108] Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention. DETAILED DESCRIPTION

[0109] The present invention is further described in detail below with reference to examples, but the embodiments of the present invention are not limited thereto.

[0110] Y62222 is a triazine small molecule inhibitor targeting the main protease (Mpro / 3CLpro) jointly developed by Hubei Jiukangtong Biotechnology Co., Ltd. and Fukang (Shanghai) Health Technology Co., Ltd. It has a broad-spectrum antiviral activity against various coronaviruses, and also exhibits strong inhibitory activity against the E166V mutant strain of the new coronavirus (SARS-CoV-2) that is resistant to the 3CL protein of nematevir (PF-07321332).

[0111]

[0112] ATV014, CAS: 2691076-98-7, was jointly developed by Zhang Xumu's team from Southern University of Science and Technology and Guo Deyin's team from Sun Yat-sen University. It is a nucleoside compound that can inhibit RNA polymerase (RdRp). It has good in vitro antiviral activity, pharmacokinetics, in vivo antiviral effects and broad-spectrum anti-coronavirus activity.

[0113]

[0114] The novel coronavirus has the characteristics of high mutation rate and frequent inter-virus recombination, which affect the therapeutic effect of drugs currently on the market. Although new structures and new mechanisms of active compounds are constantly being discovered, in the long run, the use of a single antiviral drug may lead to drug resistance. For example, there are reports that Paxlovid has developed drug resistance. Simply increasing the dosage may bring additional medication risks.

[0115] The above shows that finding new solutions to enhance the activity of Mpro and RdRp inhibitors is one of the effective solutions to drug resistance. Extending the service life of drugs that have clinical prospects for anti-new coronavirus-induced lung infections is a technical problem that needs to be urgently solved in existing technologies.

[0116] The Y62222 and ATV014 described in the present invention can be prepared by referring to the methods disclosed in the prior art, such as referring to the methods disclosed in Example 2 of patent PCT / CN2023080920 and Example 17 of CN202111083730.9, respectively.

[0117] Specifically, Y62222 and ATV014 used in the examples of the present invention are both homemade raw materials with a purity of >99%.

[0118] Example 1: Preparation of (E)-6-((6-chloro-2-methyl-2H-indazol-5-yl)imino)-3-((1-(methyl-d3)-1H-1,2,4-triazol-3-yl)methyl)-1-(2,4,5-trifluorobenzyl)-1,3,5-triazinane-2,4-dione (I-2, i.e., compound Y62222)

[0119]

[0120] Prepared by Synthesis Method 1:

[0121]

[0122] Step 1: Intermediate 2-02

[0123] Dissolve 2-01 (127.1 g, 1.0 mol) in anhydrous tetrahydrofuran (1000 mL), cool in an ice bath, add sodium hydride (60%, 44 g), react for about 30 min, then add deuterated iodomethane (159.5 g, 1.1 mol) dropwise, warm to room temperature and stir to react for 2 h, add water to quench, extract with dichloromethane, combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter and concentrate, and purify by column chromatography to obtain 2-02. 1 H NMR (400MHz, CDCl3) δ8.17 (s, 1H), 4.01 (s, 3H); LC-MS (ESI) 145.1 [M+1] + .

[0124] Step 2: Intermediate 2-03

[0125] Under nitrogen protection, 2-02 (57.6 g, 400 mmol) was dissolved in anhydrous tetrahydrofuran (500 mL), and a solution of lithium aluminum tetrahydride (18.5 g, 440 mmol) in tetrahydrofuran (100 mL) was added dropwise. The mixture was heated to reflux for 1 h, cooled to room temperature, and water was slowly added to quench. Anhydrous magnesium sulfate was then added, stirred for 1 h, filtered, concentrated, and purified by column chromatography to obtain 2-03. 1 H NMR (400MHz, CDCl3) δ8.04 (d, J = 36.0Hz, 1H), 4.76 (s, 2H), 3.48 (s, 1H); LC-MS (ESI) 117.1 [M+1] + .

[0126] Step 3: Intermediate 2-04

[0127] Dissolve 2-03 (35.1 g, 300 mmol) in anhydrous dichloromethane (100 mL), add thionyl chloride (50 mL), stir at room temperature for 3 h, and concentrate under reduced pressure to remove the solvent and excess thionyl chloride. Slurry the residue with ether, filter, and dry in vacuo to obtain 2-04. 1 H NMR (400MHz, DMSO) δ8.06 (s, 1H), 4.78 (s, 2H); LC-MS (ESI): 135 [M+H] + .

[0128] Step 4: Intermediate 2-05

[0129] Dissolve 1-06 (2.50 g, 7.88 mmol) and 2-04 (1.99 g, 11.8 mmol) in DMF (23 mL), add anhydrous potassium carbonate (3.27 g, 23.6 mmol), heat to 60 ° C and stir to react for 4 h. Cool to room temperature, pour the reaction solution into an aqueous solution of ammonium chloride, solid precipitates, filter, wash with water, and recrystallize the solid with ethanol to obtain 2-05. 1 H NMR(400MHz, DMSO-d6)δ8.36(s,1H),7.57-7.70(m,1H),7.38-7.52(m,1H),5.12(s,2H),4.98(s,2H),3.15(q,2H),1.28(t,3H); LC-MS(ESI):416[M+H] + .

[0130] Step 5: Synthesis of target compound I-2 (ie compound Y62222)

[0131] Dissolve 2-05 (5.0 g, 12.6 mmol) and 1-11 (2.06 g, 18.9 mmol) in a mixture of acetic acid (11.32 g, 189 mmol) and tert-butanol (100 mL), heat and reflux with stirring for 3 hours, cool to room temperature, add the reaction solution into a saturated sodium bicarbonate aqueous solution (500 mL), extract with ethyl acetate (500 mL), combine the organic phases, wash with water, dry with anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The residue is separated by silica gel column chromatography (eluted with dichloromethane-methanol gradient) to obtain I-2. 1 H NMR (400MHZ, DMSO-d6): 4.14(s,3H),4.92(s,2H),5.23(s,2H),7.45-7.65(m,2H),7.71(s,1H),8.29(s,1H),8.35(s,1H); 1 H NMR(400MHz,Pyridine-d5)δ8.33(s,1H),8.02-7.91(m,1H),7.87(s,2H),7.86(s,1H),7.38 (s,1H),7.13-7.22(m,1H),5.66(s,3H),5.57(s,3H),3.99(s,3H); LC-MS(ESI,m / z)535[M+H] + .

[0132] Or prepared according to Synthesis Method 2:

[0133]

[0134] Step 1: Synthesis of Intermediate 2-06

[0135] Dissolve 1-06 (6.35 g, 20.0 mmol) and 1-11 (5.45 g, 30.0 mmol) in acetic acid (50 mL), heat and reflux with stirring for 5 hours, cool to room temperature, solid precipitates, filter, wash with water, and dry to obtain 2-06. 1 H-NMR (400MHz, DMSO-d6): δ11.33(s,1H),11.63(s,1H),8.26(s,1H),7.69-7 .56(m,3H),7.13(s,1H),5.15(s,2H),4.16(s,3H); MS(ESI,m / z)437.2[M+H] + .

[0136] Step 2: Synthesis of Compound I-2 (ie Compound Y62222)

[0137] Dissolve 2-06 (4.19 g, 10.0 mmol) and 2-04 (2.56 g, 15.0 mmol) in DMA (23 mL), add anhydrous cesium carbonate (4.14 g, 30.0 mmol), heat to 60 ° C and stir to react for 6 h. Cool to room temperature, pour the reaction solution into an aqueous solution of ammonium chloride, solid precipitates, filter, wash with water, and dry to obtain a crude product, which is purified by silica gel column chromatography (dichloromethane / methanol gradient elution) to obtain I-2. 1 H NMR (400MHZ, DMSO-d6): 4.14(s,3H),4.92(s,2H),5.23(s,2H),7.45-7.65(m,2H),7.71(s,1H),8.29(s,1H),8.35(s,1H); 1 H NMR(400MHz,Pyridine-d5)δ8.33(s,1H),8.02-7.91(m,1H),7.87(s,2H),7.86(s,1H),7.38 (s,1H),7.13-7.22(m,1H),5.66(s,3H),5.57(s,3H),3.99(s,3H); LC-MS(ESI,m / z)535[M+H] + .

[0138] Example 2: Preparation of a compound pharmaceutical composition having a molar ratio of 1:1 between compound Y62222 and ATV014

[0139] 0.5349 g of Y62222 prepared in Example 1 was taken and mixed evenly with 0.4014 g of ATV014 to obtain a pharmaceutical composition with a molar ratio of 1:1.

[0140] Example 3: Preparation of a compound pharmaceutical composition having a molar ratio of 1:1.5 between compound Y62222 and ATV014

[0141] 0.5349 g of Y62222 prepared in Example 1 was taken and mixed evenly with 0.6021 g of ATV014 to obtain a pharmaceutical composition with a molar ratio of 1:1.5.

[0142] Example 4: Preparation of a compound pharmaceutical composition having a molar ratio of 1:2 between compound Y62222 and ATV014

[0143] 0.5349 g of Y62222 prepared in Example 1 was taken and mixed evenly with 0.8028 g of ATV014 to obtain a pharmaceutical composition with a molar ratio of 1:2.

[0144] Example 5: Preparation of a compound pharmaceutical composition having a molar ratio of 1:3 between compound Y62222 and ATV014

[0145] 0.5349 g of Y62222 prepared in Example 1 was taken and mixed evenly with 1.2042 g of ATV014 to obtain a pharmaceutical composition with a molar ratio of 1:3.

[0146] Example 6: Preparation of a compound pharmaceutical composition having a molar ratio of 1:5 between compound Y62222 and ATV014

[0147] 0.5349 g of Y62222 prepared in Example 1 was taken and mixed evenly with 2.007 g of ATV014 to obtain a pharmaceutical composition with a molar ratio of 1:5.

[0148] Example 7: Preparation of a compound pharmaceutical composition having a molar ratio of 1:10 between compound Y62222 and ATV014

[0149] 0.05349 g of Y62222 prepared in Example 1 was taken and mixed evenly with 0.4014 g of ATV014 to obtain a pharmaceutical composition with a molar ratio of 1:10.

[0150] Example 8: Preparation of a compound pharmaceutical composition having a molar ratio of 1:20 between compound Y62222 and ATV014

[0151] 0.05349 g of Y62222 prepared in Example 1 was taken and mixed evenly with 0.8028 g of ATV014 to obtain a pharmaceutical composition with a molar ratio of 1:20.

[0152] Example 9: Preparation of a compound pharmaceutical composition having a molar ratio of 1:30 between compound Y62222 and ATV014

[0153] 0.05349 g of Y62222 prepared in Example 1 was taken and mixed evenly with 1.2042 g of ATV014 to obtain a pharmaceutical composition with a molar ratio of 1:30.

[0154] Example 10: Preparation of a compound pharmaceutical composition having a molar ratio of 1:40 between compound Y62222 and ATV014

[0155] 0.05349 g of Y62222 prepared in Example 1 was taken and mixed evenly with 1.6056 g of ATV014 to obtain a pharmaceutical composition with a molar ratio of 1:40.

[0156] Example 11: Preparation of a compound pharmaceutical composition having a molar ratio of 1:50 between compound Y62222 and ATV014

[0157] 0.05349 g of Y62222 prepared in Example 1 was taken and mixed evenly with 2.007 g of ATV014 to obtain a pharmaceutical composition with a molar ratio of 1:50.

[0158] Example 12: Preparation of a compound pharmaceutical composition having a molar ratio of 1.5:1 between compound Y62222 and ATV014

[0159] 0.8024 g of Y62222 prepared in Example 1 was taken and mixed evenly with 0.4014 g of ATV014 to obtain a pharmaceutical composition with a molar ratio of 1.5:1.

[0160] Example 13: Preparation of a compound pharmaceutical composition having a molar ratio of 2:1 between compound Y62222 and ATV014

[0161] 1.0698 g of Y62222 prepared in Example 1 was taken and mixed evenly with 0.4014 g of ATV014 to obtain a pharmaceutical composition with a molar ratio of 2:1.

[0162] Example 14: Preparation of a compound pharmaceutical composition having a molar ratio of 3:1 between compound Y62222 and ATV014

[0163] 1.6047 g of Y62222 prepared in Example 1 was taken and mixed evenly with 0.4014 g of ATV014 to obtain a pharmaceutical composition with a molar ratio of 3:1.

[0164] Example 15: Preparation of a compound pharmaceutical composition having a molar ratio of 5:1 between compound Y62222 and ATV014

[0165] 2.6745 g of Y62222 prepared in Example 1 was taken and mixed evenly with 0.4014 g of ATV014 to obtain a pharmaceutical composition with a molar ratio of 5:1.

[0166] Example 16: Preparation of a compound pharmaceutical composition having a molar ratio of 10:1 between compound Y62222 and ATV014

[0167] 0.5349 g of Y62222 prepared in Example 1 was taken and mixed evenly with 0.04014 g of ATV014 to obtain a pharmaceutical composition with a molar ratio of 10:1.

[0168] Example 17: Preparation of a compound pharmaceutical composition having a molar ratio of 20:1 between compound Y62222 and ATV014

[0169] 1.0698 g of Y62222 prepared in Example 1 was taken and mixed evenly with 0.04014 g of ATV014 to obtain a pharmaceutical composition with a molar ratio of 20:1.

[0170] Example 18: Preparation of a compound pharmaceutical composition having a molar ratio of 30:1 between compound Y62222 and ATV014

[0171] 1.6047 g of Y62222 prepared in Example 1 was taken and mixed evenly with 0.04014 g of ATV014 to obtain a pharmaceutical composition with a molar ratio of 30:1.

[0172] Example 19: Preparation of a compound pharmaceutical composition having a molar ratio of 40:1 between compound Y62222 and ATV014

[0173] 2.1396 g of Y62222 prepared in Example 1 was taken and mixed evenly with 0.04014 g of ATV014 to obtain a pharmaceutical composition with a molar ratio of 40:1.

[0174] Example 20: Preparation of a compound pharmaceutical composition having a molar ratio of 50:1 between compound Y62222 and ATV014

[0175] 2.6745 g of Y62222 prepared in Example 1 was taken and mixed evenly with 0.04014 g of ATV014 to obtain a pharmaceutical composition with a molar ratio of 50:1.

[0176] Example 21: Screening and Optimization of Y62222 and ATV014 Compound Pharmaceutical Compositions Using A549-hACE2 Cells (Human Lung Cancer Cell Line)

[0177] Experimental strain: SARS-CoV-2 (B.1, hCoV-19 / CHN / SYSU-IHV / 2020 strain, Accession IDon GISAID:EPI_ISL_444969)

[0178] Experimental cell line: A549-hACE2 cells (human lung cancer cell line) were constructed and maintained by pLVX-EF1α-IRES-Puro lentiviral expression vector and cultured in DMEM medium containing 10% fetal bovine serum, 100 U / ml penicillin and 100 μg / ml streptomycin.

[0179] Experimental location: Biosafety Level 3 Laboratory, Sun Yat-sen University;

[0180] Experimental method: Cells in the logarithmic growth phase were inoculated with A549-hACE2 cells (10 4 Cells / well) were plated on a 96-well plate. After 24 hours of cell attachment, SARS-CoV-2 was infected with an MOI of 0.05. After infection at 37°C for 1 hour, the cells were washed twice with preheated PBS solution and culture medium containing different concentrations of the drug to be tested or DMSO was added (the final concentrations of Y62222 and / or ATV014 are shown in Table 1 or Table 2). After 48 hours, the supernatant was collected, and the virus in the cell supernatant was detected by fluorescence quantitative PCR and the drug inhibition rate was calculated, as shown in Tables 1 and Figure 1 .

[0181] The formula for calculating the inhibitory rate of the compound against the virus is as follows: Inhibition rate (%) = (1-(the number of virus copies in the cell supernatant of the compound group / the number of virus copies in the cell supernatant of the control group))×100%.

[0182] Table 1: Inhibition rate of SARS-CoV-2 virus by Y62222 and ATV014 alone / in combination in human lung cancer cells for 48 hours

[0183]

[0184] Table 2: Inhibition rate of SARS-CoV-2 virus by Y62222 and ATV014 alone / in combination after 48 hours of action on human lung cancer cells (average value)

[0185]

[0186]

[0187] The experimental results are shown in Table 1, Table 2 and Figure 1 As shown, the results show:

[0188] (1) When compound Y62222 was used alone at 0.1 μM, the inhibition rate was about 90%, and when it was used at 0.5 μM, the inhibition rate reached 99%; when ATV014 was used alone at 0.1 μM, the inhibition rate was about 15%, and when it was used at 0.5 μM, the inhibition rate was about 95%. That is, when Y62222 or ATV014 was used alone, it was observed that the anti-new coronavirus activity increased with the increase of drug treatment concentration;

[0189] (2) ATV014 alone had no antiviral effect at a concentration of 0.01 μM, and the inhibition rate of Y62222 alone at 0.05 μM was only 27%. However, when Y62222 0.05 μM was used in combination with ATV014 0.01 μM, the virus inhibition rate increased to 45%; when Y62222 0.05 μM was used in combination with ATV014 0.1 μM, the combined virus inhibition rate increased to 87%, reflecting a significant synergistic effect; when Y62222 0.1 μM was used in combination with ATV014 0.01 μM, the combined virus inhibition rate increased to 94%, also reflecting a significant synergistic effect. At 0.05 μM of Y62222, the antiviral activity showed a trend of significantly increasing with the increasing concentration of ATV014, reflecting a significant synergistic effect of combined use; in addition, at 0.01 μM of ATV014, the antiviral activity showed a trend of significantly increasing with the increasing concentration of Y62222, reflecting a significant synergistic effect of combined use. That is, the antiviral effect of Y62222 combined with ATV014 at the cellular level is improved.

[0190] (3) The other groups also showed obvious synergistic antiviral activity of combined use.

[0191] In summary, it can be seen that at the cellular level, the antiviral effect of Y62222 and ATV014 combined is improved. In vitro activity experiments show that Y62222 and ATV014 have a certain synergistic effect in vitro, and have a better anti-coronavirus effect than the experimental groups using Y62222 alone and ATV014 alone.

[0192] Example 22: Analysis of the effect of combined administration of Y62222 and ATV014

[0193] The drug combination index (CI) is a quantitative index used to evaluate the synergistic, antagonistic or additive effects of drug combination therapy. The calculation of the CI value is based on the Chou-Talalay method, which is based on the quantitative principle of the effects of multiple drugs. Based on the Median-effect Principle (or Chou-Talalay combination index method), the CombiDrug and Calcusyn statistical software are used to draw the dose-effect curve and the combination index curve under different effects. The relationship between the effect of the combination of two drugs and the combination index is used to quantitatively evaluate whether the two drugs are synergistic, antagonistic or additive. The formula for calculating the CI value is as follows: CI = D1 / Dx1 + D2 / Dx2 + α(D1D2) / (DX1 DX2). Where: D1, D2, respectively represent the actual dosage of the two drugs in the drug combination. DX1, DX2, respectively represent the dosage of the drugs required to achieve the same biological effect when the two drugs are used alone. α = 0 means two mutually exclusive drugs, and α = 1 means two mutually non-exclusive drugs. Y62222 and ATV014 have different mechanisms of action, so α=0 was taken in this experiment.

[0194] According to the Median-effect Principle, the calculated CI value can be used to evaluate the effect of the drug combination: CI < 1 indicates synergistic effect; CI = 1 indicates additive effect; CI > 1 indicates antagonistic effect. After software analysis, the compound pharmaceutical composition of the present invention has good synergistic effect. IC of Y62222 50 =0.0622μM, IC of ATV014 50 =0.1814μM, when the molar ratio of Y62222 to ATV014 is 1:1, IC 50 =0.04987 μM. The combination of Y62222 and ATV014 has a synergistic effect, especially when the molar ratio of the two is 5:1 to 1:10, the synergistic effect is the strongest.

[0195] From the above activity test results, it can be seen that when the ratio of Y62222 to ATV014 is 1:50 to 50:1, there is a good drug synergy between the active ingredients, which is manifested as a significantly better anti-new coronavirus effect than a single ingredient, and also manifested as a significantly better anti-new coronavirus effect than the pharmaceutical composition with a molar ratio outside the aforementioned specific range. Specifically, the anti-new coronavirus effect when the molar ratio of Y62222 to ATV014 is 10:1, 5:1, 3:1, 2:1, 1.5:1, 1:1, 1:1.5, 1:2, 1:3, 1:5, 1:10 is significantly better than the effect of using Y62222 alone and ATV014 alone, and is also significantly better than the anti-new coronavirus effect of the pharmaceutical composition with a molar ratio not within this specific range.

[0196] Example 23: Preparation of tablets of the compound pharmaceutical composition of Y62222 and ATV014

[0197] The pharmaceutical composition obtained in Example 2 was mixed with an appropriate amount of excipients and / or pharmaceutically acceptable carriers and directly compressed into tablets (the combined mass of Y62222 and ATV014 was: 0.5349 mg Y62222+0.4014 mg ATV014).

[0198] The pharmaceutical composition obtained in Example 3 was mixed with an appropriate amount of excipients and / or pharmaceutically acceptable carriers and then directly compressed into tablets (the combined mass of Y62222 and ATV014 was: 0.5349 mg Y62222+0.6021 mg ATV014).

[0199] The pharmaceutical composition obtained in Example 4 was mixed with an appropriate amount of excipients and / or pharmaceutically acceptable carriers and directly compressed into tablets (the combined mass of Y62222 and ATV014 was: 0.5349 mg Y62222+0.8028 mg ATV014).

[0200] The pharmaceutical composition obtained in Example 5 was mixed with an appropriate amount of excipients and / or pharmaceutically acceptable carriers and directly compressed into tablets (the combined mass of Y62222 and ATV014 was: 0.5349 mg Y62222+1.2042 mg ATV014).

[0201] The pharmaceutical composition obtained in Example 6 was mixed with an appropriate amount of excipients and / or pharmaceutically acceptable carriers and directly compressed into tablets (the combined mass of Y62222 and ATV014 was: 0.5349 mg Y62222+2.007 mg ATV014).

[0202] The pharmaceutical composition obtained in Example 7 was mixed with an appropriate amount of excipients and / or pharmaceutically acceptable carriers and directly compressed into tablets (the combined mass of Y62222 and ATV014 was: 0.05349 mg Y62222+0.4014 mg ATV014).

[0203] The pharmaceutical composition obtained in Example 8 was mixed with an appropriate amount of excipients and / or pharmaceutically acceptable carriers and directly compressed into tablets (the combined mass of Y62222 and ATV014 was: 0.05349 mg Y62222+0.8028 mg ATV014).

[0204] The pharmaceutical composition obtained in Example 9 was mixed with an appropriate amount of excipients and / or pharmaceutically acceptable carriers and directly compressed into tablets (the combined mass of Y62222 and ATV014 was: 0.05349 mg Y62222+1.2042 mg ATV014).

[0205] The pharmaceutical composition obtained in Example 10 was mixed with an appropriate amount of excipients and / or pharmaceutically acceptable carriers and then directly compressed into tablets (the combined mass of Y62222 and ATV014 was: 0.05349 mg Y62222+1.6056 mg ATV014).

[0206] The pharmaceutical composition obtained in Example 11 was mixed with an appropriate amount of excipients and / or pharmaceutically acceptable carriers and directly compressed into tablets (the combined mass of Y62222 and ATV014 was: 0.05349 mg Y62222+2.007 mg ATV014).

[0207] The pharmaceutical composition obtained in Example 12 was mixed with an appropriate amount of excipients and / or pharmaceutically acceptable carriers and directly compressed into tablets (the combined mass of Y62222 and ATV014 was: 0.8024 mg Y62222+0.4014 mg ATV014).

[0208] The pharmaceutical composition obtained in Example 13 was mixed with an appropriate amount of excipients and / or pharmaceutically acceptable carriers and directly compressed into tablets (the combined mass of Y62222 and ATV014 was: 1.0698 mg Y62222 + 0.4014 mg ATV014).

[0209] The pharmaceutical composition obtained in Example 14 was mixed with an appropriate amount of excipients and / or pharmaceutically acceptable carriers and directly compressed into tablets (the combined mass of Y62222 and ATV014 was: 1.6047 mg Y62222 + 0.4014 mg ATV014).

[0210] The pharmaceutical composition obtained in Example 15 was mixed with an appropriate amount of excipients and / or pharmaceutically acceptable carriers and directly compressed into tablets (the combined mass of Y62222 and ATV014 was: 2.6745 mg Y62222 + 0.4014 mg ATV014).

[0211] The pharmaceutical composition obtained in Example 16 was mixed with an appropriate amount of excipients and / or pharmaceutically acceptable carriers and directly compressed into tablets (the combined mass of Y62222 and ATV014 was: 0.5349 mg Y62222 + 0.04014 mg ATV014).

[0212] The pharmaceutical composition obtained in Example 17 was mixed with an appropriate amount of excipients and / or pharmaceutically acceptable carriers and directly compressed into tablets (the combined mass of Y62222 and ATV014 was: 1.0698 mg Y62222 + 0.04014 mg ATV014).

[0213] The pharmaceutical composition obtained in Example 18 was mixed with an appropriate amount of excipients and / or pharmaceutically acceptable carriers and directly compressed into tablets (the combined mass of Y62222 and ATV014 was: 1.6047 mg Y62222 + 0.04014 mg ATV014).

[0214] The pharmaceutical composition obtained in Example 19 was mixed with an appropriate amount of excipients and / or pharmaceutically acceptable carriers and directly compressed into tablets (the combined mass of Y62222 and ATV014 was: 2.1396 mg Y62222 + 0.04014 mg ATV014).

[0215] The pharmaceutical composition obtained in Example 20 was mixed with an appropriate amount of excipients and / or pharmaceutically acceptable carriers and directly compressed into tablets (the combined mass of Y62222 and ATV014 was: 2.6745 mg Y62222 + 0.04014 mg ATV014).

[0216] Example 24: Preparation of tablets of the compound pharmaceutical composition of Y62222 and ATV014

[0217] The pharmaceutical composition obtained in Example 2 was mixed with an appropriate amount of excipients and / or pharmaceutically acceptable carriers and directly compressed into tablets (the combined mass of Y62222 and ATV014 was: 5.349 mg Y62222+4.014 mg ATV014).

[0218] The pharmaceutical composition obtained in Example 3 was mixed with an appropriate amount of excipients and / or pharmaceutically acceptable carriers and directly compressed into tablets (the combined mass of Y62222 and ATV014 was: 5.349 mg Y62222+6.021 mg ATV014).

[0219] The pharmaceutical composition obtained in Example 4 was mixed with an appropriate amount of excipients and / or pharmaceutically acceptable carriers and directly compressed into tablets (the combined mass of Y62222 and ATV014 was: 5.349 mg Y62222+8.028 mg ATV014).

[0220] The pharmaceutical composition obtained in Example 5 was mixed with an appropriate amount of excipients and / or pharmaceutically acceptable carriers and directly compressed into tablets (the combined mass of Y62222 and ATV014 was: 5.349 mg Y62222+12.042 mg ATV014).

[0221] The pharmaceutical composition obtained in Example 6 was mixed with an appropriate amount of excipients and / or pharmaceutically acceptable carriers and directly compressed into tablets (the combined mass of Y62222 and ATV014 was: 5.349 mg Y62222+20.07 mg ATV014).

[0222] The pharmaceutical composition obtained in Example 7 was mixed with an appropriate amount of excipients and / or pharmaceutically acceptable carriers and directly compressed into tablets (the combined mass of Y62222 and ATV014 was: 0.5349 mg Y62222+4.014 mg ATV014).

[0223] The pharmaceutical composition obtained in Example 8 was mixed with an appropriate amount of excipients and / or pharmaceutically acceptable carriers and directly compressed into tablets (the combined mass of Y62222 and ATV014 was: 0.5349 mg Y62222+8.028 mg ATV014).

[0224] The pharmaceutical composition obtained in Example 9 was mixed with an appropriate amount of excipients and / or pharmaceutically acceptable carriers and directly compressed into tablets (the combined mass of Y62222 and ATV014 was: 0.5349 mg Y62222+12.042 mg ATV014).

[0225] The pharmaceutical composition obtained in Example 10 was mixed with an appropriate amount of excipients and / or pharmaceutically acceptable carriers and directly compressed into tablets (the combined mass of Y62222 and ATV014 was: 0.5349 mg Y62222+16.056 mg ATV014).

[0226] The pharmaceutical composition obtained in Example 11 was mixed with an appropriate amount of excipients and / or pharmaceutically acceptable carriers and directly compressed into tablets (the combined mass of Y62222 and ATV014 was: 0.5349 mg Y62222+20.07 mg ATV014).

[0227] The pharmaceutical composition obtained in Example 12 was mixed with an appropriate amount of excipients and / or pharmaceutically acceptable carriers and directly compressed into tablets (the combined mass of Y62222 and ATV014 was: 8.024 mg Y62222+4.014 mg ATV014).

[0228] The pharmaceutical composition obtained in Example 13 was mixed with an appropriate amount of excipients and / or pharmaceutically acceptable carriers and directly compressed into tablets (the combined mass of Y62222 and ATV014 was: 10.698 mg Y62222+4.014 mg ATV014).

[0229] The pharmaceutical composition obtained in Example 14 was mixed with an appropriate amount of excipients and / or pharmaceutically acceptable carriers and directly compressed into tablets (the combined mass of Y62222 and ATV014 was: 16.047 mg Y62222+4.014 mg ATV014).

[0230] The pharmaceutical composition obtained in Example 15 was mixed with an appropriate amount of excipients and / or pharmaceutically acceptable carriers and directly compressed into tablets (the combined mass of Y62222 and ATV014 was: 26.745 mg Y62222+4.014 mg ATV014).

[0231] The pharmaceutical composition obtained in Example 16 was mixed with an appropriate amount of excipients and / or pharmaceutically acceptable carriers and directly compressed into tablets (the combined mass of Y62222 and ATV014 was: 5.349 mg Y62222+0.4014 mg ATV014).

[0232] The pharmaceutical composition obtained in Example 17 was mixed with an appropriate amount of excipients and / or pharmaceutically acceptable carriers and directly compressed into tablets (the combined mass of Y62222 and ATV014 was: 10.698 mg Y62222 + 0.4014 mg ATV014).

[0233] The pharmaceutical composition obtained in Example 18 was mixed with an appropriate amount of excipients and / or pharmaceutically acceptable carriers and directly compressed into tablets (the combined mass of Y62222 and ATV014 was: 16.047 mg Y62222 + 0.4014 mg ATV014).

[0234] The pharmaceutical composition obtained in Example 19 was mixed with an appropriate amount of excipients and / or pharmaceutically acceptable carriers and directly compressed into tablets (the combined mass of Y62222 and ATV014 was: 21.396 mg Y62222 + 0.4014 mg ATV014).

[0235] The pharmaceutical composition obtained in Example 20 was mixed with an appropriate amount of excipients and / or pharmaceutically acceptable carriers and directly compressed into tablets (the combined mass of Y62222 and ATV014 was: 26.745 mg Y62222 + 0.4014 mg ATV014).

[0236] Example 25: Preparation of tablets of the compound pharmaceutical composition of Y62222 and ATV014

[0237] The pharmaceutical composition obtained in Example 2 was mixed with an appropriate amount of excipients and / or pharmaceutically acceptable carriers and directly compressed into tablets (the combined mass of Y62222 and ATV014 was: 53.49 mg Y62222+40.14 mg ATV014).

[0238] The pharmaceutical composition obtained in Example 3 was mixed with an appropriate amount of excipients and / or pharmaceutically acceptable carriers and directly compressed into tablets (the combined mass of Y62222 and ATV014 was: 53.49 mg Y62222+60.21 mg ATV014).

[0239] The pharmaceutical composition obtained in Example 4 was mixed with an appropriate amount of excipients and / or pharmaceutically acceptable carriers and directly compressed into tablets (the combined mass of Y62222 and ATV014 was: 53.49 mg Y62222+80.28 mg ATV014).

[0240] The pharmaceutical composition obtained in Example 5 was mixed with an appropriate amount of excipients and / or pharmaceutically acceptable carriers and directly compressed into tablets (the combined mass of Y62222 and ATV014 was: 53.49 mg Y62222+120.42 mg ATV014).

[0241] The pharmaceutical composition obtained in Example 6 was mixed with an appropriate amount of excipients and / or pharmaceutically acceptable carriers and directly compressed into tablets (the combined mass of Y62222 and ATV014 was: 53.49 mg Y62222+200.7 mg ATV014).

[0242] The pharmaceutical composition obtained in Example 7 was mixed with an appropriate amount of excipients and / or pharmaceutically acceptable carriers and directly compressed into tablets (the combined mass of Y62222 and ATV014 was: 5.349 mg Y62222+40.14 mg ATV014).

[0243] The pharmaceutical composition obtained in Example 8 was mixed with an appropriate amount of excipients and / or pharmaceutically acceptable carriers and directly compressed into tablets (the combined mass of Y62222 and ATV014 was: 5.349 mg Y62222+80.28 mg ATV014).

[0244] The pharmaceutical composition obtained in Example 9 was mixed with an appropriate amount of excipients and / or pharmaceutically acceptable carriers and directly compressed into tablets (the combined mass of Y62222 and ATV014 was: 5.349 mg Y62222+120.42 mg ATV014).

[0245] The pharmaceutical composition obtained in Example 10 was mixed with an appropriate amount of excipients and / or pharmaceutically acceptable carriers and directly compressed into tablets (the combined mass of Y62222 and ATV014 was: 5.349 mg Y62222+160.56 mg ATV014).

[0246] The pharmaceutical composition obtained in Example 11 was mixed with an appropriate amount of excipients and / or pharmaceutically acceptable carriers and directly compressed into tablets (the combined mass of Y62222 and ATV014 was: 5.349 mg Y62222+200.7 mg ATV014).

[0247] The pharmaceutical composition obtained in Example 12 was mixed with an appropriate amount of excipients and / or pharmaceutically acceptable carriers and directly compressed into tablets (the combined mass of Y62222 and ATV014 was: 80.24 mg Y62222+40.14 mg ATV014).

[0248] The pharmaceutical composition obtained in Example 13 was mixed with an appropriate amount of excipients and / or pharmaceutically acceptable carriers and directly compressed into tablets (the combined mass of Y62222 and ATV014 was: 106.98 mg Y62222+40.14 mg ATV014).

[0249] The pharmaceutical composition obtained in Example 14 was mixed with an appropriate amount of excipients and / or pharmaceutically acceptable carriers and directly compressed into tablets (the combined mass of Y62222 and ATV014 was: 160.47 mg Y62222+40.14 mg ATV014).

[0250] The pharmaceutical composition obtained in Example 15 was mixed with an appropriate amount of excipients and / or pharmaceutically acceptable carriers and directly compressed into tablets (the combined mass of Y62222 and ATV014 was: 267.45 mg Y62222+40.14 mg ATV014).

[0251] The pharmaceutical composition obtained in Example 16 was mixed with an appropriate amount of excipients and / or pharmaceutically acceptable carriers and directly compressed into tablets (the combined mass of Y62222 and ATV014 was: 53.49 mg Y62222+4.014 mg ATV014).

[0252] The pharmaceutical composition obtained in Example 17 was mixed with an appropriate amount of excipients and / or pharmaceutically acceptable carriers and directly compressed into tablets (the combined mass of Y62222 and ATV014 was: 106.98 mg Y62222+4.014 mg ATV014).

[0253] The pharmaceutical composition obtained in Example 18 was mixed with an appropriate amount of excipients and / or pharmaceutically acceptable carriers and directly compressed into tablets (the combined mass of Y62222 and ATV014 was: 160.47 mg Y62222+4.014 mg ATV014).

[0254] The pharmaceutical composition obtained in Example 19 was mixed with an appropriate amount of excipients and / or pharmaceutically acceptable carriers and directly compressed into tablets (the combined mass of Y62222 and ATV014 was: 213.96 mg Y62222+4.014 mg ATV014).

[0255] The pharmaceutical composition obtained in Example 20 was mixed with an appropriate amount of excipients and / or pharmaceutically acceptable carriers and directly compressed into tablets (the combined mass of Y62222 and ATV014 was: 267.45 mg Y62222+4.014 mg ATV014).

[0256] Example 26: Preparation of Y62222 and ATV014 Kit Products

[0257] 100 mg of Y62222 is mixed with an appropriate amount of excipients and / or a pharmaceutically acceptable carrier and then directly compressed into tablets, and 75 mg of ATV014 is mixed with an appropriate amount of excipients and / or a pharmaceutically acceptable carrier and then directly compressed into tablets, which are placed in the same package.

[0258] 100 mg of Y62222 is mixed with an appropriate amount of excipients and / or a pharmaceutically acceptable carrier and then directly compressed into tablets, and 112.5 mg of ATV014 is mixed with an appropriate amount of excipients and / or a pharmaceutically acceptable carrier and then directly compressed into tablets, which are placed in the same package.

[0259] 100 mg of Y62222 is mixed with an appropriate amount of excipients and / or a pharmaceutically acceptable carrier and then directly compressed into tablets, and 150 mg of ATV014 is mixed with an appropriate amount of excipients and / or a pharmaceutically acceptable carrier and then directly compressed into tablets, which are placed in the same package.

[0260] 100 mg of Y62222 is mixed with an appropriate amount of excipients and / or a pharmaceutically acceptable carrier and then directly compressed into tablets, and 225 mg of ATV014 is mixed with an appropriate amount of excipients and / or a pharmaceutically acceptable carrier and then directly compressed into tablets, which are placed in the same package.

[0261] 100 mg of Y62222 is mixed with an appropriate amount of excipients and / or a pharmaceutically acceptable carrier and then directly compressed into tablets, and 300 mg of ATV014 is mixed with an appropriate amount of excipients and / or a pharmaceutically acceptable carrier and then directly compressed into tablets, which are placed in the same package.

[0262] 100 mg of Y62222 is mixed with an appropriate amount of excipients and / or a pharmaceutically acceptable carrier and then directly compressed into tablets, and 375 mg of ATV014 is mixed with an appropriate amount of excipients and / or a pharmaceutically acceptable carrier and then directly compressed into tablets, which are placed in the same package.

[0263] 10 mg of Y62222 is mixed with an appropriate amount of excipients and / or a pharmaceutically acceptable carrier and then directly compressed into tablets. 150 mg of ATV014 is mixed with an appropriate amount of excipients and / or a pharmaceutically acceptable carrier and then directly compressed into tablets, which are placed in the same package.

[0264] 10 mg of Y62222 is mixed with an appropriate amount of excipients and / or a pharmaceutically acceptable carrier and then directly compressed into tablets. 225 mg of ATV014 is mixed with an appropriate amount of excipients and / or a pharmaceutically acceptable carrier and then directly compressed into tablets, which are placed in the same package.

[0265] 10 mg of Y62222 is mixed with an appropriate amount of excipients and / or a pharmaceutically acceptable carrier and then directly compressed into tablets, and 300 mg of ATV014 is mixed with an appropriate amount of excipients and / or a pharmaceutically acceptable carrier and then directly compressed into tablets, which are placed in the same package.

[0266] 10 mg of Y62222 is mixed with an appropriate amount of excipients and / or a pharmaceutically acceptable carrier and then directly compressed into tablets. 375 mg of ATV014 is mixed with an appropriate amount of excipients and / or a pharmaceutically acceptable carrier and then directly compressed into tablets, which are placed in the same package.

[0267] 133 mg of Y62222 is mixed with an appropriate amount of excipients and / or a pharmaceutically acceptable carrier and then directly compressed into tablets, and 100 mg of ATV014 is mixed with an appropriate amount of excipients and / or a pharmaceutically acceptable carrier and then directly compressed into tablets, which are placed in the same package.

[0268] 200 mg of Y62222 is mixed with an appropriate amount of excipients and / or a pharmaceutically acceptable carrier and then directly compressed into tablets, and 100 mg of ATV014 is mixed with an appropriate amount of excipients and / or a pharmaceutically acceptable carrier and then directly compressed into tablets, which are placed in the same package.

[0269] 266.5 mg of Y62222 is mixed with an appropriate amount of excipients and / or a pharmaceutically acceptable carrier and then directly compressed into tablets, and 100 mg of ATV014 is mixed with an appropriate amount of excipients and / or a pharmaceutically acceptable carrier and then directly compressed into tablets, which are placed in the same package.

[0270] 400 mg of Y62222 is mixed with an appropriate amount of excipients and / or a pharmaceutically acceptable carrier and then directly compressed into tablets, and 100 mg of ATV014 is mixed with an appropriate amount of excipients and / or a pharmaceutically acceptable carrier and then directly compressed into tablets, which are placed in the same package.

[0271] 533 mg of Y62222 was mixed with an appropriate amount of excipients and / or a pharmaceutically acceptable carrier and then directly compressed into tablets, and 100 mg of ATV014 was mixed with an appropriate amount of excipients and / or a pharmaceutically acceptable carrier and then directly compressed into tablets, which were placed in the same package.

[0272] 666.5 mg of Y62222 is mixed with an appropriate amount of excipients and / or a pharmaceutically acceptable carrier and then directly compressed into tablets, and 100 mg of ATV014 is mixed with an appropriate amount of excipients and / or a pharmaceutically acceptable carrier and then directly compressed into tablets, which are placed in the same package.

[0273] 133 mg of Y62222 is mixed with an appropriate amount of excipients and / or a pharmaceutically acceptable carrier and then directly compressed into tablets, and 10 mg of ATV014 is mixed with an appropriate amount of excipients and / or a pharmaceutically acceptable carrier and then directly compressed into tablets, which are placed in the same package.

[0274] 266.5 mg of Y62222 is mixed with an appropriate amount of excipients and / or a pharmaceutically acceptable carrier and then directly compressed into tablets. 10 mg of ATV014 is mixed with an appropriate amount of excipients and / or a pharmaceutically acceptable carrier and then directly compressed into tablets, which are placed in the same package.

[0275] 400 mg of Y62222 is mixed with an appropriate amount of excipients and / or a pharmaceutically acceptable carrier and then directly compressed into tablets, and 10 mg of ATV014 is mixed with an appropriate amount of excipients and / or a pharmaceutically acceptable carrier and then directly compressed into tablets, which are placed in the same package.

[0276] 533 mg of Y62222 was mixed with an appropriate amount of excipients and / or a pharmaceutically acceptable carrier and then directly compressed into tablets, and 10 mg of ATV014 was mixed with an appropriate amount of excipients and / or a pharmaceutically acceptable carrier and then directly compressed into tablets, which were placed in the same package.

[0277] 666.5 mg of Y62222 is mixed with an appropriate amount of excipients and / or a pharmaceutically acceptable carrier and then directly compressed into tablets. 10 mg of ATV014 is mixed with an appropriate amount of excipients and / or a pharmaceutically acceptable carrier and then directly compressed into tablets, which are placed in the same package.

[0278] 200 mg of Y62222 is mixed with an appropriate amount of excipients and / or a pharmaceutically acceptable carrier and then directly compressed into tablets, and 150 mg of ATV014 is mixed with an appropriate amount of excipients and / or a pharmaceutically acceptable carrier and then directly compressed into tablets, which are placed in the same package.

[0279] 200 mg of Y62222 is mixed with an appropriate amount of excipients and / or a pharmaceutically acceptable carrier and then directly compressed into tablets, and 225 mg of ATV014 is mixed with an appropriate amount of excipients and / or a pharmaceutically acceptable carrier and then directly compressed into tablets, which are placed in the same package.

[0280] 200 mg of Y62222 is mixed with an appropriate amount of excipients and / or a pharmaceutically acceptable carrier and then directly compressed into tablets, and 300 mg of ATV014 is mixed with an appropriate amount of excipients and / or a pharmaceutically acceptable carrier and then directly compressed into tablets, which are placed in the same package.

[0281] 200 mg of Y62222 is mixed with an appropriate amount of excipients and / or a pharmaceutically acceptable carrier and then directly compressed into tablets, and 450 mg of ATV014 is mixed with an appropriate amount of excipients and / or a pharmaceutically acceptable carrier and then directly compressed into tablets, which are placed in the same package.

[0282] 200 mg of Y62222 is mixed with an appropriate amount of excipients and / or a pharmaceutically acceptable carrier and then directly compressed into tablets, and 600 mg of ATV014 is mixed with an appropriate amount of excipients and / or a pharmaceutically acceptable carrier and then directly compressed into tablets, which are placed in the same package.

[0283] 200 mg of Y62222 is mixed with an appropriate amount of excipients and / or a pharmaceutically acceptable carrier and then directly compressed into tablets, and 750 mg of ATV014 is mixed with an appropriate amount of excipients and / or a pharmaceutically acceptable carrier and then directly compressed into tablets, which are placed in the same package.

[0284] 20 mg of Y62222 is mixed with an appropriate amount of excipients and / or a pharmaceutically acceptable carrier and then directly compressed into tablets, and 300 mg of ATV014 is mixed with an appropriate amount of excipients and / or a pharmaceutically acceptable carrier and then directly compressed into tablets, which are placed in the same package.

[0285] 20 mg of Y62222 is mixed with an appropriate amount of excipients and / or a pharmaceutically acceptable carrier and then directly compressed into tablets, and 450 mg of ATV014 is mixed with an appropriate amount of excipients and / or a pharmaceutically acceptable carrier and then directly compressed into tablets, which are placed in the same package.

[0286] 20 mg of Y62222 is mixed with an appropriate amount of excipients and / or a pharmaceutically acceptable carrier and then directly compressed into tablets, and 600 mg of ATV014 is mixed with an appropriate amount of excipients and / or a pharmaceutically acceptable carrier and then directly compressed into tablets, which are placed in the same package.

[0287] 20 mg of Y62222 is mixed with an appropriate amount of excipients and / or a pharmaceutically acceptable carrier and then directly compressed into tablets. 750 mg of ATV014 is mixed with an appropriate amount of excipients and / or a pharmaceutically acceptable carrier and then directly compressed into tablets, which are placed in the same package.

[0288] 266 mg of Y62222 is mixed with an appropriate amount of excipients and / or a pharmaceutically acceptable carrier and then directly compressed into tablets. 200 mg of ATV014 is mixed with an appropriate amount of excipients and / or a pharmaceutically acceptable carrier and then directly compressed into tablets, which are placed in the same package.

[0289] 400 mg of Y62222 is mixed with an appropriate amount of excipients and / or a pharmaceutically acceptable carrier and then directly compressed into tablets, and 200 mg of ATV014 is mixed with an appropriate amount of excipients and / or a pharmaceutically acceptable carrier and then directly compressed into tablets, which are placed in the same package.

[0290] 533 mg of Y62222 is mixed with an appropriate amount of excipients and / or a pharmaceutically acceptable carrier and then directly compressed into tablets, and 200 mg of ATV014 is mixed with an appropriate amount of excipients and / or a pharmaceutically acceptable carrier and then directly compressed into tablets, which are placed in the same package.

[0291] 800 mg of Y62222 is mixed with an appropriate amount of excipients and / or a pharmaceutically acceptable carrier and then directly compressed into tablets, and 200 mg of ATV014 is mixed with an appropriate amount of excipients and / or a pharmaceutically acceptable carrier and then directly compressed into tablets, which are placed in the same package.

[0292] 1066 mg of Y62222 is mixed with an appropriate amount of excipients and / or a pharmaceutically acceptable carrier and then directly compressed into tablets. 200 mg of ATV014 is mixed with an appropriate amount of excipients and / or a pharmaceutically acceptable carrier and then directly compressed into tablets, which are placed in the same package.

[0293] 1333 mg of Y62222 is mixed with an appropriate amount of excipients and / or a pharmaceutically acceptable carrier and then directly compressed into tablets. 200 mg of ATV014 is mixed with an appropriate amount of excipients and / or a pharmaceutically acceptable carrier and then directly compressed into tablets, which are placed in the same package.

[0294] 266 mg of Y62222 is mixed with an appropriate amount of excipients and / or a pharmaceutically acceptable carrier and then directly compressed into tablets, and 20 mg of ATV014 is mixed with an appropriate amount of excipients and / or a pharmaceutically acceptable carrier and then directly compressed into tablets, which are placed in the same package.

[0295] 533 mg of Y62222 is mixed with an appropriate amount of excipients and / or a pharmaceutically acceptable carrier and then directly compressed into tablets, and 20 mg of ATV014 is mixed with an appropriate amount of excipients and / or a pharmaceutically acceptable carrier and then directly compressed into tablets, which are placed in the same package.

[0296] 800 mg of Y62222 is mixed with an appropriate amount of excipients and / or a pharmaceutically acceptable carrier and then directly compressed into tablets, and 20 mg of ATV014 is mixed with an appropriate amount of excipients and / or a pharmaceutically acceptable carrier and then directly compressed into tablets, which are placed in the same package.

[0297] 1066 mg of Y62222 is mixed with an appropriate amount of excipients and / or a pharmaceutically acceptable carrier and then directly compressed into tablets. 20 mg of ATV014 is mixed with an appropriate amount of excipients and / or a pharmaceutically acceptable carrier and then directly compressed into tablets, which are placed in the same package.

[0298] 1333 mg of Y62222 is mixed with an appropriate amount of excipients and / or a pharmaceutically acceptable carrier and then directly compressed into tablets. 20 mg of ATV014 is mixed with an appropriate amount of excipients and / or a pharmaceutically acceptable carrier and then directly compressed into tablets, which are placed in the same package.

[0299] The above embodiments are preferred implementation modes of the present invention, but the implementation modes of the present invention are not limited to the above embodiments. Any other changes, modifications, substitutions, combinations, and simplifications that do not deviate from the spirit and principles of the present invention should be equivalent replacement methods and are included in the protection scope of the present invention.

Claims

1. A compound pharmaceutical composition, characterized in that: The pharmaceutical composition comprises an Mpro inhibitor and a RdRp inhibitor, wherein the Mpro inhibitor is a triazine compound selected from compound Y62222 or a pharmaceutically acceptable salt, cocrystal, isomer, metabolite, prodrug, solvate or hydrate thereof, or a combination thereof; the RdRp inhibitor is a nucleoside analogue selected from compound ATV014 or a pharmaceutically acceptable salt, cocrystal, isomer, metabolite, prodrug, solvate or hydrate thereof, or a combination thereof, and the molar ratio of the Mpro inhibitor to the RdRp inhibitor is 50:1 to 1:50, 2. The compound pharmaceutical composition according to claim 1, characterized in that: The co-crystal of the compound Y62222 is a binary co-crystal formed by Y62222 and an organic acid or a ternary co-crystal formed by Y62222, nicotinamide and an organic acid; and / or The co-crystal of the compound ATV014 is a binary co-crystal formed by ATV014 and an organic acid or a ternary co-crystal formed by ATV014, nicotinamide and an organic acid; and / or The organic acid in the organic acid of the compound Y62222 and the organic acid in the organic acid of the compound ATV014 independently include acetic acid, benzoic acid, mandelic acid, maleic acid, fumaric acid, malic acid or citric acid; and / or The pharmaceutically acceptable salt of the pharmaceutically acceptable salt of the compound Y62222 and the pharmaceutically acceptable salt of the compound ATV014 are independently selected from hydrochloride, hydrobromide, sulfate, phosphate, benzenesulfonate, p-toluenesulfonate, methanesulfonate, tartrate, camphorsulfonate, lithium salt, sodium salt, potassium salt, calcium salt, magnesium salt, aluminum salt, ammonium salt, ethylenediamine salt or triethylamine salt; and / or The molar ratio of the Mpro inhibitor to the RdRp inhibitor is 40:1 to 1:40; and / or The molar ratio of the Mpro inhibitor to the RdRp inhibitor is 30:1 to 1:30; and / or The molar ratio of the Mpro inhibitor to the RdRp inhibitor is 20:1 to 1:20; and / or The molar ratio of the Mpro inhibitor to the RdRp inhibitor is 10:1 to 1:10; and / or The molar ratio of the Mpro inhibitor to the RdRp inhibitor is 50:1, 40:1, 30:1, 20:1, 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 3:1, 2:1, 1.5:1, 1:1, 1:1.5, 1:2, 1:3, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:20, 1:30, 1:40 or 1:50; and / or The molar ratio of the Mpro inhibitor to the RdRp inhibitor is 5:1 to 1:

10.

3. A preparation, characterized in that The preparation comprises the compound pharmaceutical composition according to any one of claims 1 to 2 and a pharmaceutically acceptable carrier.

4. The preparation according to claim 3, characterized in that The pharmaceutically acceptable carrier is selected from any one or more of a filler, a binder, a disintegrant, a glidant, a lubricant or a flavoring agent; and / or The preparation is an oral preparation selected from powder, granules, pills, capsules, tablets, lozenges or oral liquids; and / or The total mass of the Mpro inhibitor and the RdRp inhibitor in a single dose of the preparation is 2 mg-2000 mg.

5. A medicine box product, characterized in that: The invention comprises a first preparation unit and a second preparation unit, wherein the first preparation unit and the second preparation unit are both independently present in a medicine kit product; The first formulation unit comprises an active ingredient A, which is an Mpro inhibitor, which is a triazine compound selected from compound Y62222 or a pharmaceutically acceptable salt, cocrystal, isomer, metabolite, prodrug, solvate or hydrate thereof, or a combination thereof; The second formulation unit includes an active ingredient B, which is an RdRp inhibitor, which is a nucleoside analogue selected from the compound ATV014 or a pharmaceutically acceptable salt, cocrystal, isomer, metabolite, prodrug, solvate or hydrate thereof, or a combination thereof; The molar ratio of the single-dose strength of the first preparation unit to the single-dose strength of the second preparation unit is 50:1 to 1:50, 6. The medicine kit product according to claim 5, characterized in that: The co-crystal of the compound Y62222 is a binary co-crystal formed by Y62222 and an organic acid or a ternary co-crystal formed by Y62222, nicotinamide and an organic acid; and / or The co-crystal of the compound ATV014 is a binary co-crystal formed by ATV014 and an organic acid or a ternary co-crystal formed by ATV014, nicotinamide and an organic acid; and / or The organic acid in the organic acid of the compound Y62222 and the organic acid in the organic acid of the compound ATV014 independently include acetic acid, benzoic acid, mandelic acid, maleic acid, fumaric acid, malic acid or citric acid; and / or The pharmaceutically acceptable salt of the pharmaceutically acceptable salt of the compound Y62222 and the pharmaceutically acceptable salt of the compound ATV014 are independently selected from hydrochloride, hydrobromide, sulfate, phosphate, benzenesulfonate, p-toluenesulfonate, methanesulfonate, tartrate, camphorsulfonate, lithium salt, sodium salt, potassium salt, calcium salt, magnesium salt, aluminum salt, ammonium salt, ethylenediamine salt or triethylamine salt; and / or The molar ratio of the single-dose strength of the first preparation unit to the single-dose strength of the second preparation unit is 40:1 to 1:40; and / or The molar ratio of the single-dose strength of the first preparation unit to the single-dose strength of the second preparation unit is 30:1 to 1:30; and / or The molar ratio of the single-dose strength of the first preparation unit to the single-dose strength of the second preparation unit is 20:1 to 1:20; and / or The molar ratio of the single-dose strength of the first preparation unit to the single-dose strength of the second preparation unit is 10:1 to 1:10; and / or The molar ratio of the single dose strength of the first formulation unit to the single dose strength of the second formulation unit is 50:1, 40:1, 30:1, 20:1, 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 3:1, 2:1, 1.5:1, 1:1, 1:1.5, 1:2, 1:3, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:20, 1:30, 1:40 or 1:50; and / or The molar ratio of the single-dose strength of the first preparation unit to the single-dose strength of the second preparation unit is 5:1 to 1:10; and / or The single dosage strength of the first preparation unit is 1 mg-1500 mg; and / or The single-dose strength of the second preparation unit is 1 mg-1500 mg.

7. The medicine kit product according to any one of claims 5-6, characterized in that: The first preparation unit further comprises a pharmaceutically acceptable carrier; the second preparation unit further comprises a pharmaceutically acceptable carrier; The pharmaceutically acceptable carrier in the first formulation unit and the pharmaceutically acceptable carrier in the second formulation unit are independently selected from any one or more of fillers, binders, disintegrants, glidants, lubricants or flavoring agents; and / or The first preparation unit and the second preparation unit are each independently an oral preparation selected from powders, granules, pills, capsules, tablets, lozenges or oral liquids.

8. Use of the compound pharmaceutical composition according to any one of claims 1-2, the preparation according to any one of claims 3-4, or the kit product according to any one of claims 5-7 in the preparation of a medicament for alleviating or treating coronavirus infection.

9. The method according to claim 8, wherein the coronavirus infection is MHV-A59, HCoV-229E, HCoV-OC43, HCoV-NL63, HCoV-HKU1, SARS-CoV, MERS-CoV, novel coronavirus, mouse hepatitis virus, feline coronavirus, canine coronavirus, bovine coronavirus, avian infectious bronchitis virus or porcine coronavirus; and / or The novel coronavirus infection is a novel coronavirus infection caused by the common type of novel coronavirus and its variants, and the novel coronavirus and its variants include Alpha variants, Beta variants, Gamma variants, Delta variants, Lambda variants and / or Omicron variants; and / or The infection is caused by coronavirus and includes fever, headache, cough, sore throat, muscle aches, pneumonia, acute respiratory tract infection, severe acute respiratory tract infection, hypoxic respiratory failure and acute respiratory distress syndrome, sepsis or septic shock.

10. The use according to any one of claims 8-9, wherein the Mpro inhibitor and the RdRp inhibitor are formulated to be administered once a day, twice a day or three times a day on the same day; and / or wherein the Mpro inhibitor and the RdRp inhibitor are formulated to be co-delivered in a common oral dosage unit; and / or wherein the Mpro inhibitor and the RdRp inhibitor are formulated to be administered in separate oral dosage units, either simultaneously or sequentially; and / or The frequency of administration of the Mpro inhibitor combined with the RdRp inhibitor is once a day, and the single dose of the Mpro inhibitor combined with the RdRp inhibitor, the single dose of the RdRp inhibitor, or the total single dose of the Mpro inhibitor and the RdRp inhibitor are independently selected from 1 mg-1500 mg; and / or The administration frequency of the Mpro inhibitor combined with the RdRp inhibitor is once a day, and the single dose of the Mpro inhibitor combined with the RdRp inhibitor, the single dose of the RdRp inhibitor, or the total single dose of the Mpro inhibitor and the RdRp inhibitor are independently selected from 1 mg, 1.5 mg, 2.0 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, 5 mg, 5.5 mg, 6.0 mg, 6.5 mg, 7.0 mg, 7.5 mg, 8.0 mg, 8.5 mg, 9.0 mg, 9.5 mg, 10 mg, 10.5 mg, 11 mg, 11.5 mg, 12 mg, 12.5 mg, 13 mg, 13.5 mg, 14 mg, 14.5 mg, 15 mg, 15.5 mg, 16 mg, 16.5 mg, 17 mg, 17.5 mg, 18 mg, 18.5 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg 9.5mg, 20mg, 22.5mg, 25mg, 27.5mg, 30mg, 32.5mg, 35mg, 37.5mg, 40mg, 42.5mg, 45mg, 47.5mg, 50 mg, 52.5mg, 55mg, 60mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 150mg, 200mg, 250mg, 3 00mg, 350mg, 400mg, 450mg, 500mg, 550mg, 600mg, 650mg, 700mg, 750mg, 800mg, 850mg, 900mg, 950 mg, 1000mg, 1050mg, 1100mg, 1150mg, 1200mg, 1250mg, 1300mg, 1350mg, 1400mg, 1450mg, 1500mg.

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