Use of compounds against coronavirus

Abstract

Provided is the application of a compound in anti-coronavirus. The application is the application of a compound or a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, or a crystal form thereof in the preparation of an anti-coronavirus preparation, wherein the compound is selected from one or more of gossypol acetic acid, mecobalamin, ertapenem, chaetocidin, netilmicin sulfate, sennoside A and ellagic acid. In the application, the compound can effectively inhibit coronavirus RNA-dependent RNA polymerase (RDRP), thereby inhibiting the proliferation of coronavirus and being applied to anti-coronavirus. The inhibition effect is strong, the cost is low, and the required dose is small, and the compound can be effectively used in anti-coronavirus.

Description

[0001] This application claims priority to Chinese patent application CN202110163244.1, filed on February 5, 2021. The entire contents of the aforementioned Chinese patent application are incorporated herein by reference. Technical Field

[0002] This invention relates to the field of biomedical technology, specifically to the application of a series of small molecule compounds in the fight against coronaviruses. Background Technology

[0003] Coronaviruses are a family of viruses closely related to humans and animals. Common coronaviruses HCoV-229E and HCoV-OC43 can cause the common cold after infecting humans. [1] Meanwhile, coronavirus infections in livestock can also severely impact the livestock industry. For example, porcine epidemic diarrhea virus (PEDV), transmissible gastroenteritis virus (TGEV), and porcine PD-coronavirus (PDCoV) can cause severe enteritis, diarrhea, vomiting, and dehydration in pigs, resulting in huge losses for the pig farming industry. [2] Coronaviruses, as RNA viruses, possess a high mutation rate, ensuring they remain a threat to humans throughout evolution. SARS-CoV-1 and SARS-CoV-2 are examples of coronaviruses associated with SARS (severe acute respiratory syndrome). [3] and Middle East Respiratory Syndrome caused by MERS coronavirus [4] All of these have had a significant impact on public health. The novel coronavirus (SARS-CoV-2), which has recently spread widely worldwide, is highly contagious. Clinical manifestations after infection mainly include fever, dry cough, and even difficulty breathing; severe cases can lead to death. [5] To date, despite the tremendous efforts made by countries around the world to combat the COVID-19 virus, the continued increase in new infections indicates that there is still a lack of effective treatments such as drugs, vaccines, and antibodies to prevent and treat the virus.

[0004] The coronavirus genome is a single-stranded, positive-sense RNA, approximately 30 kb in length. It primarily encodes structural proteins required for viral particle assembly and non-structural proteins responsible for viral genome transcription and replication. Two-thirds of the viral genome encodes the non-structural protein 1-16. The transcription and replication of the viral genome involves multiple reactions, including primer synthesis, nascent RNA strand elongation, double-strand unwinding, and 5' capping of the nascent RNA strand. Studies have found that coronaviruses primarily utilize multiple non-structural protein subunits to assemble a transcription and replication complex, which is responsible for viral genome transcription and replication. Nsp12 (the non-structural protein 12), as an RNA-dependent RNA polymerase (RDRP), is the core subunit of this complex, primarily responsible for the elongation of the nascent RNA strand. It plays an essential role in viral transcription and replication and has therefore become a focus of research. [6] As research into the coronavirus RDRP deepens, its catalytic mechanism and three-dimensional high-resolution atomic structure have been revealed, which is of great significance for the development of antiviral drugs targeting RDRP. Meanwhile, some antiviral drugs targeting viral polymerases, such as ribavirin and favipiravir, are also being developed. [7,8] The FDA approval and positive clinical results demonstrate the essential and promising potential of developing inhibitors with strong antiviral activity and high safety profiles targeting RDRP. Inhibitors of coronavirus RDRP, particularly small molecule compounds targeting its catalytically active site, may become potential treatments for coronaviruses.

[0005] Currently, first-line clinical treatment for coronavirus infections primarily uses broad-spectrum antiviral drugs, such as the anti-HIV drugs lopinavir / ritonavir (Kaletra) and arbidol, and the anti-Ebola drug remdesivir. However, none of these are specifically designed or developed for coronaviruses or have clearly significant efficacy. They all have various side effects, even causing bradycardia in some patients, and therefore are not the optimal choice for treating coronaviruses. Furthermore, there are currently no compound drugs targeting the coronavirus RDRP, making the development of drugs targeting this target both urgent and promising.

[0006] (1) Gossypol Acetate (CAS No.: 12542-36-8), molecular formula is shown below:

[0007]

[0008] Gossypol acetate is a phenolic aldehyde that can penetrate cells and acts as an inhibitor of some dehydrogenases, such as lactate dehydrogenase and NAD-linked enzymes. [9] Cellular experiments showed that gossypol acetate can interfere with Bcl-2 and Bcl-X. L It binds to anti-apoptotic proteins, thereby inducing apoptosis in cancer cells and exerting an anti-tumor effect.

[10] .

[0009] (2) Methylcobalamin (CAS No.: 13422-55-4), molecular formula is shown below:

[0010]

[0011] Methylcobalamin is one of the active forms of vitamin B12, which directly participates in homocysteine ​​metabolism. It is used to treat some nutritional disorders and other clinical conditions such as Alzheimer's disease and rheumatoid arthritis.

[0012] (3) Ertapenem Sodium (CAS No.: 153773-82-1), molecular formula is shown below:

[0013]

[0014] Ertapenem sodium is a β-lactam antibiotic with good inhibitory activity against most Gram-positive and Gram-negative bacteria. Ertapenem sodium has a long retention time in the body, making it suitable as a long-acting antibacterial agent.

[0015] (4) Chaetocin (CAS No.: 28097-03-2), molecular formula is shown below:

[0016]

[0017] Chamocinin is a class of natural products derived from the genus Chamocinus. It is a class of histone methyltransferase inhibitors, and its half-maximal inhibitory concentration (IC50) against histone methyltransferase dSU(VAR)3-9, mouse histone methyltransferase (G9a), and *Nematospora crassa* methyltransferase (DIM5) is significant. 50 ) are 0.8 respectively M, 2.5 M and 3 M

[11] Chamocin is an anticancer drug that can effectively inhibit the proliferation of many tumor cells and the formation of clones. Its IC50 value is [missing information]. 50 2-10 nM

[12] .

[0018] (5) Netilmicin Sulfate (CAS No.: 56391-57-2), molecular formula is shown below:

[0019]

[0020] Netilmicin sulfate is a member of the aminoglycoside antibiotic family and is used to treat infections of the respiratory tract, digestive tract, genitourinary system, skin and soft tissue, bone and joints, and wounds caused by Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Enterobacter spp., Citrobacter cirrhosa, Haemophilus influenzae, Salmonella, and Shigella.

[13] .

[0021] (6) Sennoside A (CAS No.: 81-27-6), molecular formula as shown below:

[0022]

[0023] Sennoside A is a stimulant laxative isolated from the rhizome of rhubarb. It exerts its laxative effect by regulating spontaneous colonic motility.

[14] It slightly regulates bovine serum monoamine oxidase, IC50. 50 17 M

[15] .

[0024] (7) Ellagic acid (CAS No.: 476-66-4), molecular formula as shown below:

[0025]

[0026] Ellagic acid is a class of polyphenolic natural compounds found in a large number of fruits and vegetables. It possesses antioxidant and anti-tumor effects. Ellagic acid can inhibit DNA mutations in cells and induce apoptosis in cancer cells, thus playing an anti-cancer role.

[16] . Summary of the Invention

[0027] The technical problem to be solved by this invention is the lack of effective drugs for treating and / or preventing diseases caused by coronaviruses in the prior art. This invention provides the application of one or more compounds selected from gossypol acetate, mecobalamin, ertapenem, chamomile, netilmicin sulfate, sennoside A, and ellagic acid, their pharmaceutically acceptable salts, their solvates, solvates of their pharmaceutically acceptable salts, or their crystal forms in the fight against coronaviruses, particularly against SARS-CoV-2. These compounds can significantly inhibit the polymerase activity of the RNA-dependent RNA polymerase (RDRP) of coronaviruses, and can be used to prepare anti-coronavirus formulations or RDRP-inhibiting formulations, thereby enabling their use in the fight against coronaviruses (e.g., for the prevention and / or treatment of patients carrying coronaviruses who do not show a disease state, or for the treatment and / or prevention of diseases caused by coronaviruses).

[0028] One of the technical solutions provided by this invention is: the use of a compound, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, or a crystal form thereof in the preparation of an anti-coronavirus formulation, wherein the compound is selected from one or more of gossypol acetate, mecobalamin, ertapenem, chamomile, netilmicin sulfate, sennoside A, and ellagic acid.

[0029] Preferably, the pharmaceutically acceptable salt is a sodium salt.

[0030] More preferably, the pharmaceutically acceptable salt of ertapenem is ertapenem sodium.

[0031] In this invention, the coronavirus may belong to the subfamily Orthocoronavirinae. Viruses of the Orthocoronavirinae subfamily are preferably viruses belonging to the genera α-coronavirus, β-coronavirus, γ-coronavirus, and / or δ-coronavirus.

[0032] Preferably, the coronavirus is selected from one or more of coronaviruses that cause upper respiratory tract infections, coronaviruses that cause lower respiratory tract infections, coronaviruses that cause gastrointestinal infections, and viruses that cause acute respiratory syndrome.

[0033] More preferably, the coronavirus causing upper respiratory tract infection is human coronavirus 229E, human coronavirus HKU1, human coronavirus OC43, human coronavirus NL63 and / or mouse hepatitis virus A59; the coronavirus causing lower respiratory tract infection is avian infectious bronchitis virus IBV; the coronavirus causing digestive tract infection is porcine transmissible gastroenteritis virus TGEV, porcine epidemic diarrhea virus PEDV, porcine type D coronavirus PDCoV, feline infectious peritonitis virus FIPV; and the coronavirus causing acute respiratory syndrome is SARS-related coronavirus or Middle East respiratory syndrome coronavirus MERS-CoV; even more preferably, the SARS-related coronavirus is SARS-CoV-1 or SARS-CoV-2.

[0034] In a preferred embodiment of the invention, the compound inhibits the RDRP of the coronavirus, for example, by blocking the synthesis of viral RNA catalyzed by RDRP and viral replication.

[0035] The second technical solution provided by the present invention is: the application of a compound, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, or a crystal form thereof in the preparation of an inhibitor of RDRP; the compound is selected from one or more of gossypol acetate, mecobalamin, ertapenem, chamomile, netilmicin sulfate, sennoside A and ellagic acid.

[0036] Preferably, the RDRP is the RDRP for coronavirus.

[0037] Preferably, the pharmaceutically acceptable salt is a sodium salt; more preferably, the pharmaceutically acceptable salt of ertapenem is ertapenem sodium.

[0038] In this invention, the coronavirus may belong to the subfamily Orthocoronavirinae. Viruses of the Orthocoronavirinae subfamily are preferably viruses belonging to the genera α-coronavirus, β-coronavirus, γ-coronavirus, and / or δ-coronavirus.

[0039] Preferably, the coronavirus is selected from one or more of coronaviruses that cause upper respiratory tract infections, coronaviruses that cause lower respiratory tract infections, coronaviruses that cause gastrointestinal infections, and viruses that cause acute respiratory syndrome.

[0040] More preferably, the coronavirus causing upper respiratory tract infection is human coronavirus 229E, human coronavirus HKU1, human coronavirus OC43, human coronavirus NL63 and / or mouse hepatitis virus A59; the coronavirus causing lower respiratory tract infection is avian infectious bronchitis virus IBV; the coronavirus causing digestive tract infection is porcine transmissible gastroenteritis virus TGEV, porcine epidemic diarrhea virus PEDV, porcine type D coronavirus PDCoV, feline infectious peritonitis virus FIPV; and the coronavirus causing acute respiratory syndrome is SARS-related coronavirus or Middle East respiratory syndrome coronavirus MERS-CoV; even more preferably, the SARS-related coronavirus is SARS-CoV-1 or SARS-CoV-2.

[0041] The third technical solution provided by the present invention is: the application of a pharmaceutical composition or kit in the preparation of an anti-coronavirus formulation, wherein the pharmaceutical composition or kit comprises a compound, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, or a crystal form thereof, wherein the compound is selected from one or more of gossypol acetate, methylcobalamin, ertapenem, chamomile, netilmicin sulfate, sennoside A, and ellagic acid.

[0042] In this invention, the coronavirus may belong to the subfamily Orthocoronavirinae.

[0043] Preferably, the viruses of the Orthocoronavirus subfamily belong to the genera α-coronavirus, β-coronavirus, γ-coronavirus, and / or δ-coronavirus.

[0044] Preferably, the compound inhibits the RDRP of the coronavirus, for example, by blocking the synthesis of viral RNA catalyzed by RDRP and viral replication.

[0045] Preferably, the pharmaceutical composition further comprises pharmaceutically acceptable excipients.

[0046] Preferably, the pharmaceutically acceptable salt of ertapenem is ertapenem sodium.

[0047] More preferably, the coronavirus is selected from one or more of coronaviruses that cause upper respiratory tract infections, coronaviruses that cause lower respiratory tract infections, coronaviruses that cause gastrointestinal infections, and viruses that cause acute respiratory syndrome.

[0048] More preferably, the coronavirus causing upper respiratory tract infection is human coronavirus 229E, human coronavirus HKU1, human coronavirus OC43, human coronavirus NL63 and / or mouse hepatitis virus A59; the coronavirus causing lower respiratory tract infection is avian infectious bronchitis virus IBV; the coronavirus causing digestive tract infection is porcine transmissible gastroenteritis virus TGEV, porcine epidemic diarrhea virus PEDV, porcine type D coronavirus PDCoV, feline infectious peritonitis virus FIPV; and the coronavirus causing acute respiratory syndrome is SARS-related coronavirus or Middle East respiratory syndrome coronavirus MERS-CoV; more preferably, the SARS-related coronavirus is SARS-CoV-1 or SARS-CoV-2.

[0049] The fourth technical solution provided by the present invention is: the application of a pharmaceutical composition or kit in the preparation of an inhibitor of RDRP, wherein the pharmaceutical composition or kit comprises a compound or a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate thereof, or a crystal form thereof, wherein the compound is selected from one or more of gossypol acetate, methylcobalamin, ertapenem, chamomile, netilmicin sulfate, sennoside A and ellagic acid.

[0050] Preferably, the RDRP is the RDRP for coronavirus.

[0051] Preferably, the pharmaceutical composition further comprises pharmaceutically acceptable excipients.

[0052] Preferably, the pharmaceutically acceptable salt of ertapenem is ertapenem sodium.

[0053] Better:

[0054] The coronavirus belongs to the subfamily Orthocoronavirinae. Viruses of the Orthocoronavirinae subfamily are preferably viruses belonging to the genera α-coronavirus, β-coronavirus, γ-coronavirus, and / or δ-coronavirus; and / or, the compound inhibits the RDRP of the coronavirus, for example, by blocking RDRP-catalyzed viral RNA synthesis and viral replication; and / or, the pharmaceutical composition further comprises a pharmaceutically acceptable excipient; and / or, the pharmaceutically acceptable salt of ertapenem is ertapenem sodium.

[0055] Further, even better:

[0056] The coronavirus is selected from one or more of the following: coronaviruses that cause upper respiratory tract infections, coronaviruses that cause lower respiratory tract infections, coronaviruses that cause gastrointestinal infections, and viruses that cause acute respiratory syndrome.

[0057] Further and better:

[0058] The coronaviruses causing upper respiratory tract infections are human coronavirus 229E, human coronavirus HKU1, human coronavirus OC43, human coronavirus NL63, and / or mouse hepatitis virus A59; the coronaviruses causing lower respiratory tract infections are avian infectious bronchitis virus IBV; the coronaviruses causing digestive tract infections are porcine transmissible gastroenteritis virus TGEV, porcine epidemic diarrhea virus PEDV, porcine type D coronavirus PDCoV, and feline infectious peritonitis virus FIPV; the coronaviruses causing acute respiratory syndrome are SARS-related coronaviruses or Middle East respiratory syndrome coronavirus MERS-CoV; more preferably, the SARS-related coronaviruses are SARS-CoV-1 or SARS-CoV-2.

[0059] The fifth technical solution provided by the present invention is: a method for inhibiting the activity of coronavirus RDRP, comprising the step of using a compound, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, or a crystal form thereof for inhibition, wherein the compound is selected from one or more of gossypol acetate, methylcobalamin, ertapenem, chamomile, netilmicin sulfate, sennoside A and ellagic acid.

[0060] The method for inhibiting coronavirus RDRP activity can be used for the inhibition of RDRP activity for diagnostic and therapeutic purposes; it can also be used for the inhibition of RDRP activity for non-diagnostic and therapeutic purposes, such as in vitro scientific studies on the properties and functions of RDRP.

[0061] Preferably, the pharmaceutically acceptable salt of ertapenem is ertapenem sodium.

[0062] The sixth technical solution provided by the present invention is: the application of a compound, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, or a crystal form thereof in inhibiting the activity of coronavirus RDRP, wherein the compound is selected from one or more of gossypol acetate, methylcobalamin, ertapenem, chamomile, netilmicin sulfate, sennoside A and ellagic acid.

[0063] The method for inhibiting coronavirus RDRP activity can be used for the inhibition of RDRP activity for diagnostic and therapeutic purposes; it can also be used for the inhibition of RDRP activity for non-diagnostic and therapeutic purposes, such as in vitro scientific studies on the properties and functions of RDRP.

[0064] Preferably, the pharmaceutically acceptable salt of ertapenem is ertapenem sodium.

[0065] Because the compound has the ability to inhibit the activity of coronavirus RDRP, and RDRP is an essential condition for coronavirus replication, the compound can also be used to prevent coronavirus infection.

[0066] The seventh technical solution provided by this invention is: a compound or a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, or a crystal form thereof, wherein the compound is selected from one or more of gossypol acetate, methylcobalamin, ertapenem, chamomile, netilmicin sulfate, sennoside A, and ellagic acid; and is used for the following purposes:

[0067] (1) Anticoronavirus; (2) Preparation of anticoronavirus agents; and / or, (3) Preparation of inhibitors that inhibit the activity of coronavirus RDRP.

[0068] Preferably, the pharmaceutically acceptable salt of ertapenem is ertapenem sodium.

[0069] The eighth technical solution provided by the present invention is: a pharmaceutical composition or a kit containing a compound or a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate thereof, or a crystal form thereof, wherein the compound is selected from one or more of gossypol acetate, methylcobalamin, ertapenem, chamomile, netilmicin sulfate, sennoside A and ellagic acid.

[0070] Preferably, the pharmaceutically acceptable salt of ertapenem is ertapenem sodium.

[0071] The ninth technical solution provided by the present invention is: a method for treating coronavirus, comprising administering to a subject in need a compound or a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate thereof, or a crystal form thereof, wherein the compound is selected from one or more of gossypol acetate, methylcobalamin, ertapenem, chamomile, netilmicin sulfate, sennoside A and ellagic acid.

[0072] Preferably, the pharmaceutically acceptable salt of ertapenem is ertapenem sodium.

[0073] In this invention, the disease is preferably a mammalian or avian disease.

[0074] In this invention, the mammals preferably include humans, pigs, and cats.

[0075] In this invention, the coronavirus belongs to the subfamily Orthocoronavirinae. The viruses of the Orthocoronavirinae subfamily are preferably viruses belonging to the genera α-coronavirus, β-coronavirus, γ-coronavirus, and / or δ-coronavirus.

[0076] Preferably, the coronavirus is selected from one or more of coronaviruses that cause upper respiratory tract infections, coronaviruses that cause lower respiratory tract infections, coronaviruses that cause gastrointestinal infections, and viruses that cause acute respiratory syndrome.

[0077] More preferably, the coronavirus causing upper respiratory tract infection is human coronavirus 229E, human coronavirus HKU1, human coronavirus OC43, human coronavirus NL63 and / or mouse hepatitis virus A59; the coronavirus causing lower respiratory tract infection is avian infectious bronchitis virus IBV; the coronavirus causing digestive tract infection is porcine transmissible gastroenteritis virus TGEV, porcine epidemic diarrhea virus PEDV, porcine type D coronavirus PDCoV, feline infectious peritonitis virus FIPV; and the coronavirus causing acute respiratory syndrome is SARS-related coronavirus or Middle East respiratory syndrome coronavirus MERS-CoV; even more preferably, the SARS-related coronavirus is SARS-CoV-1 or SARS-CoV-2.

[0078] In a preferred embodiment of the present invention, the compound can be used not only to treat diseases caused by SARS-CoV-2 (β-coronavirus), but also to treat major infectious diseases caused by other coronaviruses such as SARS-CoV-1 (β-coronavirus) and MERS-CoV, and can also be used as a common cold medicine to treat HCoV-HKU1 (…). Human coronavirus HKU1; β-coronavirus), HCoV-NL63 ( Human coronavirus NL63; α-coronavirus), HCoV-OC43 ( Human coronavirus OC43) and HCoV-229E ( Human coronavirus Diseases caused by coronaviruses such as α-coronavirus (22E; α-coronavirus genus); it can also be used as a veterinary drug to treat porcine transmissible gastroenteritis virus (TGEV) (22E; α-coronavirus genus). Transmissible gastroenteritis virus TGEV; α-coronavirus), porcine epidemic diarrhea virus ( ...) Porcine epidemic diarrhea virus PEDV; α-coronavirus genus), porcine d-coronavirus ( Porcine delta coronavirus, PDCoV δ-coronavirus), feline infectious peritonitis virus (FIPV) Feline infectious peritonitis virus, FIPV ; α-coronavirus), avian infectious bronchitis virus ( Infectious bronchitis virus, IBV Animal diseases (such as those caused by gamma coronaviruses). Additionally, the compounds can be used to treat subjects carrying the aforementioned viruses but not exhibiting corresponding symptoms.

[0079] The tenth technical solution provided by the present invention is: the application of a compound, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, or a crystal form thereof in the fight against coronaviruses, wherein the compound is selected from one or more of gossypol acetate, methylcobalamin, ertapenem, chamomile, netilmicin sulfate, sennoside A, and ellagic acid.

[0080] Preferably, the pharmaceutically acceptable salt of ertapenem is ertapenem sodium.

[0081] In all technical solutions of this invention:

[0082] The CAS number of the aforementioned gossypol acetate is 12542-36-8;

[0083] The CAS number of the methylcobalamin is 13422-55-4;

[0084] The CAS number of the chamomilein is 28097-03-2;

[0085] The CAS number of netilmicin sulfate is 56391-57-2;

[0086] The CAS number of the sennoside A is 81-27-6;

[0087] The CAS number of the ellagic acid is 476-66-4;

[0088] The CAS number for the ertapenem sodium is 153773-82-1.

[0089] The pharmaceutical compositions using various compounds of the present invention as active ingredients can all be prepared according to methods known in the art. The compounds of the present invention can be formulated into any dosage form suitable for human or animal use. The weight content of the compounds of the present invention in their pharmaceutical compositions is typically 0.1% to 99.0%.

[0090] The excipients can be any suitable physiologically or pharmaceutically acceptable pharmaceutical excipients. The pharmaceutical excipients are conventional pharmaceutical excipients in the art, preferably including pharmaceutically acceptable excipients, fillers, or diluents. More preferably, the pharmaceutical composition comprises 0.01-99.99% of the above-mentioned protein and / or the above-mentioned antibody-drug conjugate, and 0.01-99.99% of a pharmaceutical carrier, where the percentages are percentages by mass of the pharmaceutical composition.

[0091] The compounds of the present invention or pharmaceutical compositions containing them can be administered in unit dose form, and the route of administration can be enteric or non-enteric, such as oral, intravenous, intramuscular, subcutaneous, nasal, oral mucosa, eye, lung and respiratory tract, skin, vagina, rectum, etc.

[0092] The compounds described above can exist in the form of coronavirus inhibitors, such as conventional drugs used to prevent and treat coronaviruses.

[0093] In this invention, the phrase "the compound is selected from one or more of gossypol acetate, methylcobalamin, ertapenem, trachomatis, netilmicin sulfate, sennoside A, and ellagic acid" can be understood as follows: the compound is gossypol acetate, preferably also including methylcobalamin, ertapenem, trachomatis, netilmicin sulfate, sennoside A, and / or ellagic acid; or it can be understood as follows: the compound is methylcobalamin, preferably also including gossypol acetate, ertapenem, trachomatis, netilmicin sulfate, sennoside A, and / or ellagic acid; or it can be understood as follows: the compound is ertapenem, preferably also including gossypol acetate, methylcobalamin, trachomatis, netilmicin sulfate, sennoside A, and / or ellagic acid; or it can be understood as follows: the compound is trachomatis, preferably also including gossypol acetate, methylcobalamin, trachomatis, netilmicin sulfate, sennoside A, and / or ellagic acid. The compound may contain amines, ertapenem, netilmicin sulfate, sennoside A, and / or ellagic acid; or it may be understood that the compound is netilmicin sulfate, preferably further comprising gossypol acetate, methylcobalamin, ertapenem, trachomatis, sennoside A, and / or ellagic acid; or it may be understood that the compound is sennoside A, preferably further comprising gossypol acetate, methylcobalamin, ertapenem, trachomatis, netilmicin sulfate, and / or ellagic acid; or it may be understood that the compound is ellagic acid, preferably further comprising gossypol acetate, methylcobalamin, ertapenem, trachomatis, netilmicin sulfate, and / or sennoside A; it may also be understood that the compound contains 2, 3, 4, 5, 6, or 7 of these 7 compounds, and those skilled in the art should understand that all of these should fall within the protection scope of this invention.

[0094] In this invention, SARS-CoV-1 may also be referred to in the art as SARS-CoV (Severe acute respiratory syndrome coronavirus).

[0095] Based on common knowledge in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0096] Terminology Explanation

[0097] The term "pharmaceutically acceptable" means that the salts, solvents, excipients, etc., are generally non-toxic, safe, and suitable for patient use. The term "patient" preferably refers to a mammal, and more preferably a human.

[0098] The term "pharmaceutically acceptable salt" refers to a salt prepared from the compounds of the present invention and pharmaceuticals or compositions containing the same, in combination with a relatively non-toxic, pharmaceutically acceptable acid or base. When the compounds of the present invention and pharmaceuticals or compositions containing the same contain relatively acidic functional groups, base addition salts can be obtained by contacting a sufficient amount of a pharmaceutically acceptable base with the neutral form of such pharmaceuticals in a pure solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include, but are not limited to, lithium salts, sodium salts, potassium salts, calcium salts, aluminum salts, magnesium salts, zinc salts, bismuth salts, ammonium salts, and diethanolamine salts. When the pharmaceuticals of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting a sufficient amount of a pharmaceutically acceptable acid with the neutral form of such pharmaceuticals in a pure solution or a suitable inert solvent. The pharmaceutically acceptable acids include inorganic acids, including but not limited to, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, phosphoric acid, phosphorous acid, and sulfuric acid. The pharmaceutically acceptable acids include organic acids, including but not limited to: acetic acid, propionic acid, oxalic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, octanoic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, salicylic acid, tartaric acid, methanesulfonic acid, isonicotinic acid, acidic citric acid, oleic acid, tannic acid, pantothenic acid, hydrogen tartrate, ascorbic acid, gentic acid, fumaric acid, gluconic acid, glycolic acid, formic acid, ethanesulfonic acid, dihydroxynaphthyl acid (i.e., 4,4'-methylene-bis(3-hydroxy-2-naphthylcarboxylic acid)), amino acids (e.g., glutamic acid, arginine), etc. When the drug of the present invention contains functional groups with relatively acidic and relatively basic properties, it can be converted into a base addition salt or an acid addition salt. For details, see Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science 66:1-19 (1977), or Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl and Camille G. Wermuth, ed., Wiley-VCH, 2002).

[0099] The term "one or more" can refer to 2, 3, 4, 5, 6, 7, 8, 9 or more.

[0100] The compounds, drugs or pharmaceutical compositions containing them of the present invention can be administered in unit dose form, and the route of administration can be enteric or non-enteric, such as oral, topical, intravenous, intramuscular, subcutaneous, nasal, oral mucosa, eye, lung and respiratory tract, skin, vagina, rectum, etc., preferably by oral or topical administration.

[0101] Dosage forms can be liquid, solid, or semi-solid. Liquid dosage forms can include solutions (including true solutions and colloidal solutions), emulsions (including o / w, w / o, and double emulsions), suspensions, injections (including water injections, powder injections, and infusions), eye drops, nasal drops, lotions, and liniments, etc.; solid dosage forms can include tablets (including regular tablets, enteric-coated tablets, lozenges, dispersible tablets, chewable tablets, effervescent tablets, and orally disintegrating tablets), capsules (including hard capsules, soft capsules, and enteric-coated capsules), granules, powders, microcapsules, pellets, suppositories, films, patches, aerosols, and sprays, etc.; semi-solid dosage forms can include ointments, gels, and pastes, etc.

[0102] The drugs or drug compositions of the present invention can be formulated into ordinary formulations, sustained-release formulations, controlled-release formulations, targeted formulations, and various microparticle delivery systems.

[0103] "Pharmaceutical composition" refers to a mixture of one or more of the compounds of this invention, or their pharmaceutically acceptable salts, solvates, hydrates, or prodrugs, with other chemical components, such as pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate the administration of the drug to animals.

[0104] "Pharmaceuticalally acceptable excipients" refer to inactive ingredients in pharmaceutical compositions that do not cause significant irritation to the organism and do not interfere with the biological activity and properties of the administered compound, such as, but not limited to: calcium carbonate, calcium phosphate, various sugars (e.g., lactose, mannitol, etc.), starch, cyclodextrin, magnesium stearate, cellulose, magnesium carbonate, acrylic polymers or methacrylic polymers, gels, water, polyethylene glycol, propylene glycol, ethylene glycol, EZ sesame oil or hydrogenated EZ sesame oil or polyethoxylated hydrogenated EZ sesame oil, sesame oil, corn oil, peanut oil, etc.

[0105] "Pharmaceutically acceptable carriers" refer to systems that can alter the way drugs enter the human body and their distribution within the body, control the rate of drug release, and deliver drugs to target organs. These systems can improve drug utilization, safety, and efficacy and can be conventional drug carriers in the field, such as, but not limited to, microcapsules, microspheres, nanoparticles, liposomes, etc.

[0106] In addition to pharmaceutically acceptable excipients, the aforementioned pharmaceutical compositions may also include pharmaceutically commonly used excipients, such as: antibacterial agents, antifungal agents, antimicrobial agents, preservatives, colorants, solubilizers, thickeners, surfactants, complexing agents, proteins, amino acids, fats, sugars, vitamins, minerals, trace elements, sweeteners, pigments, flavorings, or combinations thereof.

[0107] The term “treatment” refers to a therapeutic approach. When a specific condition is involved, treatment means: (1) alleviating one or more biological manifestations of the disease or condition; (2) interfering with (a) one or more points in a biological cascade that causes or precipitates the condition or (b) one or more biological manifestations of the condition; (3) improving 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 development of the condition or one or more biological manifestations of the condition.

[0108] The term "solvate" refers to a substance formed by the combination of the compound of this invention with a stoichiometric or non-stoichiometric solvent. Solvent molecules in a solvate can exist in an ordered or disordered arrangement. The solvents include, but are not limited to, water, methanol, and ethanol.

[0109] The terms "pharmaceutically acceptable salt" and "solvent" in the term "pharmaceuticalally acceptable salt solvate" refer, as described above, to substances formed by combining the compounds of the present invention with 1) a relatively non-toxic, pharmaceutically acceptable acid or base, or 2) a stoichiometric or non-stoichiometric solvent. The term "pharmaceuticalally acceptable salt solvate" includes, but is not limited to, hydrochloric acid monohydrate of the compounds of the present invention.

[0110] The terms "compound," "pharmaceutically acceptable salt," "solvent," and "solvent of a pharmaceutically acceptable salt" can exist in crystalline or amorphous forms. The term "crystalline form" refers to a state in which the ions or molecules are arranged in a strictly periodic manner in three-dimensional space, exhibiting a regular repetition at certain intervals; due to different periodsic arrangements, multiple crystalline forms can exist, a phenomenon known as polymorphism. The term "amorphous" refers to a state in which the ions or molecules are distributed randomly, meaning that there is no periodic arrangement between the ions and molecules.

[0111] In this invention, "comprising, including, or containing" can mean that in addition to the components listed below, other components also exist; or it can mean "composed of," that is, only the components listed below are included and no other components exist.

[0112] The reagents and raw materials used in this invention are all commercially available.

[0113] The positive and progressive effects of this invention are as follows:

[0114] The seven compounds disclosed in this invention—gossypol acetate, methylcobalamin, ertapenem, chamomile, netilmicin sulfate, sennoside A, and ellagic acid—can effectively inhibit RDRP of coronavirus, thereby inhibiting coronavirus proliferation and can be used in anti-coronavirus applications. They exhibit strong inhibitory effects, low cost, and require small doses, making them suitable for effective anti-coronavirus treatment. Attached Figure Description

[0115] Figure 1 This study aims to determine the inhibitory activity of gossypol acetate against the novel coronavirus RDRP.

[0116] Figure 2 This study aims to determine the inhibitory activity of mecobalamin against the novel coronavirus RDRP.

[0117] Figure 3 To determine the inhibitory activity of ertapenem sodium mecobalamin against the novel coronavirus RDRP.

[0118] Figure 4 This study aims to determine the inhibitory activity of chamomilein against the novel coronavirus RDRP.

[0119] Figure 5 This study aims to determine the inhibitory activity of netilmicin sulfate against the novel coronavirus RDRP.

[0120] Figure 6 This study aims to determine the inhibitory activity of sennoside A against the novel coronavirus RDRP.

[0121] Figure 7 This study aims to determine the inhibitory activity of ellagic acid against the novel coronavirus RDRP.

[0122] Figure 8 This study aims to determine the inhibitory activity of gossypol acetate against the replication ability of SARS-CoV-2 pseudovirus.

[0123] Figure 9 This study aims to determine the inhibitory activity of methylcobalamin against the replication of SARS-CoV-2 pseudoviruses.

[0124] Figure 10 This study aims to determine the inhibitory activity of ertapenem sodium mecobalamin against the replication of SARS-CoV-2 pseudoviruses.

[0125] Figure 11 This study aims to determine the inhibitory activity of chamomile on the replication ability of SARS-CoV-2 pseudoviruses.

[0126] Figure 12 This study aims to determine the inhibitory activity of netilmicin sulfate against the replication of SARS-CoV-2 pseudoviruses.

[0127] Figure 13 This study aims to determine the inhibitory activity of sennoside A against the replication ability of SARS-CoV-2 pseudoviruses.

[0128] Figure 14 This study aims to determine the inhibitory activity of ellagic acid against the replication ability of SARS-CoV-2 pseudoviruses.

[0129] Figure 15 This study aims to determine the inhibitory activity of pyrroloquinoline quinone disodium salt against the replication ability of SARS-CoV-2 pseudoviruses. Detailed Implementation

[0130] The present invention is further illustrated below by way of embodiments, but the invention is not limited to the scope of the embodiments described herein. Experimental methods in the following embodiments that do not specify specific conditions were performed according to conventional methods and conditions, or as selected according to the product instructions.

[0131] Example 1: Test of the inhibitory effect of seven compounds on RDRP of SARS-CoV-2

[0132] Information on the compounds and instruments used in the examples is shown in Table 1.

[0133] Table 1. Compound and Instrument Information

[0134]

[0135] Following the method published by Eltahla AA, Lackovic K, Marquis C et al. (A fluorescence-based high-throughput screen to identify small compound inhibitors of the genotype 3a hepatitis C virus RNA polymerase[J]. Journal of Biomolecular Screening, 2013, 18(9):1027-1034), the inhibitory effects of seven compounds on the novel coronavirus RDRP were tested.

[0136] The specific steps are as follows:

[0137] This study uses a dye that produces a significant difference in fluorescence signal between single- and double-stranded nucleic acids as a detection method to reflect the RDRP activity of the novel coronavirus.

[0138] Dissolve and dilute the test compound to 1 mM using DMSO or ddH2O, depending on the solvent requirements. Dilute Picogreen 100 times with TE buffer (10 mM Tris-HCl, 1 mM EDTA, pH 8.0).

[0139] 4 μM Poly(C) (Sigma-Aldrich, average chain length 300 nt) and 100 μM Poly(G)9 were mixed at a volume ratio of 33:1 and reacted at 95 °C for 5 minutes, followed by gradual annealing at room temperature to serve as the nucleic acid template for the reaction. In a 384-well plate, 20 μL of the reaction mixture was added sequentially: first, 10 μL of system buffer (50 mM HEPES, 75 mM NaCl, 4 mM DTT, 7 mM MnCl2, 0.01% BSA); then, 3 μM RDRP enzyme (novel coronavirus RDRP) and 2% of the final reaction volume (0.4 μL) of the test compound; next, 1.8 μM of cofactors (novel coronavirus nsp7 and nsp8); then 2 μL of the annealed nucleic acid template; and finally, 0.5 mM GTP as the reaction substrate (i.e., 5 mM GTP substrate was added to bring the total to 20 μL). After incubation at 25°C for 120 minutes, 60 μL of Picogreen dye was added to terminate the reaction. An EnVision MultimodePlate Reader (PerkinElmer) generated excitation light at 485 nm and read the fluorescence intensity signal of the emitted light at a wavelength of 520 nm. The fluorescence intensity signal value was converted into inhibition rate using the following formula:

[0140] Inhibition rate = [1 - (sample fluorescence intensity - min) / (max - min)] × 100%

[0141] Where max represents the fluorescence intensity signal value of the compound solvent control (negative control, where 0.4 μL of the compound in the system was replaced with 0.4 μL of pure DMSO or ddH2O), and min represents the fluorescence intensity signal value of the enzyme-free control (positive control, where 2 μL of the reaction substrate GTP in the system was replaced with 2 μL of ddH2O). A curve was plotted with compound concentration and inhibition rate on the x and y axes. The curve was fitted using GraphPad Prism version 8.4.3 software, and the IC50 was calculated. 50 .

[0142] The results showed that the seven compounds in this invention had inhibitory activity against the novel coronavirus RDRP, and the inhibitory activity is shown in Table 2.

[0143] The results show that most of the tested compounds in this invention exhibit strong inhibition of RDRP activity (IC50). 50 (below 20 μM), specific activity data are shown in Table 2 and Figure 1-7 As shown.

[0144] Table 2. Inhibitory activity against RDRP of novel coronavirus (IC50) 50 (μM)

[0145]

[0146] It is evident that all seven compounds exhibited good inhibitory effects against the novel coronavirus RDRP.

[0147] Example 2: Testing the effect of eight compounds on the replication of SARS-CoV-2 pseudovirus

[0148] Following the method published by Ju X, Zhu Y, Wang Y, et al. (A Novel Cell Culture System Modeling the SARS-CoV-2 Life Cycle[J / OL]. PLOS Pathogens, 2021, 17(3):e1009439), the anti-infective ability and cytotoxicity of eight compounds against the novel coronavirus were tested.

[0149] The specific steps are as follows:

[0150] (1) Detection of compound cytotoxicity:

[0151] WST-8 in the Cell Counting Kit-8 reagent can be reduced by dehydrogenases in cells to a highly water-soluble yellow formazan product under the action of electron carriers. The absorbance of formazan at 450 nm reflects the number of live cells, and this characteristic is used to perform cytotoxicity analysis of the compound.

[0152] 10 cells were seeded in 96-well cell culture plates. 5 One 100 μl Caco-2-N cell culture plate was placed in a 37°C, 5% CO2 cell culture incubator and incubated statically for 24 hours. The compound powder was then dissolved in DMSO to a concentration of 200 mM, followed by 10-fold dilutions at a concentration gradient of 200 mM, 20 mM, 2 mM, 200 μM, 20 μM, 2 μM, and 200 nM. Different concentrations of the compound were diluted 100-fold with complete culture medium (10% FBS, 1% PS), and 100 μL was added to each well to ensure a DMSO content of 0.5% in each well. Five replicates were performed for each concentration. After incubation at 37°C, 5% CO2 for another 48 hours, the liquid in the cell culture plate was aspirated, and 10 μL of a mixture of Cell Counting Kit-8 and 90 μl of maintenance medium (2% FBS, 1% PS) was added to each well. The plate was then incubated at 37°C, 5% CO2. After 1.5 hours of static incubation in a CO2 cell culture incubator, absorbance values ​​were immediately read at 450 nm using an EnVision Multimode Plate Reader (PerkinElmer). The absorbance values ​​were then converted into cell viability data (% cell viability = (per well ABS)).450nm (value - min) / (max - min) × 100). Where max is the ABS of cells treated with only 0.5% DMSO. 450nm Value, min is for ABS only with Cell Counting Kit-8 450nm The error bar represents the standard deviation of cell viability calculated across three replicate experimental groups after discarding the maximum and minimum detection values ​​for each concentration. A curve was plotted with the logarithm of compound concentration and cell viability on the x and y axes, and the cell activity data and standard deviation were obtained using Excel.

[0153] (2) Detection of compound resistance to novel coronavirus particle infection:

[0154] Transcription and replication-competent SARS-CoV-2 virus-like particles (trVLPs) can express green fluorescent protein (GFP) to replace the viral capsid protein. Only by infecting cell lines capable of ectopically expressing SARS-CoV or SARS-CoV-2 capsid proteins can they complete their full life cycle. The inhibitory effect of compounds on trVLPs is reflected by detecting differences in green fluorescence intensity, thereby characterizing the compounds' anti-SARS-CoV activity.

[0155] 1.25 × 10⁶ cells were seeded in 96-well cells culture plates. 5One 100 μl Caco-2-N cell was placed in a 37°C, 5% CO2 cell culture incubator and incubated statically for 24 hours. The compound powder was dissolved in DMSO to a concentration of 200 mM, and then diluted 10-fold at each subsequent concentration, with concentration gradients of 200 mM, 20 mM, 2 mM, 200 μM, 20 μM, 2 μM, and 200 nM. Different concentrations of the compound were diluted 100-fold with complete culture medium (10% FBS, 1% PS), and 100 μl was added to each cell culture well to ensure a DMSO content of 0.5% in each well. Five replicates were performed for each concentration. After incubation at 37°C and 5% CO2 for 12 hours, the liquid in the cell culture plate was aspirated, and trVLP was diluted with maintenance medium (2% FBS, 1% PS). 100 μl of the diluted trVLP was seeded into each well at an MOI of 2.0. The cells were then incubated at 37°C and 5% CO2 for 48 hours. Imaging analysis was performed using the Operetta (PerkinElmer) high-content cell imaging system, and long-term dynamic live-cell imaging was performed using IncuCyte. Quantitative fluorescence intensity analysis was performed using Zoom HD / 2CLR (BioScience). Green fluorescence intensity was converted into viral infectivity data (%viral infection rate = 1 - (max - total fluorescence intensity per well) / max × 100). `max` refers to the average total fluorescence intensity of the five parallel experimental groups treated with only 0.5% DMSO. The error bar represents the standard deviation of the viral infection rate calculated from the three replicate experimental groups after discarding the maximum and minimum detection values ​​for each concentration. A curve was plotted with the logarithm of compound concentration and viral infection rate on the x and y axes, and the viral infection rate data and standard deviation were obtained using Excel.

[0156] Table 3 Inhibitory activity against SARS-CoV-2 pseudovirus replication capacity (EC) 50 (μM) and cytotoxicity (CC) 50 (μM)

[0157]

[0158] The results showed that most of the tested compounds of this invention exhibited significant inhibitory activity in the system for inhibiting the replication of SARS-CoV-2 pseudoviruses, as detailed in the following data: Figure 8-15 As shown in Table 3.

[0159] References

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Claims

1. The use of a compound or a pharmaceutically acceptable salt thereof in the preparation of an anticoronavirus formulation, said compound being selected from one or more of chamocin and netilmicin sulfate; The coronavirus is either SARS coronavirus or MERS-CoV; The compound inhibits the RDRP of the coronavirus.

2. The application as described in claim 1, characterized in that, The SARS coronavirus mentioned is either SARS-CoV-1 or SARS-CoV-2.

3. The application as described in claim 1, characterized in that, The SARS coronavirus mentioned is SARS-CoV-2.

4. The use of a compound or a pharmaceutically acceptable salt thereof in the preparation of an anticoronavirus formulation, said compound being selected from one or more of chamocin and netilmicin sulfate; The coronavirus in question is SARS-CoV-2.

5. The application as described in claim 4, characterized in that, The compound inhibits the RDRP of the coronavirus.

6. The use of a pharmaceutical composition or kit in the preparation of an anticoronavirus formulation, said pharmaceutical composition or kit comprising a compound or a pharmaceutically acceptable salt thereof, said compound being selected from one or more of chamocin and netilmicin sulfate; The coronavirus is either SARS coronavirus or MERS-CoV; The compound inhibits the RDRP of the coronavirus.

7. The application as described in claim 6, characterized in that, The pharmaceutical composition also includes pharmaceutically acceptable excipients.

8. The application as described in claim 6, characterized in that, The SARS coronavirus mentioned is either SARS-CoV-1 or SARS-CoV-2.

9. The application as described in claim 6, characterized in that, The SARS coronavirus mentioned is SARS-CoV-2.

10. The use of a pharmaceutical composition or kit in the preparation of an anticoronavirus formulation, said pharmaceutical composition or kit comprising a compound or a pharmaceutically acceptable salt thereof, said compound being selected from one or more of chamocin and netilmicin sulfate; The coronavirus in question is SARS-CoV-2.

11. The application as described in claim 10, characterized in that, The compound inhibits the RDRP of the coronavirus; or, the pharmaceutical composition further comprises a pharmaceutically acceptable excipient.

12. The application as described in claim 10, characterized in that, The compound inhibits the RDRP of the coronavirus; and the pharmaceutical composition further comprises a pharmaceutically acceptable excipient.

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