Methods and compositions for treating an RNA virus induced disease

Abstract

The present invention provides methods and compositions for treating or alleviating symptoms of RNA virus-induced diseases or preventing RNA virus-induced diseases by means of cyclohexenone compounds.

Description

Technical Field

[0001] This invention relates to methods for treating or alleviating symptoms of RNA virus-induced diseases or for preventing RNA virus-induced diseases, and more specifically, to a method of administering a cyclohexenone compound. Prior Technology

[0002] RNA viruses are viruses that use RNA (ribonucleic acid) as their genetic material. This nucleic acid is usually single-stranded RNA (ssRNA) but can be double-stranded RNA (dsRNA). Notable human diseases caused by RNA viruses include the common cold, influenza, SARS, MERS, COVID-19, dengue virus, hepatitis C, hepatitis E, West Nile fever, Ebola virus disease, rabies, poliomyelitis, mumps, and measles.

[0003] RNA virus-induced diseases, such as RNA virus pneumonia, are a common cause of death. There are approximately 450 million cases of pneumonia each year. Of these, viral pneumonia accounts for about 200 million cases, including about 100 million children and 100 million adults. Viral pneumonia is pneumonia caused by a virus. Pneumonia is an infection that causes inflammation of one or both lungs. The alveoli fill with fluid or pus, making breathing difficult.

[0004] Coronaviruses are a group of related RNA viruses that cause diseases in mammals and birds. In humans, these viruses cause respiratory infections that can range from mild to fatal. Mild symptoms include some cases of the common cold (which is also caused by several other viruses, primarily rhinoviruses), while more deadly variants can cause SARS, MERS, and COVID-19. Summary of the Invention

[0005] In one aspect, this article provides a method for treating or alleviating symptoms of RNA virus-induced diseases (such as RNA virus-induced pneumonia) and / or preventing RNA virus-induced diseases (such as RNA virus-induced pneumonia) in a subject, comprising administering to the subject a therapeutically effective amount of a cyclohexenone compound having the following structure: Formula (I) Each of X and Y is independently oxygen, NR5, or sulfur; R is hydrogen or a C(=O)C1-C8 alkyl group; Each of R1, R2, and R3 is independently hydrogen, an optionally substituted methyl group, or (CH2)m-CH3; R4 is NR5 R6, OR5, OC(=O)R7, C(=O)OR5, C(=O)R5, C(=O)NR5 R6, halogen, 5- or 6-membered lactone, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl, glucosyl, wherein the 5- or 6-membered lactone, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl, and glucosyl are optionally substituted by one or more substituents selected from NR5 R6, OR5, OC(=O)R7, C(=O)OR5, C(=O)R5, C(=O)NR5 R6, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, and C1-C8 haloalkyl; Each of R5 and R6 is independently hydrogen or a C1-C8 alkyl group; R7 is a C1-C8 alkyl group, OR5, or NR5 / R6; m = 1-12; and n=1-12; or its pharmaceutically acceptable salts, metabolites, solvates, or prodrugs. [[] [Cited and incorporated] []]

[0006] All publications, patents and patent applications mentioned in this specification are incorporated herein by reference to the extent that each individual publication, patent or patent application is specifically and individually cited and incorporated herein by reference. Simple Explanation of the Diagram

[0007] The novel features of the present invention are specifically set forth in the appended claims. The features and advantages of the invention will be better understood by referring to the following illustrative examples of embodiments in which the principles of the invention are utilized, and the accompanying drawings, in which:

[0008] Figure 1A / B shows the results of the study on the reduction of HBeAg (1A) and HBsAg (1B) expression levels by the exemplary compound 1.

[0009] Figures 2A / B show the results of the study on the reduction of HBV NDA expression (2A) and HCV RNA activity (2B) by the exemplary compound 1.

[0010] Figure 3 illustrates the potential clinical progression of SARS-CoV-2.

[0011] Figure 4 illustrates the multiple pathways of antiviral, anti-inflammatory, and anti-fibrotic effects of illustrative compound 1.

[0012] Figure 5 provides the results of Nrf-2 nuclear translocation studies comparing illustrative compound 1 with silymarin.

[0013] Figure 6 provides the results of the study on oxidative stress of illustrative compound 1.

[0014] Figure 7 provides the results of a study on renal inflammation using an NF-κB activation model of illustrative compound 1.

[0015] Figure 8 shows the results of a study on localized renal inflammation using illustrative compound 1 in the presence of MCP-1, IL-6, and CD3 biomarkers.

[0016] Figures 9A / B provide the results of the study on the antifibrotic activity of illustrative compound 1 through TGF-β1 inhibition (9A) and fibrosis-associated protein (9B).

[0017] Figure 10 shows the results of the study on the inhibition of SARS by the exemplary compound 1.

[0018] Figure 11 shows the results of a cell culture study comparing illustrative compound 1 with a control group (DMSO only).

[0019] Figures 12A-C show the gene expression levels of CXCL10 (12A), IL6 (12B), and IL18 (12C), respectively.

[0020] Figures 13A-B show the gene expression levels of TGFB1 (13A) and COL4A1 (13B), respectively. Implementation

[0021] Although many therapeutic agents have been developed for treating coronavirus-induced diseases such as SARS and MERS, none of the drugs developed to date have shown significant efficacy.

[0022] In some specific examples, cyclohexenone compounds are obtained from extracts of natural products or prepared by synthesis or semi-synthesis. In some specific examples, the present invention provides exemplary cyclohexenone compounds (e.g., compounds) for treating or alleviating symptoms of RNA virus-induced diseases in subjects or for preventing RNA virus-induced diseases in subjects. [1] ) therapeutic and preventive potential.

[0023] In some specific examples, methods are provided for treating or alleviating symptoms of RNA virus-induced diseases (such as RNA virus-induced pneumonia) in a subject and / or preventing RNA virus-induced diseases (such as RNA virus-induced pneumonia), comprising administering to the subject a therapeutically effective amount of a cyclohexenone compound having the following structure: Formula (I), Each of X and Y is independently oxygen, NR5, or sulfur; R is hydrogen or a C(=O)C1-C8 alkyl group; Each of R1, R2, and R3 is independently hydrogen, an optionally substituted methyl group, or (CH2)m-CH3; R4 is NR5 R6, OR5, OC(=O)R7, C(=O)OR5, C(=O)R5, C(=O)NR5 R6, halogen, 5- or 6-membered lactone, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl, glucosyl, wherein the 5- or 6-membered lactone, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl, and glucosyl are optionally substituted by one or more substituents selected from NR5 R6, OR5, OC(=O)R7, C(=O)OR5, C(=O)R5, C(=O)NR5 R6, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, and C1-C8 haloalkyl; Each of R5 and R6 is independently hydrogen or a C1-C8 alkyl group; R7 is a C1-C8 alkyl group, OR5, or NR5 / R6; m = 1-12; and n=1-12; or its pharmaceutically acceptable salts, metabolites, solvates, or prodrugs.

[0024] In some specific examples, pharmaceutical compositions comprising a therapeutically effective amount of a cyclohexenone compound having the following structure are provided: Formula (I), Each of X and Y is independently oxygen, NR5, or sulfur; R is hydrogen or a C(=O)C1-C8 alkyl group; Each of R1, R2, and R3 is independently hydrogen, an optionally substituted methyl group, or (CH2)m-CH3; R4 is NR5 R6, OR5, OC(=O)R7, C(=O)OR5, C(=O)R5, C(=O)NR5 R6, halogen, 5- or 6-membered lactone, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl, glucosyl, wherein the 5- or 6-membered lactone, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl, and glucosyl are optionally substituted by one or more substituents selected from NR5 R6, OR5, OC(=O)R7, C(=O)OR5, C(=O)R5, C(=O)NR5 R6, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, and C1-C8 haloalkyl; Each of R5 and R6 is independently hydrogen or a C1-C8 alkyl group; R7 is a C1-C8 alkyl group, OR5, or NR5 / R6; m = 1-12; and n=1-12; or a pharmaceutically acceptable salt, metabolite, solvate, or prodrug thereof; used to treat or alleviate symptoms of an RNA virus-induced disease (such as virus-induced pneumonia) in a subject and / or to prevent an RNA virus-induced disease (such as virus-induced pneumonia) in a subject.

[0025] In some specific examples, the therapeutically effective amount is provided with the following structure: Use of a cyclohexenone compound of formula (I) or a pharmaceutically acceptable salt, metabolite, solvate, or prodrug thereof in the preparation of a medicament for treating, alleviating, and / or preventing RNA virus-induced diseases (such as RNA virus-induced pneumonia) in a subject, wherein each of X and Y is independently oxygen, NR5, or sulfur; R is hydrogen or a C(=O)C1-C8 alkyl group; Each of R1, R2, and R3 is independently hydrogen, an optionally substituted methyl group, or (CH2)m-CH3; R4 is NR5 R6, OR5, OC(=O)R7, C(=O)OR5, C(=O)R5, C(=O)NR5 R6, halogen, 5- or 6-membered lactone, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl, glucosyl, wherein the 5- or 6-membered lactone, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl, and glucosyl are optionally substituted by one or more substituents selected from NR5 R6, OR5, OC(=O)R7, C(=O)OR5, C(=O)R5, C(=O)NR5 R6, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, and C1-C8 haloalkyl; Each of R5 and R6 is independently hydrogen or a C1-C8 alkyl group; R7 is a C1-C8 alkyl group, OR5, or NR5 / R6; m = 1-12; and n = 1 - 12.

[0026] In some specific examples, the RNA virus-induced disease is RNA virus-induced pneumonia, coronavirus-induced pneumonia, or SARS-CoV-2-induced pneumonia, etc. In some embodiments, the RNA virus is a coronavirus. In some specific examples, the RNA virus-induced disease is caused or induced by an infection of the Coronaviridae family. In some specific examples, the Coronaviridae infection is caused or associated with alpha coronavirus 229E (HCoV-229E), NL63 (HCoV-NL63, New Haven coronavirus), beta coronavirus OC43 (HCoV-OC43), HKU1, MERS-CoV (the coronavirus that causes Middle East Respiratory Syndrome), SARS-CoV (the coronavirus that causes Severe Acute Respiratory Syndrome), or SARS-CoV-2 (the coronavirus that causes Severe Acute Respiratory Syndrome, formerly known as the novel coronavirus in 2019, or 2019-nCoV). In some specific examples, the Coronaviridae infection is caused or associated with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). In some specific examples, the RNA virus-induced disease is RNA virus-induced pneumonia. In some specific instances, the coronavirus infection is caused by or associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In some specific instances, cyclohexenone compounds reduce RNA virus concentrations or prevent RNA virus replication. In some specific instances, cyclohexenone compounds reduce the concentrations of the following RNA viruses or prevent the replication of the following RNA viruses: alpha coronavirus 229E (HCoV-229E), NL63 (HCoV-NL63, New Haven coronavirus), beta coronavirus OC43 (HCoV-OC43), HKU1, MERS-CoV (the coronavirus that causes Middle East Respiratory Syndrome), SARS-CoV (the coronavirus that causes severe acute respiratory syndrome), or SARS-CoV-2 (the coronavirus that causes severe acute respiratory syndrome, formerly known as novel coronavirus or 2019-nCoV in 2019), etc. In some specific instances, the subjects are humans.

[0027] In some specific examples, a method is provided for treating, suppressing, and / or preventing coronavirus-induced pneumonia in subjects in need, the method comprising administering to the subject an effective amount of a cyclohexenone compound of formula (I).

[0028] In some specific examples, a method is provided for treating, inhibiting, and / or preventing the replication of RNA viruses (e.g., coronavirus replication) in subjects in need, the method comprising administering to the subject an effective amount of the cyclohexenone compound disclosed herein.

[0029] In some specific examples, a method for reducing the concentration of RNA virus in subjects in need is provided, the method comprising administering to the subject an effective amount of the cyclohexenone compound disclosed herein.

[0030] In some specific examples, a method for inhibiting and / or preventing RNA virus infection in subjects in need is provided, the method comprising administering to the subject an effective amount of the cyclohexenone compound disclosed herein.

[0031] In some specific examples, it has structure The cyclohexenone compound of formula (I) is prepared synthetically or semi-synthetically from any suitable starting material. In other embodiments, the cyclohexenone compound is prepared by fermentation, etc. For example, the compound... [1] and [3-7] Separation from organic solvent extracts. Non-limiting example compounds are shown below.

[0032] In other specific examples, it has structure The cyclohexenone compound of formula (I) was isolated from an organic solvent extract of *Antrodia camphorata*. In some specific examples, the organic solvent is selected from: alcohols (e.g., methanol, ethanol, propanol, etc.), esters (e.g., methyl acetate, ethyl acetate, etc.), alkanes (e.g., pentane, hexane, heptane, etc.), haloalkanes (e.g., chloromethane, chloroethane, chloroform, dichloromethane, etc.), etc. For example, exemplary compounds [1-7] It is obtained from an organic solvent extract. In some embodiments, the organic solvent is an alcohol. In some embodiments, the alcohol is ethanol. In some specific examples, the cyclohexenone compound is isolated from an aqueous extract of Antrodia camphorata. In some embodiments, the cyclohexenone compound disclosed herein is prepared synthetically or semi-synthetically.

[0033] In some specific examples, each of X and Y is independently oxygen or sulfur. It is known in the art that compounds in which each X and Y is independently sulfur can be prepared in a similar manner or via the same route as compounds in which each X and Y is independently oxygen, because oxygen and sulfur share similar chemical properties in their structure. In some specific examples, compounds in which each X and Y is independently NR5 can be prepared via a similar route to compounds in which each X and Y is independently oxygen or sulfur, by using appropriate protecting groups.

[0034] In some specific examples, R is hydrogen, C(=O)C3H8, C(=O)C2H5, or C(=O)CH3. In some specific examples, R1 is hydrogen, methyl, ethyl, propyl, butyl, pentyl, or hexyl. In some embodiments, R1 is hydrogen or methyl. In some specific examples, R2 is hydrogen, methyl, ethyl, propyl, butyl, pentyl, or hexyl. In some embodiments, R2 is hydrogen or methyl. In some specific examples, R3 is hydrogen, methyl, ethyl, propyl, butyl, pentyl, or hexyl. In some specific examples, R4 is a halogen, NH2, NHCH3, N(CH3)2, OCH3, OC2H5, C(=O)CH3, C(=O)C2H5, C(=O)OCH3, C(=O)OC2H5, C(=O)NHCH3, C(=O)NHC2H5, C(=O)NH2, OC(=O)CH3, OC(=O)C2H5, OC(=O)OCH3, OC(=O)OC2H5, OC(=O)NHCH3, OC(=O)NHC2H5, or OC(=O)NH2. In some specific examples, R4 is C2H5C(CH3)2OH, C2H5C(CH3)2OCH3, CH2COOH, C2H5COOH, CH2OH, C2H5OH, CH2Ph, C2H5Ph, CH2CH=C(CH3)(CHO), CH2CH=C(CH3)(C(=O)CH3), a 5- or 6-membered lactone, a C2-C8 alkenyl, a C2-C8 alkynyl, an aryl, or a glucosyl, wherein the 5- or 6-membered lactone, C2-C8 alkenyl, C2-C8 alkynyl, aryl, or glucosyl is optionally substituted by one or more substituents selected from NR5R6, OR5, OC(=O)R7, C(=O)OR5, C(=O)R5, C(=O)NR5R6, C1-C8 alkyl, C2-C8 Alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, and C1-C8 haloalkyl. In some embodiments, R4 is a 5- or 6-membered lactone, C2-C8 alkenyl, C2-C8 alkynyl, aryl, or glucosyl, optionally substituted with one or more substituents selected from NR5R6, OR5, OC(=O)R7, C(=O)OR5, C(=O)R5, C(=O)NR5R6, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, and C1-C8 haloalkyl. In some embodiments, R4 is CH2CH=C(CH3)2. In some embodiments, the compound is... . [Some pharmaceutical and medical terms]

[0035] Unless otherwise stated, the following terms used in this application (including the specification and claims) have the definitions given below. It must be noted that, unless the context clearly indicates otherwise, the singular forms “a,” “an,” and “the” as used in this specification and the appended claims include plural indicators of the objects. Unless otherwise stated, conventional methods such as mass spectrometry, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA technology, and pharmacology are employed. In this application, unless otherwise stated, the use of “or” or “and” means “and / or.” Furthermore, the use of the term “comprising” and other forms such as “including,” “containing,” and “comprise” is not restrictive. Section headings used herein are for organizational purposes only and should not be construed as limiting the described subject matter.

[0036] "Alkyl" refers to an aliphatic hydrocarbon group. An alkyl group can be a saturated alkyl group (meaning it does not contain any carbon-carbon double or triple bonds) or an unsaturated alkyl group (meaning it contains at least one carbon-carbon double or triple bond). Whether saturated or unsaturated, the alkyl moiety can be branched or straight-chain.

[0037] "alkyl" can have 1-12 carbon atoms (the numerical range "1-12" whenever it appears herein refers to each integer within the given range; for example, "1-12 carbon atoms" means that an alkyl group can consist of 1, 2, 3, etc., up to and including 12 carbon atoms, but this definition also covers the presence of the term "alkyl" without a specified numerical range). The alkyl group of the compounds described herein can be designated as "C1-C8 alkyl" or a similar designation. By way of example only, "C1-C8 alkyl" means that there are 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms in the alkyl chain. In one aspect, the alkyl group is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl. Typical alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, neopentyl, hexyl, allyl, but-2-enyl, but-3-enyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, etc. In one respect, alkyl groups are C1-C8 alkyl groups.

[0038] The term "alkylene" refers to a divalent alkyl group. Any monovalent alkyl group can become an alkylene group by removing a second hydrogen atom from the alkyl group. In one aspect, alkylene is a C1-C12 alkylene (e.g., -(CH2)m-CH3). In another aspect, alkylene is a C1-C8 alkylene. Typical alkylenes include, but are not limited to, -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH2-, -CH2CH(CH3)-, -CH2C(CH3)2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, etc.

[0039] As used herein, the term "aryl" refers to an aromatic ring in which each atom forming the ring is a carbon atom. An aryl ring consists of five, six, seven, eight, nine, or more carbon atoms. The aryl group may optionally be substituted. In one aspect, the aryl group is phenyl or naphthyl. In another aspect, the aryl group is phenyl. In another aspect, the aryl group is a C6-C10 aryl group. Depending on the structure, the aryl group may be a monovalent or divalent group (i.e., an arylene). In one aspect, the arylene is a C6-C10 arylene. Exemplary arylenes include, but are not limited to, phenyl-1,2-ene, phenyl-1,3-ene, and phenyl-1,4-ene.

[0040] The term "aromatic hydrocarbon" refers to a planar ring having a delocalized π-electron system comprising 4n+2 π electrons, where n is an integer. The aromatic ring can be formed from 5, 6, 7, 8, 9, 10, or more than 10 atoms. Aromatic hydrocarbons are optionally substituted. The term "aromatic hydrocarbon" includes carbocyclic aryl ("aryl", e.g., phenyl) and heterocyclic aryl (or "heteroaryl" or "heteroaromatic") groups (e.g., pyridine). The term includes monocyclic or fused-ring polycyclic (i.e., rings sharing adjacent carbon atom pairs) groups.

[0041] The term “halogenated” or alternative terms “halogen” or “halogen” refer to fluorine, chlorine, bromine or iodine.

[0042] The term "lactone" refers to a cyclic ester that can be considered as a condensation product of a hydroxyl group (-OH) and a carboxylic acid group (-COOH) in the same molecule. It is characterized by a closed ring consisting of two or more carbon atoms and one oxygen atom, with a ketone group (=O) on a carbon atom adjacent to the other oxygen atom.

[0043] The term "heterocyclic" or "heterocyclic" refers to aromatic heterocycles (also known as heteroaryl groups) and heterocyclic alkyl rings (also known as heteroalicyclic groups) containing 1-4 heteroatoms in the ring, wherein each heteroatom in the ring is selected from O, S, and N, and each heterocyclic group has 4-10 atoms in its ring system, provided that no ring contains two adjacent O or S atoms. Non-aromatic heterocyclic groups (also known as heterocyclic alkyl groups) include groups containing only 3 atoms in their ring system, while aromatic heterocyclic groups must contain at least 5 atoms in their ring system. Heterocyclic groups include benzofused ring systems. An example of a 3-membered heterocyclic group is acridinel. An example of a 4-membered heterocyclic group is aziridine. An example of a 5-membered heterocyclic group is thiazolyl. An example of a 6-membered heterocyclic group is pyridinyl, and an example of a 10-membered heterocyclic group is quinolinyl. Examples of non-aromatic heterocyclic groups include pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, oxazolidinyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiophenyl, piriminyl, morpholinyl, thiomorpholinyl, thiaoxanyl, piriminyl, aprotinyl, aziridine, oxetanyl, thietanyl, hyperpiriminyl, oxepanyl, thiepanyl, oxaziridine, diazazyl, thiazyl, 1, 2,3,6-Tetrahydropyridyl, pyrrololin-2-yl, pyrrololin-3-yl, dihydroindolyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxanyl, pyrazolinyl, dithiaalkyl, dithiocyclopentyl, dihydropyranyl, dihydrothiophenyl, dihydrofuranyl, pyrazolyl, imidazolinyl, imidazolinyl, 3-azabicyclo[3.1.0]hexyl, 3-azabicyclo[4.1.0]heptyl, 3H-indolyl, and quinolizinyl. Examples of aromatic heterocyclic groups include pyridinyl, imidazole, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furanyl, thiophene, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrroleyl, quinolinyl, isoquinolinyl, indoleyl, benzimidazolyl, benzofuranyl, cenolinyl, indazole, indazinyl, phthalazinyl, pyridazinyl, triazinyl, isoindoleyl, pteridinyl, purineyl, oxadiazolyl, thiadiazolyl, furazonyl, benzofuranyl, benzothiophene, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphridinyl, and furanopyridinyl. Where possible, the aforementioned groups can be C-linked or N-linked. For example, groups derived from pyrrole can be pyrrole-1-yl (N-linked) or pyrrole-3-yl (C-linked). Furthermore, the groups derived from imidazole can be imidazole-1-yl or imidazole-3-yl (both N-linked) or imidazole-2-yl, imidazole-4-yl or imidazole-5-yl (both C-linked). Heterocyclic groups include benzofused ring systems.Non-aromatic heterocycles can be substituted with one or two oxygen (=O) moieties, for example, pyrrolidone-2-one.

[0044] As used herein, the term "alkenyl" refers to a straight-chain, branched, or cyclic (in this case, also referred to as "cycloalkenyl") hydrocarbon containing 2 to 10 carbons and at least one carbon-carbon double bond formed by the removal of two hydrogens. In some specific examples, depending on the structure, the alkenyl group is monovalent or divalent (i.e., alkenylidene). In some specific examples, the alkenyl group is optionally substituted. Illustrative examples of alkenyl groups include, but are not limited to, vinyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl, 2-heptenyl, 2-methyl-1-heptenyl, and 3-cecenyl.

[0045] As used herein, the term "alkynyl" refers to a straight-chain, branched, or cyclic (in this case, also referred to as "cycloalkynyl") hydrocarbon containing 2-10 carbons and at least one carbon-carbon triple bond formed by the removal of four hydrogens. In some specific examples, depending on the structure, the alkynyl group is monovalent or divalent (i.e., ynylene). In some specific examples, the alkynyl group is optionally substituted. Illustrative examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentyynyl, hexynyl, heptyynyl, etc.

[0046] As used herein, the term "alkoxy" refers to an alkyl group as defined herein, which is partially attached to the parent molecule by an oxygen atom. Illustrative examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentoxy, and hexoxy.

[0047] As used herein, the term "cycloalkyl" refers to a monocyclic or polycyclic group containing only carbon and hydrogen, and includes saturated, partially unsaturated, or fully unsaturated groups. Cycloalkyl groups include groups having 3 to 10 ring atoms. Representative examples of rings include, but are not limited to, the following: In some specific examples, depending on the structure, the cycloalkyl group is monovalent or divalent (i.e., a cycloalkylene group).

[0048] As used herein, the terms “haloalkyl,” “haloalkenyl,” “haloalkynyl,” and “haloalkoxy” include alkyl, alkenyl, alkynyl, and alkoxy structures in which at least one hydrogen atom is replaced by a halogen atom. In some embodiments where two or more hydrogen atoms are replaced by halogen atoms, all halogen atoms are identical to each other. In other embodiments where two or more hydrogen atoms are replaced by halogen atoms, not all halogen atoms are identical to each other. The terms “fluoroalkyl” and “fluoroalkoxy” respectively include haloalkyl and haloalkoxy groups in which the halogenation is fluorine. In some embodiments, the haloalkyl group is optionally substituted.

[0049] As used herein, the term "glucosyl" includes glucosyl in the form of D- or L-, wherein the glucosyl is linked via any hydroxyl group on the glucose ring.

[0050] As used herein, the term “acceptable” with respect to formulations, compositions or ingredients means that it has no lasting adverse effect on the general health of the subject being treated.

[0051] *Antrodia* is a genus of fungi in the family Meripilaceae. The fruiting bodies of *Antrodia* species typically lie flat or spread out on the growing surface, with their hymenium exposed; their edges may curl up, forming narrow brackets. Most species are found in temperate and northern forests and cause brown rot.

[0052] Antrodia camphorata, also known as the camphor fungus Ganoderma camphoratum, is a species of fungus in the genus Ganoderma endemic to Taiwan. It grows only on the native tree species Cinnamomum kanehirae and causes heart rot. This unique Taiwanese mushroom has been used as a traditional medicine to combat various disease conditions.

[0053] It is known in the art that the active ingredients isolated from different parts of Antrodia camphorata vary depending on the culture medium and method. For example, some cyclohexenone compounds disclosed herein can be isolated from Antrodia camphorata through a unique solid-state fermentation process that differs from other known methods.

[0054] As used herein, the term "carrier" refers to a relatively non-toxic chemical compound or reagent that facilitates the introduction of a compound into cells or tissues.

[0055] As used herein, the term “co-administration” or similar terminology is intended to include the administration of multiple selected therapeutic agents to a patient and is intended to include treatment regimens in which multiple agents are administered via the same or different routes of administration or at the same or different times.

[0056] The term "diluent" refers to a chemical compound used to dilute a target compound prior to delivery. Diluents can also be used to stabilize compounds, as they provide a more stable environment. Salts dissolved in buffered solutions (which may also provide pH control or maintenance) are used in the art as diluents, including but not limited to phosphate-buffered saline solutions.

[0057] As used herein, the term "effective amount" or "therapeutic effective amount" refers to an amount of a drug or compound administered that is sufficient to alleviate, to a certain extent, one or more symptoms of the disease or condition being treated. The result may be a reduction and / or relief of indications, symptoms, or causes of the disease, or any other desired change in a biological system. For example, an "effective amount" for therapeutic use is an amount of a composition comprising a compound disclosed herein that is necessary to achieve a clinically significant reduction in the symptoms of the disease. In any individual case, an appropriate "effective" amount can be determined using techniques such as dose escalation studies.

[0058] As used herein, the term "enhancement" means an increase or prolongation of the potency or duration of a desired effect. Therefore, regarding the effect of an enhancing therapeutic agent, the term "enhancement" refers to the ability to increase or prolong the effect of another therapeutic agent on the system in terms of potency or duration. As used herein, "enhancing effective amount" refers to an amount sufficient to enhance the effect of another therapeutic agent on the desired system.

[0059] The "metabolites" of the compounds disclosed herein are derivatives of the compounds formed during their metabolism. The term "active metabolite" refers to a biologically active derivative of the compound formed during its metabolism. As used herein, the term "metabolism" refers to the sum of processes (including but not limited to hydrolysis and enzyme-catalyzed reactions) in which a particular substance is altered by an organism. Thus, enzymes can produce specific structural changes to compounds. For example, cytochrome P450 catalyzes a variety of oxidation and reduction reactions, while uridine diphosphate glucuronyltransferase catalyzes the transfer of activated glucuronic acid molecules to aromatic alcohols, fatty alcohols, carboxylic acids, amines, and free sulfhydryl groups. Metabolites of the compounds disclosed herein may be identified optionally by administering the compound to a host and analyzing tissue samples from that host, or by incubating the compound with hepatocytes in vitro and analyzing the resulting compound.

[0060] As used herein, the term "drug combination" refers to a product obtained by mixing or combining more than one active ingredient, and includes both fixed and non-fixed combinations of active ingredients. The term "fixed combination" means the simultaneous administration of an active ingredient, such as a compound (i.e., the cyclohexenone compound described herein), and a combination agent to a patient as a single entity or dose. The term "non-fixed combination" means the simultaneous, parallel, or sequential administration of an active ingredient, such as a compound (i.e., the cyclohexenone compound described herein), and a combination agent to a patient as separate entities without a specific time interval, wherein such administration provides an effective level of both compounds in the patient. The latter also applies to cocktail therapies, such as the administration of three or more active ingredients.

[0061] The term "pharmaceutical composition" refers to a mixture of a compound (i.e., the cyclohexenone compound described herein) with other chemical components such as carriers, stabilizers, diluents, dispersants, suspending agents, thickeners, and / or excipients. Pharmaceutical compositions facilitate the application of the compound to a living organism. Various techniques for administering the compound exist in the art, including but not limited to: intravenous, oral, aerosol, parenteral, ocular, pulmonary, and topical administration.

[0062] The terms "subject" or "patient" include mammals. Examples of mammals include, but are not limited to, any member of the class Mammalia: humans, non-human primates such as chimpanzees and other ape and monkey species; farm animals such as cattle, horses, sheep, goats, and pigs; livestock such as rabbits, dogs, and cats; laboratory animals, including rodents such as rats, mice, and guinea pigs, etc. In a specific example, the mammal is a human.

[0063] As used herein, the terms “treat,” “treating,” or “treatment” include relieving, reducing, or alleviating at least one symptom of a disease or condition, preventing additional symptoms, suppressing a disease or condition, such as preventing the development of a disease or condition, alleviating a disease or condition, causing a remission of a disease or condition, relieving a condition caused by a disease or condition, or preventively and / or therapeutically stopping the symptoms of a disease or condition. In particular, the terms “treat,” “treatment,” or “treating” refer to reducing the frequency, severity, and / or duration of coronavirus-induced disease symptoms experienced by a subject (e.g., a patient).

[0064] The terms “prevent,” “prevention,” or “preventing” refer to suppressing, reducing the risk of, reducing the onset of symptoms associated with coronavirus-induced disease, or avoiding symptoms associated with coronavirus-induced disease. [Route of administration and dosage]

[0065] Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ocular, pulmonary, mucosal, transdermal, vaginal, ocular, nasal, and local administration. Additionally, to name just a few examples, parenteral delivery includes intramuscular, subcutaneous, intravenous, intramedullary injection, as well as intrathecal, direct intracardiac, intraperitoneal, intralymphatic, and intranasal injection.

[0066] In certain specific examples, compounds as described herein are typically administered locally rather than systemically in depot preparations or sustained-release formulations, for example, by direct injection into an organ. In specific examples, long-acting formulations are administered via implantation (e.g., subcutaneously or intramuscularly) or intramuscular injection. Furthermore, in other specific examples, drugs are delivered in targeted drug delivery systems, for example, in liposomes coated with organ-specific antibodies. In such examples, the liposomes target the organ and are selectively absorbed by it. In yet another specific example, compounds as described herein are provided in rapid-release, extended-release, or immediate-release formulations. In yet another specific example, compounds as described herein are administered locally.

[0067] In some specific examples, the cyclohexenone compound, or a pharmaceutically acceptable salt, metabolite, solvate, or prodrug thereof, is administered parenterally or intravenously. In other specific examples, the cyclohexenone compound, or a pharmaceutically acceptable salt, metabolite, solvate, or prodrug thereof, is administered by injection. In some specific examples, the cyclohexenone compound, or a pharmaceutically acceptable salt, metabolite, solvate, or prodrug thereof, is administered orally.

[0068] If the patient's condition does not improve, the compound may be administered long-term, i.e., for an extended period of time, including throughout the patient's life, at the physician's discretion, to improve or otherwise control or limit the symptoms of the patient's disease or condition. If the patient's condition does improve, the compound may be administered continuously or temporarily discontinued for a period of time (i.e., a "withdrawal period") at the physician's discretion.

[0069] The aforementioned ranges are merely recommendations, as there are numerous variables regarding individual treatment regimens, and significant deviations from these recommendations are not uncommon. Such dosages can be varied based on many variables, including but not limited to the activity of the compound used, the disease or condition being treated, the route of administration, the individual's needs, the severity of the disease or condition being treated, and the physician's judgment.

[0070] The toxicity and therapeutic efficacy of such treatment regimens can be determined in cell cultures or laboratory animals using standard pharmaceutical procedures, including but not limited to those used to determine the LD50 (50% lethal dose) and ED50 (50% therapeutically effective dose). The dose ratio between toxicity and therapeutic efficacy is the therapeutic index, and it can be expressed as the ratio between LD50 and ED50. Compounds exhibiting a high therapeutic index are preferred. Data obtained from cell culture experiments and animal studies can be used to determine the dosage range for human use. The dosage of such compounds is preferably within a range that includes the ED50 and has minimal toxicity. The dosage can vary within this range depending on the dosage form and route of administration used.

[0071] It should be understood that in some specific cases, dosage regimens used to treat, prevent, or improve conditions for which remission is sought are modified based on a variety of factors. These factors include the subject's condition, as well as the subject's age, weight, sex, diet, and medical history. Therefore, in other specific cases, the actual dosage regimens used vary widely, thus deviating from the dosage regimens described herein.

[0072] [Pharmaceutical Preparations]

[0073] In some specific examples, pharmaceutical compositions are provided that comprise a therapeutically effective amount of a cyclohexenone compound having the following structure: Formula (I); Each of X and Y is independently oxygen, NR5, or sulfur; R is hydrogen or a C(=O)C1-C8 alkyl group; Each of R1, R2, and R3 is independently hydrogen, an optionally substituted methyl group, or (CH2)m-CH3; R4 is NR5 R6, OR5, OC(=O)R7, C(=O)OR5, C(=O)R5, C(=O)NR5 R6, halogen, 5- or 6-membered lactone, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl, glucosyl, wherein the 5- or 6-membered lactone, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl, and glucosyl are optionally substituted by one or more substituents selected from NR5 R6, OR5, OC(=O)R7, C(=O)OR5, C(=O)R5, C(=O)NR5 R6, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, and C1-C8 haloalkyl; Each of R5 and R6 is independently hydrogen or a C1-C8 alkyl group; R7 is a C1-C8 alkyl group, OR5, or NR5 / R6; m = 1-12; and n = 1-12; or a pharmaceutically acceptable salt, metabolite, solvate, or prodrug thereof; and a pharmaceutically acceptable excipient.

[0074] In some specific examples, the cyclohexenone compound of the pharmaceutical composition has the following structure: Formula (I); Each of X and Y is independently oxygen, NR5, or sulfur; R is hydrogen or a C(=O)C1-C8 alkyl group; Each of R1, R2, and R3 is independently hydrogen, an optionally substituted methyl group, or (CH2)m-CH3; R4 is NR5 R6, OR5, OC(=O)R7, C(=O)OR5, C(=O)R5, C(=O)NR5 R6, halogen, 5- or 6-membered lactone, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl, glucosyl, wherein the 5- or 6-membered lactone, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl, and glucosyl are optionally substituted by one or more substituents selected from NR5 R6, OR5, OC(=O)R7, C(=O)OR5, C(=O)R5, C(=O)NR5 R6, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, and C1-C8 haloalkyl; Each of R5 and R6 is independently hydrogen or a C1-C8 alkyl group; R7 is a C1-C8 alkyl group, OR5, or NR5 / R6; m = 1-12; and n = 1-12; or a pharmaceutically acceptable salt, metabolite, solvate, or prodrug thereof.

[0075] In some specific examples, R is hydrogen, C(=O)C3H8, C(=O)C2H5, or C(=O)CH3. In some specific examples, each of R1, R2, and R3 is independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, or octyl. In some embodiments, R1 is hydrogen or methyl. In some embodiments, R2 is hydrogen, methyl, ethyl, propyl, butyl, pentyl, or hexyl. In some embodiments, R3 is hydrogen, methyl, ethyl, propyl, butyl, pentyl, or hexyl. In some specific examples, R4 is a halogen, NH2, NHCH3, N(CH3)2, OCH3, OC2H5, C(=O)CH3, C(=O)C2H5, C(=O)OCH3, C(=O)OC2H5, C(=O)NHCH3, C(=O)NHC2H5, C(=O)NH2, OC(=O)CH3, OC(=O)C2H5, OC(=O)OCH3, OC(=O)OC2H5, OC(=O)NHCH3, OC(=O)NHC2H5, or OC(=O)NH2. In some embodiments, R4 is C2H5C(CH3)2OH, C2H5C(CH3)2OCH3, CH2COOH, C2H5COOH, CH2OH, C2H5OH, CH2Ph, C2H5Ph, CH2CH=C(CH3)(CHO), CH2CH=C(CH3)(C(=O)CH3), a 5- or 6-membered lactone, an aryl group, or a glucosyl group, wherein the 5- or 6-membered lactone, aryl group, and glucosyl group are optionally substituted by one or more substituents selected from NR5R6, OR5, OC(=O)R7, C(=O)OR5, C(=O)R5, C(=O)NR5R6, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, and C1-C8 haloalkyl. In some embodiments, R4 is CH2COOH, C2H5COOH, CH2OH, C2H5OH, CH2Ph, C2H5Ph, CH2CH=C(CH3)(CHO), CH2CH=C(CH3)(C(=O)CH3), a 5- or 6-membered lactone, an aryl group, or a glucosyl group, wherein the 5- or 6-membered lactone, aryl group, and glucosyl group are optionally substituted by one or more substituents selected from NR5R6, OR5, OC(=O)R7, C(=O)OR5, C(=O)R5, C(=O)NR5R6, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, and C1-C8 haloalkyl.In some embodiments, R4 is a 5- or 6-membered lactone, aryl, or glucosyl, optionally substituted with one or more substituents selected from NR5R6, OR5, OC(=O)R7, C(=O)OR5, C(=O)R5, C(=O)NR5R6, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, and C1-C8 haloalkyl.

[0076] In some specific examples, the compound is selected from... , , , , , , , , , , , , , , , , , and .

[0077] In some specific examples, the compound is selected from... , , , , , , , , , , , , , , , and .

[0078] In some specific examples, the compounds described herein are formulated into pharmaceutical compositions. In particular embodiments, the pharmaceutical compositions are formulated in a conventional manner using one or more physiologically acceptable carriers, including excipients and adjuvants, which facilitate the processing of the active compound into a pharmaceutically acceptable formulation. A suitable formulation depends on the chosen route of administration. Any pharmaceutically acceptable technology, carrier, and excipient may be suitably used to formulate the pharmaceutical compositions described herein: Remington: The Science and Practice of Pharmacy, 19th edition (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, HA and Lachman, L. (eds.), Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th edition (Lippincott Williams & Wilkins 1999).

[0079] This document provides pharmaceutical compositions comprising a compound (i.e., the cyclohexenone compound described herein) and a pharmaceutically acceptable diluent, excipient, or carrier. In some embodiments, as in combination therapy, the compound is administered in the form of a pharmaceutical composition in which the compound (i.e., the cyclohexenone compound described herein) is mixed with other active ingredients. This document includes all combinations of active ingredients set forth in the following combination therapy section and throughout the disclosure. In a particular embodiment, the pharmaceutical composition comprises one or more compounds (i.e., the cyclohexenone compound described herein).

[0080] As used herein, a pharmaceutical composition refers to a mixture of a compound (i.e., the cyclohexenone compound described herein) with other chemical components such as carriers, stabilizers, diluents, dispersants, suspending agents, thickeners, and / or excipients. In some embodiments, the pharmaceutical composition facilitates the administration of the compound to a living organism. In some specific examples, a therapeutically effective amount of the compound (i.e., the cyclohexenone compound described herein) is administered in the form of a pharmaceutical composition to a mammal suffering from a disease or condition to be treated, in order to perform the treatment or method of use provided herein. In a particular embodiment, the mammal is a human. In some embodiments, the therapeutically effective amount varies depending on the severity of the disease, the age and relative health status of the subject, the potency of the compound used, and other factors. Furthermore, the compound described herein may be used alone or in combination with one or more therapeutic agents as components of a mixture.

[0081] In one embodiment, the compound (i.e., the cyclohexenone compound described herein) is formulated as an aqueous solution. In a particular embodiment, by way of example only, the aqueous solution is selected from physiologically compatible buffers, such as Hank's solution, Ringer's solution, or physiological saline buffer. In other embodiments, the compound (i.e., the cyclohexenone compound described herein) is formulated for transmucosal administration. In a particular embodiment, the transmucosal formulation includes a permeabilizing agent suitable for penetrating the barrier to be penetrated. In other embodiments where the compound described herein is formulated for other parenteral injections, suitable formulations include aqueous or non-aqueous solutions. In a particular embodiment, such solutions include physiologically compatible buffers and / or excipients.

[0082] In other specific examples, the compounds described herein are formulated for oral administration. The compounds described herein, including the cyclohexenone compounds described herein, are formulated by mixing the active compound with, for example, a pharmaceutically acceptable carrier or excipient. In various specific examples, the compounds described herein are formulated into oral dosage forms, which, by way of example only, include tablets, powders, pills, lozenges, capsules, liquids, gels, syrups, elixirs, pastes, suspensions, etc.

[0083] In certain specific examples, pharmaceutical formulations for oral use are obtained by the following steps: mixing one or more solid excipients with one or more compounds described herein, optionally grinding the resulting mixture, and processing the mixture into granules after adding suitable excipients (if desired), thereby obtaining tablets or tablet cores. In particular, suitable excipients are: fillers, such as sugars including lactose, sucrose, mannitol, or sorbitol; cellulose preparations, such as corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methylcellulose, microcrystalline cellulose, hydroxypropyl methylcellulose, sodium carboxymethyl cellulose; or other substances such as polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. In certain specific examples, a disintegrant is optionally added. By way of example only, disintegrants include croscarmellose sodium, polyvinylpyrrolidone, agar, or alginate or its salts such as sodium alginate.

[0084] In some specific examples, dosage forms such as sugar cores and tablets have one or more suitable coatings. In certain specific examples, a concentrated sugar solution is used to coat the dosage form. The sugar solution optionally contains additional ingredients, for example only, such as gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol and / or titanium dioxide, lacquer solution, and suitable organic solvents or solvent mixtures. Dyes and / or pigments are also optionally added to the coating for identification purposes. Additionally, dyes and / or pigments are optionally used to indicate different combinations of active compound dosages.

[0085] In certain specific examples, a therapeutically effective amount of at least one of the compounds described herein is formulated into other oral dosage forms. Oral dosage forms include push-in capsules made of gelatin and sealed soft capsules made of gelatin and plasticizers (such as glycerin or sorbitol). In certain specific examples, push-in capsules contain an active ingredient mixed with one or more fillers. Fillers, by way of example only, include lactose, binders such as starch, and / or lubricants such as talc or magnesium stearate, and optionally, stabilizers. In other specific examples, soft capsules contain one or more active compounds dissolved or suspended in a suitable liquid. Suitable liquids, by way of example only, include one or more fatty oils, liquid paraffin, or liquid polyethylene glycol. Additionally, stabilizers are optionally added.

[0086] In other specific examples, a therapeutically effective amount of at least one of the compounds described herein is formulated for buccal or sublingual administration. For example only, formulations suitable for buccal or sublingual administration include tablets, lozenges, or gels. In still other specific examples, the compounds described herein are formulated for parenteral injection, including formulations suitable for bolus injection or continuous infusion. In particular specific examples, injectable formulations are provided in unit dosage forms (e.g., in ampoules) or multi-dose containers. Optionally, a preservative is added to the injectable formulation. In still other specific examples, pharmaceutical compositions of the compounds (i.e., the cyclohexenone compounds described herein) are formulated in a form suitable for parenteral injection as a sterile suspension, solution, or emulsion in an oily or aqueous carrier. Parenteral injection formulations optionally contain formulation agents such as suspending agents, stabilizers, and / or dispersants. In particular specific examples, pharmaceutical formulations for parenteral administration comprise an aqueous solution of the active compound in a water-soluble form. In still other specific examples, a suspension of the active compound is prepared into a suitable oily injectable suspension. By way of example only, suitable lipophilic solvents or carriers used in the pharmaceutical compositions described herein include fatty oils such as sesame oil, or synthetic fatty acid esters such as ethyl oleate or triglycerides, or liposomes. In certain specific examples, the aqueous injectable suspension contains substances that can increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension contains suitable stabilizers or reagents that increase the solubility of the compound to allow for the preparation of highly concentrated solutions. Alternatively, in other specific examples, the active ingredient is in powder form for reconstitution with a suitable carrier (e.g., sterile, pyrogen-free water) prior to use.

[0087] In some aspects, the compound (i.e., the cyclohexenone compound described herein) is prepared as a solution for parenteral injection as described herein or known in the art, and administered using an autoinjector. Autoinjectors are known, for example, those disclosed in U.S. Patents 4,031,893, 5,358,489, 5,540,664, 5,665,071, 5,695,472, and WO / 2005 / 087297 (each of which is incorporated herein by reference). Typically, all autoinjectors contain a volume of solution containing the compound (i.e., the cyclohexenone compound described herein). Typically, an autoinjector includes: a reservoir for containing the solution, which is in fluid communication with a needle for drug delivery; and a mechanism for automatically deploying the needle, inserting the needle into the patient, and delivering the dose to the patient. The exemplary syringe delivers approximately 0.3 mL, 0.6 mL, 1.0 mL, or other suitable volumes of solution with a concentration of approximately 0.5 mg to 50 mg of the compound (i.e., the cyclohexenone compound described herein) per 1 mL of solution. Each syringe is capable of delivering only one dose of the compound.

[0088] In other specific examples, the compound (i.e., the cyclohexenone compound described herein) is applied topically. The compounds described herein are formulated into a variety of topically applicable compositions, such as solutions, suspensions, lotions, gels, pastes, sticks, balms, creams, or ointments. Such pharmaceutical compositions optionally contain solubilizers, stabilizers, tonic agents, buffers, and preservatives.

[0089] In other specific examples, the compound (i.e., the cyclohexenone compound described herein) is formulated for transdermal administration. In particular examples, the transdermal formulation employs a transdermal delivery device and a transdermal delivery patch, and may be a lipophilic emulsion or aqueous buffer solution dissolved and / or dispersed in a polymer or binder. In various specific examples, such patches are constructed for continuous, pulsed, or on-demand delivery of pharmaceutical formulations. In other specific examples, transdermal delivery of the compound (i.e., the cyclohexenone compound described herein) is accomplished via iontophoresis patches and similar methods. In some specific examples, the transdermal patch provides controlled delivery of the compound (i.e., the cyclohexenone compound described herein). In particular examples, the absorption rate is slowed by using a rate-controlled membrane or by trapping the compound in a polymer matrix or gel. In alternative examples, absorption enhancers are used to enhance absorption. Absorption enhancers or carriers comprise absorbable, pharmaceutically acceptable solvents that facilitate penetration through the skin. For example, in one specific instance, the transdermal device is in the form of a bandage, comprising: a backing component, a reservoir containing a compound and optionally a carrier, optionally a rate control barrier for delivering the compound to the host skin at a controlled and predetermined rate over an extended period of time, and a tool for securing the device to the skin.

[0090] The transdermal formulations described herein can be administered using a variety of devices already described in the art. Such devices include, but are not limited to, U.S. Patents 3,598,122, 3,598,123, 3,710,795, 3,731,683, 3,742,951, 3,814,097, 3,921,636, 3,972,995, 3,993,072, 3,993,073, 3,996,934, 4,031,894, and 4,065. The apparatus described in Nos. 0,084, 4,069,307, 4,077,407, 4,201,211, 4,230,105, 4,292,299, 4,292,303, 5,336,168, 5,665,378, 5,837,280, 5,869,090, 6,923,983, 6,929,801 and 6,946,144.

[0091] The transdermal formulations described herein may incorporate certain pharmaceutically acceptable excipients conventional in the art. In some specific examples, the transdermal formulations described herein comprise at least three components: (1) a formulation of a compound (i.e., the cyclohexenone compound described herein); (2) a penetration enhancer; and (3) an aqueous adjuvant. Furthermore, the transdermal formulations may also comprise other components, such as, but not limited to, gelling agents, creams, and ointment bases. In some specific examples, the transdermal formulations further comprise a woven or nonwoven backing material to enhance absorption and prevent the transdermal formulation from detaching from the skin. In other specific examples, the transdermal formulations described herein are maintained in a saturated or supersaturated state to facilitate diffusion into the skin.

[0092] In other specific examples, the compound (i.e., the cyclohexenone compound described herein) is formulated for administration by inhalation. Various forms suitable for inhalation administration include, but are not limited to, aerosols, mists, or powders. Pharmaceutical compositions of the compound (i.e., the cyclohexenone compound described herein) are conveniently delivered as an aerosol spray from a pressurized pack or nebulizer using a suitable propellant (e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas). In a particular specific example, the dosage unit of the pressurized aerosol is determined by setting a valve to deliver the measured amount. In a particular specific example, by way of example only, capsules and cartridges, such as gelatin, formulated for use in inhalers or blowpipes, contain the compound and a powder mixture of a suitable powder matrix such as lactose or starch.

[0093] Intranasal formulations are known in the art and are described, for example, in U.S. Patents 4,476,116, 5,116,817, and 6,391,452 (each specifically incorporated herein by reference). Formulations containing compounds (i.e., the cyclohexenone compounds described herein) prepared according to these and other techniques known in the art are prepared in saline solution using benzyl alcohol or other suitable preservatives, fluorocarbons, and / or other solubilizers or dispersants known in the art. See, for example, Ansel, HC et al., Pharmaceutical Dosage Forms and Drug Delivery System, 6th Edition (1995). Preferably, these compositions and formulations are prepared with suitable pharmaceutically acceptable non-toxic ingredients. These ingredients can be found in numerous sources, such as the standard reference in the art, REMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY, 21st Edition, 2005. The choice of a suitable carrier depends highly on the exact properties of the desired nasal dosage form, such as a solution, suspension, ointment, or gel. Nasal dosage forms typically contain a significant amount of water in addition to the active ingredient. Small amounts of other ingredients may also be present, such as pH adjusters, emulsifiers or dispersants, preservatives, surfactants, gelling agents or buffers, and other stabilizers and solubilizers. Preferably, the nasal formulation should be isotonic with nasal secretions.

[0094] For inhalation administration, the compounds described herein may be in the form of aerosols, mists, or powders. The pharmaceutical compositions described herein are conveniently delivered as an aerosol from a pressurized pack or nebulizer using a suitable propellant (e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas). In the case of pressurized aerosols, the dosage unit can be determined by setting a valve to deliver the measured amount. By way of example only, capsules and cartridges, such as gelatin, can be formulated for use in inhalers or blowpipes, containing a mixture of the compounds described herein and a suitable powder matrix such as lactose or starch powder.

[0095] In other specific examples, the compound (i.e., the cyclohexenone compound described herein) is formulated as a rectal composition, such as an enema, rectal gel, rectal foam, rectal aerosol, suppository, gel suppository, or retention enema containing a conventional suppository matrix such as cocoa butter or other glycerides and synthetic polymers such as polyvinylpyrrolidone, PEG, etc. In the suppository form of the composition, a low-melting-point wax (e.g., but not limited to a mixture of fatty acid glycerides optionally combined with cocoa butter) is melted first.

[0096] In certain specific examples, pharmaceutical compositions are formulated in any conventional manner using one or more physiologically acceptable carriers containing excipients and adjuvants that facilitate the processing of the active compound into a pharmaceutically acceptable formulation. The appropriate formulation depends on the chosen route of administration. Appropriately and as understood in the art, any pharmaceutically acceptable technique, carrier, and excipient may be used. Pharmaceutical compositions containing the compound (i.e., the cyclohexenone compound described herein) can be produced in a conventional manner, for example, by way of conventional mixing, dissolving, granulation, tableting, grinding, emulsification, encapsulation, capture, or compression processes, by way of example only.

[0097] Pharmaceutical compositions comprise at least one pharmaceutically acceptable carrier, diluent, or excipient, and at least one compound described herein (i.e., the cyclohexenone compound described herein) as an active ingredient. The active ingredient is in the form of a free acid or free base, or in the form of a pharmaceutically acceptable salt. Furthermore, the methods and pharmaceutical compositions described herein include the use of crystalline forms (also known as polymorphs) and active metabolites of these compounds having the same type of activity. All tautomers of the compounds described herein are also included within the scope of the compounds presented herein. The term "pharmaceutically acceptable salt" refers to those salts that retain the bioavailability and properties of a free base and are obtained by reaction with an inorganic or organic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, malic acid, maleic acid, succinic acid, tartaric acid, citric acid, etc.

[0098] Furthermore, the compounds described herein include both unsolvated and solvated forms in pharmaceutically acceptable solvents such as water and ethanol. Solvated forms of the compounds presented herein are also considered to be disclosed herein. Additionally, the pharmaceutical composition optionally contains other medical or pharmaceutical reagents, carriers, adjuvants such as preservatives, stabilizers, wetting agents or emulsifiers, solution promoters, salts for adjusting osmotic pressure, buffer solutions, and / or other substances of therapeutic value.

[0099] Methods for preparing compositions comprising the compounds described herein include formulating the compound with one or more inert, pharmaceutically acceptable excipients or carriers to form a solid, semi-solid, or liquid. Solid compositions include, but are not limited to, powders, tablets, dispersible granules, capsules, pouches, and suppositories. Liquid compositions include solutions in which the compound is dissolved, emulsions containing the compound, or solutions containing liposomes, micelles, or nanoparticles containing the compounds disclosed herein. Semi-solid compositions include, but are not limited to, gels, suspensions, and creams. The pharmaceutical compositions described herein are in the form of liquid solutions or suspensions, solid forms suitable for preparation into solutions or suspensions in liquids prior to use, or as emulsions. These compositions optionally also contain small amounts of non-toxic excipients, such as wetting agents or emulsifiers, pH buffers, etc.

[0100] In some specific examples, pharmaceutical compositions comprising at least one compound (i.e., the cyclohexenone compound described herein) are illustratively presented in liquid form, wherein the pharmaceutical agent is present in a solution, a suspension, or both. Generally, when the composition is administered as a solution or suspension, a first portion of the pharmaceutical agent is present in the solution, while a second portion of the pharmaceutical agent is suspended in particulate form within the liquid matrix. In some specific examples, the liquid composition includes a gel formulation. In other specific examples, the liquid composition is aqueous.

[0101] In certain specific examples, aqueous drug suspensions contain one or more polymers as suspending agents. Polymers include water-soluble polymers such as fibrous polymers (e.g., hydroxypropyl methylcellulose) and water-insoluble polymers such as cross-linked carboxyl-containing polymers. Some pharmaceutical compositions described herein contain mucosal adhesion polymers selected from, for example, carboxymethyl cellulose, carbomer (an acrylic polymer), poly(methyl methacrylate), polyacrylamide, polycarbofil, acrylate / butyl acrylate copolymer, sodium alginate, and dextran.

[0102] Pharmaceutical compositions may also optionally contain a solubilizer to improve the solubility of the compound (i.e., the cyclohexenone compound described herein). The term "sorcerer" generally includes an agent that results in the formation of a micelle solution or a true solution of the pharmaceutical preparation. Certain acceptable nonionic surfactants, such as polysorbate 80, may be used as solubilizers, as may ocularly acceptable glycols, polyethylene glycols (e.g., polyethylene glycol 400), and glycol ethers.

[0103] In addition, the pharmaceutical composition optionally comprises one or more pH adjusters or buffers, including: acids such as acetic acid, boric acid, citric acid, lactic acid, phosphoric acid, and hydrochloric acid; bases such as sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate, and tris(hydroxymethyl)aminomethane; and buffers such as citrate / dextrose, sodium bicarbonate, and ammonium chloride. Such acids, bases, and buffers are contained in the amount required to maintain the pH of the composition within an acceptable range.

[0104] Furthermore, the pharmaceutical composition optionally comprises one or more salts in the amount required to bring the molar osmolality of the composition within an acceptable range. Such salts include those containing sodium, potassium, or ammonium cations and chloride, citrate, ascorbate, borate, phosphate, bicarbonate, sulfate, thiosulfate, or bisulfite anions; suitable salts include sodium chloride, potassium chloride, sodium thiosulfate, sodium bisulfite, and ammonium sulfate.

[0105] Other pharmaceutical compositions optionally include one or more preservatives to inhibit microbial activity. Suitable preservatives include: mercury-containing substances, such as phenylmercuric borate and thiomersal; stabilized chlorine dioxide; and quaternary ammonium compounds, such as benzalkonium chloride, cetrimonium bromide, and cetylpyridinium chloride.

[0106] Other pharmaceutical compositions may contain one or more surfactants to enhance physical stability or for other purposes. Suitable nonionic surfactants include: polyoxyethylene fatty acid glycerides and vegetable oils, such as polyoxyethylene (60) hydrogenated castor oil; and polyoxyethylene alkyl ethers and alkylphenyl ethers, such as octoxynol 10 and octoxynol 40.

[0107] Other pharmaceutical compositions may contain one or more antioxidants to enhance chemical stability when needed. Suitable antioxidants, for example only, include ascorbic acid and sodium metabisulfite.

[0108] In some specific instances, aqueous suspensions of pharmaceutical compositions are packaged in non-resealable single-dose containers. Alternatively, resealable multi-dose containers are used, in which case preservatives are typically included in the composition.

[0109] In alternative specific examples, other delivery systems for hydrophobic drug compounds are used. Liposomes and emulsions are examples of delivery media or carriers used herein. In some specific examples, organic solvents such as N-methylpyrrolidone are also used. In other specific examples, sustained-release systems, such as semi-permeable matrices containing solid hydrophobic polymers of therapeutic agents, are used to deliver the compounds described herein. Various sustained-release materials are useful here. In some specific examples, sustained-release capsules release compounds for several hours, up to a maximum of 24 hours. Depending on the chemical properties and biological stability of the therapeutic agent, additional protein stabilization strategies may be used.

[0110] In certain specific examples, the formulations described herein comprise one or more antioxidants, metal chelators, thiol-containing compounds, and / or other common stabilizers. Examples of such stabilizers include, but are not limited to: (a) glycerol at about 0.5% to about 2% w / v, (b) methionine at about 0.1% to about 1% w / v, (c) monothioglycerol at about 0.1% to about 2% w / v, (d) EDTA at about 1 mM to about 10 mM, (e) ascorbic acid at about 0.01% to about 2% w / v, (f) polysorbate 80 at about 0.003% to about 0.02% w / v, (g) polysorbate 20 at about 0.001% to about 0.05% w / v, (h) arginine, (i) heparin, (j) dextran sulfate, (k) cyclodextrin, (l) pentosan polysulfate esters and other heparin-like substances, (m) divalent cations such as magnesium and zinc ions; or (n) combinations thereof. [Example] [Example] [1.] [Preparation of exemplary cyclohexenone compounds]

[0111] Place 100 g of Antrodia camphorata mycelium, fruiting bodies, or a mixture of both in a flask. Add an appropriate amount of water and ethanol (70%–100% ethanol solution) to the flask and stir at 20–25 °C for at least 1 hour. Filter the solution through a filter and a 0.45 μm filter membrane and collect the filtrate as the extract. In some specific examples, for instance, the extract was prepared using the solid-state fermentation conditions and composition of mycelium disclosed in Lee, TH. et al., Planta Med 2007; 73:1412–1415.

[0112] The filtrate of *Antrodia camphorata* was analyzed by high-performance liquid chromatography (HPLC). Separation was performed on an RP18 column at a flow rate of 1 ml / min. The mobile phase consisted of methanol (A) and 0.3% acetic acid (B). The gradient conditions were: 0–10 min in 95%–20% B, 10–20 min in 20%–10% B, 20–35 min in 10%–10% B, and 35–40 min in 10%–95% B. The column eluent was monitored using an ultraviolet-visible light detector.

[0113] The fractions collected between 21.2 and 21.4 min were collected and concentrated to obtain the compounds. [5], a pale yellow liquid product. (Compound) [5] The analysis showed that it was 4-hydroxy-5-(11-hydroxy-3,7,11-trimethyldodec-2,6-dienyl)-2,3-dimethoxy-6-methylcyclohex-2-enone with a molecular weight of 408 (molecular formula: C24H40O5). 1 H-NMR (CDCl3) δ (ppm)= 1.21, 1.36, 1.67, 1.71, 1.75, 1.94, 2.03, 2.07, 2.22, 2.25, 3.68, 4.05, 5.71 and 5.56. 13 C-NMR (CDCl3 )δ(ppm): 12.31, 16.1, 16.12, 17.67, 25.67, 26.44, 26.74, 27.00, 30.10, 40.27, 43.34, 59.22, 60.59, 71.8, 120.97, 123.84, 124.30, 131.32, 134.61, 135.92, 138.05, 160.45 and 197.11. compound [5] :4-hydroxy-5-(11-hydroxy-3,7,11-trimethyldodec-2,6-dienyl)-2,3-dimethoxy-6-methylcyclohexane-2-enone

[0114] The fractions collected between 23.7 and 24.0 min were collected and concentrated to obtain the compounds. [7], a pale yellow liquid product. (Compound) [7] It was analyzed to be 4-hydroxy-2,3-dimethoxy-5-(11-methoxy-3,7,11-trimethyldodec-2,6-dienyl)-6-methylcyclohex-2-enone with a molecular weight of 422 (C25 H42 O5). 1 H-NMR (CDCl3) δ (ppm) = 1.21, 1.36, 1.71, 1.75, 1.94, 2.03, 2.07, 2.22, 2.25, 3.24, 3.68, 4.05, 5.12, 5.50 and 5.61. 13 C-NMR (CDCl3 )δ(ppm): 12.31, 16.1, 16.12, 17.67, 24.44, 26.44, 26.74, 27.00, 37.81, 39.81, 40.27, 43.34, 49.00, 59.22, 60.59, 120.97, 123.84, 124.30, 135.92, 138.05, 160.45 and 197.12. compound [7] :4-Hydroxy-2,3-dimethoxy-5-(11-methoxy-3,7,11-trimethyldodec-2,6-dienyl)-6-methylcyclohexyl-2-enone

[0115] The fractions collected over 25 to 30 minutes were concentrated to give a pale yellow-brown liquid product, namely 4-hydroxy-2,3-dimethoxy-6-methyl-5-(3,7,11-trimethyldodec-2,6,10-trienyl)cyclohexyl-2-enone (compound). [1] ). For compounds [1] The analysis showed that the molecular formula was C24H38O4, the molecular weight was 390, and the melting point was 48 to 52℃. NMR spectra showed: ¹H-NMR (CDCl₃) δ (ppm) = 1.51, 1.67, 1.71, 1.75, 1.94, 2.03, 2.07, 2.22, 2.25, 3.68, 4.05, 5.07, and 5.14; ¹³C-NMR (CDCl₃) δ (ppm) = 12.31, 16.1, 16.12, 17.67, 25.67, 26.44, 26.74, 27.00, 39.71, 39.81, 40.27, 43.34, 59.22, 60.59, 120.97, 123.84, 124.30, 131.32, 135.35, 135.92, 138.05, 160.45 and 197.12. compound [1] :4-hydroxy-2,3-dimethoxy-6-methyl-5-(3,7,11-trimethyldodec-2,6,10-trienyl)cyclohexyl-2-enone

[0116] In animal studies, compounds were fed to animals. [1] compounds were obtained from urine samples of rats.

[27] , i.e., compounds [1] Metabolites. Compounds

[27] It was identified as 4-hydroxy-2,3-dimethoxy-6-methyl-5-(3-methyl-2-hexenoic acid)cyclohex-2-enone, with a molecular weight of 312 (C16H24O6).

[25] It was obtained from the purification process and was identified as 2,3-dimethoxy-5-methyl-6-((2E,6E)-3,7,11-trimethyldodec-2,6,10-trienyl)cyclohexyl-2,5-diene-1,4-dione (molecular weight 386.52, C24H34O4).

[0117] compound

[26] , namely 4-hydroxy-2-methoxy-6-methyl-5-((2E,6E)-3,7,11-trimethyldodec-2,6,10-trienyl)cyclohexyl-2-enone, was also prepared by purification process, with a molecular weight of 350.53 (C23H36O3). Compounds were also prepared.

[28]

[0118] Alternatively, the exemplary compound can be prepared from 4-hydroxy-2,3-dimethoxy-6-methylcyclohexane-2,5-dienone, etc. See, for example, the examples in U.S. Patent No. 9,365,481 and U.S. Patent Publication No. 2016-0237012. Similarly, having a structure Cyclohexenone compounds are isolated from Antrodia camphorata or prepared by synthesis or semi-synthesis from suitable starting materials. Such synthesis will be readily performed by those skilled in the art under suitable conditions. [Example] [2] [:compound] [1] [Study on the antiviral, anti-inflammatory, and antifibrotic activities of (androidquinol)]

[0119] The antiviral, anti-inflammatory and antifibrotic activities of the exemplary compound (compound 1) were studied.

[0120] [Materials and methods]

[0121] Cell culture. The HepG2.2.15 cell line was cultured at 37 °C in a 5% CO2 incubator in MEM medium supplemented with 10% fetal bovine serum, penicillin (100 IU / ml; Gibco, USA), and streptomycin (100 ug / ml; Gibco, USA). This is a cell line derived from the human hepatoblastoma cell line HepG2, characterized by stable HBV expression. Qs5 is an HBV-producing rat hepatocellular carcinoma cell line.

[0122] Lamivudine (3TC) and adefovir dipivoxil (Adv) were purchased as positive controls for HBV treatment. Arroquinol (G4) and lamivudine (3TC) were dissolved in dimethyl sulfoxide (DMSO) for stock solutions only and diluted in culture medium. The final concentration of DMSO in cells was less than 0.1%. The drugs were treated with 2 x 10⁴ cells in 96-well plates for 72 hours.

[0123] The levels of HBsAg and HBeAg were measured in the HepG2.2.15 supernatant using their commercial enzyme-linked immunosorbent assay (ELISA) kit, according to the manufacturer's instructions.

[0124] MTT assay. 1.25 x 10⁵ cells / well were seeded into 24-well plates. Cells were incubated for 72 hours with different concentrations of G4 and 3TC (1, 5, 25, 50, 100, and 200 uM). 1 mg / ml of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) was added to each well, and the plates were incubated at 37°C for 2 hours to form colored crystals. DMSO was used instead of the culture medium, and the plates were incubated at room temperature with shaking for 15 minutes to dissolve the crystals. Absorbance was measured using a microplate reader. Optical density was measured at 490 nm.

[0125] Southern blot analysis of viral DNA. HBV core-particle-associated DNA was resolved on 1.2% natural agarose gels and detected by Southern blot analysis using specific HBV DNA probes. Each lane of the Southern blot gel contained the total amount of core-particle-associated viral DNA extracted from each treated culture dish, seeded at the same cell density the night before transfection. [result]

[0126] To examine the effects of androidquinol on HBV protein expression, including surface antigen (HBsAg) and e antigen (HBeAg), ELISA was used to quantify HBV replication. The results showed that compound 1 (i.e., androidquinol) reduced the expression levels of HBeAg (see Figure 1A) and HBsAg (see Figure 1B). Compared to lamivudine, compound 1 showed a 50% and 40% reduction in the expression levels of the two major HBV biomarkers, HBeAg and HBsAg, respectively. Therefore, in summary, the exemplary compound 1, at different doses, showed significant inhibitory effects not only on HBeAg but also on HBsAg.

[0127] To evaluate exemplary compounds [1] Effects on viral replication were investigated by isolating and analyzing DNA associated with intracellular HBV core particles. By Southern blotting, illustrative compound 1 (androquinol) showed significant inhibition of HBV replication intermediates (relaxed circular, linear, and single-stranded DNA). As shown in Figures 2A / B, the compound… [1] (Androquinol) reduced HBV DNA expression (2A) and decreased HCV RNA activity (2B). In particular, compared with lamivudine and adefovir dipivoxil, the compound... [1] It showed more significant results in reducing HBV DNA expression levels. Compound [1] It also showed that HCV RNA activity was significantly reduced by 95%.

[0128] The inhibition of HBV production by androidquinol is likely a consequence of its cytotoxicity, and this possibility was examined using an MTT assay. No significant cytotoxicity was detected at exposures up to 5 μM androidquinol, indicating that the inhibitory effect of androidquinol on viral protein and DNA levels in the supernatant is not due to its cytotoxicity. Notably, androidquinol at concentrations exceeding 25 μM exhibits cytotoxic effects on HepG2.2.15 cells.

[0129] To treat, alleviate symptoms of coronavirus infection (e.g., SARS-CoV-2) in subjects, or prevent the course of coronavirus infection (e.g., SARS-CoV-2) in subjects, it should be understood that multiple approaches are needed in addition to antiviral activity, as shown in Figure 3. Following viral infection, the virus replicates and its viral load increases, leading to inflammation and a cytokine storm, resulting in tumor fibrosis. Therefore, compounds with antiviral, anti-inflammatory, and even anti-fibrotic capabilities (such as the exemplary compounds) are needed. [1] ) is a suitable drug for combating coronavirus infection, as shown in Figure 4. For example, this indicates that the compound [1] Inhibits the function of mTOR and inhibits endocytosis.

[0130] In particular, the results (see Figure 5) provide information on the compounds. [1] Compared with silymarin, it showed an efficient increase in Nrf-2 nuclear translocation at lower application concentrations. Figure 6 provides the compounds. [1] Significantly reduced ethanol-induced increases in ALT and AST and inhibited oxidative stress. (Compound) [1] Other anti-inflammatory results included a 36% inhibition of NF-κB expression and a 2-fold increase in nuclear Nrf-2 expression, as shown in Figure 7. In Figure 8, the compound... [1] It also showed that it effectively inhibited the expression of MCP-1, IL-6, and CD3 by approximately 50%, 57%, and 66%, respectively. All of the above results indicate that the compound [1] Its effectiveness in anti-inflammatory activity.

[0131] Additionally, exemplary compound 1 was found to possess anti-fibrotic activity. Figure 9A illustrates the exemplary compound. [1] It effectively inhibited TGF-β1 expression by approximately 64%. In studies utilizing fibrosis-related proteins (Col 1 and Col III), the compound... [1] Anti-fibrotic properties were also shown as in Figure 9B. Therefore, the data clearly indicate that the compound [1] It eliminated viral activity, protein expression of inflammatory effectors, and TGFβ1 signaling-mediated fibrosis. [Example] [3] [:Exemplary compounds] [1] [right] [COVID-19] [Impact Study of Progress]

[0132] This study aims to evaluate exemplary compounds. [1] Through anti-SARS-CoV-2 ( [Specific target] [1] ), anti-SARS-CoV-2 induced cytokine storm and anti-SARS-CoV-2 induced fibrosis ( [Specific target] [2] The effect of the compound on the progression of COVID-19 (i.e., SARS-CoV-2). The overall goal is to identify exemplary compounds. [1] Whether (i.e., androidquinol) offers a potential triple role in the treatment of COVID-19 and provides a new treatment option for SARS-CoV-2 patients.

[0133] [Specific target] [1.] [Research on the Android Quinolant Countermeasure] [SARS-CoV-2] [Functions and Effects]

[0134] The yield reduction assay was used to determine the inhibitory rate (EC50) of droquinol against SARS-CoV-2. Briefly, Vero E6 cells were seeded into 24-well culture plates containing 2% FBS in DMEM and treated with the compound... [1] (i.e., daroquinol, 10 or 20 μM) was used to treat for 1 hour. Untreated plates in DMSO were used as controls. The resulting cells were then infected with SARS-CoV-2 (multiple of infection, MOI=0.1) for 1 hour. After removing daroquinol and the virus, the cells were washed once with PBS and covered with covering medium containing different concentrations of daroquinol for 24 hours. Cell culture was collected for viral plaque assay to determine the number of plaque-forming units. One day before infection, Vero E6 cells were seeded into 24-well culture plates in DMEM containing 10% FBS and antibiotics. Cell culture was added to the cell monolayer and incubated at 37°C for 1 hour. Subsequently, the cell culture was removed, and the cell monolayer was washed once with PBS and covered with medium containing 1% methylcellulose for 5 days. The cells were fixed with 10% formaldehyde for 1 hour. After removing the covering medium, the cells were stained with 0.5% crystal violet and the plaques were counted. Cells were collected using AMRESCO's RIPA cell lysis buffer and NucleoSpin RNA kit (Macherey-Nagel) for protein and RNA extraction, respectively. The expression levels of nucleocapsid protein and the E gene were then detected by Western blotting (antibody catalog number 40143-R019) and quantitative real-time PCR (qRT-PCR), respectively. Furthermore, the isolated RNA was used for... [Specific target] [2]. Furthermore, the cytotoxicity (i.e., IC50) of androidquinol to Vero E6 cells will be measured by an acid phosphatase assay. In this study, remdesivir (1 μM) treatment will be used as a control. All results will be presented as mean ± sd from at least three independent trials.

[0135] The results showed that both 20 μM and 10 μM of compound 1 significantly reduced the concentration of SARS-CoV-2 (99.93% at 20 μM and 91.20% at 10 μM). See Figure 10. Figure 11 also provides cell culture results, showing cell culture discs treated with d'Androquinol and the control (DMSO discs).

[0136] [Specific target] [2.] [Exploring the Android Quinol Pair] [SARS-CoV-2] [Induced cytokine storm and its effects] [SARS-CoV-2] [The effects of induced fibrosis]

[0137] Current research indicates that multiple cytokines / chemokines are significantly associated with COVID-19 disease. For example, plasma IP-10 (also known as CXCL10) is highly correlated with disease severity and can predict COVID-19 progression. IL-6 can also serve as a predictor of progression to severe COVID-19, suggesting that targeting cytokines is a treatment option for COVID-19 patients. Regarding the long-term effects of COVID-19, TGF-β-mediated collagen deposition may be an important factor contributing to irreversible pulmonary fibrosis.

[0138] To reveal the effects of roxiquinol on SARS-CoV-2-induced cytokine storm and SARS-CoV-2-induced fibrosis, [Specific target] The RNA described in [1] was used to detect gene expression of cytokines / chemokines (such as CXCL10, IL6, and IL18, see Figures 12A-C), profibrotic growth factors (such as TGFB1, see Figure 13A), and collagen (such as COL1A1, COL3A1, and COL4A1). Briefly, 5.4 μg of RNA was reverse transcribed into cDNA using the M-MLV reverse transcriptase kit. Real-time PCR analysis was established using the SYBR™ Green Master Mix kit and performed in a QuantStudio™ 5 real-time PCR system. The relative extent of the target mRNA was determined by normalizing actin rRNA. [Research Results:]

[0139] Figures 12A-C show the gene expression levels of CXCL10 (12A), IL6 (12B), and IL18 (12C), respectively. Using 20 μM androidquinolol, CXCL10 expression showed a 1.01-fold change, while 3.40-fold and 9.04-fold changes were observed using 10 μM androidquinolol and DMSO, respectively. Using 10 μM androidquinolol, IL6 expression showed an 11.88-fold change, while 47.81-fold changes were observed using DMSO. Using 20 μM androidquinolol, IL18 expression showed a 0.89-fold change, while 1.36-fold changes were observed using DMSO.

[0140] Figures 13A-B show the gene expression levels of TGFB1 (13A) and COL4A1 (13B), respectively. Using 20 μM androidquinolol, TGFB1 expression changed by 0.99-fold, while a 2.59-fold change was observed using DMSO. Using 20 μM androidquinolol, COL4A1 expression changed by 0.65-fold, while a 2.37-fold change was observed using DMSO.

[0141] Therefore, it is clearly demonstrated that the exemplary compound androidquinol provides excellent effects against SARS-CoV-2-induced cytokine storm and SARS-CoV-2-induced fibrosis. [Example] [4] [Used for evaluating compounds] [1] [In cases of cause] [COVID 19] [Safety and efficacy in hospitalized patients with mild to moderate pneumonia caused by the disease] [2] [Phase-one clinical trial]

[0142] This study The main objective is: ․ Evaluate the efficacy of daroquinol in treating mild to moderate pneumonia caused by COVID-19, as measured by the following: o Clinical improvement time o Disease progression. ․ To evaluate the safety of droquinol treatment in patients with mild to moderate pneumonia caused by COVID-19. The secondary objective is: ․ Further evaluate the efficacy of droquinol compared to placebo in this patient population by the following measures: o Duration of hospitalization o Virological clearance o Life status (death) ․ Assess the pharmacokinetic (PK) plasma concentrations of roxiquinol in this patient population. ․ Assess the safety of droquinol in this patient population. [Research Design] [:]

[0143] This is a phase 2 clinical trial designed to evaluate the safety and efficacy of droquinol in hospitalized patients with mild to moderate pneumonia caused by COVID-19.

[0144] The primary characteristic of hospitalized patients included in this study was: adult patients with fever and a respiratory rate >24 / min within 5 days prior to screening. Symptoms of mild to moderate pneumonia due to COVID-19 must be present (confirmed by chest X-ray or computed tomography [CT] scan). The planned duration of treatment was 10 days of standard of care (SoC) therapy, either droquinolone or placebo, in accordance with local SoC policy.

[0145] The plan is to recruit a total of 166 patients and randomly assign them to either androidquinolone or placebo in a 1:1 ratio.

[0146] Given that daroquinol has demonstrated antiviral and anti-inflammatory activity in previous clinical studies, it is planned for use in the treatment of patients with COVID-19 infection. Therefore, treatment is planned for an initial sentinel cohort to evaluate the safety of daroquinol. This sentinel cohort will initially include 20 patients (10 assigned to daroquinol and 10 to placebo). Recruitment will be paused once the initial 20 patients begin treatment.

[0147] Once the first 20 patients have completed at least 10 days of treatment, the Data Monitoring Committee (DMC) will evaluate the safety and tolerability of droquinol in the marker co-population. The DMC may disclose the data from this evaluation.

[0148] Once 20 patients in the identifiable population have been treated for at least 10 days and the study has been assessed by the DMC as safe to continue, recruitment will resume.

[0149] All patients recruited in the study (including those in the labeled cogroup) will be included in the primary analysis of the efficacy and safety of the study treatment. DMC will continue to review safety and assess the risk / benefit profile. Once all patients have achieved clinical improvement, or have been followed up for 28 days since the start of treatment, a primary efficacy analysis will be conducted. [Number of patients:]

[0150] This study plans to recruit a total of 166 patients (83 patients in the androidquinolone group and 83 patients in the placebo group). This level of recruitment ensures approximately 135 improvement events. Recruitment will be based on the following assumptions: The randomization ratio between the antagonist group and the placebo group was 1:1; Clinical improvement was defined as a median improvement from 7 days to 4 days. Each patient will be followed up for up to 28 days. 90% performance The two-sided α was 0.05. [Diagnosis, and key inclusion and exclusion criteria:]

[0151] Unless otherwise stated, patients must meet all of the following inclusion criteria at the time of screening: 1. Willing and able to provide informed consent. 2. Male or female patients aged ≥18 years and ≤80 years. 3. Hospitalization due to fever (defined as oral temperature ≥38.6℃) and respiratory rate >24 / min. Fever (axillary ≥36.6℃, or oral ≥37.2℃, or rectal or ear ≥37.8℃… Gilead) Note: Hospitalized patients may also include patients admitted to hospital-conditional centers used to treat COVID-19 patients. 4. Chest X-ray or CT scan is consistent with pneumonia. Status: Unilateral and bilateral pneumonia (infiltrative / interstitial) 5. Fever started within 5 days before screening. 6. SARS-CoV2 infection confirmed by PCR testing (not serological testing) of nasopharyngeal samples. 7. Male and female patients with fertility potential must agree to use the contraceptive method specified in the agreement. 8. Female patients of childbearing age must have a negative pregnancy test before screening and treatment on day 1. 9. Male patients must agree not to donate sperm from the first dose of the study drug until 90 days after the last dose. 10. The researchers believe that the patient is willing and able to comply with the study drug protocol and all other study requirements. 11. Hospital stay <48 hours and randomization within 48 hours of meeting inclusion criteria.

[0152] Unless otherwise stated, patients will be excluded from the study if they meet any of the following exclusion criteria at the time of their screening visit: 1. Female patients who are pregnant or breastfeeding. 2. Any life-threatening condition accompanying the patient, including but not limited to: need for mechanical ventilation, acute respiratory distress syndrome (ARDS), shock, or heart failure. The patient requires invasive mechanical ventilation; or other organ failure requiring ICU monitoring; is oxygen therapy (O2 inhalation) via face mask acceptable? 3. Evidence of lobar or sublobar consolidation on chest X-ray. 4. Indoor air oxygen saturation (SpO2) <90%, or arterial oxygen partial pressure (PaO2) / inspired oxygen percentage (FiO2) <200 mmHg, indicating severe dyspnea or requiring positive pressure ventilation (with or without intubation). 5. Drug or alcohol abuse that, in the researcher's judgment, may interfere with adherence to research requirements. 6. Treatment with other drugs believed to be potentially active against COVID-19 within 7 days prior to recruitment. 7. Use of other investigational drugs within 30 days of administration, or plans to recruit for another investigational drug clinical trial while participating in this study. 8. Clinically significant abnormal ECG at the time of screening, as determined by the investigator. 9. Patients require frequent or long-term use of systemic corticosteroids or other immunosuppressive drugs (e.g., for organ transplants or autoimmune conditions). 10. Abnormal laboratory values ​​during screening: a. Estimated glomerular filtration rate (GFR) < 50 mL / min. b. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 5 × upper limit of normal (ULN), or ALT / AST > 3 × ULN plus total bilirubin > 2 × ULN. c. Platelet count <100×10⁹ / L. d. Total bilirubin >1.5×ULN, unless the patient has known Gilbert's syndrome. e. Female hemoglobin <9 g / dL or male hemoglobin <11 g / dL. f. Total white blood cell (WBC) count <3,500 / mm3 or absolute neutrophil count (ANC) <1,500 / mm3. 11. Treatment with any antiviral drug or any drug known to be a strong inducer or inhibitor of CYP2C19, CYP3A4, CYP2C8 and CYP2E1 within 14 days prior to the start of study treatment. 12. Any other clinically significant medical condition or laboratory abnormality that, in the investigator's view, would jeopardize patient safety or potentially affect patient compliance or safety / efficacy observations in the study. 13. Viral pneumonia caused by viruses other than 2019-nCoV. 14. The patient cannot take oral medication. 15. Patients who were already intubated or required immediate intubation at the time of randomization. 16. Severe cognitive and mental disorders [Test sample, dosage, and method of administration:]

[0153] Administer 200 mg (2 capsules) orally twice daily (BID) for 10 days.

[0154] [Reference therapy, dosage, dosage form and administration]: Placebo (capsule) BID orally administered for 10 days.

[0155] Duration of patient participation in the study: The total study duration is planned to be a maximum of 28 ± 2 days. The screening period is planned to last a maximum of 2 days. The planned treatment duration is 10 days. Subsequent safety assessments will be performed on day 14 and day 28 (±2 days).

[0156] [Study population:] Full Analysis Set (FAS): All randomized patients who have received at least one dose of the study drug. Patients will be analyzed based on the treatment they were randomly assigned to. Per Protocol Set (PPS): All patients from the FAS who did not have significant protocol deviations during the study. Patients with any significant protocol deviations should be excluded from the PPS before the database is locked. Safety Set (SS): All patients who received at least one dose of the study drug. Patient analysis will be based on the actual study treatment received. Pharmacokinetic Set (PKS): All patients who have received at least one dose of the study drug and have at least one evaluable plasma concentration, and who have no significant protocol deviations or events considered to significantly affect PK. [end:]

[0157] [Primary efficacy endpoint] is: time to clinical improvement [time range: within 28 days of starting medication] Clinical improvement was defined as the time (in days) from the start of study treatment to normalization of fever ≤37.2℃, oral and indoor air respiratory rate ≤24 / min, and indoor air oxygen saturation (SpO2) >94%. (Individual or collective) Eliminate hypoxia (defined as SpO2 ≥ 93% or PaO2 / FiO2 ≥ 300 mmHg in indoor air). ․ Disease remission rate [Time range: Day 14 and Day 28 after starting medication] Disease progression Disease progression was defined as requiring positive pressure ventilation (with or without intubation) or ICU care. For a subgroup of patients who remained hospitalized and underwent arterial blood gas (ABG) testing as part of their SoC, PaO2 / FiO2 <200 mmHg was also used as a measure of disease progression. Rate of invasive mechanical ventilation in cases of respiratory failure [Time range: 10 days]

[0158] [Secondary efficacy endpoint is:] ․ Length of hospital stay (days). Virological clearance from nasopharyngeal or respiratory samples o Virological clearance time, measured as the number of study days from the start of treatment to the first negative SARS-CoV-2 PCR test. The rate of change in viral load will be evaluated based on the validity of the quantitative analysis (real-time RT-PCR test). Life status (death) will be collected until day 14 and day 28. Time to improvement in lung imaging [Time range: within 10 days after medication] Safety endpoints include the following variables: Adverse events (AEs). ․ Chest imaging (X-ray or CT scan) results. ․ Vital signs: blood pressure, pulse rate. Physical examination: general appearance, HEENT, lymph nodes, cardiovascular system, respiratory system, gastrointestinal system, skeletal muscle system, neurology, and dermatology. ․ 12-lead electrocardiogram (ECG). [Pharmacokinetic Evaluation] The PK parameters assessed from plasma samples are: ․ Crust (initial dose) plasma concentration Maximum plasma concentration (Cmax). [Statistical Methods:] [General Principles:] Continuous variables will be summarized using standard descriptive statistics: number of patients (n), mean, standard deviation (SD), median, minimum (min), and maximum (max). The frequency and percentage of patients or events will be summarized as categorical variables. Results with α on the side of 0.025 will be considered statistically significant, while results with α on the side of 0.2 will be considered to indicate a promising trend. [Efficacy Analysis:] Main efficacy analysis The hazard ratio (HR) and its 95% confidence interval (CI) for clinical recovery will be estimated using a Cox proportional hazards model, with data truncated at death, when patients were given any non-investigation antiviral treatment, or on day 28 if they had not yet recovered. The median time to clinical improvement will be estimated using the Kaplan-Meier (KM) method, and KM curves will be provided. p-values ​​for intergroup comparisons will be obtained using a log-rank test. For disease progression, logistic regression was used to calculate the proportion of patients requiring positive pressure ventilation and ICU care in both groups, along with the inter-group differences and 95% confidence intervals. P-values ​​were calculated based on chi-square tests. PaO2 / FiO2 was also evaluated for patient subgroups with ABG data collected as part of the SoC. Secondary efficacy analysis Hospital stay, virological clearance (time to virological clearance, rate of change in viral load), and vital signs will be analyzed using statistical methods similar to those used for the primary efficacy endpoint. [Security Analysis:] Adverse events will be coded according to the Medical Dictionary for Regulatory Activities (MedDRA). The number and percentage of patients with treatment-emergent adverse events (TEAEs), severe adverse events (SAEs), investigational treatment-related TEAEs, investigational treatment-related TEAEs leading to treatment interruption, investigational treatment-related TEAEs leading to treatment interruption, and investigational treatment-related TEAEs leading to death were summarized according to system organ classification (SOC), preferred terminology (PT), and treatment group. Furthermore, the severity of TEAEs and their relationship to investigational treatment were summarized by SOC, PT, and treatment group. The following standardized MedDRA query (SMQ) identifies AEs of special concern (AESIs) and will be reported: . respiratory failure Opportunistic infections This will descriptively summarize the test values ​​and changes relative to baseline for specific laboratory test results, vital signs, SpO2, physical examination, and EGG results. Where applicable, a transfer schedule by treatment group will be presented. [Pharmacokinetic Analysis:] Descriptive statistics on roximate plasma concentrations and / or PK parameters will be provided. Table 1: Assessment Timeline [During the research period] [Screening] [Hospitalization] [Follow-up] [Visit Name] (Baseline) Treatment [Discharge and] [ / ] [or] [EOT] [Number of research days] [-2] [to] [0] [1] [2] [to] [10, a , ] [14±2, a , ] [28±2] [or] [EOS, a , ] Informed Consent Form X Randomization b X Inclusion / Exclusion Criteria X Demographics, medical history X Physical Examination C X X X X X Height and weight X Vital signs (body temperature, respiratory rate, blood pressure, and pulse) C X X X X X Chest X-ray or CT scan X X Urine pregnancy test e X X Study drug or placebo X X [Efficacy] f COVID-19 PCR testing X X X X X Ventilator support status X X X Clinical deterioration assessment X X SpO2 X X X X X Arterial blood gas assessment (PaO2 / FiO2) X X X [Security] g Adverse events X X X X Laboratory assessment X X electrocardiogram X X Previous and concomitant medications X X X X X Pharmacokinetics [ h , ] PK parameters X X Abbreviations: AE = Adverse Event; Cmax = Maximum Plasma Concentration; Ctrough = Valley Plasma Concentration (pre-dose); CT = Computerized Scan; DMC = Data Monitoring Committee; ECG = Electrocardiogram; EOS = End of Study; EOT = End of Treatment; FiO2 = Percentage of Inhaled Oxygen; HEENT = Head, Eyes, Ears, Nose, and Throat; ICU = Intensive Care Unit; PaO2 = Partial Pressure of Arterial Oxygen; PCR = Polymerase Chain Reaction; PD = Pharmacodynamics; PK = Pharmacokinetics; SpO2 = Oxygen Saturation / Pulse Oxygen Measurement. Footnote: Patients who achieve clinical remission (defined as the time [number of days] from the start of study treatment to the normalization of fever, respiratory rate, and oxygenation) may be discharged at any time between day 2 and day 10 after the start of treatment. Patients will then be instructed to receive treatment at home (as prescribed) and to be followed up by telephone on days 14 and 28 for symptom assessment. Discharged patients are required to return to the hospital / site for a day 10 assessment / EOT visit. b. An initial cohort of 20 patients will be recruited to assess safety and tolerability. Once the DMC confirms that there are no safety issues, the study will resume recruiting the remaining patients. c. Within 5 days prior to screening, body temperature (oral, forehead, axillary, tympanic cavity) ≥38.6℃ and respiratory rate >24 / min. A complete physical examination (general appearance, hematuria, lymphatic, cardiovascular, respiratory, gastrointestinal, musculoskeletal, nervous, and dermatological systems) will be performed at screening. A COVID-19 symptom-targeted physical examination will be conducted during hospitalization. Vital signs (respiratory rate, blood pressure, and pulse rate) will be assessed daily during hospitalization. Height and weight will only be measured at screening. d. Chest X-ray or CT scan should show results consistent with COVID-19 pneumonia and will be performed at screening and discharge. e. Perform urine pregnancy tests on female patients with fertility potential at the local (site) laboratory. f. Evaluation of efficacy parameters: [1] PCR testing for COVID 19 was performed at a local laboratory during screening and follow-up visits (until a negative result). This test was available at a central laboratory for discharged patients to use for their follow-up testing; [2] Clinical deterioration was assessed if a patient required prolonged hospitalization or disease progression (defined as requiring positive pressure ventilation (intubated or unintubated) or ICU care. PaO2 / FiO2 was also used as a measure of disease progression for a subgroup of patients who remained hospitalized and underwent arterial blood gas (ABG) testing as part of their SoC; [3] Daily SpO2 monitoring on day 1: the average of three consecutive readings over a 5-minute period; [4] Arterial blood gas evaluation of PaO2 / FiO2 was performed during screening and hospitalization (until discharge). g Safety parameter assessment: [1] AEs will be assessed from the start of treatment (during hospitalization and at home after discharge) until EOS; [5] Standard safety laboratory tests will include all parameters of hematology, chemistry and urinalysis and will be performed on days 1, 5 and 10 before administration; [6] 12-lead EGG will be performed at screening when the patient is in a supine position; [7] Previous and concomitant medications will be recorded from screening until EOS. h Pharmacokinetic parameters include Ctrough and Cmax. Blood samples for these parameters will be evaluated on days 5 and 10 (if the patient is still hospitalized), before administration, and 2 hours after administration. [Example] [5] [Oral preparations]

[0159] To prepare a pharmaceutical composition for oral delivery, an equiweight amount of exemplary compound 1 was mixed with an equiweight amount of corn oil (e.g., 25 mg, 50 mg, 100 mg, 200 mg). This mixture was incorporated into an oral dosage unit in a capsule suitable for oral administration.

[0160] In some cases, 100 mg of the compound described herein is mixed with 750 mg of starch. This mixture is then incorporated into an oral dosage unit suitable for oral administration, such as a hard gelatin capsule. [Example] [6] [Sublingual (tablet) preparation]

[0161] To prepare a pharmaceutical composition for buccal delivery, such as a hard tablet, one part of the compound described herein is mixed with four to five parts of powdered sugar, which is then mixed with appropriate amounts of low-alcohol corn syrup, distilled water, and peppermint extract. The mixture is gently stirred and poured into a mold to form a tablet suitable for buccal administration. [Example] [7] [Inhalation composition]

[0162] To prepare a pharmaceutical composition for inhalation delivery, 20 mg of the compound described herein was mixed with 50 mg of anhydrous citric acid and 100 mL of 0.9% sodium chloride solution. This mixture was then introduced into an inhalation delivery unit suitable for inhalation administration, such as a nebulizer.

[0163] While preferred embodiments of the invention have been shown and described herein, it will be apparent to those skilled in the art that these embodiments are provided by way of example only. Many variations, modifications, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. The scope of the invention is intended to be defined by the following claims, thereby also encompassing the methods and structures within the scope of those claims and their equivalents.

[0164] none

[0165] none

Claims

1. The use of a therapeutically effective amount of a cyclohexenone compound having the following structure or a pharmaceutically acceptable salt or solvate thereof in the preparation of a medicament for treating, alleviating symptoms of, and / or preventing RNA virus-induced diseases in subjects, wherein the RNA virus-induced disease is caused or induced by an infection of the Coronaviridae family.

2. The use as described in claim 1, wherein the RNA virus is a coronavirus.

3. The use as described in claim 1, wherein the cyclohexenone compound reduces RNA virus concentration or prevents RNA virus infection.

4. The use as described in claim 1, wherein the disease induced by the RNA virus is coronavirus-induced pneumonia.

5. The use as described in claim 4, wherein the coronavirus-induced pneumonia is SARS-CoV-2-induced pneumonia.

6. The use as described in claim 1, wherein the coronavirus infection is caused by or related to α-coronavirus 229E (HCoV-229E), NL63 (HCoV-NL63, New Haven coronavirus), β-coronavirus OC43 (HCoV-OC43), HKU1, MERS-CoV (the coronavirus that causes Middle East Respiratory Syndrome), SARS-CoV, or SARS-CoV-2 (2019-nCoV).

7. The use as described in claim 7, wherein the coronavirus infection is caused by or related to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

8. The use according to any one of claims 1-7, wherein the cyclohexenone compound or a pharmaceutically acceptable salt or solvate thereof is administered orally or intravenously.

9. The use according to any one of claims 1-7, wherein the cyclohexenone compound or a pharmaceutically acceptable salt or solvate thereof is administered by injection or parenteral administration.

10. The use as described in claim 1, wherein the subject is a human being.

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