The present invention relates to the treatment and preven tion of COVID-19.

In December 2019 starting in Wuhan/China a novel corona vi rus (SARS-CoV-2) caused a pandemic which will last until an ef fective and safe vaccine can be provided or causal drug treat ment of the disease can help to avoid severe and fatal cases of the illness. By now millions of infected persons with increasing number all over the world are waiting for an effective treatment of the disease.

To date, no specific drug in controlling this disease has been identified. Developing the new treatment is usually time consuming, therefore using the repurposing broad-spectrum anti viral drugs was generally regarded as an effective strategy to respond immediately. Accordingly, the effects of already known antiviral compounds were heavily investigated.

Especially "repurposing" naturally occurring or previously developed synthetic antiviral compounds with a broad spectrum of biochemical mechanisms for COVID-19 were viewed as a promising strategy to combat this pandemic.

Substances like griffithsin, nafamostat (targeting cell en try), disulfiram, lopinavir/ritonavir , danoprevir, nelfinavir (targeting the SARS-CoV-2 protease), favipiravir, ribavirin, penciclovir, remdesivir, galidesivir (targeting the RNA- dependent RNA polymerase (RdRp)) have been discussed as promis ing candidates, yet without providing a specific treatment effi cient to SARS-CoV-2 in patients with COVID-19 infection (Ghanba- ri et al., Fut. Microbiol. 15 (2020), 1747-1758; Harrison, Nat. Biotechnol . 38 (2020), 379-381).

Phenolic compounds are uniformly dispersed phytochemicals contained and abundant in any tissue of most plant families around the world, especially in fruits and vegetables that are part of the plant. Phenolic compounds are classified based on their chemical structures into phenolic acids, flavonoids, tan nins, coumarins, lignans, quinones, stilbenes, and curcuminoids. Phenolic compounds are synthesized through the shikimic acid pathway in plants as secondary metabolites are generally in volved in plant adaptation to environmental stress conditions. Phenolic and flavonoids compounds are secondary metabolites of the plant that possess an aromatic ring with at least one hy droxyl group. Among the chemically diverse natural therapeutic agents, flavonoid and phenolic compounds were speculated to be most promising active compounds against SARS-CoV-2, due to their excellent pharmacokinetic properties.

Phenolic related compounds have been reported to possess nu merous biological activities such as antioxidants, anti-cancer, anti-inflammatory, antibacterial, cardioprotective and immune system promoting activities. Several studies have shown that phenol and flavonoids related compounds from medicinal plants increases human health and boost human immune power. Natural polyphenolic compounds are mainly derived from plant origins. These phenolic and flavonoid class of compounds possess antivi ral activities against a number of viruses such as rhinoviruses, hepatitis C virus, HIV, yellow fever, herpes simplex virus, and influenza viruses. Nowadays, pharmacology companies manufacture potential drug molecules in a short period of time with the aid of bioinformatics tools and applications.

With such in silico predictions and biochemical in vitro binding assays to SARS-CoV-2 components, a number of natural compounds, which have shown previously inhibitory effects against other pathogens, such as polyphenols, were suggested to be used in the treatment of COVID-19 patients, also based on in silico screening (i.a. Rathinavel et al., Bioint. Res. Appl. Chem. 11 (2021), 10161-10173; Mhatre et al., Phytomed. (2020), 153286; Chojnacka et al., J. Funct. Food 73 (2020), 104146; Ghosh et al., J. Biom. St. Dyn. (2020), 1-13-doi.org-10.1080- 07391102.2020; Islam et al., Phytother. Res. 3 (2020), 2471- 2492; WO 2020/037095 Al). The advantage of such compounds is that they are "generally regarded as safe" ("GRAS"; e.g. Sect. 201 (s) and 409 of the U.S. Fed. Food, Drug and Cosmetic Act) and can therefore be administered without preclinical studies (also e.g. as food supplements) and might instantly be used to treat COVID-19 patients and prevent them from severe illness.

Wahedi et al. (J. Biomol. Struct. Dyn. 39 (2021): 3225-3234) suggest mainly resveratrol and i.a. also 3',4',2,4 tetrahy- droxy (-trans-) stilbene as a drug candidate against COVID-19. Zhang et al. (Cell Discovery 6 (2020), 80) report that heparan sulfate assists SARS-CoV-2 in cell entry and can be targeted by approved drugs in vitro with mitoxantrone (as potent heparan sulfate inhibitor) und sunitinib and BNTX as possible candidates for such an approach. It was further reported that piceatannol binds to heparin. CN 111 228 343 A appears to disclose that an extract i.a. comprising piceatannol can be used to address in fections with "2019-nCoV". Han et al. (J. Med. Virol. 87(2015): 2054-2060) report the HIV-inhibiting activity of 3,3', 4,4', 5,5' - hexahydroxy-trans-stilbene.

However, none of these substances was yet shown to have ap propriate antiviral activity against SARS-CoV-2 to provide an efficient treatment or prevention option for patients infected with SARS-CoV-2.

It is therefore an object of the present invention to pro vide realistic and effective repurposing alternatives for the prevention or treatment of COVID-19. These alternatives should effectively prevent or hinder SARS-CoV-2 from becoming pathogen ic for human patients. Accordingly, the substances should be able to inhibit SARS-CoV-2 and/or to prevent or hinder SARS-CoV- 2 from entering human cells at least to a certain extent to pro vide significant advantage for the patient to reduce the risk of developing COVID-19 or to reduce the risk of becoming severely affected by COVID-19. Another object is that these substances are easily accessible, well tolerated and can successfully ap plied to humans without the need of invasive methods, preferably by inhalation, aerosol delivery, etc..

Therefore, the present invention provides a compound with the general formula I wherein Ri to R ₆ are identical or not and are H, OH-, or OR ₇ , wherein R ₇ is a Ci to C ₃ alkyl group or a Ci to C ₄ acyl group, with the proviso that at least four, preferably at least five, especially at least six, of Ri to R ₆ are different than H, for use in the treatment and prevention of COVID-19 in a human sub ject, especially for inhibiting SARS-CoV-2.

The compounds according to the present invention were iden tified in the course of the present invention to exhibit realis tic and effective inhibitory activity towards SARS-CoV-2. The compounds according to the present invention can therefore ef fectively prevent or hinder SARS-CoV-2 from becoming pathogenic for human patients. Accordingly, the compounds according to the present invention are able to inhibit SARS-CoV-2 and/or to pre vent or hinder SARS-CoV-2 from entering human cells at least to a certain extent to provide significant advantage for the pa tient to reduce the risk of developing COVID-19 or to reduce the risk of becoming severely affected by COVID-19. The compounds of the present invention are easily accessible, well tolerated and can successfully applied to humans without the need of invasive methods. Moreover, the compounds according to the present inven tion are regarded as "GRAS", i.e. they are "generally recognised as safe (i.a. under sections 201(s) and 409 of the US Federal Food, Drug, and Cosmetic Act.

Preferably, the compound for use according to the present invention is selected from the group 3,3',5,5'- tetramethoxystilbene, 3,4,4' ,5-tetramethoxystilbene, 3,3',4,5'- tetramethoxystilbene, 3,3',4,5,5'-pentamethoxystilbene, 3,3',5,5'-tetrahydroxystilbene, 3,4,4',5-tetrahydroxystilbene, 3,3',4,5'-tetrahydroxystilbene, 3,3',4,4',5- pentahydroxystilbene, 3,3',4,5,5'-pentahydroxystilbene, 3,4,4',5,5'-pentahydroxystilbene, 3,3',4',5,5'- pentahydroxystilbene, 3,3' ,4,4',5,5'-hexahydroxystilbene, pref erably 3,3',4,5,5'-pentamethoxystilbene, 3,3',4,4',5- pentahydroxystilbene, 3,3',4,5,5'-pentahydroxystilbene, 3,4,4',5,5'-pentahydroxystilbene, 3,3',4',5,5'- pentahydroxystilbene, 3,3',4,4',5,5'-hexahydroxystilbene,, espe cially 3,3',4,4',5,5'-hexahydroxystilbene.

The compounds according to the present invention have sur prisingly turned out to be significantly more active in inhibit ing SARS-CoV-2 than comparable polyphenolic substances suggested as being virus-inhibiting. Although also (-) epigallocatechin gallate or (-)-gallocatechin gallate show significant inhibitory effect concerning SARS-CoV-2 compared to other polyphenols, es pecially other compounds from green tea and black tea, the com- pounds according to the present invention have significantly en hanced inhibitory effect over these substances.

The compounds according to the present invention are prefer ably inhibiting replication of SARS-CoV-2 and/or for preventing the cytopathic effect of an active virus replication of SARS- CoV-2 and/or preventing viral infections with SARS-CoV-2 through airborne channels.

In the course of the present invention, the in vitro antivi ral effects of nine polyphenolic plant ingredients and a syn thetic polyphenolic compound, 3,3',4,4',5,5'-hexahydroxy-trans- stilbene, which was synthesized as an analogue of resveratrol, an ingredient of wine, were tested. Nine natural compounds, gal lic acid, (-)-catechin, (-)-catechin gallate, (-) epigallocate- chin gallate, (-)-epicatechin, (-)-epicatechin gallate, (-)- epigallocatechin, (-)-gallocatechin gallate, ellagic acid, which have been suggested in the prior art as potential antiviral com pounds, and a hexahydroxy-trans-stilbene (as a representative example of synthetic resveratrol (trans-3,5,4'- trihydroxystilbene) analoga) were studied regarding their abil ity to inhibit virus replication in vitro.

Stilbene derivatives according to the present invention were previously disclosed e.g. in WO 02/50007 A2, WO 02/057219 Al, WO 2005/016860 Al and WO 2007/002973 A2.

These (poly-) hydroxylated phenols were described to have increased anti-cancer and anti-inflammatory effects in compari son to resveratrol due to the increased number of OH-groups in para position on polyhydroxylated stilbenes. Hexahydroxystilbene showed most effective anti-inflammatory and anti-cancer activity in vitro and anticancer effects in animal studies and was shown to inhibit HIV infection in vitro at a very early stage. These substances were also disclosed as regulators of T cells, neutro phils, macrophages and corresponding cytokines.

In CN 1736986 A, stilbene derivates were suggested as anti viral substances for SARS-CoV-1 wherein the compounds disclosed to have antiviral activity were pyridine-group containing com pounds and 2,2' -OH or CH ₃ 0- substituted compounds as well as 3, 3 methyl-butenyl substituted compounds. Moreover, the nature of the compounds with actual anti-SARS activity were not disclosed.

All tested compounds are excellent free radical scavengers, exhibiting a broad range of biochemical effects, such as inhib- iting key enzymes of DNA synthesis or inflammation. In addition, some of them were shown to inhibit different virus infections through unspecific inhibition of virus entry or replication. The compounds were selected due to their chemical structure and availability in natural sources such as tea or fruits.

All compounds were investigated regarding their inhibitory effects on virus infection using in vitro cell culture models.

The receptor for docking of SARS-CoV-2 on to the cell is the ACE 2 receptor. Binding studies were performed for three com pounds, which showed most effective anti-viral effects.

In contrast to other suggestions in the prior art in which several polyphenolic substances from green and black tea were described to have potential anti-SARS-CoV-2 properties, it turned out with the present invention that polyphenolic sub stances highly vary in their effect against SARS-CoV-2 and that only a few of these substances are effective.

These experiments performed in the course of the present in vention showed that the synthetic resveratrol analoga according to the present invention, preferably the tetra-, penta- and hexa-hydroxy-forms thereof, especially hexahydroxystilbene, ex hibit inhibiting activity against SARS-CoV-2 which significantly outperforms other natural polyphenolic compounds, even the few natural polyphenolic compounds which also turned out to have a real-world antiviral activity against SARS-CoV-2 (in contrast to the optimistic prediction based on analogies with other viruses or computer predictions).

The compounds of the present invention are in principle known as pharmaceutical substances. Accordingly, the formula tions already known and proven to be effective for delivery of these compounds to the human subject are also applicable for the present invention. The route of administration can be divided into enteral or parenteral, such as oral, sublingual, intramus cular, subcutaneous, nasal, oral mucosa, skin, peritoneum or rectum, etc., preferably oral, sublingual or nasal, especially as an inhalable and/or aerosol composition. The compounds of the present invention or the pharmaceutical composition containing it can be administered in a unit dosage form. The dosage form for administration can be a liquid dosage form or a solid dosage form. For example, the liquid dosage form can be a true solution type, colloid type, microparticle dosage form, emulsion type, or suspension type. Examples of dosage forms include tablets; caplets; capsules, such as hard gelatin capsules and soft elas tic gelatin capsules; cachets; troches; lozenges; dispersions; suppositories; ointments; cataplasms (poultices); pastes; pow ders; dressings; creams; plasters; solutions; patches; aerosols (e.g., nasal sprays or inhalers); sublingual films or tablets; lollipops; gels; liquid dosage forms suitable for oral or muco sal administration to a patient, including suspensions (e.g., aqueous or non-aqueous liquid suspensions, oil-in-water emul sions, or water-in-oil liquid emulsions), solutions, and elix irs. The compounds of the present invention can be made into or dinary preparations, and can also be slow-release agents, con- trolled-release agents, targeted preparations, and various par ticulate drug delivery systems.

Therefore, the present invention relates to the use of a pharmaceutical preparation comprising the compounds according to the present invention with a pharmaceutically acceptable excipi ent. A pharmaceutically acceptable excipient may be any excipi ent known to be suitable and used for the compounds according to the present invention, especially a carrier or diluent.

In order to make a unit dosage form, various carriers known in the art can be widely used.

Examples of carriers or diluents are, for example, absor bents, such as starch, dextrin, calcium sulfate, lactose, manni tol, sucrose, sodium chloride, glucose, urea, kaolin, microcrys talline cellulose, aluminium silicate, etc.; wetting agents and binders, such as water, glycerin, polyethylene glycol, ethanol, propanol, starch syrup, dextrin, syrup, honey, glucose solution, acacia syrup, gelatin syrup, sodium carboxymethyl cellulose, purple Gum, methyl cellulose, potassium phosphate, polyvinylpyr rolidone, etc.; disintegrants, such as dried starch, alginate, agar powder, alginate, sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitol fat acid esters, sodium lauryl sul fonate, methyl cellulose, ethyl cellulose, etc.; disintegration inhibitors, such as sucrose, glyceryl tristearate, cocoa butter, hydrogenated oil, etc.; absorption enhancers, such as quaternary ammonium salts, sodium lauryl sulfate, etc.; lubricants, such as talc, silicon dioxide, corn starch, stearic acid, boric acid, liquid paraffin, polyethylene glycol, etc.. Other carriers such as polyacrylic resins, liposomes, water-soluble carriers such as PEG4000 and PEG6000, PVP and so on. The tablets can also be fur ther made into coated tablets, such as sugar-coated tablets, film-coated tablets, enteric-coated tablets, or double-layered and multi-layered tablets. For example, in order to make the ad ministration unit into a pill, various carriers known in the art can be widely used. Examples of carriers are, for example, dilu ents and absorbents, such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, polyvinylpyrrolidone, kao lin, talc, etc.; binders, such as acacia, tragacanth, gelatin, Ethanol, honey, liquid sugar, rice paste or batter, etc.; disin- tegrants, such as agar powder, dried starch, alginate, sodium lauryl sulfonate, methyl cellulose, ethyl cellulose, etc.. For example, in order to make the dosing unit into a capsule, the compound of the present invention as an active ingredient is mixed with the aforementioned various carriers, and the result ing mixture is placed in a hard gelatin capsule or a soft cap sule. The active ingredient of the compound of the present in vention can also be made into microcapsules, suspended in an aqueous medium to form a suspension, or filled into hard cap sules or made into injections, inhalations or aerosols, for ap plication. For example, the compound of the present invention is prepared into an injection, an inhalation or aerosol prepara tion, such as a solution, a suspension solution, an emulsion, a lyophilized powder, and this preparation may be aqueous or non- aqueous.

The pharmaceutical preparation of the present invention may contain one and/or more pharmacodynamically acceptable excipi ents, such as carriers, diluents, binders, lubricants, preserva tives, surfactants or dispersants. For example, the diluent can be selected from water, ethanol, polyethylene glycol, 1,3- propanediol, ethoxylated isostearyl alcohol, polyoxylated isos- tearyl alcohol, polyoxyethylene sorbitol fatty acid ester, etc.. In addition, in order to prepare an isotonic inhalation solu tion/suspension, aerosol, injection, an appropriate amount of sodium chloride, glucose or glycerin can be added to the injec tion preparation. In addition, conventional solubilizers, buff ers, pH adjusters, etc. can also be added. These auxiliary mate rials are commonly used in this field. In addition, if neces sary, colouring agents, preservatives, flavours, sweeteners, or other materials can also be added to the pharmaceutical prepara- tion.

In order to achieve the purpose of medication and enhance the therapeutic effect, the drug or pharmaceutical composition of the present invention can be administered by any known admin istration method. The dosage of the extract or compound or phar maceutical composition of the present invention depends on many factors, such as the nature and severity of the disease to be prevented or treated, the gender, age, weight, personality and individual response of the patient or animal, the route of ad ministration, the number of administrations and the purpose of treatment, so the therapeutic dose of the present invention can have a wide range of changes. Generally speaking, the dosage of the pharmacodynamic ingredient of the present invention is well known to those skilled in the art. According to the actual amount of the drug contained in the final formulation of the compound composition of the present invention, appropriate ad justments can be made to meet the requirements of the therapeu tically effective dose, and the dosage of the compound of the present invention can be completed, most preferably 0.1-20 mg/Kg body weight.

The above-mentioned dosage can be administered in a single dosage form or divided into several, for example, two, three or four dosage forms, which is limited by the clinical experience of the administering doctor and the dosage regimen including the use of other treatment means.

According to a preferred embodiment, the polyphenolic com pounds according to the present invention are be formulated for delivery into the upper respiratory system. Exemplary formula tions include nasal, bronchial, oral, and pulmonary formula tions. However, the compounds according to the present invention may also be formulated for topical administration including a liquid, gel, wax, or paste. It is specifically preferred to for mulate the present composition as an aerosol. The aerosol can be a liquid or powdered aerosol. In some embodiments, the composi tion contains one or more pharmaceutically acceptable excipients such as glycerol. The composition can contain 0.01%-20% w/v of the effective ingredient according to the present invention and 10% to 20% glycerol.

Pharmaceutical compositions and unit dosage forms of the disclosure typically also include one or more pharmaceutically acceptable excipients, especially carriers or diluents. Ad vantages provided by specific compounds of the disclosure, such as increased solubility and/or enhanced flow, purity, or stabil ity (e.g., hygroscopicity) characteristics can make them better suited for pharmaceutical formulation and/or administration to patients than the prior art.

Suitable excipients are well known to those skilled in the art of pharmacy or pharmaceutics. Whether a particular excipient is suitable for incorporation into a pharmaceutical composition or dosage form depends on a variety of factors well known in the art including the way in which the dosage form will be adminis tered to a patient. For example, oral dosage forms such as tab lets or capsules may contain excipients not suited for use in parenteral dosage forms. The suitability of a particular excipi ent may also depend on the specific active ingredients in the dosage form. For example, the decomposition of some active in gredients can be accelerated by some excipients such as lactose, or when exposed to water. Active ingredients that include prima ry or secondary amines are particularly susceptible to such ac celerated decomposition.

Specifically preferred pharmaceutically acceptable excipi ents are antioxidants (reduction agents). Antioxidants commonly used in pharmaceutical compositions include citric acid and its salts (E330-E333), tartaric acid and its salts (E334-E337), phosphoric acid and its salts (E338-E343) and ethylenedia- minetetraacetic acid (EDTA) and its salts (calcium disodium EDTA, E385), vitamins C, E, etc..

The disclosure further encompasses pharmaceutical composi tions and dosage forms that include one or more compounds that reduce the rate by which an active ingredient will decompose. Examples of such compounds are stabilizers, such as antioxidants such as ascorbic acid, pH buffers, or salt buffers. In addition, pharmaceutical compositions or dosage forms of the disclosure may contain one or more solubility modulators, such as sodium chloride, sodium sulfate, sodium or potassium phosphate or or ganic acids. A specific solubility modulator is tartaric acid.

Like the amounts and types of excipients, the amounts and specific type of compounds according to the present invention in a dosage form may depend on factors such as the route by which it is to be administered to patients. Typical dosage forms of the compounds of the present invention contain the effective in gredient according to the present invention in an amount of from about 100 pg to about 10 g, preferably in an amount of from about 1 mg to about 1 g, more preferably in an amount of from 10 mg to 500 mg, even more preferably in an amount of from about 20 mg to about 300 mg. Preferred dosage forms contain the compounds of the present invention in an amount of from about 10 mg to about 1000 mg, preferably in an amount of from about 25 mg to about 750 mg, more preferably in an amount of from 50 mg to 500 mg, even more preferably in an amount of from about 30 mg to about 100 mg.

Preferably, the pharmaceutical compositions may also include a carrier, for example a sugar alcohol such as but not limited to glycerol, mannitol, sorbitol, xylitol, and erythritol. In a specific embodiment, the sugar alcohol is glycerol.

Typical topical dosage forms include liquids, creams, lo tions, ointments, gels waxes, pastes, sprays, aerosols, solu tions, emulsions, and other forms know to one of skill in the art. In a preferred embodiment, the present compounds are deliv ered to oral, nasal, or bronchial tissue in a suitable topical dosage form.

For non-sprayable topical dosage forms, viscous to semi solid or solid forms including a carrier or one or more excipi ents compatible with topical application and having a dynamic viscosity preferably greater than water are typically employed. Suitable formulations include solutions, suspensions, emulsions, creams, ointments, powders, gels, waxes, pastes, liniments, salves, and the like, which are, if desired, sterilized or mixed with auxiliary agents (e.g., preservatives, stabilizers, wetting agents, buffers, or salts) for influencing various properties, such as, for example, osmotic pressure.

Nasal spray drug products contain therapeutically active in gredients dissolved or suspended in solutions or mixtures of ex cipients in non-pressurized dispensers that deliver a spray con taining a metered dose of the active ingredient. The dose can be metered by the spray pump or could have been pre-metered during manufacture. A nasal spray unit can be designed for unit dosing or can discharge up to several hundred metered sprays of formu lation containing the drug substance. Nasal sprays are applied to the nasal cavity for local and/or systemic effects. According to another preferred embodiment, the compounds ac cording to the present invention are provided as inhalation so lution and suspension drug products. Such products are typically aqueous-based formulations that contain therapeutically active ingredients and can also contain additional excipients. Aqueous- based oral inhalation solutions and suspension must be sterile. Inhalation solutions and suspensions are intended for delivery to the lungs by oral inhalation for local and/or systemic ef fects and are to be used with a specified nebulizer. An inhala tion spray drug product consists of the formulation and the con tainer closure system. The formulations are typically aqueous based and must be sterile. Inhalation sprays are intended for delivery to the lungs by oral inhalation for local and/or sys temic effects. Other suitable topical dosage forms include sprayable aerosol preparations wherein the active ingredient, preferably in combination with a solid or liquid inert carrier, is packaged in a mixture with a pressurized volatile (e.g., a gaseous propellant, such as freon), or in a squeeze bottle. Ex amples of sprayable aerosol preparations include metered dose inhalers, dry powder inhalers, and nebulizers. Moisturizers or humectants can also be added to pharmaceutical compositions and dosage forms if desired.

It may also be advantageous to provide the pharmaceutical compositions according to the present invention in transdermal and mucosal dosage forms, such as ophthalmic solutions, patches, sprays, aerosols, creams, lotions, suppositories, ointments, gels, solutions, emulsions, suspensions, or other forms known to one of skill in the art. Dosage forms suitable for treating mu cosal tissues within the oral cavity can be formulated as mouth washes, as oral gels, or as buccal patches. Additional transder mal dosage forms include reservoir type or matrix type patches, which can be applied to the skin and worn for a specific period of time to permit the penetration of a desired amount of active ingredient. Suitable excipients (e.g., carriers and diluents) and other materials that can be used to provide transdermal and mucosal dosage forms are well known to those skilled in the pharmaceutical field, and depend on the particular tissue or or gan to which a given pharmaceutical composition or dosage form will be applied. With that fact in mind, typical excipients in clude water, acetone, ethanol, ethylene glycol, propylene gly- col, butane-1,3-diol, isopropyl myristate, isopropyl palmitate, mineral oil, and mixtures thereof, to form dosage forms that are non-toxic and pharmaceutically acceptable. Depending on the spe cific tissue to be treated, additional components may be used prior to, in conjunction with, or subsequent to treatment with the compounds according to the present invention. For example, penetration enhancers can be used to assist in delivering the active ingredients to or across the tissue. Suitable penetration enhancers include acetone; various alcohols such as ethanol, oleyl, a tetrahydrofuryl; alkyl sulfoxides such as dimethyl sul foxide; dimethyl acetamide; dimethyl formamide; polyethylene glycol; pyrrolidones such as polyvinylpyrrolidone; Kollidon grades (Povidone, Polyvidone); urea; and various water-soluble or insoluble sugar esters such as TWEEN 80 (polysorbate 80) and SPAN 60 (sorbitan monostearate).

The pH of a pharmaceutical composition or dosage form, or of the tissue to which the pharmaceutical composition or dosage form is applied, may also be adjusted to improve delivery of the active ingredient(s). Similarly, the polarity of a solvent car rier, its ionic strength, or tonicity can be adjusted to improve delivery. Compounds such as stearates can also be added to phar maceutical compositions or dosage forms to advantageously alter the hydrophilicity or lipophilicity of the active ingredient(s) so as to improve delivery. In this regard, stearates can serve as a lipid vehicle for the formulation, as an emulsifying agent or surfactant, and as a delivery-enhancing or penetration enhancing agent.

The compounds of the present invention can also be formulat ed as extended or delayed release formulations. Extended and de layed release formulations for various active ingredients are known in the art, for example by encapsulation.

The compounds of the present invention are present in the pharmaceutical composition in about 0.001% to about 50% w/v, typically from about 0.01% to about 0.1% w/v, more typically about 1 % to about 20% w/v. In a preferred embodiment, compounds of the present invention are present in about 0.01% to about 20% w/v. The pharmaceutically acceptable excipient and eventually other compounds or agents present in the pharmaceutical composi tion then add up to the 100%.

The compounds and compositions of the present invention are useful for the treatment of one of more symptoms of viral infec tion with SARS-CoV-2. Preferably, the pharmaceutical composi tions according to the present invention are formulated for na sal or oral application, such as drops, applicators, or sprays. One embodiment provides the compositions according to the pre sent invention for prophylactically or therapeutically treating patients which are infected by or are at risk of being infected by SARS-CoV-2, especially for use to prevent viral infections through airborne channels.

According to a further aspect, the present invention relates to the use a compound according to the present invention for the manufacture of a pharmaceutical preparation according to the present invention for the treatment and prevention of COVID-19 in a human subject, especially for inhibiting SARS-CoV-2. Pref erably, the use is for inhibiting replication of SARS-CoV-2 and/or for preventing the cytopathic effect of an active virus replication of SARS-CoV-2 and/or preventing viral infections with SARS-CoV-2through airborne channels.

According to another aspect, the present invention relates to a method for the treatment and prevention of COVID-19 in a human subject, especially for inhibiting SARS-CoV-2, wherein to a subject which is infected by or are at risk of being infected by SARS-CoV-2 an effective amount of a compound according to the present invention or a pharmaceutical preparation according to the present invention is administered. This method is in partic ular suitable for inhibiting replication of SARS-CoV-2 and/or for preventing the cytopathic effect of an active virus replica tion of SARS-CoV-2 and/or preventing viral infections with SARS- CoV-2through airborne channels in a human subject.

The present invention is further illustrated by the follow ing examples and the drawing figures, yet without being re stricted thereto.

Fig. 1 shows the compounds tested and their chemical struc ture; compound I: gallic acid, compound II: (-)-catechin, com pound III: (-)-catechin gallate, compound IV: (-) epigallocate- chin gallate, compound V: (-)-epicatechin, compound VI: (-)- epicatechin gallate, compound VII: (-)-epigallocatechin, com pound VIII: (-)-gallocatechin gallate, compound IX: ellagic ac id, and compound X: hexahydroxy-trans-stilbene;

Fig. 2 shows the effect of preincubations with indicated substances on TCID50 of SARS-CoV-2

Fig. 3, 4 and 5 show the performance of compounds IV, VIII and X in a Vero cell culture assay with SARS-CoV-2 infected cells, wherein cells were incubated then infected and virus load was determined after 48h incubation with different concentra tions of the compounds; RT PCR assay in the supernatant was used to quantify virus infection;

Figs. 6 and 7 show RT PCR assays in the supernatant to quan tify virus infection of compounds I to X ("si" to "slO") and remdesivir;

Fig. 8 shows two runs of virus inhibition;

Fig. 9 shows the structure of resveratrol, piceatannol and hexahydroxystilbene (compound X);

Fig. 10 shows the viral copy numbers at different concentra tions of compounds (dots: resveratrol, squares: piceatannol, triangles up: hexahydroxystilbene (compound X); triangles down: positive control);

Fig. 11 shows the viral copy numbers at different concentra tions of compounds wherein a RT PCR assay in the supernatant was used to quantify virus infection; the column at the right side is the positive control: (A) resveratrol, (B) piceatannol, (C) hexahydroxystilbene (compound X);

Figs 12 to 14 show the performance of hexahydroxystilbene (compound X), resveratrol, and piceatannol in a Vero cell cul ture assay with SARS-CoV-2 infected cells, wherein cells were incubated then infected and virus load was determined after 48h incubation with different concentrations of the compounds.

Examples :

In the present examples, the SARS-CoV-2 inhibiting effects of compounds I to X were investigated, including TCID50 of SARS- CoV-2 and a Vero cell culture assay with SARS-CoV-2 infected cells.

Materials and Methods

Cells were infected and incubated with different concentra tions of all compounds.

Median tissue culture infective dose (TCID ₅₀₎ assay

Vero cells were plated in growth medium (DMEM containing 10% FCS, IOOmM non-essential amino acids, ImM sodium pyruvate and penicillin/streptomycin) into a 96-well plate at a density of 1.5-2 x 10 ⁴ /well on the evening before the experiment. On the next day in the morning, growth medium was removed and 95% con fluent Vero cells were preincubated for 45 minutes with either DMSO or substance I, IV, VII, VIII and X at a dose of 50 mM and infected with 100 pL of serial dilutions of a SARS-CoV-2 virus stock. Preincubation and Virus infection was carried out in me dium containing only 2%FCS instead of 10% FCS. After 5 to 7 days all wells were checked for cell viability and the TCID50 dose in the presence or absence of indicated substances was calculated using the Reed and Munch method (Reed et al., Am. J. Epidemiol. 27 (1938), 493- 497). Wells with viable and infected cells were identified using an inverse light microscope showing either a nicely visible and intact monolayer of Vero cells (viable), or wells with a massive CPE (cytopathic effect), characterized by a large amount of dead cells and the absence of a monolayer (in fected).

After 5 to 7 days all wells were checked for cytopathic ef fects (CPE) and the TCID50 dose in the presence or absence of in dicated substances was calculated using the Reed et al. method.

Cell culture

African green monkey kidney epithelial cells VeroE6 (ob tained from biomedica) cells were maintained in Gibco's Minimum Essential Medium supplemented with Earle's Salts and L-Glutamine (Gibco 11095-080, 500 mL) with 5 % FCS and 1 % PenStrep, in the following referred to as MEM 5 %. Incubation at 37 °C, 5 % CO2 if not stated otherwise.

Virus: Stock preparation and titre determination Viral SARS-CoV-2 strain: Human 2019-nCoV Isolate

Product Description Ref-SKU: 026V-03883 Infectious cell cul ture supernatant of human 2019-nCoV Product Risk Group: RG3 ICTV Taxonomy: ssRNA (+)/Nidovirales/Coronaviridae/Coronavirinae/Betacoronavirus Virus name: Human 2019-nCoV ex China Strain: BavPatl/2020 Iso late: Germany ex China

Based on this stock solution of 2.2 E+06 PFU/mL of Human

2019-nCoV Isolate, a viral working stock (VPN3) was cultured in EMEM (Gibco) + 10 % FCS. For the working stock, titre determina tion via TCID50 and Plaque assay were made in parallel and re vealed a concentration of l,30E+06 viral RNA copies per pL stock. Aliquots were stored at -80 °C. For the infection as says, the working stock was thaw and diluted in MEM 2 % to a MOI of 0,002.

The European Commission classifies SARS-CoV-2 as a risk group 3 pathogen. Experiments with active virus and high concen tration virus stocks require working under biosafety level 3 conditions (BSL-3). At the Institute of Pathology at the Medical University of Graz, all working steps with the active virus were performed under BSL-3 conditions and with an increased personal safety equipment, to avoid transmission of virus via aerosols.

Substances

Substances were dissolved in DMSO (Sigma) to substance stock concentrations of 5 mM or 1 mM, respectively. Further 1:2 dilu tions were made to gain 2,5 mM and 0,5 mM stocks from certain substances. For the final assay concentration, a 1:100 dilution of the substance stocks in MEM 2 % per well was made. Substance stocks were prepared freshly prior to every assay.

Cytotox assay

For cytotoxicity assays VeroE6 cells were seeded in 96-well plates with 8500 to 10000 cells per well, using MEM supplemented with 2 % FCS, 24 hrs. before substance treatment. Incubation at 37 °C, 5 % C0 ₂ .

After incubation, the cells were exposed to 1:100 dilutions of substances stocks in MEM + 2 % FCS (as described above). Triplicates per substance and concentration were tested. Direct ly after substance addition, 24 hrs. and 48 hrs. later, the met abolic activity was measured using a resazurin-based assay. Af ter the addition of Resazurin (10 mM concentration) the increase of relative fluorescent units (RFU) was measured for 3 hrs. and a linear regression analysis was performed. Slopes of substance treated cells were normalized to that of untreated cells (un treated cells = cells + respective amount of medium) to calcu late the relative metabolic activity.

Infection assay VeroE6 Cells used in infection assays were seeded with a density of 2,5 x 10 ⁴ to 3,0 x 10 ⁴ cells per well (300 pL) in a 48-well plate (Corning Costar, cell culture treated) in MEM + 2 % FCS 24 hrs. prior, if not stated otherwise.

At the infection day the seeding medium was removed and the cells were treated with medium (MEM 2 % FCS) containing 1 % DMSO + dissolved substances in certain concentrations) in a final volume of 198 pL. Subsequently, 2 pL of the diluted virus stock containing SARS-CoV-2 (calculated to a MOI 0,002) were added. The cells were infected with virus for 1 h at 5 % CO2 and 37 °C. After the incubation step, the infection medium was removed and the cells were washed 2 times with MEM without FCS. 440 pi fresh MEM 2 % FCS, either containing substances or not were given on the cells. 10 minutes later, the supernatant for time point 0 was collected (140 pL) and frozen at -80 °C or inactivated with 560 pi AVL buffer.

The cells were incubated for additional 48 hrs. at 5 % CO2 and 37 °C until supernatant was harvested for time point 48 and inactivated with 560 pi AVL buffer. In addition, either cells were lysed in the well for intracellular virus detection (RTX buffer from Qiagen RNeasy Kit, followed by RNA preparation based the protocol of this kit), or the plate was fixed in 4 % forma lin for SARS- specific immune histochemical staining (IHC).

RNA isolation and RT-qPCR

After inactivation of the supernatant samples containing vi rus with AVL buffer (Qiagen), the viral RNA was isolated using the QIamp viral RNA mini Kit (QiAmp Viral RNAMini Kit, Qiagen), following the manufacture's protocol as recommended by CDC. The RNA was eluated in 40 pL ultra-pure ¾0 and stored at -80 °C.

The RT-qPCR, to detect the viral load of the samples, was performed based on the CDC recommendation using QuantiTect Mul tiplex RT-PCR Kit with a Rotor Gene Q cycler:

2019-nCoV_Nl-F 2019-nCoV_Nl Forward Primer 5'-GAC CCCAAA ATCAGC GAA AT-3'

2019-nCoV_Nl-R 2019-nCoV_Nl Reverse Primer 5'-TCT GGT TAC TGC CAG TTGAAT CTG-3'

2019-nCoV_Nl-P 2019-nCoV_Nl Probe 5'-FAM-ACC CCG CAT TAC GTT TGG TGGACC-BHQl-3' FAM,BHQ-1

Rotorgene qRT-PCR analysis was performed using Rotorgene and following the manufacturer's protocol. 25 pL approach Temperature profile for amplification

QuantiTect Mastermix 12,5 o Hold 1:50°C, 30Min mΐ o Hold 2:95°C, 15Min

Primer forward 1 mΐ o Cycling (2 Step Cycling):95°C

Primer reverese 1 mΐ 3 sec + 55°C, 30 sec

Qt Probe 0,5 o Cycle:45 mΐ

RT-Mix 0,25 mΐ water 4,75 mΐ sample 5 mΐ

Total volume 25 mΐ

Immunohistochemistry

After fixation of the cells with 4 % formalin and washing with PBS, the cells were permeabilized using 0,1 % Triton X 100 in PBS for 10 min (200 mΐ per well), followed by 3 washing steps with 200 mΐ PBS. The endogen peroxidases were blocked with 3 % H2O2 in methanol for 30 min. After this, 3 washing steps with 200 mΐ PBS followed and the cells were incubated for 1 h with 100 pL primary antibody (SARS-CoV-2 nucleocapsid; 1:1000 dilution in antibody diluent) per well. 3 washing steps with 200 mΐ PBS fol lowed and during another incubation step, the cells were treated with the secondary antibody (Envision) for at least 30 min. (protected from light).

After washing (PBS 3x), the substrate AEC was dropped (2 drops) on the cells and incubated until viral infected cells were stained red (watch under the microscope) but not later than 3 minutes. Reaction was stopped with PBS washing (3x). Wells were kept in PBS until photo documentation.

Reagent: Company Cat #

SARS-CoV-2 (2019-nCoV) Nucleocapsid Antibody, Rab- Sinobiological 40143-R019 bit MAb

REALAntibody Diluent Agilent Technologie,Dako S202230-2 Envision™ + Dual Link System HRP Agilent Technologie,Dako K5007 AEC Substrate-Chromogen Agilent Technologie,Dako K346430-2 Molecular interaction assay to detect inhibition of RBD to ACE2 receptor binding

The molecular interaction assay to detect inhibition of RBD to ACE2 receptor binding was performed as described (Gattinger et al., Allergy, 76 (2021), 878-883) with following alterations: 200 ng His-tagged RBD was incubated with various doses (100, 50, 25, 12.2, and 6 mM) of substance X for three hours at RT fol lowed by a 3-hours overlay onto plate bound ACE2 (2pg/ml). Bound RBD was then detected with a mouse monoclonal anti-His antibody followed by an HRP-labelled anti-mouse IgGi antibody and detected with ABTS detected. All measurements were performed in dupli cates with a variation of <5%.

Results

In a first set of experiments, the TCID50 of SARS-CoV-2 was analysed using Vero cells after preincubation with DMSO or indi cated substances (I-X) dissolved in DMSO was determined. As ex pected DMSO reduced the TCID50 of SARS-CoV-2 by 1 Log. Cells were seeded and then infected for 1 hour, then compounds were added in different concentration for 48 hours. All substances showed cell protective effects and reduced the TCID50 by at least 1 Log scale. TCID50 was significantly lowered by 50 mM of substances IV (99,7- and 802-fold reduction), VIII (99,7- and 5,14-fold reduc tion) and X (99,7 and 2107 fold reduction) showing inhibition of virus replication (Table 1 and Figure 2).

Table 1: The in vitro inhibition of virus proliferation was repeated in another laboratory:

Vero cells were seeded in 48 well plates as described in the methods section and then cells were infected and incubated with different concentrations of all 10 compounds for 48 hours. Com pounds IV, and VIII and X showed inhibition of virus prolifera tion which is in line with the results seen in the first set of experiments (TCID50 assay). Then qPCR of SARS-CoV-2 was performed in the supernatant after RNA isolation. Compound IV caused an increase of ct values above 30 at concentration of 50 mM in one of two duplicates. An increase of ct values greater 30 were also seen after incubation with 50 mM substance VIII. Compound X caused increased ct values (above 30) after treatment with 25 and 50 mM for 48 hours showing inhibition of virus proliferation (see also: Figs. 3, 4 and 5).

In order to determine whether inhibition of virus prolifera tion was due to alterations of virus uptake into the host cells, the cells were further incubated with compounds IV, VIII and X (the compounds which proved effective in previous experiments) for one hour together with cell infection and then the compounds were washed out. Cell supernatant was then tested by qPCR as de scribed above. Interestingly, compounds IV and VIII did not have any effects on the virus proliferation in comparison with un treated controls, while compound X could inhibit virus prolifer ation in a concentration dependent manner after short term incu bation for one hour. Results are shown in figure 7; ct values significantly increased after incubation with 25 or 50 mM for one hour.

This result shows that virus uptake into the host cell could be inhibited by compound X. It was therefore investigated wheth er compound X is capable to block ACE2 receptor, which was de scribed to act as entry of the virus into the cell.

The effects of compounds IV, VIII and X on the ACE2 receptor were then tested. Compounds IV and VIII did not show any inhibi tory effects on the binding of ACE 2 receptor in this test. Com pound X could inhibit binding to ACE2 in a concentration depend ent manner. At 100 mM it inhibited ACE2 binding between 21 and 31 percent (see Fig. 8). This shows that compound X can inhibit virus uptake into the cell at a very early stage, which at least in part can be attributed to the binding of the compound to the ACE2 receptor.

Comparative example with respect to trihydroxystilbene (resvera- trol), tetrahydroxystilbene (piceatannol) and hexahydroxystil- bene (compound X according to the present invention)

Comparative tests with respect to resveratrol, piceatannol and hexahydroxystilbene, compound X according to the present in vention, was carried out as disclosed above. Vero E6 cells were uses as cellular system. Cells were infected with the virus for 1 h, then the test compound was added. Then washing and incuba tion with the test compound for 48 hrs was performed. Re sults/readout were obtained by qPCR of the supernatant and IHC.

Results

The results of these comparative tests are displayed in Figs. 9 to 14. Hexahydroxystilbene was able to inhibit viral replication completely (100 mM and 80 mM); trihydroxystilbene showed a low inhibition of viral replication (100 mM, shows con centration dependency); tetrahydroxystilbene showed no inhibi tion of viral replication.

In view of this disclosure and the examples, the following preferred embodiments are disclosed with the present specifica tion:

1. A compound with the general formula I wherein Ri to R6 are identical or not and are H, OH-, or OR7, wherein R ₇ is a Ci to C ₃ alkyl group or a Ci to C4 acyl group, with the proviso that at least four of Ri to R6 are different than H, for use in the treatment and prevention of COVID-19 in a human subject, especially for inhibiting SARS-CoV-2. 2. A compound for use according to embodiment 1, wherein the compound is selected from the group 3,5,4'- trimethoxystilbene, 3,3',5,5'-tetramethoxystilbene, 3,4,4',5- tetramethoxystilbene, 3, 3',4,5'-tetramethoxystilbene, 3,3',4,5,5'-pentamethoxystilbene, 3,3',5,5'- tetrahydroxystilbene, 3,4,4' ,5-tetrahydroxystilbene, 3,3',4,5'- tetrahydroxystilbene, 3,3' ,4,4',5-pentahydroxystilbene, 3,3',4,5,5'-pentahydroxystilbene, 3,4,4',5,5'- pentahydroxystilbene, 3,3' ,4',5,5'-pentahydroxystilbene, 3,3',4,4',5,5'-hexahydroxystilbene, preferably 3,3',4,5,5'- pentamethoxystilbene, 3,3' ,4,4',5-pentahydroxystilbene, 3,3',4,5,5'-pentahydroxystilbene, 3,4,4',5,5'- pentahydroxystilbene, 3,3' ,4',5,5'-pentahydroxystilbene, 3,3',4,4',5,5'-hexahydroxystilbene, , especially 3,3',4,4',5,5'- hexahydroxystilbene .

3. A compound for use according to embodiment 1 or 2, wherein inhibiting SARS-CoV-2 is inhibiting replication of SARS- CoV-2 and/or for preventing the cytopathic effect of an active virus replication of SARS-CoV-2 and/or preventing viral infec tions with SARS-CoV-2 through airborne channels.

4. A pharmaceutical preparation comprising or consisting of a compound according to any one of embodiments 1 to 3 as ac tive ingredient and a pharmaceutically acceptable excipient.

5. A pharmaceutical preparation for use according to em bodiment 4, wherein the preparation is for oral, sublingual, in tramuscular, subcutaneous, nasal, oral mucosa, bronchial, pulmo nary, skin, peritoneum or rectum administration, preferably for oral, sub-lingual or nasal administration, especially wherein the preparation is provided as an inhalable and/or aerosol com position or as a nasal or oral spray and/or as sublingual films or tablets and/or as lollipops.

6. A pharmaceutical preparation for use according to em bodiment 4 or 5, wherein the pharmaceutically acceptable excipi ent is selected from diluents, such as water, acetone, ethanol, polyethylene glycol, polypropylene glycol, 1,3-propanediol, bu- tane-1,3-diol, isopropyl myristate, isopropyl palmitate, mineral oil, ethoxylated isostearyl alcohol, polyoxylated isostearyl al cohol, polyoxyethylene sorbitol fatty acid ester; carrier, such as glycerol, mannitol, sorbitol, xylitol, and erythritol absor bents, such as starch, dextrin, calcium sulfate, lactose, manni- tol, sucrose, sodium chloride, glucose, urea, kaolin, microcrys talline cellulose, aluminium silicate; wetting agents and bind ers, such as water, glycerin, polyethylene glycol, ethanol, pro panol, starch syrup, dextrin, syrup, honey, glucose solution, acacia syrup, gelatin syrup, sodium carboxymethyl cellulose, purple Gum, methyl cellulose, potassium phosphate, polyvinylpyr rolidone; disintegrants, such as dried starch, alginate, agar powder, alginate, sodium bicarbonate, calcium carbonate, polyox yethylene sorbitol fat acid esters, sodium lauryl sulfonate, me thyl cellulose, ethyl cellulose; disintegration inhibitors, such as sucrose, glyceryl tristearate, cocoa butter, hydrogenated oil; absorption enhancers, such as quaternary ammonium salts, sodium lauryl sulfate; lubricants, such as talc, silicon diox ide, corn starch, stearic acid, boric acid, liquid paraffin, polyethylene glycol; polyacrylic resins, liposomes, water- soluble carriers such as PEG4000 and PEG6000, PVP; antioxidants; pH buffers and/or salt buffers; solubility modulators; penetra tion enhancers; antioxidants, such as citric acid and its salts, tartaric acid and its salts, phosphoric acid and its salts, and ethylenediaminetetraacetic acid (EDTA) and its salts, vitamins C, E; or mixtures thereof.

7. A pharmaceutical preparation for use according to any one of embodiments 4 to 6, wherein the preparation is an inhala tion or aerosol preparation, especially an isotonic inhalation solution or suspension or a liquid or powdered aerosol.

8. A pharmaceutical preparation for use according to any one of embodiments 4 to 7, wherein the preparation contains the compound in an amount of from about 100 pg to about 10 g, pref erably in an amount of from about 1 mg to about 1 g, more pref erably in an amount of from 10 mg to 500 mg, even more prefera bly in an amount of from about 20 mg to about 300 mg.

9. A pharmaceutical preparation for use according to any one of embodiments 4 to 8, wherein the preparation contains the compound in an amount of from about 10 mg to about 1000 mg, preferably in an amount of from about 25 mg to about 750 mg, more preferably in an amount of from 50 mg to 500 mg, even more preferably in an amount of from about 30 mg to about 100 mg.

10. A pharmaceutical preparation for use according to any one of embodiments 4 to 9, wherein the preparation is contained in a metered dose inhaler, in a dry powder inhaler, or in a neb- ulizer.

11. A pharmaceutical preparation for use according to any one of embodiments 4 to 9, wherein the preparation contains the compound in 0.001% to 50% w/v, preferably in 0.01% to 20% w/v, more preferred in 0.1% to 20% w/v, especially in 1 % to 20% w/v.

12. Use of a compound according to any one of embodiments 1 to 3 for the manufacture of a pharmaceutical preparation according to any one of embodiments 4 to 11 for the treatment and prevention of COVID-19 in a human subject, especially for inhibiting SARS- CoV-2.

13. Use according to embodiment 12 for inhibiting replica tion of SARS-CoV-2 and/or for preventing the cytopathic effect of an active virus replication of SARS-CoV-2 and/or preventing viral infections with SARS-CoV-2 through airborne channels.

14. Method for the treatment and prevention of COVID-19 in a human subject, especially for inhibiting SARS-CoV-2, wherein to a subject which is infected by or are at risk of being in fected by SARS-CoV-2 an effective amount of a compound according to any one of embodiments 1 to 3 or a pharmaceutical preparation according to any one of embodiments 4 to 11 is administered.

15. Method for inhibiting replication of SARS-CoV-2 and/or for preventing the cytopathic effect of an active virus replica tion of SARS-CoV-2 and/or preventing viral infections with SARS- CoV-2 through airborne channels in a human subject, wherein to a subject which is infected by or are at risk of being infected by SARS-CoV-2 an effective amount of a compound according to any one of embodiments 1 to 3 or a pharmaceutical preparation ac cording to any one of embodiments 4 to 11 is administered.

1. A compound selected from (-) epigallocatechin gallate,

(-)-gallocatechin gallate or mixtures thereof, preferably (-)- gallocatechin gallate or mixtures thereof, for use in the treat ment and prevention of COVID-19 in a human subject, especially for inhibiting SARS-CoV-2.

2. A compound for use according to embodiment 1, wherein the compound is (-)-gallocatechin gallate ("Substance no. VIII").

3. A compound for use according to embodiment 1 or 2, wherein inhibiting SARS-CoV-2 is inhibiting replication of SARS- CoV-2 and/or for preventing the cytopathic effect of an active virus replication of SARS-CoV-2 and/or preventing viral infec- tions with SARS-CoV-2 through airborne channels.

4. A pharmaceutical preparation comprising or consisting of a compound according to any one of embodiments 1 to 3 as ac tive ingredient and a pharmaceutically acceptable excipient.

5. A pharmaceutical preparation for use according to em bodiment 4, wherein the preparation is for oral, sublingual, in tramuscular, subcutaneous, nasal, oral mucosa, bronchial, pulmo nary, skin, peritoneum or rectum administration, preferably for oral, sub-lingual or nasal administration, especially wherein the preparation is provided as an inhalable and/or aerosol com position or as a nasal or oral spray and/or as sublingual films or tablets and/or as lollipops.

6. A pharmaceutical preparation for use according to em bodiment 4 or 5, wherein the pharmaceutically acceptable excipi ent is selected from diluents, such as water, acetone, ethanol, polyethylene glycol, polypropylene glycol, 1,3-propanediol, bu- tane-1,3-diol, isopropyl myristate, isopropyl palmitate, mineral oil, ethoxylated isostearyl alcohol, polyoxylated isostearyl al cohol, polyoxyethylene sorbitol fatty acid ester; carrier, such as glycerol, mannitol, sorbitol, xylitol, and erythritol absor bents, such as starch, dextrin, calcium sulfate, lactose, manni tol, sucrose, sodium chloride, glucose, urea, kaolin, microcrys talline cellulose, aluminium silicate; wetting agents and bind ers, such as water, glycerin, polyethylene glycol, ethanol, pro panol, starch syrup, dextrin, syrup, honey, glucose solution, acacia syrup, gelatin syrup, sodium carboxymethyl cellulose, purple Gum, methyl cellulose, potassium phosphate, polyvinylpyr rolidone; disintegrants, such as dried starch, alginate, agar powder, alginate, sodium bicarbonate, calcium carbonate, polyox yethylene sorbitol fat acid esters, sodium lauryl sulfonate, me thyl cellulose, ethyl cellulose; disintegration inhibitors, such as sucrose, glyceryl tristearate, cocoa butter, hydrogenated oil; absorption enhancers, such as quaternary ammonium salts, sodium lauryl sulfate; lubricants, such as talc, silicon diox ide, corn starch, stearic acid, boric acid, liquid paraffin, polyethylene glycol; polyacrylic resins, liposomes, water- soluble carriers such as PEG4000 and PEG6000, PVP; antioxidants; pH buffers and/or salt buffers; solubility modulators; penetra tion enhancers; antioxidants, such as citric acid and its salts, tartaric acid and its salts, phosphoric acid and its salts, and ethylenediaminetetraacetic acid (EDTA) and its salts, vitamins C, E; or mixtures thereof.

7. A pharmaceutical preparation for use according to any one of embodiments 4 to 6, wherein the preparation is an inhala tion or aerosol preparation, especially an isotonic inhalation solution or suspension or a liquid or powdered aerosol.

8. A pharmaceutical preparation for use according to any one of embodiments 4 to 7, wherein the preparation contains the compound in an amount of from about 100 pg to about 10 g, pref erably in an amount of from about 1 mg to about 1 g, more pref erably in an amount of from 10 mg to 500 mg, even more prefera bly in an amount of from about 20 mg to about 300 mg.

9. A pharmaceutical preparation for use according to any one of embodiments 4 to 8, wherein the preparation contains the compound in an amount of from about 10 mg to about 1000 mg, preferably in an amount of from about 25 mg to about 750 mg, more preferably in an amount of from 50 mg to 500 mg, even more preferably in an amount of from about 30 mg to about 100 mg.

10. A pharmaceutical preparation for use according to any one of embodiments 4 to 9, wherein the preparation is contained in a metered dose inhaler, in a dry powder inhaler, or in a neb ulizer.

11. A pharmaceutical preparation for use according to any one of embodiments 4 to 9, wherein the preparation contains the compound in 0.001% to 50% w/v, preferably in 0.01% to 20% w/v, more preferred in 0.1% to 20% w/v, especially in 1 % to 20% w/v.

12. Use of a compound according to any one of embodiments 1 to 3 for the manufacture of a pharmaceutical preparation accord ing to any one of embodiments 4 to 11 for the treatment and pre vention of COVID-19 in a human subject, especially for inhibit ing SARS-CoV-2.

13. Use according to embodiment 12 for inhibiting replica tion of SARS-CoV-2 and/or for preventing the cytopathic effect of an active virus replication of SARS-CoV-2 and/or preventing viral infections with SARS-CoV-2 through airborne channels.

14. Method for the treatment and prevention of COVID-19 in a human subject, especially for inhibiting SARS-CoV-2, wherein to a subject which is infected by or are at risk of being in fected by SARS-CoV-2 an effective amount of a compound according to any one of embodiments 1 to 3 or a pharmaceutical preparation according to any one of embodiments 4 to 11 is administered.

15. Method for inhibiting replication of SARS-CoV-2 and/or for preventing the cytopathic effect of an active virus replica tion of SARS-CoV-2 and/or preventing viral infections with SARS- CoV-2 through airborne channels in a human subject, wherein to a subject which is infected by or are at risk of being infected by SARS-CoV-2 an effective amount of a compound according to any one of embodiments 1 to 3 or a pharmaceutical preparation ac cording to any one of embodiments 4 to 11 is administered.