Treatment and prevention of diseases caused by influenza virus with 3,3',4,4',5,5'-hexahydroxy-trans-stilbene

Abstract

The invention discloses 3, 3', 4, 4', 5, 5' -hexahydroxy-trans-stilbene or a pharmaceutically acceptable ester thereof, for use in the treatment and prevention of infections with influenza virus in a human subject, especially for inhibiting human influenza virus.

Description

[0001] Treatment and prevention of diseases caused by influenza virus

[0002] The present invention relates to the treatment and prevention of diseases caused by influenza virus .

[0003] Influenza, commonly known as the flu, is a contagious respiratory illness caused by influenza viruses . These viruses belong to the Orthomyxoviridae family and are characteri zed by their segmented RNA genome . Influenza viruses are primarily classi fied into four types : A, B, C, and D . Of these , influenza A and B are the most clinically signi ficant as they are responsible for the annual flu epidemics in humans . Influenza C causes milder respiratory illness and does not lead to epidemics , while influenza D primarily af fects cattle and is not known to infect humans .

[0004] The history of influenza is marked by several pandemics that have had profound impacts on global health . The most notorious of these was the Spanish flu of 1918- 1919 , which resulted in an estimated 50 million deaths worldwide . Subsequent pandemics , including the Asian flu ( 1957 - 1958 ) , the Hong Kong flu ( 1968- 1969 ) , and the H1N1 pandemic in 2009 , underscore the virus ' s ability to cause widespread illness and death .

[0005] Influenza A viruses are further divided into subtypes based on the hemagglutinin (HA) and neuraminidase (NA) proteins on their surface . There are 18 HA and 11 NA subtypes identified to date . The combination of these proteins defines the speci fic characteristics of the virus , such as H1N1 or H3N2 . Influenza B viruses , on the other hand, are categori zed into two lineages : B / Yamagata and B / Victoria .

[0006] Influenza viruses are spherical or filamentous particles , approximately 80- 120 nm in diameter . The viral envelope is derived from the host cell membrane and contains the HA and NA glycoproteins , along with matrix proteins Ml and M2 . The viral genome consists of eight negative-sense RNA segments , each encoding one or more proteins essential for viral replication and assembly .

[0007] The li fe cycle of the influenza virus begins with the attachment of the HA protein to sialic acid receptors on the host cell surface . This binding facilitates the endocytosis of the virus into the host cell . Once inside , the acidic environment of the endosome triggers a conformational change in HA, leading to the fusion of the viral envelope with the endosomal membrane and release of the viral RNA into the cytoplasm . The viral RNA is then transported to the nucleus , where it undergoes transcription and replication. Newly synthesized viral RNA and proteins are assembled into virions, which are transported to the cell surface and released through budding, aided by the NA protein.

[0008] Immune Response and Pathogenesis

[0009] The host immune response to influenza involves both innate and adaptive mechanisms. The innate immune system provides the first line of defense through the activation of pattern recognition receptors (PRRs) that detect viral components, leading to the production of interferons and pro-inflammatory cytokines. This response limits viral replication and spread. The adaptive immune response involves the activation of B cells, which produce neutralizing antibodies against HA and NA, and T cells, which eliminate infected cells.

[0010] The severity of influenza infection can vary from mild to severe, depending on factors such as the virulence of the virus, the age and health status of the host, and pre-existing immunity. Complications from influenza can include secondary bacterial pneumonia, exacerbation of chronic medical conditions, and, in severe cases, acute respiratory distress syndrome (ARDS) .

[0011] Vaccination remains the most effective method for preventing influenza. Seasonal influenza vaccines are formulated based on predictions of circulating strains and typically include components from both influenza A and B viruses. These vaccines induce an immune response that provides protection against infection. However, due to the high mutation rate of influenza viruses, known as antigenic drift, the vaccine composition needs to be updated annually to match the circulating strains.

[0012] Antiviral medications, such as neuraminidase inhibitors (e.g., oseltamivir and zanamivir) and polymerase inhibitors (e.g., baloxavir marboxil) , are available for the treatment of influenza. These drugs can reduce the duration and severity of symptoms if administered early in the course of the illness.

[0013] However, these antiviral medications are still not satisfactory with respect to their antiviral activity, efficacy and applicability. Ongoing research for providing new antiviral medications for influenza virus combat is still regarded as being necessary to mitigate the impact of influenza on global health.

[0014] In US 8,431, 617 B2 and CA 2379703 Al the use of resveratrol for the treatment of influenza infection is disclosed. US 2024 / 166587 Al and WO 2022 / 200086 Al compare the effect of hexahydroxystilbene, resveratrol and picatannol in cells infected with SARS-CoV-2. Xie et al. (Inflamm. 35 (2012) , 1392-1401) report that hexahydroxystilbene is a potent HIV-1 inhibitor. CN 116 270 564 A report a 4, 3' , 5' -trihydro-resveratrol compound as Coronavirus 3CL protease inhibitor. WO 2005 / 016860 A2 discloses hexahydroxystilbene compounds as selective COX-2 inhibitors. Lee et al. (Antiviral Research 91 (2011) , 330-334) report that selective COX-2 inhibitors can suppress virus replication of H5N1 influenza virus in human macrophages.

[0015] Accordingly, there is still a significant need to provide specific antiviral agents against influenza virus to combat the disease in human patients.

[0016] Thus, it is desirable to have additional methods for inhibiting the formation of influenza virus and / or for preventing and treating influenza virus infections or the diseases caused by such infections. Such method should be useful for limiting the severity of an influenza virus infection within an infected individual and the likelihood of transmission of the influenza virus infection from the infected individual to a non-infected individual.

[0017] Therefore, the present invention provides 3, 3' , 4, 4' , 5, 5' -hex- ahydroxy-trans-stilbene or a pharmaceutically acceptable ester thereof for use in the treatment and prevention of infections by or of diseases caused by influenza virus.

[0018] 3,3\4,4\5,5,~Hexahydroxy-trans~stilbene (HHS)

[0019] 3, 3' , 4, 4' , 5, 5' -hexahydroxy-trans-stilbene and pharmaceutically acceptable esters thereof according to the present invention was identified in the course of the present invention to exhibit realistic and effective inhibitory activity towards influenza virus. The compounds according to the present invention can therefore effectively prevent or hinder influenza virus from becoming pathogenic for human patients. Accordingly, the compounds according to the present invention are able to inhibit influenza virus from entering human cells at least to a certain extent to provide significant advantage for the patient to reduce the risk of developing diseases caused by these viruses. 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 invention 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) .

[0020] Resveratrol, a stilbene compound (3, 5, 4 ' -trihydroxystilbene) , has been reported to show promising antiviral activity against numerous viruses responsible for severe respiratory infections, such as influenza virus, respiratory syncytial virus and SARS-CoV-2, which are known to cause pneumonia, acute respiratory distress syndrome or multiorgan failure, especially, in vulnerable individuals like immunocompromised patients or the elderly (Filardo et al., Pharm Ther. 214 (2020) , 107613; Liu et al., J. Virol. 88 (2014) , 4229-4236; Mattio et al., Eur . J. Med. Chem. 202 (2020) , 11254; Huang et al., Phytomed. 120 (2023) , 155058) . Resveratrol was assumed to have potential value for its antiinflammatory activity, since most of the severe virus-associated complications are related to the overactivation of the host-immune response, leading to lung damage.

[0021] WO 00 / 712534 A2 suggests the use of hydroxylated stilbenes against herpes viruses, including resveratrol and piceatannol ( 3 , 3 ' , 4 , 5 ' -tetrahydroxy-trans-stilbene ) , alleging both, the cis form or trans form being suitable for inhibiting the formation of herpes virus particles (see also: US 2023 / 089605 Al) .

[0022] According to the present invention, 3, 3' , 4, 4' , 5, 5' -hexahy- droxy-trans-stilbene and pharmaceutically acceptable esters thereof have surprisingly turned out to be significantly more active in inhibiting influenza virus than comparable poly-phenolic substances suggested as being virus-inhibiting, such as resveratrol and oseltamivir. Although resveratrol and oseltamivir show some inhibitory effect concerning influenza virus, 3, 3' , 4, 4' , 5, 5' - hexahydroxy-trans-stilbene and pharmaceutically acceptable esters thereof have significantly enhanced inhibitory effect over resveratrol and oseltamivir, as shown in detail in the example section of the present invention.

[0023] 3, 3' , 4, 4' , 5, 5' -hexahydroxy-trans-stilbene and pharmaceutically acceptable esters thereof used according to the present invention are preferably used for inhibiting influenza virus, especially by inhibiting replication of influenza virus, and / or for preventing the cytopathic effect of an active virus replication of influenza virus, and / or preventing viral infections influenza virus through airborne channels.

[0024] The present invention has shown efficiency for influenza viruses in principle; accordingly, the present invention is preferably used for the treatment and prevention of infections by or of diseases caused by influenza virus A or influenza virus B.

[0025] As already stated above, influenza A and B are the most clinically significant as they are responsible for the annual flu epidemics in humans. The major characteristics of influenza A and influenza B can be summarised as follows:

[0026] Influenza A viruses are classified based on two surface proteins: hemagglutinin (HA) and neuraminidase (NA) . There are 18 HA subtypes (Hl to H18) and 11 NA subtypes (N1 to Nil) . The combinations of these subtypes (e.g., H1N1, H3N2) define the specific strains of Influenza A. Influenza A viruses have a wide host range, infecting humans, birds, pigs, horses, dogs, and other animals. Wild aquatic birds are the primary natural reservoir, which contributes to the virus's genetic diversity and potential for interspecies transmission. Influenza A viruses are known for causing pandemics. This potential arises from their ability to undergo significant genetic changes through antigenic drift (i.e. minor changes in the HA and NA proteins due to point mutations) and antigenic shift (i.e. major changes resulting from the reassortment of gene segments when a single host is co-infected with different strains, potentially leading to new subtypes) . The virus spreads primarily through respiratory droplets when an infected person coughs, sneezes, or talks. It can also be transmitted by touching surfaces contaminated with the virus and then touching the mouth, nose, or eyes. Influenza A infections can range from mild respiratory illness to severe disease and complications, including pneumonia, bronchitis, sinus infections, and exacerbation of chronic conditions. Symptoms typically include fever, cough, sore throat, body aches, headaches, chills, and fatigue. Seasonal vaccines are formulated annually to target the most prevalent strains of influenza A ( and influenza B ) . Antiviral drugs such as neuraminidase inhibitors ( oseltamivir, zanamivir ) and polymerase inhibitors (baloxavir marboxil ) are ef fective against influenza A i f administered early .

[0027] Influenza B viruses are classi fied into two main lineages : B / Yamagata and B / Victoria . Unlike influenza A, influenza B does not have subtypes but still undergoes antigenic dri ft . Influenza B viruses primarily infect humans and are not known to infect animals signi ficantly . This limited host range reduces the likelihood of interspecies transmission and genetic reassortment . Influenza B viruses are not associated with pandemics . Their evolutionary changes are slower and more predictable compared to influenza A, limiting the emergence of new, highly virulent strains . Similar to influenza A, influenza B spreads through respiratory droplets and contact with contaminated surfaces . The symptoms of influenza B infection are similar to those of influenza A, including fever, cough, sore throat , body aches , headaches , chills , and fatigue . Influenza B is generally associated with milder epidemics , but it can still cause severe illness , especially in high- risk populations such as children, the elderly, and those with underlying health conditions . Seasonal influenza vaccines include components to protect against both influenza A and B strains . The ef fectiveness of the vaccine varies each year based on the match between the vaccine strains and circulating strains . Antiviral medications ef fective against influenza A, such as neuraminidase inhibitors , are also ef fective against influenza B .

[0028] In comparing influenza A and B, di f ferences in host range , genetic diversity, and pandemic potential are relevant : Influenza A has a broader host range compared to influenza B, which primarily infects humans . Genetic Diversity : Influenza A exhibits greater genetic diversity and undergoes both antigenic dri ft and shi ft , while influenza B undergoes only antigenic dri ft . Influenza A has a higher potential for causing pandemics due to its ability to undergo antigenic shi ft , whereas influenza B is limited to causing seasonal epidemics . Both types are included in the seasonal influenza vaccine , but the speci fic strains targeted by the vaccine may vary each year based on surveillance data . Understanding these characteristics is essential for ef fective prevention, surveillance , and treatment strategies against influenza infections , especially with respect to the active vaccination . The combination of an effective active vaccine strategy against influenza viruses together with the use of the 3, 3' , 4, 4' , 5, 5' -hexahydroxy-trans- stilbene and pharmaceutically acceptable esters thereof according to the present invention allow an improved combat of influenza diseases, both individually and also with respect to epidemic or even pandemic combatting due to the completely different attack strategies of both concepts.

[0029] According to a preferred embodiment of the present invention, the treatment and prevention according to the present invention is combined with an active vaccination against the influenza virus

[0030] 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, WO 2007 / 002973 A2 and WO 2022 / 200086 Al.

[0031] These (poly-) hydroxylated phenols were described to have increased anti-cancer and anti-inflammatory effects in comparison 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, neutrophils, macrophages and corresponding cytokines.

[0032] In CN 1736986 A, stilbene derivates were suggested as antiviral substances for SARS-CoV-1 wherein the compounds disclosed to have antiviral activity were pyridine-group containing compounds and 2,2' -OH or CHsO- 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.

[0033] 3, 3' , 4, 4' , 5, 5' -hexahydroxy-trans-stilbene and pharmaceutically acceptable esters thereof are excellent free radical scavengers, exhibiting a broad range of biochemical effects, such as inhibiting 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. Those compounds were selected due to their chemical structure and availability in natural sources such as tea or fruits.

[0034] In the course of the present invention, 3, 3' , 4, 4' , 5, 5' -hexa- hydroxy-trans-stilbene and pharmaceutically acceptable esters thereof were investigated regarding their inhibitory effects on virus infection using in vitro cell culture models.

[0035] In contrast to other suggestions in the prior art in which several substances were described to have potential anti-influenza virus properties, it turned out with the present invention that polyphenolic substances highly vary in their effect against influenza virus and that only a few of these substances are effective .

[0036] These experiments performed in the course of the present invention showed that the synthetic resveratrol analogon according to the present invention and its pharmaceutically acceptable esters exhibit inhibiting activity against influenza virus 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 influenza virus (at least - for resveratrol and oseltamivir - in human cells) .

[0037] Preferred examples pharmaceutically acceptable esters of 3, 3' , 4, 4' , 5, 5' -hexahydroxy-trans-stilbene for use according to the present invention include formyl ester, acetyl ester, propionyl ester, butyryl ester, fumaryl ester, sulfuryl ester, hydroxamate ester, and enanthate ester. Esterification of trans-stilbene compounds is well available to a person skilled in the art, e.g. by Tain et al. (Antiox. 10 (2021) , 420) , WO 2004 / 000302 Al, US 2017 / 0183290 Al, US 2014 / 134117 Al, and WO 2018 / 164662 Al. Specifically, the pharmaceutically acceptable esters of 3, 3' , 4, 4' , 5, 5' -hexahydroxy-trans-stilbene may be provided (e.g. as pro-drugs) , for example as mono-, di-, tri-, tetra-, penta- or hexa-esters, preferably as mono-esters.

[0038] 3, 3' , 4, 4' , 5, 5' -hexahydroxy-trans-stilbene and pharmaceutically acceptable esters thereof used in the present invention are in principle known as pharmaceutical substances. Accordingly, the formulations 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, intramuscular, subcutaneous, nasal, oral mucosa, topical, especially a topical application to the eye, to the oral cavity, or to the lips; bronchial, pulmonary, skin, peritoneum or rectum, etc., preferably oral, sublingual or nasal, especially as an inhalable and / or aerosol composition or as a nasal or oral spray and / or as sublingual films or tablets and / or as lollipops. 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 elastic gelatin capsules; cachets; troches; lozenges; dispersions; suppositories; ointments; cataplasms (poultices) ; pastes; powders; 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 mucosal administration to a patient, including suspensions (e.g., aqueous or non-aqueous liquid suspensions, oil-in-water emulsions, or water-in-oil liquid emulsions) , solutions, and elixirs. The compounds of the present invention can be made into ordinary preparations, and can also be slow-release agents, controlled-release agents, targeted preparations, and various particulate drug delivery systems, including inhalation systems (i.e. in the form of a kit comprising the pharmaceutical composition according to the present invention and an inhalator, such as the Diskhaler and other inhalators already used as inhalators for pharmaceutical compositions) .

[0039] Preferably, the pharmaceutical composition is administered to an infected site during the prodromal stage of infection.

[0040] Therefore, the present invention also relates to the use of a pharmaceutical preparation comprising 3, 3' , 4, 4' , 5, 5' -hexahy- droxy-trans-stilbene and pharmaceutically acceptable esters thereof according to the present invention with a pharmaceutically acceptable excipient. A pharmaceutically acceptable excipient may be any excipient known to be suitable and used for the compounds according to the present invention, especially a carrier or diluent. According to a preferred embodiment, 3, 3' , 4, 4' , 5, 5' -hexahy- droxy-trans-stilbene is provided as the single active ingredient in the pharmaceutical preparation. This means that the pharmaceutical preparation contains 3, 3' , 4, 4' , 5, 5' -hexahydroxy-trans-stil- bene as the single effective agent with specific antiviral activity. Accordingly, no further antiviral agent in an effective antiviral amount is present in this preferred composition.

[0041] In order to make a unit dosage form, various carriers known in the art can be widely used.

[0042] Examples of carriers or diluents are, for example, absorbents, such as starch, dextrin, calcium sulfate, lactose, mannitol, sucrose, sodium chloride, glucose, urea, kaolin, microcrystalline 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, polyvinylpyrrolidone, etc.; disintegrants , such as dried starch, alginate, agar powder, alginate, sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitol fat acid esters, sodium lauryl sulfonate, 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 further 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 administration unit into a pill, various carriers known in the art can be widely used. Examples of carriers are, for example, diluents and absorbents, such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, polyvinylpyrrolidone, kaolin, talc, etc.; binders, such as acacia, tragacanth, gelatin, Ethanol, honey, liquid sugar, rice paste or batter, etc.; disintegrants, 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 compounds of the present invention as an active ingredient are mixed with the aforementioned various carriers, and the resulting mixture is placed in a hard gelatin capsule or a soft capsule. The active ingredient of the compound of the present invention can also be made into microcapsules, suspended in an aqueous medium to form a suspension, or filled into hard capsules or made into injections, inhalations or aerosols, for application. For example, the compounds of the present invention are prepared into an injection, an inhalation or aerosol preparation, such as a solution, a suspension solution, an emulsion, a lyophilized powder, and this preparation may be aqueous or non-aqueous.

[0043] The pharmaceutical preparation of the present invention may contain one and / or more pharmacodynamically acceptable excipients, such as carriers, diluents, binders, lubricants, preservatives, surfactants or dispersants. For example, the diluent can be selected from water, ethanol, polyethylene glycol, 1 , 3-propanediol , ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitol fatty acid ester, etc.. In addition, in order to prepare an isotonic inhalation solution / suspension, aerosol, injection, an appropriate amount of sodium chloride, glucose or glycerin can be added to the injection preparation. In addition, conventional solubilizers, buffers, pH adjusters, etc. can also be added. These auxiliary materials are commonly used in this field. In addition, if necessary, colouring agents, preservatives, flavours, sweeteners, or other materials can also be added to the pharmaceutical preparation.

[0044] 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 administration method. The dosage of the compound or pharmaceutical 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 administration, 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 adjustments can be made to meet the requirements of the therapeutically effective dose, and the dosage of the compounds of the present invention can be completed, most preferably 0.1-20 mg / Kg body weight.

[0045] 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.

[0046] According to a preferred embodiment, 3, 3' , 4, 4' , 5, 5' -hexahy- droxy-trans-stilbene and pharmaceutically acceptable esters thereof according to the present invention are formulated for delivery into the upper respiratory system. Exemplary formulations include nasal, bronchial, oral, and pulmonary formulations. However, the compounds according to the present invention may also be formulated for topical administration including a liquid, gel , wax, or paste . It is speci fically preferred to formulate the present composition as an aerosol . The aerosol can be a liquid or powdered aerosol . In some embodiments , the composition contains one or more pharmaceutically acceptable excipients such as glycerol . The composition can contain 0 . 01%-20% w / v of the ef fective ingredient according to the present invention and 10% to 20% glycerol .

[0047] Pharmaceutical compositions and unit dosage forms of the present invention typically also include one or more pharmaceutically acceptable excipients , especially carriers or diluents . Advantages provided by speci fic compounds of the disclosure , such as increased solubility and / or enhanced flow, purity, or stability ( e . g . , hygroscopicity) characteristics can make them better suited for pharmaceutical formulation and / or administration to patients than the prior art .

[0048] 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 administered to a patient . For example, oral dosage forms such as tablets or capsules may contain excipients not suited for use in parenteral dosage forms . The suitability of a particular excipient may also depend on the speci fic active ingredients in the dosage form . For example , the decomposition of some active ingredients can be accelerated by some excipients such as lactose , or when exposed to water . Active ingredients that include primary or secondary amines are particularly susceptible to such accelerated decomposition .

[0049] Speci fically preferred pharmaceutically acceptable excipients 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 ethylenediaminetetraacetic acid (EDTA) and its salts ( calcium disodium EDTA, E385 ) , vitamins C, E , etc . .

[0050] The disclosure further encompasses pharmaceutical compositions 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 stabili zers , such as antioxidants such as ascorbic acid, pH buf fers , or salt buf fers . 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 organic acids. A specific solubility modulator is tartaric acid.

[0051] 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 ingredient 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.

[0052] 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.

[0053] Typical topical dosage forms include liquids, creams, lotions, ointments, gels waxes, pastes, sprays, aerosols, solutions, emulsions, and other forms know to one of skill in the art. In a preferred embodiment, the present compounds are delivered to oral, nasal, or bronchial tissue in a suitable topical dosage form.

[0054] For non-sprayable topical dosage forms, viscous to semi-solid or solid forms including a carrier or one or more excipients 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.

[0055] Nasal spray drug products contain therapeutically active ingredients dissolved or suspended in solutions or mixtures of excipients in non-pressurized dispensers that deliver a spray containing 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 formulation containing the drug substance. Nasal sprays are applied to the nasal cavity for local and / or systemic effects.

[0056] According to another preferred embodiment, the compounds according to the present invention are provided as inhalation solution and suspension drug products. Such products are typically aqueous-based formulations that contain therapeutically active ingredients and can also contain additional excipients. Aqueousbased 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 effects and are to be used with a specified nebulizer. An inhalation spray drug product consists of the formulation and the container 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 systemic 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. Examples 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.

[0057] 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 mucosal tissues within the oral cavity can be formulated as mouthwashes, as oral gels, or as buccal patches. Additional transdermal 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 organ to which a given pharmaceutical composition or dosage form will be applied. With that fact in mind, typical excipients include water, acetone, ethanol, ethylene glycol, propylene glycol, 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 specific 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 sulfoxide; 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) .

[0058] 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 carrier, its ionic strength, or tonicity can be adjusted to improve delivery. Compounds such as stearates can also be added to pharmaceutical 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.

[0059] The compounds of the present invention can also be formulated as extended or delayed release formulations. Extended and delayed release formulations for various active ingredients are known in the art, for example by encapsulation.

[0060] 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 composition then add up to the 100%.

[0061] The compounds and compositions of the present invention are useful for the treatment of one of more symptoms of viral infection with influenza virus (i.e. an infection of a patient with an influenza virus (influenza infection) ) ; especially wherein the treatment and prevention is combined with an active vaccination against the influenza virus. Preferably, the pharmaceutical compositions according to the present invention are formulated for nasal or oral application, such as drops, applicators, or sprays. One embodiment provides the compositions according to the present invention for prophylact ically or therapeutically treating patients which are infected by or are at risk of being infected by influenza virus, especially for use to prevent viral infections through airborne channels.

[0062] According to a further aspect, the present invention relates to the use 3, 3' , 4, 4' , 5, 5' -hexahydroxy-trans-stilbene or a pharmaceutically acceptable ester thereof, according to the present invention for the manufacture of a pharmaceutical preparation according to the present invention for the treatment and prevention of diseases, disorders and symptoms associated with or caused by influenza virus infections in a human subject (influenza infections) , especially by inhibiting influenza virus. Preferably, the use is for inhibiting replication of influenza virus, and / or for preventing the cytopathic effect of an active virus replication of influenza virus, and / or preventing viral infections with influenza virus through airborne channels. The present invention is also specifically suited in combination with an active vaccination against the influenza virus. The vaccination is thereby usually provided at a different (earlier) point in time and allows the immune system to create, maintain or improve an appropriate immune response against infections with influenza viruses, whereas the present invention is usually applied shortly before a potential infection with influenza viruses or after an infection, preferably within a short period after infection, e.g. at the first manifestation of influenza symptoms.

[0063] According to another aspect, the present invention relates to a method for the treatment and prevention of infections by or of diseases, disorders or symptoms caused by or associated with infectious influenza virus in a human subject (influenza infections) , especially for inhibiting influenza virus, wherein to a subject which is infected by or are at risk of being infected by influenza virus, an effective amount of 3, 3' , 4, 4' , 5, 5' -hexahy- droxy-trans-stilbene or a pharmaceutically acceptable ester thereof according to the present invention or a pharmaceutical preparation according to the present invention is administered; especially wherein the treatment and prevention is combined with an active vaccination against the influenza virus. This method is in particular suitable for inhibiting replication of influenza virus, and / or for preventing the cytopathic effect of an active virus replication of influenza virus, and / or preventing viral infections with influenza virus through airborne channels in a human subj ect .

[0064] The present invention is further illustrated by the following examples and the drawing figures, yet without being restricted thereto .

[0065] Fig. 1 shows the effect of 3 , 3 ' , 4 , 4 ' , 5, 5 ' -hexahydroxy-trans- stilbene on influenza A virus.

[0066] Fig. 2 shows the effect of oseltamivir on influenza A virus.

[0067] Fig. 3 shows the effect of 3 , 3 ' , 4 , 4 ' , 5, 5 ' -hexahydroxy-trans- stilbene on influenza B virus.

[0068] Fig. 4 shows the effect of oseltamivir on influenza B virus.

[0069] Fig. 5 shows the effect of 3, 3 ' , 4, 4 ' , 5, 5 ' -hexahydroxy-trans- stilbene, resveratrol and oseltamivir on influenza A virus (as in Figs . 1 und 2 ) .

[0070] Fig. 6 shows the effect of 3 , 3 ' , 4 , 4 ' , 5, 5 ' -hexahydroxy-trans- stilbene, resveratrol and oseltamivir on influenza B virus (as in Figs . 3 and 4 ) .

[0071] Examples :

[0072] In the present examples, human influenza virus inhibiting effects of 3 , 3 ' , 4 , 4 ' , 5, 5 ' -hexahydroxy-trans-stilbene were investigated in comparison with resveratrol and oseltamivir.

[0073] The compound M8 (3, 3 ', 4, 4 ', 5, 5 ' -hexahydroxy-trans-stilbene) shows, when used as pre-treatment of the virus, a significant antiviral effect. Even the lowest tested concentration of 0,097pM, M8 shows antiviral activity, with complete inhibition observed at 1,56 pM .

[0074] The effect was compared with Resveratrol. Resveratrol has a significantly lower antiviral effect than M8, especially against influenza B, where the effect is considerably reduced. Resveratrol does not reach complete inhibition. For influenza A it reduced the viral load to 15%, but for influenza B only up to 59%.

[0075] Oseltamivir (OS) was used as reference treatment. For OS, treatment was added only post-infection, without any pre-treat- ment . OS shows antiviral effect from the lowest tested concentration, achieving a complete inhibition at concentrations from 50 pM and above .

[0076] Materials and Methods

[0077] Cell assay

[0078] In this study, we used Influenza A Virus, A / Brisbane / 10 / 2007 (H3N2) and Influenza B Virus, B / Brisbane / 60 / 2008 (Victoria Lineage) provided by the International Reagent Resource established by the Centers for Disease Control and Prevention. The viruses were produced in Madin-Darby canine kidney (MDCK) cells using Dulbec- co ' s Modified Eagle Medium (DMEM) supplemented with GlutaMax, Non- Essential Amino Acids, and TPCK Trypsin. MDCK cells were infected when reaching confluence, and after a 90-minute incubation period, the viral inoculum was replaced with fresh culture medium. Upon the observation of a total cytopathic effect (CPE) , the viral supernatant was harvested and stored at -80°C.

[0079] For functional plaque reduction assays, MDCK cells were seeded in 12-well plates. The virus (40 plaque forming units per well) was pre-treated with M8 (hexahydroxystilbene (3, 3 ' , 4, 4 ' , 5, 5 ' -hex- ahydroxy-trans-stilbene ; HHS) ) or resveratrol in the indicated concentrations for 90 minutes. Following pre-treatment , the virus was used to infect the MDCK cells for an additional 90 minutes. After infection, the cells were then overlaid with medium containing 0.4% low-melting point agarose. After solidification of the agarose layer, the plates were incubated for 2 days at 34°C in a CO2 incubator, fixed with 4% formaldehyde, and analyzed for plaque numbers after staining with 1:6 diluted methylene blue. Plaque numbers were normalized to the mean of virus-control samples. As a control, oseltamivir (OS) (Sigma Aldrich) was added at the indicated concentrations at the time of infection and the treatment was continued post-infection.

[0080] Substances

[0081] 3, 3 ' , 4, 4 ' , 5, 5 ' -hexahydroxy-trans-stilbene, resveratrol and oseltamivir were dissolved in DMSO (Sigma) to substance stock concentrations of 10 mM. Substance stocks were prepared freshly prior to every assay. Further dilutions were made in DMEM supplemented with 2mM L-glutamine / 10% FCS to gain the final assay concentrations .

[0082] Results

[0083] To investigate whether 3, 3 ' , 4, 4 ' , 5, 5 ' -hexahydroxy-trans- stilbene and resveratrol inhibit the replication of influenza virus, assays in influenza virus-infected MDCK cells were performed. In these experiments, 3, 3 ' , 4, 4 ' , 5, 5 ' -hexahydroxy-trans-stilbene, resveratrol and oseltamivir showed a significant inhibition of influenza virus replication. The inhibition capacity of 3, 3 ', 4, 4 ', 5, 5 ' -hexahydroxy-trans-stilbene (IC50 of 0.3pM for H3N2 (Fig. 5) and an IC50 of 1.4pM for influenza B (Fig. 6) ) was, however, a factor of at least 2,3 higher than the inhibition capacity of resveratrol (IC50 of 0.7pM for H3N2 (Fig. 5) and an IC50 >100pM for influenza B (Fig. 6) ) and oseltamivir (IC50 of 0.8pM for H3N2 (Fig. 5) and an IC50 of 0.7pM for influenza B (Fig. 6) ) .

[0084] In view of this disclosure and the examples, the following preferred embodiments are disclosed with the present specification :

[0085] 1. 3, 3' , 4, 4' , 5, 5' -hexahydroxy-trans-stilbene or a pharmaceutically acceptable ester hereof for use in the treatment and prevention of infections by or of diseases, disorders or symptoms caused by or associated with infectious influenza virus, preferably influenza A virus and influenza B virus.

[0086] 2. 3, 3' , 4, 4' , 5, 5' -hexahydroxy-trans-stilbene or a pharmaceutically acceptable ester thereof for inhibiting formation of influenza virus particles in a host cell.

[0087] 3. 3, 3' , 4, 4' , 5, 5' -hexahydroxy-trans-stilbene or a pharmaceutically acceptable ester thereof for blocking replication of an influenza virus in a cell infected with influenza virus.

[0088] 4. 3, 3' , 4, 4' , 5, 5' -hexahydroxy-trans-stilbene or a pharmaceutically acceptable ester thereof for use according to any one of embodiments 1 to 3, wherein 3, 3' , 4, 4' , 5, 5' -hexahydroxy-trans- stilbene or a pharmaceutically acceptable ester thereof is administered prior to or within 6 hours of infection of the host cell with influenza virus.

[0089] 5. 3, 3' , 4, 4' , 5, 5' -hexahydroxy-trans-stilbene or a pharmaceutically acceptable ester thereof for use according to any one of embodiments 1 to 4, wherein the pharmaceutically acceptable ester thereof is selected from formyl ester, acetyl ester, propionyl ester, butyryl ester, fumaryl ester, sulfuryl ester, hydrox- amate ester, and enanthate ester, preferably a mono-, di-, tri-, tetra-, penta- or hexa-ester of any one of these esters, especially a mono-ester thereof.

[0090] 6. 3, 3' , 4, 4' , 5, 5' -hexahydroxy-trans-stilbene or a pharmaceutically acceptable ester thereof for use according to any one of embodiments 1 to 5, wherein 3, 3' , 4, 4' , 5, 5' -hexahydroxy-trans- stilbene or a pharmaceutically acceptable ester thereof is included in a pharmaceutical composition which further comprises a topical carrier and which is administered is by topical administration to the skin.

[0091] 7. 3, 3' , 4, 4' , 5, 5' -hexahydroxy-trans-stilbene or a pharmaceutically acceptable ester thereof for use according to any one of embodiments 1 to 6, wherein the treatment and prevention of infections with influenza virus is performed by inhibiting influenza virus and wherein this inhibiting is performed by inhibiting replication of influenza virus and / or for preventing the cyto- pathic effect of an active virus replication of influenza virus and / or preventing viral infections with influenza virus through airborne channels.

[0092] 8. A pharmaceutical preparation comprising or consisting of 3, 3' , 4, 4' , 5, 5' -hexahydroxy-trans-stilbene or a pharmaceutically acceptable ester thereof according to any one of embodiments 1 to 7 as active ingredient, preferably as the single active ingredient, and a pharmaceutically acceptable excipient for use in the treatment and prevention of infections by or of diseases caused by infectious influenza virus.

[0093] 9. A pharmaceutical preparation for use according to embodiment 8, wherein the preparation is for oral, sublingual, intramuscular, subcutaneous, nasal, oral mucosa, topical, especially a topical application to the eye, to the oral cavity, or to the lips; bronchial, pulmonary, 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 composition or as a nasal or oral spray and / or as sublingual films or tablets and / or as lollipops.

[0094] 10. A pharmaceutical preparation for use according to embodiment 8 or 9, wherein the pharmaceutical composition is administered to an infected site during the prodromal stage of infection.

[0095] 11. A pharmaceutical preparation for use according to any one of embodiments 8 to 10, wherein the pharmaceutical is applied at or proximate a known site of infection or a site which is suspected of being infected.

[0096] 12. A pharmaceutical preparation for use according to any one of embodiments 8 to 11, for reducing the symptoms of an influenza virus infection.

[0097] 13. A pharmaceutical preparation for use according to any one of embodiment 8 to 12, wherein the pharmaceutically acceptable excipient is selected from diluents, such as water, acetone, ethanol, polyethylene glycol, polypropylene glycol, 1 , 3-propanediol , butane-1 , 3-diol , isopropyl myristate, isopropyl palmitate, mineral oil, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitol fatty acid ester; carrier, such as glycerol, mannitol, sorbitol, xylitol, and erythritol absorbents, such as starch, dextrin, calcium sulfate, lactose, mannitol, sucrose, sodium chloride, glucose, urea, kaolin, microcrystalline cellulose, aluminium silicate; 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, polyvinylpyrrolidone; disinte- grants, such as dried starch, alginate, agar powder, alginate, sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitol fat acid esters, sodium lauryl sulfonate, methyl 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 dioxide, 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; penetration 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.

[0098] 14. A pharmaceutical preparation for use according to any one of embodiments 8 to 13, wherein the preparation is an inhalation or aerosol preparation, especially an isotonic inhalation solution or suspension or a liquid or powdered aerosol.

[0099] 15. A pharmaceutical preparation for use according to any one of embodiments 8 to 14, wherein the preparation contains 3, 3' , 4, 4' , 5, 5' -hexahydroxy-trans-stilbene or a pharmaceutically acceptable ester thereof 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.

[0100] 16. A pharmaceutical preparation for use according to any one of embodiments 8 to 15, wherein the preparation contains 3, 3' , 4, 4' , 5, 5' -hexahydroxy-trans-stilbene or a pharmaceutically acceptable ester thereof 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.

[0101] 17. A pharmaceutical preparation for use according to any one of embodiments 8 to 16, wherein the preparation is contained in a metered dose inhaler, in a dry powder inhaler, or in a nebulizer .

[0102] 18. A pharmaceutical preparation for use according to any one of embodiments 8 to 17, wherein the preparation contains 3, 3' , 4, 4' , 5, 5' -hexahydroxy-trans-stilbene or a pharmaceutically acceptable ester thereof 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.

[0103] 19. Use of 3, 3' , 4, 4' , 5, 5' -hexahydroxy-trans-stilbene or a pharmaceutically acceptable ester thereof according to any one of embodiments 1 to 7 for the manufacture of a pharmaceutical preparation according to any one of embodiments 8 to 18 for the treatment and prevention of diseases caused by influenza virus in a human subject, preferably by inhibiting influenza virus; especially wherein the treatment and prevention is combined with an active vaccination against the influenza virus.

[0104] 20. Use according to embodiment 19 for inhibiting replication of a influenza virus, and / or for preventing the cytopathic effect of an active virus replication of influenza virus and / or preventing viral infections with influenza virus through airborne channels .

[0105] 21. Method for the treatment and prevention of diseases caused by influenza virus, in a human subject, especially for inhibiting an influenza virus, wherein to a subject which is infected by or are at risk of being infected by influenza virus, an effective amount of 3, 3' , 4, 4' , 5, 5' -hexahydroxy-trans-stilbene or a pharmaceutically acceptable ester thereof according to any one of embodiments 1 to 7 or a pharmaceutical preparation according to any one of embodiments 8 to 18 is administered; especially wherein the treatment and prevention is combined with an active vaccination against the influenza virus.

[0106] 22. Method for inhibiting replication of influenza virus, and / or for preventing the cytopathic effect of an active virus replication of influenza virus, and / or preventing viral infections with influenza virus through airborne channels in a human subject, wherein to a subject which is infected by or are at risk of being infected by influenza virus, an effective amount of 3, 3' , 4, 4' , 5, 5' -hexahydroxy-trans-stilbene or a pharmaceutically acceptable ester thereof according to any one of embodiments 1 to 7 or a pharmaceutical preparation according to any one of embodiments 8 to 18 is administered; especially wherein inhibiting replication is combined with an active vaccination against the influenza virus.

[0107] 23. A kit comprising

[0108] (1) a container comprising an effective amount of 3, 3' , 4, 4' , 5, 5' - hexahydroxy-trans-stilbene or a pharmaceutically acceptable ester thereof according to any one of embodiments 1 to 7 or a pharmaceutical preparation according to any one of embodiments 8 to 18, suitable for inhalation; and

[0109] (2) an inhalator.

Claims

Claims1. 3, 3' , 4, 4' , 5, 5' -hexahydroxy-trans-stilbene or a pharmaceutically acceptable ester thereof, for use in the treatment and prevention of infections with influenza virus, preferably influenza A virus and influenza B virus, in a human subject.

2. 3, 3' , 4, 4' , 5, 5' -hexahydroxy-trans-stilbene or a pharmaceutically acceptable ester thereof, for use according to claim 1, wherein the treatment and prevention of infections with influenza virus is performed by inhibiting influenza virus and wherein this inhibiting is performed by inhibiting replication of influenza virus and / or for preventing the cytopathic effect of an active virus replication of influenza virus and / or preventing viral infections with influenza virus through airborne channels.

3. A pharmaceutical preparation comprising or consisting of 3, 3' , 4, 4' , 5, 5' -hexahydroxy-trans-stilbene or a pharmaceutically acceptable ester thereof, for use according to claim 1 or 2 as active ingredient, preferably as the single active ingredient, and a pharmaceutically acceptable excipient.

4. A pharmaceutical preparation for use according to claim 3, wherein the preparation is for oral, sublingual, intramuscular, subcutaneous, nasal, oral mucosa, bronchial, pulmonary, skin, peritoneum or rectum administration, preferably for oral, sub-lingual or nasal administration.

5. A pharmaceutical preparation for use according to claim 3 or 4, wherein the preparation is provided as an inhalable and / or aerosol composition 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 any one of claims 3 to 5, wherein the pharmaceutically acceptable excipient is selected from diluents, such as water, acetone, ethanol, polyethylene glycol, polypropylene glycol, 1 , 3-propanediol , butane- 1,3-diol, isopropyl myristate, isopropyl palmitate, mineral oil, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitol fatty acid ester; carrier, such as glycerol, mannitol, sorbitol, xylitol, and erythritol absorbents, suchas starch, dextrin, calcium sulfate, lactose, mannitol, sucrose, sodium chloride, glucose, urea, kaolin, microcrystalline cellulose, aluminium silicate; 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, polyvinylpyrrolidone; disinte- grants, such as dried starch, alginate, agar powder, alginate, sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitol fat acid esters, sodium lauryl sulfonate, methyl 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 dioxide, 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; penetration 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 claims 3 to 6, wherein the preparation is an inhalation 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 claims 3 to 7, wherein the preparation contains 3, 3' , 4, 4' , 5, 5' - hexahydroxy-trans-stilbene or a pharmaceutically acceptable ester 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.

9. A pharmaceutical preparation for use according to any one of claims 3 to 8, wherein the preparation contains 3, 3' , 4, 4' , 5, 5' - hexahydroxy-trans-stilbene or a pharmaceutically acceptable ester 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 anamount of from about 30 mg to about 100 mg.

10. A pharmaceutical preparation for use according to any one of claims 3 to 9, wherein the preparation is contained in a metered dose inhaler, in a dry powder inhaler, or in a nebulizer.

11. A pharmaceutical preparation for use according to any one of claims 3 to 9, wherein the preparation contains 3, 3' , 4, 4' , 5, 5' - hexahydroxy-trans-stilbene or a pharmaceutically acceptable ester 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 3, 3' , 4, 4' , 5, 5' -hexahydroxy-trans-stilbene or a pharmaceutically acceptable ester thereof according to claim 1 or 2 for the manufacture of a pharmaceutical preparation according to any one of claims 3 to 11 for the treatment and prevention of a influenza virus infection or a disease caused by a influenza virus infection in a human subject, preferably by inhibiting influenza virus; especially wherein the treatment and prevention is combined with an active vaccination against the influenza virus.

13. Use according to claim 12 for inhibiting replication of human influenza virus and / or for preventing the cytopathic effect of an active virus replication of human influenza virus and / or preventing viral infections with human influenza virus through airborne channels .

14. Method for the treatment and prevention of human influenza virus in a human subject, especially for inhibiting human influenza virus, wherein to a subject which is infected by or are at risk of being infected by human influenza virus an effective amount of 3, 3' , 4, 4' , 5, 5' -hexahydroxy-trans-stilbene or a pharmaceutically acceptable ester thereof according to claim 1 or 2 or a pharmaceutical preparation according to any one of claims 3 to 11 is administered; especially wherein the treatment and prevention is combined with an active vaccination against the influenza virus.15 . Method for inhibiting replication of influenza virus in a human subj ect , especially for inhibiting human influenza virus and / or for preventing the cytopathic ef fect of an active virus replication of influenza virus and / or preventing viral infections with influenza virus through airborne channels in a human subj ect , wherein to a subj ect which is infected by or are at risk of being infected by influenza virus an ef fective amount of 3 , 3 ' , 4 , 4 ' , 5 , 5 ' - hexahydroxy-trans-stilbene or a pharmaceutically acceptable ester thereof according to claim 1 or 2 or a pharmaceutical preparation according to any one of claims 3 to 11 is administered; especially wherein inhibiting replication is combined with an active vaccination against the influenza virus .

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