Diphenyl derivatives for use in the therapy of viral diseases, especially corona infections, especially COVID-19

Description

[0001] The present invention relates to the field of therapy for viral infections, in particular infections with coronaviruses, especially COVID-19. In particular, the present invention relates to active ingredients and medicaments for use in such therapy.

[0002] In particular, the present invention relates to active ingredients and medicaments for use in the prophylactic and / or therapeutic treatment of viral diseases, in particular coronavirus infections, in particular COVID-19, or to the use of active ingredients and medicaments for the prophylactic and / or therapeutic treatment of viral diseases, in particular coronavirus infections, in particular COVID-19. Within the scope of the present invention, specific active ingredients based on diphenyl derivatives or medicaments containing these specific active ingredients are used, as defined in the following description and in the patent claims of the present invention.

[0003] Coronaviridae is a family of viruses within the order Nidovirales. The viruses within this family are also known colloquially as coronaviruses and are among the RNA viruses with the largest genomes. The first coronaviruses were discovered and described in the mid-1960s. The roughly spherical viruses appear in electron microscopy and are characterized by a ring of petal-like extensions reminiscent of a solar corona, which gives this virus family its name.

[0004] Members of the Coronaviridae virus family cause very different diseases in all four classes of terrestrial vertebrates (i.e., mammals, birds, reptiles, and amphibians). They are highly genetically variable and can thus infect multiple host species. In humans, seven species of coronaviruses are known to cause everything from mild respiratory infections (especially colds and flu-like infections) to severe acute respiratory syndrome (SARS and / or SARS). S evere A cute R espiratory S yndrome ) is important.

[0005] Among the human coronaviruses, the following coronaviruses have become particularly well-known: SARS-CoV-1 (Severe Acute Respiratory Syndrome Coronavirus 1), MERS-CoV (Middle East Respiratory Syndrome Coronavirus) and SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2 These coronaviruses are the triggers of the SARS pandemic in 2002 / 2003, the MERS epidemic in 2012, and the COVID-19 pandemic starting in 2019.

[0006] COVID-19 (ie the abbreviation for English Coronavirus Disease 2019Coronavirus disease 2019 (also known colloquially as coronavirus disease or the like) is an infectious disease resulting from infection with the novel coronavirus SARS-CoV-2. The disease, which primarily affects the respiratory tract, was first described in Wuhan, China, at the end of 2019. It then developed into an epidemic in January 2020, initially in the People's Republic of China, and eventually spread worldwide into the COVID-19 pandemic.

[0007] COVID-19 is typically transmitted through droplet transmission. The incubation period for COVID-19 averages five to six days, although it can sometimes take up to two weeks between infection and the onset of symptoms, and in isolated cases, the first symptoms may appear within 24 hours of infection with SARS-CoV-2. The most common symptoms are fever, dry cough, and fatigue. Less common symptoms include muscle pain, nasal congestion, headache, conjunctivitis, sore throat, diarrhea, loss of taste or smell, or a rash or discoloration of fingers or toes. Infected individuals without symptoms can still be potential carriers of the coronavirus. In mild cases, symptoms generally subside within two weeks. If COVID-19 is more severe, recovery can take three to six weeks or even longer.In approximately 81% of registered infections, the disease progresses with a mild course of fever or mild pneumonia; however, in approximately 14% of cases, the disease progresses more severely, and in approximately 5% of cases, the disease progresses so severely that patients require intensive care.

[0008] COVID-19 is currently the subject of intensive research. Effective and specific causal therapies or vaccines are not yet available.

[0009] The COVID-19-causing virus SARS-CoV-2 – like SARS-CoV-1 in SARS – typically enters human cells by binding to the enzyme ACE2 (angiotensin-converting enzyme 2), anchored in the cell membrane. The viral spike protein interacts with ACE2. This process requires the cooperation of the serine protease TMPRSS2 (transmembrane serine protease 2). In experiments with HeLa cells expressing ACE2 from humans, the Chinese horseshoe bat (Rhinolophus sinicus), a civet species, the domestic pig, and mice, SARS-CoV-2 was able to use the respective ACE2 protein as a receptor to enter the cell; only the mouse ACE2 enzyme was unable to do this – nor was it able to do so with HeLa cells, which do not produce ACE2. In contrast, SARS-CoV-2 does not bind to receptors used by other coronaviruses.

[0010] In addition to the route via ACE2, an alternative route of entry has been experimentally demonstrated in T lymphocytes that carry little or no ACE2 on their surface: The virus enters these cells via a fusion of the viral membrane with the lymphocyte cell membrane mediated by the spike protein.

[0011] A reverse search in a human gene database ( Human Cell Atlas or briefly HCA) by cell type and tissue, in which TMPRSS 2 is present on membrane surfaces in addition to ACE2, shows that the highest concentrations of these two proteins occur in the nasal mucosa, particularly in the goblet cells, but also in the ciliated epithelium, which is why these cells are considered to be the entry point for SARS-CoV-2 and are also suspected to be a reservoir. The proteins are also produced in the corneal cells of the eye, in the intestinal mucosa, and in the heart in pericytes of the blood capillaries, cardiac muscle cells, and fibroblasts. The initial phase of infection in the nasopharynx remains almost symptom-free, whereas when the disease progresses to a severe form, the lungs are predominantly affected, since a large proportion of the ACE-2-expressing cells in humans are found in the type II pneumocytes of the lungs.Further reasons for the particular vulnerability of the lungs are cited as their large surface area; in addition, the ACE-2-expressing type II pneumocyte cells possess various genes that promote the replication and transmission of SARS-CoV-2.

[0012] Studies on cryopreserved lung tissue samples from non-infected individuals have also shown that lung tissue barely produces ACE2 or the transmembrane protease TMPRSS2, whereas type II pneumocytes are increased in the lungs. These precursor cells tend to be more prevalent in men and in older adults. In addition to different ACE2 levels in men and women, gender-specific hormonal imbalances are suspected to be a cause of the different severity of the disease: estrogen promotes an immune response, whereas testosterone suppresses it.

[0013] Recent findings also show that the proprotease furin is co-expressed in the lung epithelium and neighboring tissue cells, which in turn facilitates cell entry for the virus because it has a furin-specific cleavage site on the spike protein.

[0014] In addition to the lungs, ACE2 has also been detected in the small and large intestines, the respiratory tract, and the kidneys. Replication of the virus in intestinal cells has also been confirmed.

[0015] Regarding clinical symptoms and laboratory findings, it is difficult to differentiate the virus from other viral diseases, such as influenza, based on symptoms alone. After an incubation period of typically five to six days, in rare cases up to 14 days, fever, muscle pain, and a dry cough may occur, as described above. The disease often also presents with a general feeling of severe illness. As the disease progresses, severe shortness of breath due to a lower respiratory tract infection or even pneumonia may develop. This may be accompanied by chest pain similar to pleurisy. Approximately 85% of severely ill COVID-19 patients develop lymphopenia.Severely ill patients also often develop hypercytokinemia (a so-called cytokine storm), which is caused by an overreaction of the immune system. This overreaction is characterized by a significant increase in inflammatory cytokines, particularly interleukin-6, interleukin-8, interleukin-1β, and TNF-α. The increased release of these cytokines leads to an overproduction of immune cells, especially in lung tissue.

[0016] The diagnosis of COVID-19 can be made primarily through laboratory diagnostic testing, particularly by means of specific virus and antibody detection.

[0017] An effective and specific causal therapy has not yet been established. The nucleoside analogue remdesivir has shown a shortened duration of illness in hospitalized patients in a preliminary published randomized trial. This drug is approved in the European Union for COVID-19 patients requiring oxygen and can be considered for critically ill patients according to guidelines from the DIVI (German Interdisciplinary Association for Intensive Care and Emergency Medicine).

[0018] Chloroquine and hydroxychloroquine, on the other hand, show no evidence of effectiveness - contrary to initial expectations.

[0019] Tocilizumab, a monoclonal antibody approved for the treatment of various forms of rheumatoid arthritis and cytokine release syndrome, among others, has also been shown to be ineffective.

[0020] Antibody-rich plasma from recovered patients, on the other hand, appears to be suitable for treating acute cases, but can only demonstrate success in the early stages of the disease.

[0021] Further studies show that dexamethasone reduces the mortality rate in patients on ventilators from 41% to 29% and in patients receiving oxygen from 26% to 23%. In patients who do not require oxygen, however, treatment with dexamethasone has no positive effect. Dexamethasone is intended to reduce an excessive immune system reaction, particularly the so-called cytokine storm.

[0022] In severely ill COVID-19 patients, administration of low-molecular-weight heparin is also recommended to reduce the risk of thrombosis and pulmonary embolism. Due to the high incidence of pulmonary embolism and deep vein thrombosis associated with severe COVID-19, the administration of stronger anticoagulant drugs is being considered; however, there are currently insufficient data on the benefits and risks of this.

[0023] It is also still unclear to what extent previous infection confers immunity. Based on findings from animal models, it is currently assumed that acute immunity exists, although it is not known how long this lasts. The current state of research on long-term effects and the assessment of the risk of death is also still uncertain.

[0024] WO 2011 / 000566 A2 relates to the compounds and pharmaceutical compositions described therein and to their use for the manufacture of a medicament for the treatment, alleviation or prevention of disease states caused by a viral infection with negative-sense ssRNA viruses.

[0025] WO 02 / 48147 A2 relates to the compounds described therein, pharmaceutical formulations comprising these compounds, and the use of these compounds in therapy, with particular reference to the prophylaxis and treatment of infections with herpes viruses.

[0026] Chen et al., "Isolation, identification and antiviral activities of metabolites of calycosin-7-O-β-D-glucopyranoside", Journal of Pharmaceutical and Biomedical Analysis, Vol. 56, No. 2, May 25, 2011, pages 382 to 389, concerns studies on in vivo and in vitro metabolites of calycosin-7-O-β-D-glucopyranoside.

[0027] Furthermore, Wyatt PG et al., "Benzophenone Derivatives: A Novel Series of Potent and Selective Inhibitors of Human Immunodeficiency Virus Type 1 Reverse Transcriptase", Journal of Medicinal Chemistry, Vol. 38, No. 10, 1 January 1995, pages 1657 to 1665, relates to studies on synthesized benzophenone derivatives with a related evaluation of their properties as inhibitors of HIV-1 reverse transcriptase and of HIV-1 growth in MT-4 cells.

[0028] In addition, Neamati N. et al., "Depsides and Depsidones as Inhibitors of HIV-1 Integrase: Discovery of Novel Inhibitors through 3D Database Searching", Journal of Medicinal Chemistry, Vol. 40, No. 6, 1 January 1997, pages 942 to 951, concerns studies on various lichen acids based on depsides or depsidones and their synthetic derivatives with regard to their inhibitory activity against HIV-1 integrase, whereby pharmacophores have been identified which are associated with the inhibition of this enzyme.

[0029] Furthermore, Manfroni G. et al., "Inhibition of Subgenomic Hepatitis C Virus RNA Replication by Acridone Derivatives: Identification of an NS3 Helicase Inhibitor", Journal of Medicinal Chemistry, Vol. 52, No. 10, 28 May 2009, pages 3354 to 3365, concerns the synthesis and structure-activity relationship (SAR) of acridones and acridone fragment derivatives developed based on the selective anti-hepatitis C virus (HCV) activity of acridone 2.

[0030] WO 2012 / 122969 A1 relates to substituted diphenyl derivatives or triacene-substituted diphenyl derivatives, which are said to be suitable as chemotherapeutic agents for the treatment of carcinomas in humans and animals.

[0031] Furthermore, DE 10 2015 008 631 A1 concerns benzophenone derivatives, which are said to be suitable as active ingredients in the medicinal treatment of cancer.

[0032] WO 2012 / 130850 A1 relates to substituted bridged diphenyl derivatives described therein, which contain at least one dialkyltriazenyl group and at least one selected oxycarboxylic acid group per molecule, their salts, solvates and the solvates of these salts, wherein the use of these derivatives for the treatment or prevention of diseases, in particular cancers, such as cancers of the sexual organs, is described.

[0033] As a result, most measures worldwide are aimed at preventing COVID-19 infections, particularly through increased individual hygiene measures such as wearing face masks, hand disinfection, surface cleaning, etc., since there is currently no established causal therapy for curative treatment or vaccination for prevention purposes.

[0034] Against this background, one object of the present invention is to provide an efficient, preferably causal, therapy of viral diseases or viral infections (viral infections), in particular infections with corona viruses, in particular COVID-19.

[0035] In particular, it is an object of the present invention to find or provide active ingredients and medicaments containing these active ingredients which are suitable for use in the prophylactic and / or therapeutic treatment of viral diseases or viral infections (viral infections), in particular corona infections, in particular COVID-19, preferably within the framework of an efficient, in particular causal, therapy.

[0036] However, in a completely surprising way, the applicant has now discovered that special active ingredients based on diphenyl derivatives, as defined in more detail in the following description and in the patent claims of the present invention, which have so far only been considered or used for the treatment of tumors or cancers, are unexpectedly also suitable in an efficient manner for the preferably causal treatment of viral diseases or viral infections (viral infections), in particular infections with corona viruses, in particular COVID-19.

[0037] To solve the problem described above, the present invention proposes - according to a first Aspect of the present invention - active ingredients or diphenyl derivatives for use in the prophylactic and / or therapeutic treatment of viral infections (viral infections), in particular infections with corona viruses, in particular COVID-19, according to patent claim 1. Advantageous further developments and embodiments of this aspect of the invention are the subject of the relevant subclaims (i.e., patent claims 2 and 6).

[0038] The present invention also describes the use of the aforementioned active ingredients or diphenyl derivatives for the prophylactic and / or therapeutic treatment of viral infections (viral infections), in particular infections with coronaviruses, in particular COVID-19, or the use of the aforementioned active ingredients or diphenyl derivatives for the production of a medicament or drug for the prophylactic and / or therapeutic treatment of viral infections (viral infections), in particular infections with coronaviruses, in particular COVID-19. The present invention also describes the use of the aforementioned active ingredients or diphenyl derivatives as antiviral agents for the prophylactic and / or therapeutic treatment of viral diseases, in particular coronavirus infections, in particular COVID-19, or for the production of an antiviral agent for the prophylactic and / or therapeutic treatment of viral diseases, in particular coronavirus infections, in particular COVID-19.

[0039] Furthermore, a method for the prophylactic and / or therapeutic treatment of viral diseases, in particular corona infections, in particular COVID-19, is described.

[0040] Also subject of the present invention - according to a second Aspect of the present invention - is a pharmaceutical or medicament for use in the prophylactic and / or therapeutic treatment of viral diseases, in particular corona infections, in particular COVID-19, in particular antiviral agents according to patent claim 2. Advantageous further developments and embodiments of this aspect of the invention are the subject of the relevant subclaim (ie patent claim 6).

[0041] Finally, the subject of the present invention is - according to a third Aspect of the present invention - equally a pharmaceutical combination for use in the prophylactic and / or therapeutic treatment of viral diseases, in particular corona infections, in particular COVID-19, according to patent claim 4. Advantageous further developments and embodiments of this aspect of the invention are the subject of the relevant subclaims (ie patent claims 5 and 6).

[0042] It goes without saying that embodiments, forms of embodiment, advantages and the like which are listed below for the purpose of avoiding repetition of one aspect of the invention naturally also apply accordingly to the other aspects of the invention without this requiring separate mention.

[0043] Furthermore, with regard to the following description of the present invention, the features of the present invention cited in connection with the specific configurations, embodiments, advantages, examples, or the like are also deemed to be disclosed in their combination. Thus, higher-level combinations of individual or multiple features cited for respective configurations, embodiments, application examples, or the like are also deemed to be disclosed.

[0044] Subject of the present invention - according to a first Aspect of the present invention - is thus a diphenyl derivative for use in the prophylactic and / or therapeutic treatment of viral diseases, in particular corona infections, in particular COVID-19, wherein the diphenyl derivative is a diphenyl derivative according to the following formula (IV-A1) or (IV-A2): wherein: Met' denotes a monovalent metal ion, in particular an alkali metal ion, preferably a sodium ion, and Met" denotes a divalent metal ion, in particular an alkaline earth metal ion; or wherein the diphenyl derivative is a diphenyl derivative according to the following formula (IV-A3): or wherein the diphenyl derivative is a diphenyl derivative according to the following formula (IV-A) and its salts: or wherein the diphenyl derivative is a diphenyl derivative according to the following formulas (IV-B) and its salts: or wherein the diphenyl derivative is a diphenyl derivative according to the following formulas (III-A) and its salts: or wherein the diphenyl derivative is a diphenyl derivative according to the following formula (VI-A) and its salts: or wherein the diphenyl derivative is a diphenyl derivative according to the following formula (VIII-A) and its salts:

[0045] The active ingredients or compounds (ie diphenyl derivatives) used according to the invention as such and their preparation or provision are basically known from the prior art (cf. in particular the documents WO 2012 / 122969 A1, DE 10 2015 008 631 A1, EP 2 557 075 A1 and WO 2009 / 004060 A1).

[0046] However, the active substances or compounds described therein (i.e. diphenyl derivatives of the aforementioned type) have so far only been considered or used for cancer and tumor therapy.

[0047] As already described at the beginning, the applicant has now for the first time - completely surprisingly and unexpectedly - found that these special active ingredients based on diphenyl derivatives are also suitable in an efficient manner for the preferential causal therapy of viral diseases or viral infections (viral infections), in particular infections with corona viruses, in particular COVID-19.

[0048] Many viruses exploit and manipulate certain signaling or communication pathways of their host cells to promote their own replication. The applicant has now discovered, in a completely surprising and unexpected way, that the diphenyl derivatives in question can disrupt or interrupt the relevant viral signaling or communication pathways, and that such an interruption of these signaling pathways leads to the viruses no longer being able to replicate.

[0049] An advantage of the fact that the applicant can use active ingredients that are known per se but have not yet been considered for the application or therapeutic purpose according to the invention is that these active ingredients are readily accessible and, above all, have a decisive development advantage over novel active ingredients, since numerous properties of the active ingredients have already been investigated, in particular stability behaviour, toxicities, pharmaceutical-pharmacological formulations and types of application, etc. Therefore, any clinical studies for the purposes of the antiviral therapy according to the invention can in principle begin immediately and without further extensive preliminary investigations.

[0050] As the applicant has discovered, the diphenyl derivatives used according to the invention lead in particular (without wishing to be bound to a specific theory), to the downregulation of certain repair systems in the cells. These systems are also used by viruses to generate a so-called DNA damage response (DDR), which drives the host cell into cell cycle arrest and apoptosis, with the degradation products released being used by the viruses to promote their own replication. By downregulating these cell repair systems, the viruses are deprived of the ability to reproduce, so that on this basis, an efficient, particularly causal, therapy for viral diseases or viral infections (viral infections), in particular infections with coronaviruses, in particular COVID-19, can be provided for the first time using the diphenyl derivatives used according to the invention.

[0051] In other words, the applicant has surprisingly found that the previously described shutdown of the cell's repair mechanisms not only damages tumor cells but also blocks virus replication in infected host cells by depriving the viruses of the ability to access these systems.

[0052] Specific investigations regarding the shutdown of the cell's repair mechanisms were carried out by the applicant, particularly on ovarian carcinoma cancer cells or ovarian carcinoma cancer cell lines, but also on other cell systems and relevant models.

[0053] Due to the mechanism of action shown above, the diphenyl derivatives used according to the invention provide for the first time an efficient, in particular causal, broad-spectrum antiviral therapy or the diphenyl derivatives used according to the invention are unexpectedly suitable as a broad-spectrum antiviral agent (i.e. with regard to the therapy of infections caused by a large number of viruses, but in particular also infections with corona viruses, in particular COVID-19, since the latter in particular rely on the previously described repair (mechanisms) of the host cells).

[0054] The diphenyl derivatives used according to the invention are distinguished from other antiviral active ingredients (e.g. Remdesivir, etc.) and in particular from other diphenyl derivatives by a better therapeutic range, but in particular also by fewer side effects with a high antiviral effect, in particular also by improved uptake into cells which are preferentially infected by coronaviruses or SARS-type viruses (e.g. lungs, kidneys, heart, CNS, etc.).

[0055] The diphenyl derivatives used according to the invention are particularly equipped with a triazene group. However, such triazene derivatives have so far only been known as active ingredients with antitumor activity (e.g., dacarbazine or temozolomide), but have never been widely used even as cytostatic agents (i.e., melanoma or glioblastoma). An indication beyond antitumor activity has so far remained unrecognized and therefore not been considered.

[0056] The diphenyl derivatives used according to the invention – in addition to their antitumor effect – quite surprisingly also possess a pronounced broad antiviral effect (e.g., against DNA and RNA viruses), particularly with regard to RNA viruses (e.g., SARS-based viruses). These compounds are particularly characterized by their excellent tolerability and their adaptability for therapeutic use in humans and animals, particularly for the treatment of severe SARS-type viral diseases in the acute phase, or for preventing or containing infection and the spread of viruses in the body, avoiding life-threatening complications with long-term damage and death, etc.

[0057] Without wishing to be bound to a particular theory, the novel medical indication and mode of action of the diphenyl derivatives used for the first time as antiviral agents in the present invention is based in particular on the fact that the compounds used according to the invention, in therapeutically effective doses and concentrations (e.g. 10-1,000 µmol / l), suppress the DNA expression of genes in the nucleus of the host cell that encode a series of important repair systems (HR; NER;...), so that the invading virus, in particular RNA virus, is unable to generate the decisive metabolic shift at the DNA level in the nucleus of the host cell, namely to trigger a repair system-mediated DNA damage response (DDR) and, as a result, to force cell cycle arrest and apoptosis, which generally leads to the death of the host cell.Non-expression of important repair genes by the compounds used according to the invention thus deprives the virus of the basis for using these processes which are essential for its own replication.

[0058] Treating host cells with the compounds used according to the invention thus results in a shutdown of important repair systems, which the virus requires to initiate and maintain its own replication. Even the blockade of a single specific repair system has significantly inhibitory effects on virus replication. What is particularly surprising is that the compounds used according to the invention temporarily broadly interfere with the expression of a number of important repair systems, thus protecting the infected host cell from the virus-induced transformation process.

[0059] The present invention and the therapy concept according to the invention are therefore associated with a multitude of advantages and special features.

[0060] As regards the diphenyl derivative used according to the invention for use in the prophylactic and / or therapeutic treatment of viral diseases, in particular corona infections, in particular COVID-19, the diphenyl derivative contains - as described above - per molecule (i) at least one dialkyltriazenyl group and (ii) at least one sulfooxy group (cf. also claim 1).

[0061] As previously stated, the subject of the present invention - according to a first aspect of the present invention - is thus a diphenyl derivative for use in the prophylactic and / or therapeutic treatment of viral diseases, in particular corona infections, in particular COVID-19, wherein the diphenyl derivative is a diphenyl derivative according to the following formula (IV-A1) or (IV-A2): wherein: Met' denotes a monovalent metal ion, in particular an alkali metal ion, preferably a sodium ion, and Met" denotes a divalent metal ion, in particular an alkaline earth metal ion; or wherein the diphenyl derivative is a diphenyl derivative according to the following formula (IV-A3): or wherein the diphenyl derivative is a diphenyl derivative according to the following formula (IV-A) and its salts: or wherein the diphenyl derivative is a diphenyl derivative according to the following formulas (IV-B) and its salts: or wherein the diphenyl derivative is a diphenyl derivative according to the following formulas (III-A) and its salts: or wherein the diphenyl derivative is a diphenyl derivative according to the following formula (VI-A) and its salts: or wherein the diphenyl derivative is a diphenyl derivative according to the following formula (VIII-A) and its salts: According to the present first aspect of the invention, the present invention particularly equally relates to a diphenyl derivative, in particular a benzophenone derivative, for use in the prophylactic and / or therapeutic treatment of viral diseases, in particular corona infections, in particular COVID-19, in particular a diphenyl derivative as defined above, wherein the diphenyl derivative, in particular a benzophenone derivative, is a diphenyl derivative according to the following formulas (III-A): and its salts.

[0062] According to the present first aspect of the invention, the present invention thus also relates in particular to a diphenyl derivative, in particular a benzophenone derivative, for use in the prophylactic and / or therapeutic treatment of viral diseases, in particular corona infections, in particular COVID-19, in particular a diphenyl derivative as defined above, wherein the diphenyl derivative, in particular a benzophenone derivative, is a diphenyl derivative according to the following formulas (IV-A) to (IV-B): and its salts.

[0063] According to the present first aspect of the invention, the present invention thus relates in particular to a diphenyl derivative, in particular a benzophenone derivative, for use in the prophylactic and / or therapeutic treatment of viral diseases, in particular corona infections, in particular COVID-19, in particular a diphenyl derivative as defined above, wherein the diphenyl derivative, in particular benzophenone derivative, is a diphenyl derivative according to the following formula (IV-A1) or (IV-A2): wherein: Met' denotes a monovalent metal ion, in particular an alkali metal ion, preferably a sodium ion, and Met" denotes a divalent metal ion, in particular an alkaline earth metal ion.

[0064] According to the present first aspect of the invention, the present invention thus also relates in particular to a diphenyl derivative, in particular a benzophenone derivative, for use in the prophylactic and / or therapeutic treatment of viral diseases, in particular corona infections, in particular COVID-19, in particular a diphenyl derivative as defined above, wherein the diphenyl derivative, in particular a benzophenone derivative, is a diphenyl derivative according to the following formula (IV-A3):

[0065] According to the present first aspect of the invention, the present invention thus also relates in particular to a diphenyl derivative, in particular a benzophenone derivative, for use in the prophylactic and / or therapeutic treatment of viral diseases, in particular corona infections, in particular COVID-19, in particular a diphenyl derivative as defined above, wherein the diphenyl derivative, in particular a benzophenone derivative, is a diphenyl derivative according to the following formula (IV-A):

[0066] According to the present first aspect of the invention, the present invention thus also relates in particular to a diphenyl derivative, in particular a benzophenone derivative, for use in the prophylactic and / or therapeutic treatment of viral diseases, in particular corona infections, in particular COVID-19, in particular a diphenyl derivative as defined above, wherein the diphenyl derivative, in particular a benzophenone derivative, is a diphenyl derivative according to the following formula (VI-A): and its salts.

[0067] Finally - according to the present first aspect of the invention - the present invention also relates in particular to a diphenyl derivative, in particular a benzophenone derivative, for use in the prophylactic and / or therapeutic treatment of viral diseases, in particular corona infections, in particular COVID-19, in particular a diphenyl derivative as defined above, wherein the diphenyl derivative, in particular a benzophenone derivative, is a diphenyl derivative according to the following formula (VIII-A): and its salts.

[0068] With regard to the first aspect of the invention, in particular with regard to all previously described embodiments, it should be noted in particular that the diphenyl derivative is preferably applied and used systemically.

[0069] With regard to the first aspect of the invention, in particular with regard to all previously described embodiments, it should also be noted that optionally the diphenyl derivative, in particular the medicament or drug containing the diphenyl derivative, can be used or applied together with at least one further active ingredient, wherein the at least one further active ingredient can in particular be selected from anti-inflammatory active ingredients (in particular corticosteroids, such as dexamethasone), blood-thinning active ingredients, antiviral active ingredients and combinations thereof.

[0070] Also described herein is the use of a diphenyl derivative, as defined above, for the prophylactic and / or therapeutic treatment of viral diseases, in particular corona infections, in particular COVID-19, or the use according to the invention of the aforementioned active ingredients or diphenyl derivatives for the production of a medicament or drug for the prophylactic and / or therapeutic treatment of viral infections (viral infections), in particular infections with corona viruses, in particular COVID-19.

[0071] Within the scope of the use described here, it is particularly intended that the active ingredient or the diphenyl derivative is administered systemically.

[0072] Furthermore, within the scope of the use described here, it may be necessary for the active ingredient or diphenyl derivative to be used or administered together with at least one other active ingredient. The other active ingredient can be selected, in particular, from anti-inflammatory agents (in particular corticosteroids, such as dexamethasone), blood-thinning agents, antiviral agents, and combinations thereof. The other active ingredient is, in particular, also used or administered systemically.

[0073] For further details on the use described here, reference can be made to the above statements on the first aspect of the invention, which statements apply equally to the use described here.

[0074] Also described herein is the use of a diphenyl derivative, as defined above, as an antiviral agent for the prophylactic and / or therapeutic treatment of viral diseases, in particular corona infections, in particular COVID-19, or for the production of an antiviral agent for the prophylactic and / or therapeutic treatment of viral diseases, in particular corona infections, in particular COVID-19.

[0075] Within the scope of the use described here, it is particularly intended that the active ingredient or the diphenyl derivative is administered systemically.

[0076] Furthermore, within the scope of the use described here, it may be necessary for the active ingredient or diphenyl derivative to be used or administered together with at least one other active ingredient. The other active ingredient can be selected, in particular, from anti-inflammatory agents (in particular corticosteroids, such as dexamethasone), blood-thinning agents, antiviral agents, and combinations thereof. The other active ingredient is, in particular, also used or administered systemically.

[0077] For further details on the use described here, reference can be made to the above statements on the aspects described above, which statements apply equally to the use described here.

[0078] Furthermore, a method for the prophylactic and / or therapeutic treatment of viral diseases, in particular corona infections, in particular COVID-19, is described herein, wherein the method comprises administering to a patient a pharmaceutically effective or therapeutically effective amount of a diphenyl derivative, as defined above.

[0079] Within the scope of the method described here according to this aspect of the invention, it is particularly provided that the active ingredient or the diphenyl derivative is administered systemically.

[0080] Furthermore, within the scope of the method described here, it may be necessary for the active ingredient or diphenyl derivative to be used or administered together with at least one other active ingredient. The other active ingredient can be selected, in particular, from anti-inflammatory agents (in particular corticosteroids, such as dexamethasone), blood-thinning agents, antiviral agents, and combinations thereof. The other active ingredient is, in particular, also used or administered systemically.

[0081] For further details of the method described here, reference can be made to the above statements on the aspects described above, whereby these statements apply equally to the method described here.

[0082] Also subject of the present invention - according to a second Aspect of the present invention - is a pharmaceutical composition or medicament for use in the prophylactic and / or therapeutic treatment of viral diseases, in particular corona infections, in particular COVID-19, in particular antiviral agents, wherein the pharmaceutical composition or medicament, in particular antiviral agents, contains at least one diphenyl derivative as defined above, together with a pharmaceutically acceptable carrier or excipient.

[0083] Within the scope of this aspect of the invention, it is also particularly intended that the active ingredient or the diphenyl derivative is administered systemically.

[0084] Furthermore, within the scope of the inventive use according to this aspect of the invention, it may be provided, if necessary, that the active ingredient or the diphenyl derivative is used or applied together with at least one further active ingredient. The further active ingredient can in particular be selected from anti-inflammatory active ingredients (in particular corticosteroids, such as dexamethasone), blood-thinning active ingredients, antiviral active ingredients, and combinations thereof. The further active ingredient is in particular also used or applied systemically.

[0085] For further details on this aspect of the invention, reference may be made to the above statements on the previously described aspects of the invention, which statements apply equally to the present aspect of the invention.

[0086] Finally, the subject of the present invention is - according to a third Aspect of the present invention - equally a pharmaceutical combination for (use in the) prophylactic and / or therapeutic treatment of viral diseases, in particular corona infections, in particular COVID-19, wherein the pharmaceutical combination comprises (A) at least one diphenyl derivative as defined above or as defined in any one of claims 1, 3, and 6; and (B) at least one further active ingredient selected from anti-inflammatory active ingredients, in particular corticosteroids, blood-thinning active ingredients, antiviral active ingredients, and combinations thereof.

[0087] Within the scope of this aspect of the invention, it is also particularly intended that the active ingredient or the diphenyl derivative is administered systemically.

[0088] The other active ingredient is also used or applied systemically.

[0089] For further details on this aspect of the invention, reference may be made to the above statements on the previously described aspects of the invention, which statements apply equally to the present aspect of the invention.

[0090] The active ingredients or the diphenyl derivatives used according to the invention (as defined above) also have, in particular, a general (i.e., universally valid) or comprehensive or virus-nonspecific antiviral activity potential and / or activity spectrum. Consequently, the active ingredients or the diphenyl derivatives used according to the invention can be used to treat almost all types of viral diseases. This applies to all previously described aspects of the invention (i.e., the first to sixth aspects of the present invention, as described above). Thus, according to all previously described aspects of the invention, the active ingredients or the diphenyl derivatives used according to the invention (as defined above) can be used for the prophylactic and / or therapeutic treatment of viral diseases.wherein the viral diseases can be selected in particular from the group of corona infections, such as MERS and SARS, in particular COVID-19, HIV infections, influenza, parainfluenza, cytomegalovirus infections (HCMV infections), papillomavirus infections (HPV infections), viral hepatitis (viral hepatitis), enterovirus infections, Epstein-Barr virus infections, herpes virus infections, varicella virus infections, in particular varicella zoster virus infections, adenovirus infections, rotavirus infections, yellow fever virus infections, viral hemorrhagic fever (VHF), TBE virus infections, West Nile virus infections, Ebola virus infections, rabies, Marburg virus infections, hantavirus infections, Lassa virus infections, dengue virus infections, Arena virus infections, arbovirus infections, coxsackie virus infections, measles, mumps, rubella and fifth disease virus infections and poliovirus infections,preferably from the group of corona infections, in particular COVID-19, HIV infections, influenza, parainfluenza, cytomegalovirus infections (HCMV infections), papillomavirus infections (HPV infections) and viral hepatitis (viral hepatitis), particularly preferably from the group of corona infections, in particular COVID-19.

[0091] Further embodiments, modifications and variations - insofar as they are covered by the claims - as well as advantages of the present invention are readily apparent and achievable for a person skilled in the art upon reading the description, without thereby departing from the scope of the present invention.

[0092] The following embodiments serve only to illustrate the present invention, but without limiting the present invention thereto. Examples of implementation 1. Shutdown of cell repair systems as a new approach for antiviral therapeutics

[0093] Within the scope of the present invention, it has surprisingly been discovered that the diphenyl derivatives used according to the invention possess an antiviral effect. Without wishing to be limited to this theory, it is assumed that the antiviral effect is based on the downregulation of certain cellular repair systems.

[0094] In this context, initial experiments were carried out with a diphenyl derivative according to the above formula (IV-A3) (where this diphenyl derivative, which is also a triazene, is hereinafter referred to simply as "Compound (IV-A3)") and with a diphenyl derivative according to the above formula (III-A) (where this diphenyl derivative, which is also a triazene, is hereinafter referred to simply as "Compound (III-A)") carried out.

[0095] In addition, further experiments were carried out with the diphenyl derivatives according to the structures of the original patent claims 13, 14, 16, 18 and 19, which provide essentially the same results.

[0096] For the sake of simplicity, only the test results for compound (IV-A3) and compound (III-A) are presented below.

[0097] Compound (IV-A3) strongly induced CDKN1A (cyclin-dependent kinase inhibitor 1A) transcription, suggesting cell cycle blockade as the primary molecular mechanism of action. Furthermore, the substance (Compound (IV-A3)) reduced the expression of certain gene segments involved in the regulation of certain DNA repair mechanisms, such as homologous recombination (HR), DNA dealkylation, mismatch repair (MMR), and nucleotide excision repair (NER).

[0098] RNA Isolation and Whole Transcriptome Sequencing: For whole transcriptome sequencing (RNA-Seq), different cell batches (3.5 x 10-6 cells UWB1.289 or 3.3 x 10-6 cells UWB1.289 + BRCA1) were grown in T75 culture vessels. After 24 hours, the medium was removed and replaced with new medium containing 1,000 µM of compound (IV-A3) or 40 µM of compound (III-A). Standard culture medium served as a control. After 24 hours of exposure, the cells were harvested, and the RNA was extracted using the standard miRNeasy procedure (Qiagen, Hilden, Germany). A column purification step was performed to remove contamination with residual genomic DNA. All experiments were performed in triplicate and analyzed according to the manufacturer's protocol. For gene library preparation, the TruSeq Stranded mRNA Library Prep Kit (Illumina) was used according to the manufacturer's instructions, starting with 1 µg total RNA.The coded libraries (barcoded) were pooled and sequenced on an Illumina NextSeq500 platform.

[0099] Bioinformatic analysis of the transcriptome results: The evaluation was performed using Trimmomatic and STAR software. Hierarchical clustering was performed using Euclid distance and association analysis and visualized with complex heatmaps. Furthermore, a principal component analysis (PCA) plot was performed using the R Stats package from the R Institute for Statistical Computing, Vienna, Austria. The DESeq2 method was used to identify differentially expressed genes according to standard criteria. Only genes with multiple-corrected p-values ​​of less than 0.05 (padj of DESeq2) were considered significant.

[0100] Transcription profiles of ovarian cancer cells treated with compound (IV-A3) and compound (III-A): To investigate the mechanism of action of the diphenyl derivatives and triazenes used according to the invention in ovarian cancer, a comprehensive gene expression analysis was performed on UWB1.289 cell pairs treated with compound (IV-A3) and compound (III-A), respectively. Samples of BRCA1-deficient and BRAC1-proficient UWB1.289 cells were subjected to a short-term treatment (1,000 µM compound (IV-A3) and 40 µM compound (III-A) for 24 hours, respectively, in duplicate. At the time of RNA isolation and transcriptome sequencing, no signs of morphological changes were found in the cells.Hierarchical clustering and principal component analysis revealed a significant difference in the transcriptome profiles between the two cell lines, depending on the active ingredients used (Compound (IV-A3) and Compound (III-A)). Furthermore, cells treated with Compound (IV-A3) showed greater differences from the untreated controls in the PCA plot compared to cells treated with Compound (III-A). This indicates that Compound (IV-A3) induces more pronounced changes in the transcriptome than Compound (III-A). Nevertheless, despite the differences, both compounds cause sufficient changes in the transcriptome to suggest a therapeutic effect.This finding was further supported by the fact that a higher number of differentially transcribed genes were found in compound (IV-A3) compared to compound (III-A) and the control cells.

[0101] In addition, a differential gene expression analysis was performed, focusing on genes involved in cell cycle regulation, drug membrane transport, metabolism, cellular adhesion, and other disease-related pathways, such as fibroblast growth factor (FGF) and the SMAD signaling pathway. The intersections of the genes differentially expressed in both cell lines after drug treatment were determined (log2FC values).

[0102] Treatment with compound (IV-A3) leads to a significant downregulation of several genes from the CDK family and concomitantly to a strong induction of CDKN1A (log2FC = 4.49).

[0103] This suggests activation of the cyclin-dependent protein kinase inhibitor pathway and cell cycle arrest as an early response to treatment. Consistent with the enhanced cell detachment following treatment with compound (IV-A3), some cadherin cell adhesion molecule genes, particularly CDH6, were downregulated (see Figure 1). Figure 1A ).

[0104] In addition to certain gene regulatory effects of compound (IV-A3) and compound (III-A) on the expression of drug efflux pump mechanisms (ABC transporter family) and on some cytochrome enzymes, it was found that a number of DNA repair systems, such as mismatch repair (MMR), base excision repair (BER; XRCC2), nucleotide excision repair (NER; ERCC6), DNA damage signaling sensory systems (ATM and ATR kinases), or homologous recombination repair (HR; XRC2), are downregulated at the transcriptional level (log2FC = -1.09). In particular, the main proteins of the DNA dealkylation pathway (APEX1, TET1 or ALKBH2), which play an important role in triazene-mediated DNA dealkylation, were consistently downregulated after treatment with compound (IV-A3) in both cell lines (cf. Figure 1B). Treatment with compound (IV-A3) or compound (III-A) also leads to consistent upregulation of CDKN1A, accompanied by downregulation of CDK proteins and essential DNA repair enzymes. Compound (IV-A3) also induces certain changes at the transcriptome level that play a role in cell cycle regulation, membrane transport, drug metabolism, and cell adhesion. Furthermore, compound (IV-A3) causes a comprehensive downregulation of transcripts that play a functionally important role in various DNA repair systems.

[0105] Fig. 1A and Fig. 1B Using waterfall plots, they show purely exemplary transcription patterns of UWB1.289 ovarian carcinoma cells treated with compound (IV-A3): Fig. 1Ashows the differentially regulated gene expression of genes involved in cell cycle regulation, drug membrane transport, drug metabolism, cell adhesion, and other selected metabolic pathways in UWB1.289 cells after treatment with compound (IV-A3). Fig. 1B shows the differential gene expression of genes involved in pathways regulating DNA repair in UWB1.289 cells after treatment with compound (IV-A3).

[0106] From the transcription analyses described above, it can be deduced that the compounds based on diphenyl derivatives or triazenes used according to the invention have a significant influence on the gene expression of genes involved in various DNA repair mechanisms, but also genes involved in cell cycle regulation, drug membrane transport, drug metabolism, cell adhesion, and other selected metabolic pathways. Without wishing to be limited to this theory, it is assumed within the scope of the present invention that, in particular, the influence on the expression of genes that regulate or coordinate cellular repair systems simultaneously forms the basis for the antiviral efficacy of the compounds based on diphenyl derivatives or triazenes used according to the invention. 2. Investigation of the antiviral efficacy of compounds according to the invention

[0107] In order to investigate the antiviral activity of the compound according to the invention, the experiments described below were carried out.

[0108] Further experimental tests were carried out with the following compounds: Compound of the above formula (VI-A), hereinafter also simply referred to as "Compound (VI-A)" or "(VI-A)" (used in the form of the sodium salt) Compound of the above formula (VIII-A), hereinafter also simply referred to as "Compound (VIII-A)" or "(VIII-A)" Compound of the above formula (IV-A) (according to the invention), hereinafter also simply referred to as "Compound (IV-A)" or "(IV-A)"; Compound of the above formula (IV-B), hereinafter also simply referred to as "Compound (IV-B)" or "(IV-B)" Investigations of the therapeutic effect in the mouse model

[0109] To investigate the therapeutic effect of compound (VI-A) against SARS-CoV-2 infections in a mouse model, transgenic K18-hACE2 mice were used. The viruses used were a German isolate of SARS-CoV-2. The study was conducted as a feasibility study with two groups (test group, control group), each consisting of six mice, i.e., a total of 12 animals. The two groups of mice were lightly anesthetized by inhalation of 3% isoflurane and intranasally inoculated with 300 KWSIU (FFU) of SARS-CoV-2. Treatment with compound (VI-A) was administered by intraperitoneal injection or application. Treatment of the first group began 30 minutes before infection with an active ingredient concentration or dosage of 150 mg / kg. In addition, three hours after infection, the test mice were given another 500 mg / kg of the compound (dissolved in 100 µl total volume of single-strength PBS buffer with pH 7.4).In the second group (positive control or control group), the mice were similarly infected but treated with PBS buffer alone without the addition of diphenyl derivatives or triazenes (sham treatment). Two days post-infection, the animals were euthanized. The clinical score, comprising weight and clinical symptoms, was determined. To assess treatment success, the viral load in the lungs was determined using qPCR. In addition, immunohistochemical and histopathological examinations were performed on the lungs, namely lung histology based on hematoxylin-eosin staining and immunostaining for the detection of SARS-CoV-2 viruses.

[0110] qPCR showed that the viral load in the lungs of animals treated with compound (VI-A) was significantly lower than in the positive control group. Furthermore, histological examinations of the lung tissue also showed a significantly reduced infection rate compared to the control group.

[0111] The experiments were also conducted or repeated with the other compounds (VIII-A), (IV-A), and (IV-B). These compounds also yielded equally excellent results, suggesting a significant antiviral effect due to the significantly reduced viral load in the lungs following treatment of SARS-CoV-2 infection with the aforementioned compounds. Investigation of the antiviral mode of action using icELISA

[0112] Using an icELISA (in-cell ELISA), the amount of viral SARS-CoV-2 N -or S proteins in infected cells after treatment with compounds of the invention. Compound (VIII-A), compound (VI-A), compound (IV-A), and compound (IV-B) were used for these investigations. Human Caco-2 cells and Vero E6 cells were used for the icELISA studies.

[0113] The experimental setup is described below. Cells, viruses and infection

[0114] For the ELISA assays, Vero-E6 (ATCC CRL-1586) and Caco-2 (ATCC HTB-37) cells were initially cultured in Dulbecco's Modified Eagle's Medium (DMEM) with high glucose concentration, supplemented with 10% fetal calf serum (FCS), penicillin, and streptomycin. Cultivation was carried out at 37°C at atmospheric pressure with 5% CO2. SARS-CoV-2 strains for subsequent cell infection were isolated from patients, with isolation and viral propagation performed in Vero-E6 cells. SARS-CoV-2 virus isolation was confirmed diagnostically using qRT-PCR. Virus titers were determined using CCID50 titration. Diphenyl derivatives or triazenes used

[0115] For the following icELISA, solutions and dilutions of compound (VI-A), compound (VIII-A), compound (IV-A), and compound (IV-B) were prepared. The concentrations and the solvents used are shown in the table below: Connection Stock solutions medium 1 / 4000 1 / 2000 1 / 1000 1 / 500 (VIA) 200 mg / ml H2O 50 µg / ml 100 µg / ml 200 µg / ml 400 µg / ml (VIII-A) 500 mg / ml DMSO 125 µg / ml 250 µg / ml 500 µg / ml 1000 µg / ml (IV-A) 100 mg / ml H2O 25 µg / ml 50 µg / ml 100 µg / ml 200 µg / ml (IV-B) 100 mg / ml DMSO 25 µg / ml 50 µg / ml 100 µg / ml 200 µg / ml

[0116] The dilutions 1 / 4000, 1 / 2000, 1 / 1000 and 1 / 500 specified in the table were subsequently used to treat the cells for the icELISA. In-cell ELISA (icELISA)

[0117] The icELISA was performed to quantify the amount of viral SARS-CoV-2 proteins in infected cells. Caco-2 cells and Vero E6 cells were used for the ELISA studies, with two assays being run for each cell type. The ELISA was performed according to the protocol described in Scholer et al.: "A Novel In-Cell-ELISA Assay Allows Rapid and Automated Quantification of SARS-CoV-2 to Analyze Neutralizing Antibodies and Antiviral Compounds," Front Immunol 11, 573526 (2020). Before performing the icELISA, the cells were infected with SARS-CoV-2 and fixed with 4% w / v (w / v) paraformaldehyde in PBS 20 hours after infection for ELISA. The cells were permeabilized with 1 vol% Triton X-100 in PBS and blocked with 3 vol% fetal calf serum in PBS. The first antibody was then added and incubated for two hours at room temperature or overnight at 4 °C.The mixture was then incubated with a peroxidase-labeled secondary antibody for one to two hours. This was followed by a wash step with 0.05 vol% Tween-20 in PBS. To visualize the enzyme reaction, tetramethylbenzidine was added as a substrate. The reaction was stopped with 0.5 M HCl before the absorbance was determined using a microtiter plate reader and evaluated with appropriate software.

[0118] The icELISA results obtained for the two approaches with Caco-2 cells are shown in the Figures 2A and 2B The results with Vero E6 cells are shown in the Figures 3A and 3B shown.

[0119] The ELISA was used to quantify the amount of virus in the cells. For this purpose, the viral load measured in untreated cells was set at 100% as the reference value in the subsequent analysis. The percentage change in the viral load compared to the reference value for untreated cells with the different compounds at different concentrations was determined.

[0120] In Fig. 2A and 2B The mean values ​​from three independent experiments with SARS-CoV-2-infected Caco-2 cells are shown. Fig. 2A as well as Fig. 2BIt can be seen that all compounds achieved a significant reduction in viral load in the treated cells compared to untreated cells. Particularly good results were achieved with compounds (VIII-A) and (IV-B). For compound (IV-B), even at the highest dilution, i.e., the lowest active ingredient concentration, a reduction in viral load of 50% and 40%, respectively, was still achieved. The best results in terms of viral load reduction were achieved overall with compound (VIII-A) at a dilution of 1 / 500 (see table above).

[0121] Similar observations were made in the icELISA results with SARS-CoV-2-infected Vero E6 cells (see Fig. 3A and Fig. 3B). Here, too, the greatest reduction in viral load was achieved with compound (VIII-A). Compounds (VI-A) and (IV-B) also showed significant reductions in viral load following treatment in Vero E6 cells.

[0122] The icELISA results show that the diphenyl derivatives or triazenes used according to the invention lead overall to a significant reduction in the SARS-CoV-2 viral load in infected cells.

[0123] Overall, the diphenyl derivatives or triazenes according to the invention therefore represent a promising starting point for use as therapeutic agents for the treatment of viral diseases, in particular viral diseases caused by corona viruses. Conclusion and outlook

[0124] Given that the infection pathways of different viruses and the mechanisms by which different viruses infect human cells in particular are sometimes similar, it can be assumed that the diphenyl derivatives or triazenes according to the invention are suitable not only for the treatment of coronavirus infections, but also for the treatment of infections with other types of viruses, in particular RNA viruses. In particular, the diphenyl derivatives or triazenes according to the invention also appear to be a suitable starting point for the treatment of HIV infections. Initial efficacy of the compounds (VI-A), (VIII-A), (IV-A), and (IV-B) according to the invention was determined using the EASY-HIT assay. An initial inhibitory effect on HIV viruses has already been observed.

Claims

1. Diphenyl derivative for use in the prophylactic and / or therapeutic treatment of viral diseases, in particular corona infections, especially COVID-19, wherein the diphenyl derivative is a diphenyl derivative according to formula (IV-A1) or (IV-A2) below: wherein: Met' denotes a monovalent metal ion, in particular an alkali metal ion, preferably a sodium ion, and Met" denotes a divalent metal ion, in particular an alkaline earth metal ion; or wherein the diphenyl derivative is a diphenyl derivative according to the following formula (IV-A3): or wherein the diphenyl derivative is a diphenyl derivative according to formula (IV-A) below and salts thereof: or wherein the diphenyl derivative is a diphenyl derivative according to the following formulae (IV-B) and salts thereof: or wherein the diphenyl derivative is a diphenyl derivative according to the following formula (VI-A) and salts thereof: or wherein the diphenyl derivative is a diphenyl derivative according to the following formula (VIII-A) and salts thereof:

2. A drug or medicament for use in the prophylactic and / or therapeutic treatment of viral diseases, in particular corona infections, in particular COVID 19, in particular antiviral agents, comprising at least one diphenyl derivative as defined in claim 1, together with a pharmaceutically acceptable carrier or excipient.

3. A diphenyl derivative for use according to claim 1 or a drug or medicament for use according to claim 2, wherein the diphenyl derivative, in particular the drug or medicament, is applied systemically and / or wherein the diphenyl derivative, in particular the drug or medicament, is used or applied together with at least one further active ingredient, in particular selected from anti-inflammatory active ingredients, in particular corticosteroids, blood-thinning active ingredients, antiviral active ingredients and combinations thereof.

4. Pharmaceutical combination for use in the prophylactic and / or therapeutic treatment of viral diseases, in particular corona infections, in particular COVID-19, comprising (A) at least one diphenyl derivative as defined in claim 1; and (B) at least one further active ingredient selected from anti-inflammatory active ingredients, in particular corticosteroids, blood-thinning active ingredients, antiviral active ingredients and combinations thereof.

5. Pharmaceutical combination for use according to claim 4, wherein the diphenyl derivative, in particular the drug or medication, is applied systemically.

6. Diphenyl derivative for use according to claim 1, drug or medicament for use according to claim 2 or pharmaceutical combination for use according to claim 4 or 5, wherein the viral diseases are selected from the group of corona infections, such as MERS and SARS, in particular COVID-19, HIV infections, influenza, parainfluenza, cytomegalovirus infections (HCMV infections), papillomavirus infections (HPV infections), viral hepatitis (viral hepatitis), enterovirus infections, Epstein-Barr virus infections, herpes virus infections, varicella virus infections, in particular varicella zoster virus infections, adenovirus infections, rotavirus infections, yellow fever virus infections, viral haemorrhagic fever (VHF), TBE virus infections, West Nile virus infections, Ebola virus infections, rabies, Marburg virus infections, hantavirus infections, Lassa virus infections, dengue virus infections, arena virus infections, arbovirus infections, Coxsackie virus infections, measles, mumps, rubella and rubella virus infections and poliovirus infections, preferably from the group of corona infections, in particular COVID-19, HIV infections, influenza, parainfluenza, cytomegalovirus infections (HCMV infections), papillomavirus infections (HPV infections) and viral hepatitis (viral hepatitis), particularly preferably from the group of corona infections, in particular COVID-19.