5-amino-2,3-dihydro-1,4-phthalazinedione for the treatment of infections with an RNA virus

Abstract

The present application relates to the use of 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts in the prevention or treatment of an infection with an RNA virus. In particular, the invention relates to the use of 5-amino-2,3-dihydro-1,4- phthalazinedione sodium salt for said purposes. Pharmaceutical compositions, combinations and advantageous formulation techniques are disclosed.

Description

[0001] 5-amino-2,3-dihydro-1 ,4-phthalazinedione for the treatment of infections with an RNA virus

[0002] The present application relates to the use of 5-amino-2,3-dihydro-1 ,4-phthalazinedione or one of its pharmaceutically acceptable salts in the prevention or treatment of an infection with an RNA virus. In particular, the invention relates to the use of 5-amino-2,3-dihydro-1 ,4- phthalazinedione sodium salt for said purposes. Pharmaceutical compositions, combinations and advantageous formulation techniques are disclosed.

[0003] BACKGROUND OF THE INVENTION

[0004] RNA viruses build a major group of viruses. They have ribonucleic acid (RNA) as their genetic material. Most RNA viruses possess a single-stranded RNA (ssRNA), but some are double-stranded (dsRNA). Many human-pathogenic viral infections are due to RNA viruses e.g., rhinitis, influenza, HRSV, SARS-CoV, SARS-CoV-2, MERS, Dengue fever, West Nile fever, Ebola, rabies, polio, mumps and measles.

[0005] These viral infections are either treated symptomatically or with a virostatic drug. Virostatics, however, display usually an efficacy against one or more specific virus families or species. Moreover, RNA viruses are known to have a high mutation rate (approximately 10-6to 10’4s / n / c) due mainly to their lack of exonuclease proofreading activity displayed by their RNA polymerases (cf. Steinhauer et al. (1992) Gene 122: 281-288). As most virostatic drugs act on a viral target they are at risk to lose their efficacy over time when the genetic drift of a virus starts to escape the actions of a virostatic. Therefore, it would be desirable to have a broad-spectrum anti-RNA-viral pharmaceutically active agent at hand that acts on targets of the host cells which are much less likely to undergo mutations.

[0006] End of 2019 beginning of 2020 the SARS-CoV-2 pandemic started to spread all over the world causing up to 20 million casualties (WHO estimate from May 2023). Before the development of anti-SARS-CoV-2 vaccines and the establishment of pharmaceutic treatment regimes, the infected patients with a severe, potentially life-threatening manifestation of COVID-19 could only be treated symptomatically. There was no effective antiviral drug available to tackle this new and overwhelming challenge of mankind. A favored hypothesis is that SARS-CoV-2 arose from a zoonosis. It is generally believed that such an event can occur any time again, confronting mankind with an uncontrollable novel virus. This may also occur by malicious mutations of hitherto harmless viruses, or even by gain-of-function modified viruses that would be released by accident or intentionally. This situation increased the scientific awareness to develop drugs that may combat such novel virus threats immediately from the beginning of a pandemic, independently from the novel virus species. This goal can be mainly achieved by a drug that acts on host cell targets.

[0007] Further, it would be desirable that such a drug can be given prophylactically. A prerequisite for a prophylactic use is that such a drug has no or only mild adverse side effects.

[0008] Surprisingly, this task is solved by the administration of 5-amino-2,3-dihydro-1 ,4- phthalazinedione or one of its pharmaceutically acceptable salts or solvates, hydrates, crystalline polymorphs, tautomers or isotopically enriched forms thereof. It was found that 5- amino-2,3-dihydro-1 ,4-phthalazinedione or one of its pharmaceutically acceptable salts is able to modify gene expression in host cells in such a way that the inborn defense mechanism of the affected organism is boosted in such a way that the replication of virtually all RNA viruses can be effectively and specifically suppressed.

[0009] In WO 2021 / 249667 Applicant disclosed the efficacy of 5-amino-2,3-dihydro-1 ,4- phthalazinedione or one of its pharmaceutically acceptable salts in suppressing the replication of coronaviruses, more specifically of SARS-CoV-2. The beforementioned general mechanism of action against RNA virus replication was not recognized therein nor in the state-of-the-art since then. Thus, the present disclosure does expressly not refer to coronaviruses, they are disclaimed.

[0010] Thus, the present application discloses 5-amino-2,3-dihydro-1 ,4-phthalazinedione or one of its pharmaceutically acceptable salts for use in the prophylaxis or treatment of an infection with an RNA virus, with the proviso that said infection with an RNA virus does not include a coronaviral infection.

[0011] DESCRIPTION OF THE INVENTION

[0012] 5-amino-2,3-dihydro-1 ,4-phthalazinedione (luminol) belongs to the pharmaceutical class of the phthalazinediones. Compounds of this class are known for their beneficial antiinflammatory action. 5-amino-2,3-dihydro-1 ,4-phthalazinedione is also known under the name luminol. Luminol has excellent chemiluminescent properties. It is widely applied in diagnostic assays as a detection means and in forensic medicine, for example for tracing blood spots. In medicine, 5-amino-2,3-dihydro-1 ,4-phthalazinedione has been developed in the form of a sodium salt. In some countries it is approved for a broad range of acute and chronic inflammatory disorders, including a.o. acute infections of bacterial and viral origin, particularly of the intestinal tract, gastroenteritis, inflammations such as prostatitis, endometriosis, throat inflammation, bronchial asthma, pneumonia, periodontitis, pyelonephritis and autoimmune diseases such as Crohn’s disease, ulcerative colitis, lupus erythematosus and scleroderma. 5-amino-2,3-dihydro-1,4-phthalazinedione could effectively prevent cytokine storms caused by excessive immune reactions. Further, there is still a long list of indications in scientific and patent literature in the treatment of which 5-amino-2,3- dihydro-1 ,4-phthalazinedione sodium salt was allegedly tested or a beneficial use was suggested (cf. WO 2004 / 041169; WO 2007 / 018546; WO 2012 / 127441; WO 2016 / 096143; WO 2017 / 202496; WO 2018 / 082814, a.o.).

[0013] While most conventional immunomodulatory drugs show serious adverse reactions, or are at least problematic in long-term treatment, 5-amino-2,3-dihydro-1 ,4-phthalazinedione and its pharmaceutically acceptable salts are well tolerated and have a high safety margin with respect to administered dosages.

[0014] To ensure a better solubility and bioavailability pharmaceutically acceptable salts of 5-amino- 2,3-dihydro-1 ,4-phthalazinedione are used. Sodium, potassium and lithium salts have been described for therapeutic applications (cf. WO 2010 / 082858). Crystal structures for lithium, sodium, potassium, rubidium and cesium salts were described in Guzei et al. (2013) Journal of Coordination Chemistry 66, 3722-3739. Thus, the present patent application refers also to the use of all pharmaceutically acceptable salts of 5-amino-2,3-dihydro-1 ,4-phthalazinedione.

[0015] In another aspect the present application refers to 5-amino-2,3-dihydro-1 ,4-phthalazinedione or one of its pharmaceutically acceptable salts for use in the reduction or inhibition of the replication of an infection with an RNA virus in a human, with the proviso that said infection with an RNA virus does not include a coronaviral infection.

[0016] In another aspect the present application refers to 5-amino-2,3-dihydro-1 ,4-phthalazinedione or one of its pharmaceutically acceptable salts for use in the reduction of the viral load of an RNA virus in a human, with the proviso that said infection with an RNA virus does not include a coronaviral infection.

[0017] In another aspect the present application refers to 5-amino-2,3-dihydro-1 ,4-phthalazinedione or one of its pharmaceutically acceptable salts for use in the prophylaxis or treatment of an RNA virus infection in a human, with the proviso that said infection with an RNA virus does not include a coronaviral infection, wherein said human shows mild RNA virus infection- related symptoms and is not in need of hospitalization.

[0018] In another aspect the present application refers to 5-amino-2,3-dihydro-1 ,4-phthalazinedione or one of its pharmaceutically acceptable salts for use in the treatment of an RNA virus infection in a human, with the proviso that said infection with an RNA virus does not include a coronaviral infection, wherein said human shows severe RNA virus infection-related symptoms and is in need of hospitalization. In another aspect the present application refers to 5-amino-2,3-dihydro-1 ,4-phthalazinedione or one of its pharmaceutically acceptable salts for use in the treatment of an RNA virus infection in a human, with the proviso that said infection with an RNA virus does not include a coronaviral infection, wherein said human shows severe RNA virus infection-related symptoms and is undergoing acute lung injury.

[0019] In particular, the present application discloses 5-amino-2,3-dihydro-1 ,4-phthalazinedione or one of its pharmaceutically acceptable salts for use in the prophylaxis or treatment of an RNA virus infection in a human, with the proviso that said infection with an RNA virus does not include a coronaviral infection, wherein the pharmaceutically acceptable salt of 5-amino-

[0020] 2.3-dihydro-1 ,4-phthalazinedione is 5-amino-2,3-dihydro-1 ,4-phthalazinedione sodium salt.

[0021] In another aspect the present application refers to 5-amino-2,3-dihydro-1 ,4-phthalazinedione or one of its pharmaceutically acceptable salts for use in the reduction or inhibition of the replication of an RNA virus in a human, with the proviso that said infection with an RNA virus does not include a coronaviral infection,, wherein the pharmaceutically acceptable salt of 5- amino-2,3-dihydro-1 ,4-phthalazinedione is 5-amino-2,3-dihydro-1 ,4-phthalazinedione sodium salt.

[0022] In another aspect the present application refers to 5-amino-2,3-dihydro-1 ,4-phthalazinedione or one of its pharmaceutically acceptable salts for use in the reduction of the viral load of an RNA virus in a human, with the proviso that said infection with an RNA virus does not include a coronaviral infection, wherein the pharmaceutically acceptable salt of 5-amino-2,3-dihydro-

[0023] 1 .4-phthalazinedione is 5-amino-2,3-dihydro-1 ,4-phthalazinedione sodium salt.

[0024] In another aspect the present application refers to 5-amino-2,3-dihydro-1 ,4-phthalazinedione or one of its pharmaceutically acceptable salts for use in the prophylaxis or treatment of an RNA virus infection in a human, with the proviso that said infection with an RNA virus does not include a coronaviral infection, wherein the pharmaceutically acceptable salt of 5-amino-

[0025] 2.3-dihydro-1 ,4-phthalazinedione is 5-amino-2,3-dihydro-1 ,4-phthalazinedione sodium salt and said human shows mild RNA virus-infection related symptoms and is not in need of hospitalization.

[0026] In another aspect the present application refers to 5-amino-2,3-dihydro-1 ,4-phthalazinedione or one of its pharmaceutically acceptable salts for use in the treatment of an RNA virus infection in a human, with the proviso that said infection with an RNA virus does not include a coronaviral infection, wherein the pharmaceutically acceptable salt of 5-amino-2,3-dihydro-

[0027] 1 .4-phthalazinedione is 5-amino-2,3-dihydro-1 ,4-phthalazinedione sodium salt and said human shows severe RNA virus -infection related symptoms and is in need of hospitalization. In another aspect the present application refers to 5-amino-2,3-dihydro-1 ,4-phthalazinedione or one of its pharmaceutically acceptable salts for use in the treatment of an RNA virus infection in a human, with the proviso that said infection with an RNA virus does not include a coronaviral infection, wherein the pharmaceutically acceptable salt of 5-amino-2,3-dihydro- 1 ,4-phthalazinedione is 5-amino-2,3-dihydro-1 ,4-phthalazinedione sodium salt and said human shows severe an RNA virus-infection related symptoms and is undergoing acute lung injury.

[0028] 5-amino-2,3-dihydro-1 ,4-phthalazinedione is often used as a hydrate, for example as sodium salt dihydrate. Thus, the present patent application refers also to the use of all hydrates and other solvates of 5-amino-2,3-dihydro-1 ,4-phthalazinedione and its pharmaceutically acceptable salts. 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts may build complexes with suitable ligands. Thus, the present patent application refers also to such complexes. In the scope of the present disclosure all hydrates and solvates shall be included in the term “5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts”.

[0029] In order to ensure a reproducible and standardized API production and to provide improved stability features of an active agent anhydrous formulations are often preferred. Anhydrate forms of 5-amino-2,3-dihydro-1 ,4-phthalazinedione sodium salt have been described as crystalline polymorphs in WO 2011 / 107295 (Form I, Form II) and WO 2016 / 096143 (Form III). These crystalline polymorphs are virtually free from phase impurities and were characterized by means of X-ray powder diffraction. This method yields a set of characteristic d-values indicating interplanar spacings [A] and of the corresponding 2-theta (26) angles [°] under which Bragg reflections occur. This yields a unique and unambiguous fingerprint of the respective polymorphs.

[0030] For Form I the following values were determined: d values: 13.5; 6.9; 5.2; 4.6; 3.9; 3.5; 3.4; 3.3; 3.1; 3.0 and / or

[0031] 2-theta values: 6.5; 12.7; 16.9; 19.3; 22.8; 25.8; 26.6; 27.2; 28.7; 30.3.

[0032] Form II is characterized by the following values: d values: 12.9; 7.9; 7.1 ; 6.5; 5.3; 4.0; 3.7; 3.6; 3.3; 3.2 and / or

[0033] 2-theta values: 6.8; 11.2; 12.5; 13.7; 16.7; 22.4; 24.3; 24.9; 27.2; 27.8.

[0034] Form III yielded the following values: d values: 13.131; 7.987; 7.186; 6.566; 6.512; 5.372; 3.994; 3.662; 3.406; 3.288; 3.283;

[0035] 3.222; 3.215; 3.127; 2.889 and / or 2-theta values: 6.73; 11.07; 12.31 ; 13.48; 13.59; 16.49; 22.24; 24.29; 26.14; 27.10; 27.14; 27.67; 27.72; 28.52; 30.93.

[0036] The use of anhydrous Form I of 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt is preferred.

[0037] In a murine COPD model, an ex vivo lung was exposed to cigarette smoke. The application of 5-amino-2,3-dihydro-1 ,4-phthalazinedione sodium salt Form I led to a nearly complete reduction of 3-nitrotyrosine. Therefore it is assumed that 5-amino-2,3-dihydro-1,4- phthalazinedione sodium salt may protect the lung from oxidative and nitrosative stress which are major players in the pathophysiology of COPD and other inflammatory pulmonary diseases (https: / / copdnewstoday.com / 2020 / 04 / 16 / mp1032-may-protect-lungs-from-oxidative- stress-inhibit-biomarker-3-nitrotyrosine-preclinical-study / , as of 2021-03-03).

[0038] 5-amino-2,3-dihydro-1,4-phthalazinedione itself shows also polymorphism. A Form I (Paradies (1992) Ber. Bunsen-Ges. Phys. Chem 96 1027-1031 ) and a Form II (WO 2017 / 140430) have been disclosed.

[0039] WO 2017 / 140430 discloses also that 5-amino-2,3-dihydro-1 ,4-phthalazinedione has a great potential in the immunomodulatory treatment of inflammatory and autoimmune diseases. Crystalline Form II is particularly useful in the treatment of inflammatory and autoimmune respiratory diseases such as upper and lower respiratory tract infections.

[0040] Thus, the present patent application refers also to the use according to the invention of all crystalline forms and polymorphs thereof of 5-amino-2,3-dihydro-1 ,4-phthalazinedione and its pharmaceutically acceptable salts. The use of Form II of 5-amino-2,3-dihydro-1 ,4- phthalazinedione is preferred.

[0041] Similar therapeutic effects are known for a variety of phthalazinediones, respectively of derivatives of 5-amino-2,3-dihydro-1 ,4-phthalazinedione and its pharmaceutically acceptable salts. An example is 6-amino-2,3-dihydrophthalazine-1 ,4-dione (isoluminol). An overview of suitable phthalazinediones is given in WO 2007 / 018546. It is reasonable to assume that these compounds show comparable effects when being used for the therapeutic applications according to the invention.

[0042] In EP 0 531 370 A1 the use of a PARP (poly(ADP-ribose) polymerase) inhibitor such as luminol is disclosed for the treatment of a viral infection in which the virus DNA is integrated into a host chromosome during the replication cycle. The virus is preferably a retrovirus such as HIV. RNA viruses, however, cannot integrate into the human DNA. Therefore EP 0 531 370 A1 does not suggest the use of 5-amino-2,3-dihydro-1 ,4-phthalazinedione or one of its pharmaceutically acceptable salts for the use in the treatment of an RNA virus infection. Tautomerism relates to a rapid intraconversion of organic compounds in which a hydrogen atom or proton formally migrates inside the compound. This is accompanied by a switch of a single bond and adjacent double bond. The single forms are called tautomers. For example, keto-enol tautomerism occurs in 5-amino-2,3-dihydro-1 ,4-phthalazinedione (Proescher and Moody (1939) J Lab Clin Med, 1183-1189). Thus, the present patent application refers also to the use of all tautomers of 5-amino-2,3-dihydro-1 ,4-phthalazinedione and its pharmaceutically acceptable salts.

[0043] As used throughout the present application the term “5-amino-2,3-dihydro-1 ,4- phthalazinedione or one of its pharmaceutically acceptable salts” shall encompass all the aforementioned molecular variants of 5-amino-2,3-dihydro-1 ,4-phthalazinedione, i.e. 5- amino-2,3-dihydro-1 ,4-phthalazinedione or one of its pharmaceutically acceptable salts or solvates, hydrates, crystalline polymorphs, tautomers or isotopically enriched forms thereof.

[0044] A virus is a submicroscopic infectious agent that replicates only inside the living cells of an organism. Viruses can infect all life forms such as animals, plants and bacteria. When infected, a host cell is often forced to rapidly produce thousands of copies of the original virus. When not inside an infected cell or in the process of infecting a cell, viruses exist in the form of independent viral particles, or virions, consisting of (i) genetic material, i.e., long molecules of DNA or RNA that encode the structure of the proteins by which the virus acts; (ii) a protein coat, the capsid, which surrounds and protects the genetic material; and in some cases (iii) an outside envelope of lipids. The shapes of these virus particles range from simple helical and icosahedral forms to more complex structures.

[0045] An RNA virus is a virus - other than a retrovirus - that has ribonucleic acid (RNA) as its genetic material. RNA viruses can have single-stranded RNA (ssRNA) or double-stranded RNA (dsRNA).

[0046] RNA viruses are a very broad realm of viruses. They can affect humans, other animals and plants. By unfavorable mutations such RNA viruses from animals and plants can become pathogenic in humans in the future. It can be reasonably assumed that such mutations will not affect the underlying mechanism of action of 5-amino-2,3-dihydro-1 ,4-phthalazinedione or its pharmaceutically acceptable salts. Therefore, the present disclosure refers to all known RNA virus families. In particular, the present disclosure refers to 5-amino-2,3-dihydro-1 ,4- phthalazinedione or one of its pharmaceutically acceptable salts for use in the prophylaxis or treatment of an infection with an RNA virus, with the proviso that said infection with an RNA virus does not include a coronaviral infection, wherein said infection with an RNA virus is selected from an infection with a virus from a virus family consisting of chrysoviridae, megabirnaviridae, quadriviridae, totiviridae, sedoreoviridae, spinareoviridae, cystoviridae, amalgaviridae, curvulaviridae, fusariviridae, hypoviridae, partitiviridae, picobirnaviridae, hadakaviridae, birnaviridae, permutotetraviridae, botybirnaviridae, polymycoviridae, alphatetraviridae, benyviridae, hepeviridae, matonaviridae, bromoviridae, closteroviridae, endornaviridae, kitaviridae, mayoviridae, togaviridae, virgaviridae, alphaflexiviridae, betaflexiviridae, gammaflexiviridae, deltaflexiviridae, tymoviridae, flaviviridae, noaviridae, sinhalaviridae, carmotetraviridae, tombusviridae, narnaviridae, mitoviridae, Atkinsviridae, Duinviridae, Fiersviridae, solspiviridae, Blumeviridae, Steitzviridae, botourmiaviridae, hypoviridae, abyssoviridae, arteriviridae, cremagaviridae, gresnaviridae, olifoviridae, medioniviridae, mesoniviridae, hexponiviridae, mononiviridae, Nanghoshaviridae, euroniviridae, roniviridae, tobaniviridae, caliciviridae, dlcistroviridae, iflaviridae, marnaviridae, picornaviridae, polycipiviridae, secoviridae, solinviviridae, alvernaviridae, barnaviridae, solemoviridae, potyviridae, astroviridae, Yadokariviridae, Hadakaviridae, sarthroviridae, qinviridae, aspiviridae, aliusviridae, chuviridae, crepuscuviridae, myriaviridae, natareviridae, artoviridae, bornaviridae, filoviridae, lispiviridae, mymonaviridae, nyamiviridae, paramyxoviridae, pneumoviridae, rhabdoviridae, sunviridae, xinmoviridae, Yueviridae, arenaviridae, cruliviridae, discoviridae, hantaviridae, leishbuviridae, mypoviridae, nairovipridae, peribunyaviridae, phasmaviridae, phenuiviridae, tospoviridade, wupedeviridae, lincruviridae, amnoonviridae, orthomyxoviridae, kolmioviridae.

[0047] Particularly preferred is a use of 5-amino-2,3-dihydro-1 ,4-phthalazinedione or one of its pharmaceutically acceptable salts in the prophylaxis or treatment of an infection with an RNA virus, wherein the RNA virus is highly pathogenic in humans and / or is widely spread among mankind.

[0048] Such RNA viruses are in particular:

[0049] - Orthomyxoviridae (single-stranded negative-sense RNA viruses). This family includes i.a., influenza viruses.

[0050] Influenza virus families pathogenic in humans and other vertebrates are Alphainfluenzavirus (species: Influenzavirus A; IVA; IAV), Betainfluenzavirus (species: Influenzavirus B; IVB;

[0051] IBV), Gammainfluenzavirus (species: Influenzavirus C; IVC; ICV), Deltainfluenzavirus (species: Influenzavirus D; IVD, IDV). For pathologic infections in humans IVA and IVB are of particular concern.

[0052] IAV subtypes are categorized according to their specific serotypes hemagglutinin (H) and neuraminidase (N). The most important hemagglutinin serotypes are H1, H2, H3, H5, H7 and H9. The most important neuraminidase serotypes are N1 , N2 and N7. The most important IAV subtypes are thus H1 N1 (e.g., Spanish influenza, Russian influenza; Swine influenza), H2N2 (e.g., Asian influenza), H3N2 (e.g., Hong Kong influenza), H5N1 (e.g., Avian flu), H7N9 (e.g., Avian influenza). In the scope of the present disclosure the term IAV shall thus encompass all these subtypes. The most important IBV subtypes are B / Victoria lineage, B / Yamagata lineage, B / Yamaguchi lineage, B / Yokohama lineage, B / Yunnan lineage, B / Zhuhai lineage. In the scope of the present disclosure the term IBV shall thus encompass all these subtypes.

[0053] ICV subtypes differ only in an insignificantly. ICV affects mostly humans and porcines. In children ICV causes a rather harmless flu.

[0054] IDV is rather similar to ICV and infects mainly bovines and porcines. Two subtypes are known.

[0055] Picornaviridae (non-enveloped single-stranded positive sense RNA viruses).

[0056] Notable examples are enterovirus (incl. rhinoviruses (RVs) and poliovirus (PV)), aphthovirus, cardiovirus and hepatovirus.

[0057] - Pneumoviridae (single-stranded negative sense RNA viruses).

[0058] Notable examples are human respiratory syncytial virus (HRSV, also RSV), bovine respiratory syncytial virus (BRSV) and human metapneumovirus (HMPV).

[0059] HRSV has mainly two subtypes A and B and can infect the upper airways and cause a cold (rhinitis, cough, acute bronchitis, otitis media).

[0060] Hepeviridae (non-enveloped single-stranded positive sense RNA viruses).

[0061] Notable examples are hepevirus and hepatitis E virus (HEV).

[0062] - Reoviridae (non-enveloped double-stranded RNA viruses).

[0063] A notable example is Rotavirus (RoV; species A, B, C, D, E, F, G, H, I, J) which causes diarrheal disease in infants and young children.

[0064] - Togaviridae (enveloped single-stranded positive sense RNA viruses).

[0065] A notable example is Rubella virus (RuV) which causes rubella.

[0066] Flaviviridae (enveloped single-stranded positive sense RNA viruses).

[0067] Notable examples are tick-borne encephalitis virus (TBEV), Japanese encephalitis virus (JEV), Zika virus (ZIKV), Yellow fever virus (YFV), West Nile virus (WNV) and Dengue virus (DENV).

[0068] Arenaviridae (enveloped single-stranded ambisense RNA viruses)

[0069] A notable example is Lassa mammarenavirus (LASV) which causes Lassa fever.

[0070] Filoviridae (enveloped single-stranded positive sense RNA viruses) Notable examples are Zaire ebolavirus (EBOV) which causes Ebola and Marburg Marburgvirus (MARV) which causes hemorrhagic fever.

[0071] - Hantaviridae (enveloped single-stranded mostly negative sense RNA viruses).

[0072] Notable examples are Hantaan virus (HTNV), Puumala virus (PUUV), Dobrava-Belgrade virus (DOBV), Seoul virus (SEOV), Sin nombre virus (SNV) and Andes virus (ANDV).

[0073] Rhabdoviridae (enveloped single-stranded negative sense RNA viruses).

[0074] A notable example is Rabies lyssavirus (RABV) which causes rabies.

[0075] In a preferred embodiment, the present disclosure refers to 5-amino-2,3-dihydro-1 ,4- phthalazinedione or one of its pharmaceutically acceptable salts for use in the prophylaxis or treatment of an infection with an RNA virus, with the proviso that said infection with an RNA virus does not include a coronaviral infection, wherein said infection with an RNA virus is selected from the group comprising the viral families of orthomyxoviridae, picornaviridae, pneumoviridae, hepeviridae, reoviridae, togaviridae, flaviviridae, arenaviridae, filoviridae, hantaviridae and rhabdoviridae.

[0076] In a preferred embodiment, the present disclosure refers to 5-amino-2,3-dihydro-1 ,4- phthalazinedione or one of its pharmaceutically acceptable salts for use in the reduction or inhibition of the replication of an RNA virus, with the proviso that said infection with an RNA virus does not include a coronaviral infection, wherein said infection with an RNA virus is selected from the group comprising the viral families of orthomyxoviridae, picornaviridae, pneumoviridae, hepeviridae, reoviridae, togaviridae, flaviviridae, arenaviridae, filoviridae, hantaviridae and rhabdoviridae.

[0077] In a preferred embodiment, the present disclosure refers to 5-amino-2,3-dihydro-1 ,4- phthalazinedione or one of its pharmaceutically acceptable salts for use in the reduction of the viral load of an RNA virus, with the proviso that said infection with an RNA virus does not include a coronaviral infection, wherein said infection with an RNA virus is selected from the group comprising the viral families of orthomyxoviridae, picornaviridae, pneumoviridae, hepeviridae, reoviridae, togaviridae, flaviviridae, arenaviridae, filoviridae, hantaviridae and rhabdoviridae.

[0078] In a preferred embodiment, the present disclosure refers to 5-amino-2,3-dihydro-1 ,4- phthalazinedione or one of its pharmaceutically acceptable salts for use in the reduction of the viral load of an RNA virus, with the proviso that said infection with an RNA virus does not include a coronaviral infection, wherein said human shows mild RNA virus infection-related symptoms, is not in need of hospitalization and said infection with an RNA virus is selected from the group comprising the viral families of orthomyxoviridae, picornaviridae, pneumoviridae, hepeviridae, reoviridae, togaviridae, flaviviridae, arenaviridae, filoviridae, hantaviridae and rhabdoviridae.

[0079] In a preferred embodiment, the present disclosure refers to 5-amino-2,3-dihydro-1 ,4- phthalazinedione or one of its pharmaceutically acceptable salts for use in the reduction of the viral load of an RNA virus, with the proviso that said infection with an RNA virus does not include a coronaviral infection, wherein said human shows severe RNA virus infection- related symptoms, is in need of hospitalization and said infection with an RNA virus is selected from the group comprising the viral families of orthomyxoviridae, picornaviridae, pneumoviridae, hepeviridae, reoviridae, togaviridae, flaviviridae, arenaviridae, filoviridae, hantaviridae and rhabdoviridae.

[0080] In a preferred embodiment, the present disclosure refers to 5-amino-2,3-dihydro-1 ,4- phthalazinedione or one of its pharmaceutically acceptable salts for use in the prophylaxis or treatment of an infection with an RNA virus, wherein said infection with an RNA virus is selected from the group comprising an infection with IAV, IBV, ICV, IDV, RVs, PV, HRSV, HMPV, HEV, RoV, RuV, TBEV, JEV, ZIKV, YFV, WNV, DENV, LASV, EBOV, MARV, HTNV, PUUV, DOBV, SEOV, SNV, ANDV and RABV.

[0081] In a preferred embodiment, the present disclosure refers to 5-amino-2,3-dihydro-1 ,4- phthalazinedione or one of its pharmaceutically acceptable salts for use in the reduction or inhibition of the replication of an RNA virus, wherein said infection with an RNA virus is selected from the group comprising an infection with IAV, IBV, ICV, IDV, RVs, PV, HRSV, HMPV, HEV, RoV, RuV, TBEV, JEV, ZIKV, YFV, WNV, DENV, LASV, EBOV, MARV, HTNV, PUUV, DOBV, SEOV, SNV, ANDV and RABV.

[0082] In a preferred embodiment, the present disclosure refers to 5-amino-2,3-dihydro-1 ,4- phthalazinedione or one of its pharmaceutically acceptable salts for use in the reduction of the viral load of an RNA virus, wherein said infection with an RNA virus is selected from the group comprising an infection with IAV, IBV, ICV, IDV, RVs, PV, HRSV, HMPV, HEV, RoV, RuV, TBEV, JEV, ZIKV, YFV, WNV, DENV, LASV, EBOV, MARV, HTNV, PUUV, DOBV, SEOV, SNV, ANDV and RABV.

[0083] In a preferred embodiment, the present disclosure refers to 5-amino-2,3-dihydro-1 ,4- phthalazinedione or one of its pharmaceutically acceptable salts for use in the reduction of the viral load of an RNA virus, wherein said human shows mild RNA virus infection-related symptoms, is not in need of hospitalization and said infection with an RNA virus is selected from the group comprising an infection with IAV, IBV, ICV, IDV, RVs, PV, HRSV, HMPV, HEV, RoV, RuV, TBEV, JEV, ZIKV, YFV, WNV, DENV, LASV, EBOV, MARV, HTNV, PUUV, DOBV, SEOV, SNV, ANDV and RABV. In a preferred embodiment, the present disclosure refers to 5-amino-2,3-dihydro-1 ,4- phthalazinedione or one of its pharmaceutically acceptable salts for use in the reduction of the viral load of an RNA virus, wherein said human shows severe RNA virus infection-related symptoms, is in need of hospitalization and said infection with an RNA virus is selected from the group comprising an infection with IAV, IBV, ICV, IDV, RVs, PV, HRSV, HMPV, HEV, RoV, RuV, TBEV, J EV, ZIKV, YFV, WNV, DENV, LASV, EBOV, MARV, HTNV, PUUV, DOBV, SEOV, SNV, ANDV and RABV.

[0084] In the scope of the present application the term “respiratory RNA virus” shall comprise IAV, IBV, ICV, IDV, RVs and HRSV.

[0085] In a particularly preferred embodiment, the present disclosure refers to 5-amino-2,3-dihydro-

[0086] 1 ,4-phthalazinedione or one of its pharmaceutically acceptable salts for use in the prophylaxis or treatment of an infection with a respiratory RNA virus, wherein said infection with a respiratory RNA virus is selected from the group comprising an infection with IAV, IBV, ICV and IDV.

[0087] In a particularly preferred embodiment, the present disclosure refers to 5-amino-2,3-dihydro-

[0088] 1 ,4-phthalazinedione or one of its pharmaceutically acceptable salts for use in the reduction or inhibition of the replication of a respiratory RNA virus, wherein said infection with a respiratory RNA virus is selected from the group comprising an infection with IAV, IBV, ICV and IDV.

[0089] In a particularly preferred embodiment, the present disclosure refers to 5-amino-2,3-dihydro-

[0090] 1 ,4-phthalazinedione or one of its pharmaceutically acceptable salts for use in the reduction of the viral load of a respiratory RNA virus, wherein said infection with a respiratory RNA virus is selected from the group comprising an infection with IAV, IBV, ICV and IDV.

[0091] In a particularly preferred embodiment, the present disclosure refers to 5-amino-2,3-dihydro-

[0092] 1 ,4-phthalazinedione or one of its pharmaceutically acceptable salts for use in the reduction of the viral load of a respiratory RNA virus, wherein said human shows mild RNA virus infection-related symptoms, is not in need of hospitalization and said infection with a respiratory RNA virus is selected from the group comprising an infection with IAV, IBV, ICV and IDV.

[0093] In a particularly preferred embodiment, the present disclosure refers to 5-amino-2,3-dihydro-

[0094] 1 ,4-phthalazinedione or one of its pharmaceutically acceptable salts for use in the reduction of the viral load of a respiratory RNA virus, wherein said human shows severe RNA virus Infection-related symptoms, is in need of hospitalization and said infection with a respiratory RNA virus is selected from the group comprising an infection with IAV, IBV, ICV and IDV. In a particularly preferred embodiment, the present disclosure refers to 5-amino-2,3-dihydro-

[0095] 1 ,4-phthalazinedione or one of its pharmaceutically acceptable salts for use in the prophylaxis or treatment of an infection with a respiratory RNA virus, wherein said infection with a respiratory RNA virus is selected from the group comprising an infection with HRSV.

[0096] In a particularly preferred embodiment, the present disclosure refers to 5-amino-2,3-dihydro-

[0097] 1 ,4-phthalazinedione or one of its pharmaceutically acceptable salts for use in the reduction or inhibition of the replication of a respiratory RNA virus, wherein said infection with a respiratory RNA virus is selected from the group comprising an infection HRSV.

[0098] In a particularly preferred embodiment, the present disclosure refers to 5-amino-2,3-dihydro-

[0099] 1 ,4-phthalazinedione or one of its pharmaceutically acceptable salts for use in the reduction of the viral load of a respiratory RNA virus, wherein said infection with a respiratory RNA virus is selected from the group comprising an infection with HRSV.

[0100] In a particularly preferred embodiment, the present disclosure refers to 5-amino-2,3-dihydro-

[0101] 1 ,4-phthalazinedione or one of its pharmaceutically acceptable salts for use in the reduction of the viral load of a respiratory RNA virus, wherein said human shows mild RNA virus infection-related symptoms, is not in need of hospitalization and said infection with a respiratory RNA virus is selected from the group comprising an infection with HRSV.

[0102] In a particularly preferred embodiment, the present disclosure refers to 5-amino-2,3-dihydro-

[0103] 1 ,4-phthalazinedione or one of its pharmaceutically acceptable salts for use in the reduction of the viral load of a respiratory RNA virus, wherein said human shows severe RNA virus infection-related symptoms, is in need of hospitalization and said infection with a respiratory RNA virus is selected from the group comprising an infection with HRSV.

[0104] It is most preferred that in all the beforementioned preferred and particularly preferred embodiments the pharmaceutically acceptable salt of 5-amino-2,3-dihydro-1 ,4- phthalazinedione is 5-amino-2,3-dihydro-1 ,4-phthalazinedione sodium salt.

[0105] 5-amino-2,3-dihydro-1 ,4-phthalazinedione or one of its acceptable salts can be used as monotherapy or can further be combined with at least one further active ingredient selected from a group comprising active ingredients used in disease-modifying therapies for an RNA virus infection, in symptomatic therapies of an RNA virus infection and in the treatment of comorbidities.

[0106] For an effective treatment of an RNA virus infection, it may be advantageous to provide to a patient in need thereof a combinational therapy by combining 5-amino-2,3-dihydro-1 ,4- phthalazinedione or one of its pharmaceutically acceptable salts with at least one antiviral agent. For example, from HIV, respectively anti-retroviral therapy the following classes are known:

[0107] Reverse transcriptase inhibitors suitable for such a combination therapy are nucleoside reverse transcriptase inhibitors (NRTI) and non-nucleoside reverse transcriptase inhibitors (NNRTI). Examples of NRTI include, but are not limited to, abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir, zidovudine, zalcitabine, entecavir, adefovir, elvucitabine, fosalvudine(-tidoxil), fozivudintidoxil, lagiciclovir, alamifovir, clevudine, pradefovir, telbivudine. Examples of NNRTI include, but are not limited to, efavirenz, etravirine, nevirapine, rilpivirine, delavirdine, emivirine, lersivirine.

[0108] Suitable for a combination therapy according to the invention are integrase inhibitors such as raltegravir, elvitegravir, dolutegravir, MK-2048.

[0109] Examples of HIV protease inhibitors suitable for a combination therapy according to the invention are saquinavir, indinavir, ritonavir, nelfinavir, amprenavir, lopinavir, atazanavir, fosamprenavir, tipranavir, darunavir, brecanavir, mozenavir, tipranavir.

[0110] Examples of entry inhibitors suitable for a combination therapy according to the invention are enfuvirtide and maraviroc.

[0111] Further, general virostatic agents suitable for a combination therapy according to the invention can be selected from the group comprising ancriviroc, aplaviroc, cenicriviroc, enfuvirtide, maraviroc, vicriviroc, amantadine, rimantadine, pleconaril, idoxuridine, aciclovir, brivudine, famciclovir, penciclovir, sorivudine, valaciclovir, cidofovir, ganciclovir, valganciclovir, sofosbuvir, foscarnet, ribavirine, taribavirine, filibuvir, nesbuvir, tegobuvir, fosdevirine, favipiravir, avifavir, merimepodib, asunaprevir, balapiravir, boceprivir, ciluprevir, danoprevir, daclatasvir, narlaprevir, telaprevir, simeprevir, vanipevir, rupintrivir, remdesivir, fomivirsen, amenamevir, alisporivir, bevirimat, letermovir, laninamavir, oseltamivir, peramivir, zanamivir.

[0112] General immunostimulatory agents suitable for a combination therapy according to the invention can be selected from the group comprising interferons (alpha-, beta-, gamma-, tau- interferon), interleukins, CSF, PDGF, EGF, IGF, THF, levamisol, dimepranol, inosine.

[0113] Furthermore, possible combinations according to the invention include adjuvants such as cobicistat.

[0114] Comorbidities can result from impairments due to an RNA virus infection or are independent thereof. Thus, 5-amino-2,3-dihydro-1 ,4-phthalazinedione or one of its pharmaceutically acceptable salts can be combined with at least one further active ingredient selected from a group comprising steroidal and non-steroidal anti-inflammatory drugs; immunomodulators; immunosuppressive agents; anti-infective agents like antibiotics, antiretroviral agents, antiviral agents, antifungal agents and antiprotozoal agents; analgesics; anticoagulants; antiplatelet drugs; bronchodilators; pulmonary vasodilators; mucolytic agents; pulmonary surfactants; antioxidants; ENaC-activating agents; HMG-CoA reductase inhibitors or ATi receptor antagonists for use in the prophylaxis or treatment of an RNA virus infection, with the proviso that said infection with an RNA virus does not include a coronaviral infection.

[0115] Suitable examples for such steroidal anti-inflammatory drugs comprise corticosteroids, glucocorticoids, prednisone, prednisolone, deflazacort, vamorolone, flumethasone, triamcinolone acetonide, betamethasone, dexamethasone, beclomethasone, betamethasone valerate, betamethasone dipropionate, budesonide, beclomethasone dipropionate, isoflupredone, fluocinonide, fluocinolone, methylprednisolone, halcinonide, desonide, deltasone, triamcinolone, triamcinolone acetonide, tixocortol pivalate, mometasone furoate, amcinonide, fluocortolone, halometasone, alclometasone dipropionate, prednicarbate, clobetasone-17-butyrate, clobetasol-17-propionate, fluocortolone caproate, fluocortolone pivalate, fluprednidene acetate, ciclesonide, flunisolide, fluticasone furoate, fluticasone propionate, cortisol, hydrocortisone, hydrocortisone acetate, hydrocortisone-17-valerate, hydrocortisone-17-butyrate, hydrocortisone-17-aceponate, hydrocortisone-17-buteprate, cortisone and cortisone acetate.

[0116] Suitable examples for such non-steroidal anti-inflammatory drugs (NSAIDs) comprise salicylates such as acetylsalicylic acid, salicylic acid, imidazole salicylate, magnesium salicylate, trolamine salicylate, choline magnesium trisalicylate, salsalate, diflunisal, salicylamide, carbasalate calcium, nitroaspirin, guacetisal, ethenzamide, mesalazine, sulfasalazine, olsalazine, balsalazide, benorilate, clonixin; acetic acid derivatives such as indomethacin, sulindac, tolmetin, diclofenac, etodolac, ketorolac, aceclofenac, bromfenac, nabumetone, acemetacin, proglumetacin, difenpiramide, bendazac, fentiazac, zomepirac; propionic acid derivatives such as ibuprofen, dexibuprofen, flurbiprofen, zaltaprofen, fenoprofen, pirprofen, naproxen, ketoprofen, dexketoprofen, loxoprofen, pelubiprofen, oxaprozin, tiaprofenic acid, suprofen, alminoprofen, indoprofen, pranoprofen, flunoxaprofen, ibuproxam, fenbufen; oxicam derivatives such as piroxicam, meloxicam, tenoxicam, lornoxicam, droxicam, isoxicam, alclofenac, felbinac, lonazolac; pirazolones such as phenylbutazone, aminophenazone, bumadizone, feprazone, kebuzone, nifenazone, suxibuzone, propyphenazone, oxyphenbutazone, antipyrine; fenamates such as flufenamic acid, tolfenamic acid, mefenamic acid, meclofenamic acid, flunixin; para-aminophenol derivatives such as acetaminophen (paracetamol), propacetamol; phenylpiperazine derivatives such as antrafenine; indazole derivatives such as benzydamine; triterpenoid derivatives such as betulinic acid; amide derivatives such as bufexamac; pyrimidine derivatives such as epirizole; anthranilic acid derivatives such as floctafenine; omega-3 fatty acid derivatives such as icosapent; butanoic acid derivatives such as indobufen; pyrazolone derivatives such as metamizole; flavonol derivatives such as taxifolin; selective COX-2 inhibitors such as rofecoxib, lumiracoxib, valdecoxib, parecoxib, celecoxib, etoricoxib, firocoxib, the sulfonanilide nimesulide and the phytochemical H-harpagide, LOX / COX inhibitors such as tenidap, tepoxalin and licofelone.

[0117] Suitable examples for such immunomodulators amongst others comprise thalidomide, lenalidomide, pomalidomide and apremilast.

[0118] Suitable examples for such immunosuppressive drugs comprise the groups of glucocorticoids such as listed above; cytostatic drugs such as alkylating agents (such as cyclophosphamide), antimetabolites such as methotrexate, azathioprine, mercaptopurine, fluorouracil, leflunomide, protein synthesis inhibitors and certain antibiotics such as dactinomycin, anthracyclines, mitomycin C, bleomycin and mithramycin, intercalating agents such as mitoxantrone; antibodies such as muromonab-CD3, rituximab, ustekinumab, alemtuzumab, natalizumab, basiliximab, tocilizumab and daclizumab; drugs acting on immunophilins such as ciclosporin, tacrolimus and sirolimus, non-classified immunosuppressive agents such as beta-interferon and gamma-interferon, opioids, TNF binding proteins such as infliximab, etanercept, adalimumab; or curcumin, catechins, mycophenolic acid, fingolimod, myriocin and fumaric acid dimethyl esters.

[0119] Anti-infective agents is a generic term for compounds that are useful in the treatment of bacterial, viral, fungal, and parasite infections (e.g. protozoa or worms) and comprises antibiotics, antimycotics agents, antiprotozoal agents and the aforementioned antiviral agents.

[0120] Suitable examples for such antibiotics comprise imipenem, meropenem, ertapenem, cephalosporins, aztreonam, penicillins such as penicillin G and penicillin V, piperacillin, mezlocillin, ampicillin, amoxicillin, flucloxacillin, methicillin, oxacillin, clavulanic acid, sulbactam, tazobactam, sultamicillin, fosfomycin, teicoplanin, vancomycin, bacitracin, colistin, gramicidin, polymyxin B, tyrothricin, teixobactin, fosmidomycin, amikacin, gentamicin, kanamycin, neomycin, netilmicin, streptomycin, tobramycin, chloramphenicol, fusidic acid, cethromycin, narbomycin, telithromycin, clindamycin, lincomycin, daptomycin, dalfopristin, quinupristin, azithromycin, clarithromycin, erythromycin, roxithromycin, linezolid, doxycycline, minocycline, tetracycline, oxytetracycline, tigecycline, norfloxacin, enoxacin, ciprofloxacin, ofloxacin, levofloxacin, moxifloxacin, metronidazole, tinidazole, aminocumarine, sulfadiazine, sulfadoxin, sulfamethoxazole, sulfasalazine, pyrimethamine, trimethoprim, rifampicin. Suitable examples for such antifungal (antimycotic) drugs comprise abafungin, amphotericin B, candicidin, filipin, hamycin, natamycin, nystatin, rimocidin, bifonazole, butoconazole, clotrimazole, econazole, fenticonazole, isoconazole, ketoconazole, luliconazole, miconazole, omoconazole, oxiconazole, sertaconazole, sulconazole, tioconazole, albaconazole, efinaconazole, epoxiconazole, fluconazole, isavuconazole, itraconazole, posaconazole, propiconazole, ravuconazole, terconazole, voriconazole, amorolfin, butenafine, nafitifine, terbinafine, anidulafungin, caspofungin, micafungin, benzoic acid, ciclopirox, flucytosine, griseofulvin, haloprogin, tolnaftate, undecylenic acid, crystal violet, balsam of Peru.

[0121] Suitable examples for such antiprotozoal drugs comprise metronidazole, tinidazole, ornidazole, atovaquone, clioquinol, chlorquinaldol, emetin, pentamidine isethionate, eflornithine, nitrofural, halofuginone, miltefosine, chloroquine, hydroxychloroquine, mepacrine, primaquine, amodiaquine, pamaquine, piperaquine, proguanil, cyclohunailembonate, mefloquine, pyrimethamine, artmether, artemisinin, artesunate, dihydroartemisinin, halofantrine, lumefantrine, sulfadoxine.

[0122] Suitable examples for further antiparasitic drugs comprise meglumine antimoniate, benznidazole, sodium stibogluconate, fumagillin, halofantrine, melarsoprol, nifurtimox, nitazoxanide, permethrin, lindane, malathion, carbaryl, pyrethrum, phenothrin, bio-allethrin, imidacloprid, moxidectin, nitenpyram, fipronil, pyriprol, selamectin, dimpylate, spinosad, indoxacarb, methoprene, pyriproxyfen, lufenuron, neem oil, citronella oil, clove oil, peppermint oil, eucalyptus oil.

[0123] Suitable examples for analgesics comprise the NSAIDs listed above; opioid analgesics such as morphine, fentanyl, methadone, oxycodon, carfetanyl, dihydroetorphin, ohmefentanyl, etorphin, sufentanil, remifentanil, alfentanil, buprenorphine, hydromorphone, levomethadone, hydrocodone, pintramide, nalbuphine, tapentadol, pentazocin, dihydrocodeine, codeine, pethidine, tramadol, tilidine, meptazinol, naloxone, naltrexone, diprenorphine, loperamide, apomorphine; epibatidine; scopolamine; ziconitide; cannabinoids such as tetrahydrocannabinol, cannabidiol, marinol; flupirtine; ketamine and local anesthetics listed above.

[0124] Suitable examples for such anticoagulants comprise heparins, coumarins such as phenprocoumon (marcumar) and warfarin, apixaban, rivaroxaban, edoxaban, dabigatran, ximelagatran, hirudine, lepirudine, bivalirudine, citrate, EDTA, fondaparinux, argatroban, otamixaban.

[0125] Suitable examples for such antiplatelet agents comprise abciximab, acetylsalicylic acid, dipyridamole, clopidogrel, eptifibatide, ilomedin, prostacyclin, prasugrel, ticagrelor, ticlopidine and tirofiban. Suitable bronchodilators such as beta-2 adrenergic receptor agonists comprise short-acting beta-2 agonists (SABAs) such as salbutamol, albuterol, bitolterol, fenoterol, isoprenaline, levosalbutamol, levalbuterol, orciprenaline, pirbuterol, procaterol, ritodrine and terbutaline; long-acting beta-2 agonists (LABAs) such as arformoterol, bambuterol, clenbuterol, formoterol and salmeterol; ultra-long-acting beta-2 agonists such as abediterol, carmoterol, indacaterol, olodaterol and vilanterol, alone or combined with umeclidinium bromide and / or fluticasone furoate; beta-2 agonists with unknown time of action such as isoxsuprine, mabuterol or zilpaterol.

[0126] Suitable muscarinic anticholinergics (bronchodilating M3 receptor antagonists) comprise ipratropium bromide, tiotropium bromide, oxitropium bromide, glycopyrronium bromide, aclidinium bromide, umeclidinium bromide, atropine, hyoscyamine, aclidinium bromide, 4- DAMP, darifenacin, DAU-5884, HL-031 , HL-120, J-104, J-129, procyclidine, oxybutynin, tolterodine and zamifenacin.

[0127] Further bronchodilators comprise epinephrine, ephedrine, theophylline and TSG12.

[0128] A potent pulmonary vasodilator is nitric oxide. Further suitable pulmonary vasodilators are prostacyclin (prostaglandin PGI2) analogues such as iloprost, epoprostenol and treprostinil.

[0129] Suitable mucolytic agents comprise N-acetylcysteine (NAC), ambroxol, bromhexine, carbocisteine, erdosteine, mecysteine and dornase alfa.

[0130] Suitable pulmonary surfactants comprise synthetic compositions such as Colfosceril palmitate, Pumactant, KL-4, Venticute and Lucinactant as well as animal-derived surfactants such as Beractant, Calfactant and Poractant alfa.

[0131] A potent antioxidant is inhaled carbon monoxide (CO).

[0132] Suitable ENaC (epithelium sodium channel) activating peptides comprise AP301 and S3969.

[0133] Suitable HMG-CoA reductase inhibitors (statins) comprise atorvastatin, alone or in combination with amlodipine and / or perindopril, cerivastatin, fluvastatin, lovastatin, alone or in combination with niacin, mevastatin, pitavastatin, pravastatin, rosuvastatin, alone or in combination with ezetimibe, simvastatin, alone or in combination with ezetimibe or niacin.

[0134] Suitable AT1 antagonists (angiotensin II receptor blockers; sartans) comprise losartan, valsartan, candesartan, telmisartan, irbesartan, olmesartan, eprosartan, fimasartan, azilsartan, milfasartan, pomisartan, pratosartan, ripisartan, tasosartan, saprosartan and EXP 3174.

[0135] 5-amino-2,3-dihydro-1 ,4-phthalazinedione or one of its pharmaceutically acceptable salts and the further active ingredient can be used simultaneously, separately or sequentially in order to treat or prevent disease symptoms. The two active agents may be provided in a single dosage form or as separate formulation, each formulation containing at least one of the two active agents. One or both of the two active agents may be formulated as a bolus.

[0136] In particular, the present application discloses 5-amino-2,3-dihydro-1 ,4-phthalazinedione or one of its pharmaceutically acceptable salts, a composition according to the invention or a combination according to the invention for use in the treatment of an RNA virus infection, with the proviso that said infection with an RNA virus does not include a coronaviral infection, wherein a previous treatment with at least one other pharmaceutically active agent was refractory.

[0137] Unless otherwise stated, any technical or scientific term used in the present invention has the meaning that a man skilled in the relevant technical art will attribute to them.

[0138] According to the application the terms “drug substance”, “active substance", “active agent”, “pharmaceutically active agent”, “active ingredient” or “active pharmaceutical ingredient" (API) refer to 5-amino-2,3-dihydro-1 ,4-phthalazinedione or its pharmaceutically acceptable salts, if not stated otherwise or used in a general sense.

[0139] The terms “medicine" or “medical" comprise human as well as veterinary medicine.

[0140] The term “organism" refers to a living being, especially a human or an animal, possessing a self-regulating immunological system.

[0141] The term “host organism" is used in terms of the application for those organisms exploited for replication by viruses, herein especially retroviruses, following an infection with them.

[0142] The terms "subject” and “patient” comprise individuals suffering from disease symptoms or disabilities related to an RNA virus infection wherein said diagnosis is either approved or suspected. Individuals are mammals, in particular humans.

[0143] The term “living being" refers to every animal, especially vertebrate, including human. A "patient" in terms of the application is a living being who suffers from a definable and diagnosable disease, and to whom a suitable active agent can be administered.

[0144] The term "active agent" in this application refers to 5-amino-2,3-dihydro-1 ,4-phthalazinedione or one of its pharmaceutically acceptable salts, if not stated otherwise. Moreover, this term can comprise further pharmaceutical agents, known from the state of the art.

[0145] The terms “composition” and “pharmaceutical composition" comprise 5-ami no-2, 3-d ihydro- 1 ,4-phthalazinedione or one of its pharmaceutically acceptable salts in any pharmacologically suitable defined dose and dosage form together with at least one suitable excipient or carrier substance as well as all substances which are directly or indirectly generated as a combination, accumulation, complex formation or crystal of the aforementioned ingredients, or come into being as a result of other reactions or interactions as well as optionally at least one further pharmaceutical agent known in the state of the art.

[0146] The term "excipient" is used in this application to describe each component of a pharmaceutical composition in addition to the active agent. The selection of a suitable excipient depends on factors such as dosage form and dose as well as the influence on the solubility and stability of the composition by the excipient itself.

[0147] The term “action" describes the inherent specific mode of action of the respective agent in the scope of the present application.

[0148] The terms “effect", “therapeutic effect", “action”, “therapeutic action” regarding at least one active agent according to the invention refer to causally occurring beneficial consequences for the organism, to which the at least one active agent has been administered.

[0149] In terms of the application, “therapeutically effective dose", “effective amount” and “therapeutically effective amount” mean that a sufficient dose of 5-amino-2,3-dihydro-1,4- phthalazinedione or one of its pharmaceutically acceptable salts is administered to a living being or to a patient in need of such a treatment.

[0150] The terms “joint administration", “combined administration" or "simultaneous administration" of at least one pharmaceutical agent according to the invention and / or of at least one pharmaceutical agent from the state of the art comprise the administration of the mentioned agents at the same time or at time points factually related close to each other, as well as administrations of said agents at different times within a coherent experiment. The chronological order of the administration of said agents is not limited by these terms. Those skilled in the art will have no difficulties to deduce the described administrations in respect to their chronological or local order from his knowledge and experience.

[0151] The terms “prophylaxis", “prophylactic treatment”, “treatment" and “therapy" comprise the administration of 5-amino-2,3-dihydro-1 ,4-phthalazinedione or one of its pharmaceutically acceptable salts, alone or in combination with at least one further pharmaceutical agent known in the art, to a living being, in order to prevent the development of a certain disease, to inhibit, and to alleviate the symptoms, or to initiate a healing process of the respective disease. They are independently of the chronological order of the administration. . Such an administration is intended to substantially improve the disease course of an RNA virus infection by either completely curing the disease or by stopping or decelerating the increase of disabilities during the course of the disease. 5-amino-2,3-dihydro-1 ,4-phthalazinedione or one of its pharmaceutically acceptable salts, a composition according to the invention or a drug combination according to the invention can be applied in the prophylaxis or treatment of an RNA virus infection, with the proviso that said infection with an RNA virus does not include a coronaviral infection, by any medically acceptable administration route to a patient in need thereof. Such medically acceptable administration routes can be e.g. by inhalation, by intubation, orally, parenterally, intraperitoneally, intravenously, intraarterially, intramuscularly, topically, transdermally, subcutaneously, intradermally, sublingually, conjunctivally, intravaginally, rectally or nasally.

[0152] Preferred oral formulations for use in the prophylaxis or treatment of an RNA virus infection, with the proviso that said infection with an RNA virus does not include a coronaviral infection, are capsules or tablets containing 5-amino-2,3-dihydro-1 ,4-phthalazinedione or one of its pharmaceutically acceptable salts in an amount of 50 mg, 100 mg, 150 mg, 200 mg, 300 mg, 400 mg, 500 mg or 600 mg, preferably 100 mg, 150 mg, 200 mg, 300 mg or 400 mg, most preferably 300 mg.

[0153] In another aspect of the invention a composition for use in the prophylaxis or treatment of an RNA virus infection is disclosed, with the proviso that said infection with an RNA virus does not include a coronaviral infection, wherein said composition contains 5-amino-2,3-dihydro- 1 ,4-phthalazinedione or one of its pharmaceutically acceptable salts, a carrier and at least one pharmaceutically acceptable excipient.

[0154] The term “pharmaceutically acceptable excipient(s)” refers to natural or synthetic compounds that are added to a pharmaceutical formulation alongside the pharmaceutical active agent. They may help to bulk up the formulation, to enhance the desired pharmacokinetic properties or the stability of the formulation, as well as being beneficial in the manufacturing process. Advantageous classes of excipients according to the invention include, carriers, binding agents, colorants, buffers, preservatives, antioxidants, coatings, sweeteners, thickening agents, pH-regulators, acidity regulators, acidifiers, solvents, isotonizing agents, disintegrants, glidants, lubricants, emulsifiers, solubilizing agents, stabilizers, diluents, anticaking agents (antiadherents), sorbents, foaming agents, anti-foaming agents, opacifiers, fatliquors, consistency enhancers, hydrotropes, aromatic and flavoring substances.

[0155] In general, one or more pharmaceutically acceptable carriers are added to a pharmaceutically active agent. Eligible are all carriers known in the art and combinations thereof. In solid dosage forms they can be for example plant and animal fats, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silica, talcum, zinc oxide. For liquid dosage forms and emulsions suitable carriers are for example solvents, solubilizing agents, emulsifiers such as water, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1 ,3-butyl glycol, cotton seed oil, peanut oil, olive oil, castor oil, sesame oil, glycerol fatty acid esters, polyethylglycols, fatty acid esters of sorbitan. Suspensions according to the invention may use carriers known in the art such as diluents (e.g., water, ethanol or propylene glycol), ethoxylated isostearyl alcohols, polyoxyethylene and polyoxyethylene sorbitan esters, microcrystalline cellulose, bentonites, agar agar, tragacanth.

[0156] The term binding agents refers to substances that bind powders or glue them together, rendering them cohesive through granule formation. They serve as a “glue” of the formulation. Binding agents increase the cohesive strength of the provided diluent or filler.

[0157] Suitable binding agents are for example starch from wheat, corn, rice or potato, gelatin, naturally occurring sugars such as glucose, sucrose or beta-lactose, sweeteners from corn, natural and synthetic gums such as acacia, tragacanth or ammonium calcium alginate, sodium alginate, carboxymethyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl carboxymethyl cellulose, polyethylene glycol, polyvinyl pyrrolidone, magnesium aluminum silicate, waxes and others. The percentage of the binding agent in the composition can range from 1 - 30 % by weight, preferred 2 - 20 % by weight, more preferred 3 - 10 % by weight and most preferred 3 - 6 % by weight.

[0158] Colorants are excipients that bestow a colorization to the pharmaceutical formulation. These excipients can be food colorants. They can be adsorbed on a suitable adsorption means such as clay or aluminum oxide. A further advantage of a colorant is that it may visualize spilled aqueous solution on the nebulizer and / or the mouthpiece to facilitate cleaning. The amount of the colorant may vary between 0.01 and 10 % per weight of the pharmaceutical composition, preferred between 0.05 and 6 % per weight, more preferred between 0.1 and 4 % per weight, most preferred between 0.1 and 1 % per weight.

[0159] Suitable pharmaceutical colorants are for example curcumin, riboflavin, riboflavin-5’- phosphate, tartrazine, alkannin, quinolione yellow WS, Fast Yellow AB, riboflavin-5’-sodium phosphate, yellow 2G, Sunset yellow FCF, orange GGN, cochineal, carminic acid, citrus red 2, carmoisine, amaranth, Ponceau 4R, Ponceau SX, Ponceau 6R, erythrosine, red 2G, Allura red AC, Indanthrene blue RS, Patent blue V, indigo carmine, Brilliant blue FCF, chlorophylls and chlorophyllins, copper complexes of chlorophylls and chlorophyllins, Green S, Fast Green FCF, Plain caramel, Caustic sulphite caramel, ammonia caramel, sulphite ammonia caramel, Black PN, Carbon black, vegetable carbon, Brown FK, Brown HT, alpha-carotene, beta-carotene, gamma-carotene, annatto, bixin, norbixin, paprika oleoresin, capsanthin, capsorubin, lycopene, beta-apo-8’-carotenal, ethyl ester of beta-apo-8’-carotenic acid, flavoxanthin, lutein, cryptoxanthin, rubixanthin, violaxanthin, rhodoxanthin, canthaxanthin, zeaxanthin, citranaxanthin, astaxanthin, betanin, anthocyanins, saffron, calcium carbonate, titanium dioxide, iron oxides, iron hydroxides, aluminum, silver, gold, pigment rubine, tannin, orcein, ferrous gluconate, ferrous lactate.

[0160] Moreover, buffer solutions are preferred for liquid formulations, in particular for pharmaceutical liquid formulations. The terms buffer, buffer system and buffer solution, in particular of an aqueous solution, refer to the capacity of the system to resist a pH change by the addition of an acid or a base, or by dilution with a solvent. Preferred buffer systems may be selected from the group comprising formate, lactate, benzoic acid, oxalate, fumarate, aniline, acetate buffer, citrate buffer, glutamate buffer, phosphate buffer, succinate, pyridine, phthalate, histidine, MES (2-(N-morpholino) ethanesulfonic acid), maleic acid, cacodylate (dimethyl arsenate), carbonic acid, ADA (N-(2-acetamido)imino diacetic acid, PIPES (4- piperazine-bis-ethanesulfonic acid), BIS-TRIS propane (1,3- bis[tris(hydroxymethyl)methylamino] propane), ethylene diamine, ACES (2-[(amino-2- oxoethyl)amino]ethanesulfonic acid), imidazole, MOPS (3-(N-morphino) propanesulfonic acid), diethyl malonic acid, TES (2-[tris(hydroxymethyl)methyl]aminoethanesulfonic acid), HEPES (N-2-hydroxyethylpiperazine-N’-2-ethanesulfonic acid), as well as other buffers with a pKabetween 3.8 and 7.7.

[0161] Preferred are carbonic acid buffers such as acetate buffer and dicarboxylic acid buffers such as fumarate, tartrate and phthalate as well as tricarboxylic acid buffers such as citrate.

[0162] A further group of preferred buffers are inorganic buffers such as sulfate hydroxide, borate hydroxide, carbonate hydroxide, oxalate hydroxide, calcium hydroxide and phosphate buffers. Another group of preferred buffers are nitrogen-containing puffers such as imidazole, diethylene diamine and piperazine. Furthermore preferred are sulfonic acid buffers such as TES, HEPES, ACES, PIPES, [(2-hydroxy-1 ,1-bis-(hydroxymethyl)ethyl)amino]-1- propanesulfonic acid (TAPS), 4-(2-hydroxyethyl)piperazine-1 -propanesulfonic acid (EEPS), MOPS and N,N-bis-(2-hydroxyethyl)-2-aminoethanesulfonic acid (BES). Another group of preferred buffers are glycine, glycyl-glycine, glycyl-glycyl-glycine, N,N-bis-(2- hydroxyethyl)glycine and N-[2-hydroxy-1 ,1-bis(hydroxymethyl)ethyl]glycine (tricine). Preferred are also amino acid buffers such as glycine, alanine, valine, leucine, isoleucine, serine, threonine, phenylalanine, tyrosine, tryptophan, lysine, arginine, histidine, aspartate, glutamate, asparagine, glutamine, cysteine, methionine, proline, 4-hydroxy proline, N,N,N- trimethyllysine, 3-methyl histidine, 5-hydroxy lysine, o-phosphoserine, gammacarboxyglutamate, [epsilon]-N-acetyl lysine, [omega]-N-methyl arginine, citrulline, ornithine and their derivatives. Particularly preferred is KH2PO4 buffer. Preservatives for liquid and / or solid dosage forms can be used on demand. They may be selected from the group comprising, but not limited to, sorbic acid, potassium sorbate, sodium sorbate, calcium sorbate, methyl paraben, ethyl paraben, methyl ethyl paraben, propyl paraben, benzoic acid, sodium benzoate, potassium benzoate, calcium benzoate, heptyl p-hydroxy benzoate, sodium methyl para-hydroxy benzoate, sodium ethyl parahydroxybenzoate, sodium propyl para-hydroxybenzoate, benzyl alcohol, benzalkonium chloride, phenylethyl alcohols, cresols, cetylpyridinium chloride, chlorbutanol, thiomersal (sodium 2-(ethylmercurithio) benzoic acid), sulfur dioxide, sodium sulfite, sodium bisulfite, sodium metabisulfite, potassium metabisulfite, potassium sulfite, calcium sulfite, calcium hydrogen sulfite, potassium hydrogen sulfite, biphenyl, orthophenyl phenol, sodium orthophenyl phenol, thiabendazole, nisin, natamycin, formic acid, sodium formate, calcium formate, hexamine, formaldehyde, dimethyl dicarbonate, potassium nitrite, sodium nitrite, sodium nitrate, potassium nitrate, acetic acid, potassium acetate, sodium acetate, sodium diacetate, calcium acetate, ammonium acetate, dehydroacetic acid, sodium dehydroacetate, lactic acid, propionic acid, sodium propionate, calcium propionate, potassium propionate, boric acid, sodium tetraborate, carbon dioxide, malic acid, fumaric acid, lysozyme, copper- (ll)-sulfate, chlorine, chlorine dioxide and other suitable substances or compositions known to the person skilled in the art.

[0163] The addition of a sufficient amount of antioxidants is particularly preferable for liquid and topical dosage forms. Suitable examples for antioxidants include sodium metabisulfite, alphatocopherol, ascorbic acid, maleic acid, sodium ascorbate, ascorbyl palmitate, butylated hydroxyanisol, butylated hydroxytoluene, fumaric acid or propyl gallate. Preferred is the use of sodium metabisulfite, alpha-tocopherol and ascorbyl palmitate.

[0164] Tablets or pills are usually coated, i.e. the coating constitutes the outer layer. This can be a film coating, a sugar coating with saccharides and a compression coating. Pharmaceutically acceptable varnishes or waxes, HPMC (hydroxypropylmethylcellulose), MC (methylcellulose) or HPC (hydroxypropylcellulose) can be used. Such a coating may help to disguise the taste, to ease the swallowing or the identification. Often plasticizers and pigments are included in the coating. Capsules normally have a gelatinous envelope that encloses the active substance. The specific composition and thickness of this gelatinous layer determines how fast absorption takes place after ingestion of the capsule. Of special interest are sustained release formulations, as known in the art.

[0165] Suitable sweeteners can be selected from the group comprising mannitol, glycerol, acesulfame potassium, aspartame, cyclamate, isomalt, isomaltitol, saccharin and its sodium, potassium and calcium salts, sucralose, alitame, thaumatin, glycyrrhizin, neohesperidine dihydrochalcone, steviol glycosides, neotame, aspartame-acesulfame salt, maltitol, maltitol syrup, lactitol, xylitol, erythritol.

[0166] Suitable thickening agents can be selected from the group comprising, but not limited to, polyvinyl pyrrolidone, methyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, dextrins, polydextrose, modified starch, alkaline modified starch, bleached starch, oxidized starch, enzyme-treated starch, monostarch phosphate, distarch phosphate esterified with sodium trimetaphosphate or phosphorus oxychloride, phosphate distarch phosphate, acetylated distarch phosphate, starch acetate esterified with acetic anhydride, starch acetate esterified with vinyl acetate, acetylated distarch adipate, acetylated distarch glycerol, distarch glycerin, hydroxypropyl starch, hydroxy propyl distarch glycerin, hydroxypropyl distarch phosphate, hydroxypropyl distarch glycerol, starch sodium octenyl succinate, acetylated oxidized starch, hydroxyethyl cellulose.

[0167] Suitable pH-regulators for liquid dosage forms are e.g. sodium hydroxide, hydrochloric acid, buffer substances such as sodium dihydrogen phosphate or disodium hydrogenphosphate.

[0168] Suitable acidity regulators can be selected from the group comprising acetic acid, potassium acetate, sodium acetate, sodium diacetate, calcium acetate, carbon dioxide, malic acid, fumaric acid, sodium lactate, potassium lactate, calcium lactate, ammonium lactate, magnesium lactate, citric acid, mono-, di-, trisodium citrate, mono-, di-, tripotassium citrate, mono-, di-, tricalcium citrate, tartaric acid, mono-, disodium tartrate, mono-, dipotassium tartrate, sodium potassium tartrate, ortho-phosphoric acid, lecithin citrate, magnesium citrate, ammonium malate, sodium malate, sodium hydrogen malate, calcium malate, calcium hydrogen malate, adipic acid, sodium adipate, potassium adipate, ammonium adipate, succinic acid, sodium fumarate, potassium fumarate, calcium fumarate, ammonium fumarate, 1 ,4-heptonolactone, triammonium citrate, ammonium ferric citrate, calcium glycerophosphate, isopropyl citrate, potassium carbonate, potassium bicarbonate, ammonium carbonate, ammonium bicarbonate, magnesium carbonate, magnesium bicarbonate, ferrous carbonate, ammonium sulfate, aluminum potassium sulfate, aluminum ammonium sulfate, sodium hydroxide, potassium hydroxide, ammonium hydroxide, magnesium hydroxide, gluconic acid.

[0169] Acidifiers use to be inorganic chemicals that either produce or become acid. Suitable examples are: Ammonium chloride, calcium chloride.

[0170] Suitable solvents may be selected from the group comprising, but not limited to, water, carbonated water, water for injection, water with isotonizing agents, saline, isotonic saline, alcohols, particularly ethyl and n-butyl alcohol, and mixtures thereof. Suitable isotonizing agents are for example pharmaceutically acceptable salts, in particular sodium chloride and potassium chloride, sugars such as glucose or lactose, sugar alcohols such as mannitol and sorbitol, citrate, phosphate, borate and mixtures thereof.

[0171] Suitable disintegrants can be selected from the group comprising starch, cold water-soluble starches such as carboxymethyl starch, cellulose derivatives such as methyl cellulose and sodium carboxymethyl cellulose, microcrystalline cellulose and cross-linked microcrystalline celluloses such as croscarmellose sodium, natural and synthetic gums such as guar, agar, karaya (Indian tragacanth), locust bean gum, tragacanth, clays such as bentonite, xanthan gum, alginates such as alginic acid and sodium alginate, foaming compositions a.o. Moisture expansion is supported by for example starch, cellulose derivatives, alginates, polysaccharides, dextrans, cross-linked polyvinyl pyrrolidone. The amount of the disintegrant in the composition may vary between 1 and 40% per weight, preferred between 3 and 20% per weight, most preferred between 5 and 10% per weight.

[0172] Glidants are materials that prevent a baking of the respective supplements and improve the flow characteristics of granulations so that the flow is smooth and constant. Suitable glidants comprise silicon dioxide, magnesium stearate, sodium stearate, starch and talcum. The amount of the glidant in the composition may vary between 0.01 and 10% per weight, preferred between 0.1 and 7% per weight, more preferred between 0.2 and 5% per weight, most preferred between 0.5 and 2% per weight.

[0173] The term “lubricants” refers to substances that are added to the dosage form in order to facilitate tablets, granulates etc. to be released from the press mold or the outlet nozzle. They diminish friction or abrasion. Lubricants are usually added shortly before pressing, as they should be present on the surface of the granules and between them and the parts of the press mold. The amount of the lubricant in the composition may vary between 0.05 and 15% per weight, preferred between 0.2 and 5% per weight, more preferred between 0.3 and 3% per weight, most preferred between 0.3 and 1.5% per weight. Suitable lubricants are a.o. sodium oleate, metal stearates such as sodium stearate, calcium stearate, potassium stearate and magnesium stearate, stearic acid, sodium benzoate, sodium acetate, sodium chloride, boric acid, waxes having a high melting point, polyethylene glycol.

[0174] Emulsifiers can be selected for example from the following anionic and non-ionic emulsifiers: Anionic emulsifier waxes, cetyl alcohol, cetylstearyl alcohol, stearic acid, oleic acid, polyoxyethylene polyoxypropylene block polymers, addition products of 2 to 60 mol ethylene oxide to castor oil and / or hardened castor oil, wool wax oil (lanolin), sorbitan esters, polyoxyethylene alkyl esters, polyoxyethylene sorbitan fatty acid esters, polyoxyethene sorbitan monolaurate, polyoxyethene sorbitan monooleate, polyoxyethene sorbitan monopalmitate, polyoxyethene sorbitan monostearate, polyoxyethene sorbitan tristearate, polyoxyethene stearate, polyvinyl alcohol, metatartaric acid, calcium tartrate, alginic acid, sodium alginate, potassium alginate, ammonium alginate, calcium alginate, propane-1 ,2-diol alginate, carrageenan, processed Eucheuma seaweed, locust bean gum, tragacanth, acacia gum, karaya gum, gellan gum, gum ghatti, glucomannane, pectin, amidated pectin, ammonium phosphatides, brominated vegetable oil, sucrose acetate isobutyrate, glycerol esters of wood rosins, disodium phosphate, trisodium diphosphate, tetrasodium diphosphate, dicalcium diphosphate, calcium dihydrogen diphosphate, sodium triphosphate, pentapotassium triphosphate, sodium polyphosphates, sodium calcium polyphosphate, calcium polyphosphates, ammonium polyphosphate, beta-cyclodextrin, powdered cellulose, methyl cellulose, ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, ethyl methyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, ethyl hydroxyethyl cellulose, croscarmellose, enzymically hydrolyzed carboxymethyl cellulose, mono- and diglycerides of fatty acids, glyceryl monostearate, glyceryl distearate, acetic acid esters of mono- and diglycerides of fatty acids, lactic acid esters of mono- and diglycerides of fatty acids, citric acid esters of mono- and diglycerides of fatty acids, tartaric acid esters of mono- and diglycerides of fatty acids, mono- and diacetyl tartaric acid esters of mono- and diglycerides of fatty acids, mixed acetic and tartaric acid esters of mono- and diglycerides of fatty acids, succinylated monoglycerides, sucrose esters of fatty acids, sucroglycerides, polyglycerol esters of fatty acids, polyglycerol polyricinoleate, propane-1, 2-diol esters of fatty acids, propylene glycol esters of fatty acids, lactylated fatty acid esters of glycerol and propane-1 , thermally oxidized soy bean oil interacted with mono- and diglycerides of fatty acids, dioctyl sodium sulphosuccinate, sodium stearoyl-2-lactylate, calcium stearoyl-2- lactylate, stearyl tartrate, stearyl citrate, sodium stearoyl fumarate, calcium stearoyl fumarate, stearyl tartrate, stearyl citrate, sodium stearoyl fumarate, calcium stearoyl fumarate, sodium laurylsulfate, ethoxylated mono- and diglycerides, methyl glucoside-coconut oil ester, sorbitan monostearate, sorbitan tristrearate, sorbitan monolaurate, sorbitan monooleate, sorbitan monopalmitate, sorbitan trioleate, calcium sodium polyphosphate, calcium polyphosphate, ammonium polyphosphate, cholic acid, choline salts, distarch glycerol, starch sodium octenyl succinate, acetylated oxidized starch. Preferred are glycerin monooleate, stearic acid, phospholipids such as lecithin.

[0175] Suitable as surface-active solubilizing agents (solubilizers) are for example diethylene glycol monoethyl ester, polyethyl propylene glycol co-polymers, cyclodextrins such as a- and 0- cyclodextrin, glyceryl monostearates such as Solutol HS 15 (Macrogol-15-hydroxystearate from BASF, PEG 660-15 hydroxystearates), sorbitan esters, polyoxyethylene glycol, polyoxyethylene sorbitanic acid esters, polyoxyethylene sorbitan monooleate, polyoxyethylene oxystearic acid triglyceride, polyvinyl alcohol, sodium dodecyl sulfate, (anionic) glyceryl monooleates. Stabilizers are substances that can be added to prevent unwanted changes. Though stabilizers are not real emulsifiers they may also contribute to the stability of emulsions. Suitable examples for stabilizers are oxystearin, xanthan gum, agar, oat gum, guar gum, tara gum, polyoxyethene stearate, aspartame-acesulfame salt, amylase, proteases, papain, bromelain, ficin, invertase, polydextrose, polyvinyl pyrrolidone, polyvinyl polypyrrolidone, triethyl citrate, maltitol, maltitol syrup.

[0176] Diluents or fillers are inactive substances added to drugs for handling minimal amounts of active agents. Examples for suitable diluents are water, mannitol, pre-gelatinized starch, starch, microcrystalline cellulose, powdered cellulose, silicified microcrystalline cellulose, dibasic calcium phosphate dihydrate, calcium phosphate, calcium carbonate, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose, polyethylene glycol, xanthan gum, gum arabic or any combination thereof.

[0177] Anti-caking agents (antiadherents) can be added to a supplement or a composition of supplements for preventing the formation of lumps and for easing packaging, transport, release from the at least one chamber of the dispensing cap and consumption. Suitable examples include tricalcium phosphate, powdered cellulose, magnesium stearate, sodium bicarbonate, sodium ferrocyanide, potassium ferrocyanide, calcium ferrocyanide, bone phosphate, sodium silicate, silicon dioxide, calcium silicate, magnesium trisilicate, talcum powder, sodium aluminosilicate, potassium aluminum silicate, calcium aluminosilicate, bentonite, aluminum silicate, stearic acid, polydimethyl siloxane.

[0178] Sorbents are materials that soak up oil from the water. Suitable examples include natural sorbents such as peat moss, sawdust, feathers, and anything else natural that contains carbon and synthetic sorbents such as polyethylene and nylon. Sorbents are used for tablet / capsule moisture-proofing by limited fluid sorbing (taking up of a liquid or a gas either by adsorption or by adsorption) in a dry state.

[0179] In some galenic formulations it may be desirable that a liquid oral dosage form generates some foam on being dissolved. Such an effect can be supported through the addition of a foaming agent that reduces the surface tension of the liquid, thus facilitating the formation of bubbles, or it increases its colloidal stability by inhibiting coalescence of bubbles. Alternatively, it may stabilize foam. Suitable examples include mineral oil, quillaia extract, triethyl citrate, sodium lauryl ether sulfate, sodium lauryl sulfate, ammonium lauryl sulfate.

[0180] Alternatively, some liquid oral dosage forms may appear slightly foamy upon preparation. Though this does not interfere with the desired application it may affect patient compliance in case of a medication or the commercial success in case of dietary supplements. Therefore, it may be desirable to add a pharmaceutically acceptable anti-foaming agent (defoamer). Examples are polydimethylsiloxane or silicone oil in dietary supplements or simethicone in pharmaceuticals.

[0181] Opacifiers are substances that render the liquid dosage for, opaque, if desired. They must have a refractive index substantially different from the solvent, in most cases here water. At the same time, they should be inert to the other components of the composition. Suitable examples include titanium dioxide, talc, calcium carbonate, behenic acid, cetyl alcohol, or mixtures thereof.

[0182] Suitable fatliquors are e.g. oleic acid decyl ester, hydrated castor oil, light mineral oil, mineral oil, polyethylene glycol, sodium laurylsulfate.

[0183] Consistency enhancers are e.g. cetyl alcohol, cetyl ester wax, hydrated castor oil, microcrystalline waxes, non-ionic emulsifier waxes, beeswax, paraffin or stearyl alcohol.

[0184] Suitable hydrotropes are alcohols such as ethanol, isopropyl alcohol or polyols such as glycerin.

[0185] Suitable aromatic and flavoring substances comprise above all essential oils that can be used for this purpose. In general, this term refers to volatile extracts from plants or parts of plants with the respective characteristic smell. They can be extracted from plants or parts of plants by steam distillation.

[0186] Suitable examples are: Essential oils, respectively aromatic substances from achillea, sage, cedar, clove, chamomile, anise, aniseed, star anise, thyme, tea tree, peppermint, mint oil, menthol, cineol, borneol, zingerol, eucalyptus, mango, figs, lavender oil, chamomile blossoms, pine needle, cypress, orange, rose, rosewood, plum, currant, cherry, birch leaves, cinnamon, lime, grapefruit, tangerine, juniper, valerian, lemon, lemon balm, lemon grass, palmarosa, cranberry, pomegranate, rosemary, ginger, pineapple, guava, echinacea, ivy leave extract, blueberry, kaki, melon, alpha- or beta-pinene, alpha-pinene oxide, alpha- campholenic aldehyde, alpha-citronellol, alpha-isoamyl-cinnamic, alpha-cinnamic terpinene, alpha-terpineol, alpha-terpinene, aldehyde C16, alpha-phellandrene, amyl cinnamic aldehyde, amyl salicylate, anisic aldehyde, basil, anethole; bay, benzyl acetate, benzyl alcohol, bergamont, bitter orange peel, black pepper, calamus, camphor, cananga oil, cardamom, carnation, carvacrol, carveol, cassia, castor, cedarwood, cinnamaldehyde, cinnamic alcohol, cis-pinane, citral, citronella, citronellal, citronellol dextro, citronellol, citronellyl acetate; citronellyl nitrile, citrus unshiu, clary sage, clove bud, coriander, corn, cotton seed, d- di hydrocarvone, decyl aldehyde, diethyl phthalate, dihydroanethole, dihydrocarveol, dihydrolinalool, dihydromyrcene, dihydromyrcenol, dihydromyrcenyl acetate; dihydroterpineol, dimethyl salicylate, dimethyloctanal, dimethyloctanol, dimethyloctanyl acetate, diphenyl oxide, dipropylene glycol, d-limonen, d-pulegone, estragole, ethyl vanillin, eucalyptol; eucalyptus citriodora, eucalyptus globulus, eugenol, evening primrose, fenchol, fennel, ferniol, fish, florazon, galaxolide, geraniol, geranium, geranyl acetate, geranyl nitrile, guaiacol, guaiacwood, gurjun balsam, heliotropin, herbanate, hiba, hydroxycitronellal, i- carvone, i-methyl acetate, ionone, isobutyl quinoleine, isobornyl acetate, isobornyl methylether, isoeugenol, isolongifolene, jasmine, lavender, limonen, linallol oxide, linallol, linalool, linalyl acetate, linseed, litsea cubeba, l-methyl acetate, longifolene, mandarin, mentha, menthane hydroperoxide, menthol crystals, menthol laevo, menthone laevo, methyl anthranilate, methyl cedryl ketone, methyl chavicol, methyl hexyl ether, methyl ionone, methyl salicylate, mineral, mint, musk ambrette, musk ketone, musk xylol, myrcene, nerol, neryl acetate, nonyl aldehyde, nutmeg, orris root, para-cymene, parahydroxy phenyl butanone crystals, patchouli, p-cymene, pennyroyal oil, pepper, perillaldehyde, petitgrain, phenyl ethyl alcohol, phenyl ethyl propionate, phenyl ethyl-2methylbutyrate, pimento berry, pimento leaf, pinane hydroperoxide, pinanol, pine ester, pine, pinene, piperonal, piperonyl acetate, piperonyl alcohol, plinol, plinyl acetate, pseudo ionone, rhodinol, rhodinyl acetate, rosalin, ryu, sandalwood, sandenol, sassafras, sesame, soybean, spearmint, spice, spike lavender, spirantol, starflower, tea seed, terpenoid, terpineol, terpinolene, terpinyl acetate, tert-butylcyclohexyl acetate, tetrahydrolinalool, tetrahydrolinalyl acetate, tetrahydromyrcenol, thulasi, thymol, tomato, trans-2-hexenol, trans-anethole, turmeric, turpentine, vanillin, vetiver, vitalizair, white cedar, white grapefruit, Wintergreen etc. or mixtures thereof, as well as mixtures of menthol, peppermint and star anise oil or menthol and cherry flavor.

[0187] These aromatic or flavoring substances can be included in the range of 0.0001 to 10 % per weight (particularly in a composition), preferred 0.001 to 6% per weight, more preferred 0.001 to 4% per weight, most preferred 0.01 to 1% per weight, with regard to the total composition. Application- or single case-related it may be advantageous to use differing quantities.

[0188] According to the invention all of the aforementioned excipients and classes of excipients can be used without limitation alone or in any conceivable combination thereof, as long as the inventive use is not thwarted, toxic actions may occur, or respective national legislations are infracted.

[0189] In another aspect of the invention the present application relates to 5-amino-2,3-dihydro-1 ,4- phthalazinedione or one of its pharmaceutically acceptable salts, a composition according to the invention or a combination according to the invention for use in a formulation for oral administration in the prophylaxis or treatment of an RNA virus infection, with the proviso that said infection with an RNA virus does not include a coronaviral infection. Pharmaceutical formulations suitable for oral dosage forms of 5-amino-2,3-dihydro-1 ,4- phthalazinedione or one of its pharmaceutically acceptable salts, a composition according to the invention or a combination according to the invention may be administered as separate units such as tablets, soft gelatin capsules, hard gelatin capsules, sugar-coated tablets or pills; powders or granulates; juices, syrups, drops, teas, solutions or suspensions in aqueous or non-aqueous liquids; edible foams or mousses; or in oil-in-water or water-in-oil in emulsions.

[0190] In oral dosage forms such as tablets or capsules the active agent can thus be combined with a non-toxic and pharmaceutically acceptable inert carrier such as ethanol, glycerol or water. Powders are produced by grinding the compound to a suitably tiny particle size and mixing them with a pharmaceutical carrier in a similar manner, e.g. an edible carbohydrate such as starch or mannitol. A flavor, preservative, dispersant or colorant can also be present.

[0191] Tablets are formulated by producing, granulating or dry-pressing a powder mixture, adding a lubricant and a disintegrants and pressing the mixture to a tablet. A powder mixture is produced by mixing a suitably ground compound with a diluent or a base as described before, and if applicable, with a binding agent such as carboxymethyl cellulose, an alginate, gelatin or polyvinyl pyrrolidone, a dissolution retardant, such as, for example, paraffin, an absorption accelerator, such as, for example, a quaternary salt, and / or an absorbent, such as, for example, bentonite, kaolin or dicalcium phosphate. The powder mixture can be granulated by wetting it with a binder, such as, for example, syrup, starch paste, acacia mucilage or solutions of cellulose or polymer materials and pressing it through a sieve. As an alternative to granulation, the powder mixture can be run through a tableting machine, giving lumps of non-uniform shape which are broken up to form granules. The granules can be lubricated by addition of stearic acid, a stearate salt, talc or mineral oil in order to prevent sticking to the tablet casting mold. The lubricated mixture is then pressed to give tablets. The compounds according to the invention can also be combined with a free-flowing inert excipient and then pressed directly to give tablets without carrying out the granulation or drypressing steps.

[0192] In another aspect of the invention 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts is provided in hard gelatin capsules. They are fabricated by producing a powder mixture as described before and filling it into shaped gelatin covers. Glidants and lubricants such as highly dispersed silica, talcum, magnesium stearate, calcium stearate or polyethylene glycol can be added to the powder mixture as solids. A disintegrant or solubilizer such as agar agar, calcium carbonate or sodium carbonate can be added likewise in order to improve the availability of the medication after intake of the capsule. Additionally, suitable binding agents and / or colorants can be added to the mixture, if desirable or necessary.

[0193] In another aspect of the invention 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts is included in soft gelatin capsules (SGC). SGCs are dissolved on their passage through the gastrointestinal tract. They consist mainly of gelatin enriched with variable amounts of plasticizers such as glycerol or sorbitan. The release rate depends on the specific formulation of the SGC carrier material. They are also suitable for a sustained release of the active agent. SGCs are particularly useful for the administration of poorly water-soluble active agents.

[0194] In another aspect of the invention 5-amino-2,3-dihydro-1 ,4-phthalazinedione or one of its pharmaceutically acceptable salts is included in chewable tablets or hard caramels. Herein the substance is integrated into the matrix of the tablets or caramels.

[0195] In another aspect of the invention the present application relates to 5-amino-2,3-dihydro-1 ,4- phthalazinedione or one of its pharmaceutically acceptable salts, a composition according to the invention or a combination according to the invention for use in the prophylaxis or treatment of an RNA virus infection in a formulation for inhalatory administration, with the proviso that said infection with an RNA virus does not include a coronaviral infection.

[0196] For an effective prophylactic or therapeutic treatment of an RNA virus infection that may cause pneumonia, pulmonary edema and / or acute lung injury it is advantageous that 5- amino-2,3-dihydro-1 ,4-phthalazinedione or one of its pharmaceutically acceptable salts, a composition according to the invention or a combination according to the invention reaches the patient’s alveoli. Therefore, the particle size must be sufficiently small to reach the lowest parts of the airways of the pulmonary tissue. The best inhalatory device class for inhalatory application of a pharmaceutically active agent are the so-called mesh nebulizers. In the scope of the present application practically all mesh nebulizers known in the art can be used, from rather simple single-use mesh nebulizers for cough and cold or for fancy purposes to sophisticated high-end mesh nebulizers for clinical or domestic treatment of serious diseases or conditions of the lower airways.

[0197] Suitable commercially available mesh nebulizers, jet nebulizers, ultrasonic nebulizers, dry powder inhalers and (pressurized) metered-dose inhalers comprise, without being limiting, PARI eFlow®rapid, PARI LC STAR®, PARI Velox and PARI Velox Junior (PARI GmbH, Starnberg, Germany), Philips Respironics l-neb and Philips InnoSpire Go (Koninklijke Philips N.V., Eindhoven, Netherlands), VENTA-NEB®-ir, OPTI-NEB®, M-neb® dose+mesh nebulizer inhalation MN-300 / 8, M-Neb Flow+ and M-neb® mesh nebulizer MN-300 / X (NEBU-TEC, Eisenfeld, Germany), Hcmed Deepro HCM-86C and HCM860 (HCmed Innovations Co., Ltd, Taipei, Taiwan), OMRON MicroAir U22 and U100 (OMRON, Kyoto, Japan), Aerogen® Solo, Aerogen® Ultra and Aerogen® PRO (Aerogen, Galway, Ireland), KTMED NePlus NE-SM1 (KTMED Inc., Seoul, South Korea), Vectura Bayer Breelib™ (Bayer AG, Leverkusen, Germany), Vectura Fox, MPV Truma and MicroDrop® Smarty (MPV MEDICAL GmbH, Kirchheim, Germany), MOBI MESH (APEX Medical, New Taipei City, Taiwan), B.Well WN- 114, TH-134 and TH-135 (B.Well Swiss AG, Widnau, Switzerland), Babybelle Asia BBU01 (Babybelle Asia Ltd., Hongkong), CA-MI Kiwi and others (CA-MI sri, Langhirano, Italy), Diagnosis PRO MESH (Diagnosis S.A., Bialystok, Poland), DIGI O2 (DigiOs International Co., Ltd., New Taipei City, Taiwan), feellife AIR PLUS, AEROCENTRE+, AIR 360+, AIR GARDEN, AIRICU, AIR MASK, AIRGEL BOY, AIR ANGEL, AIRGEL GIRL and AIR PRO 4 (Feellife Health Inc., Shenzhen, China), Hannox MA-02 (Hannox International Corp., Taipei, Taiwan), Health and Life HL100 and HL100A (HEALTH & LIFE Co., Ltd., New Taipei City, Taiwan), Honsun NB-810B (Honsun Co., Ltd., Nantong, China), K-jump® KN-9100 (K-jump Health Co., Ltd., New Taipei City, Taiwan), microlife NEB-800 (Microlife AG, Widnau, Switzerland), OK Biotech Docspray (OK Biotech Co., Ltd., Hsinchu City, Taiwan), Prodigy Mini-Mist® (Prodigy Diabetes Care, LLC, Charlotte, USA), Quatek NM211 , NE203, NE320 and NE403 (Big Eagle Holding Ltd., Taipei, Taiwan), Simzo NBM-1 and NBM-2 (Simzo Electronic Technology Ltd., Dongguan, China), Mexus® BBU01 and BBU02 (Tai Yu International Manufactory Ltd., Dongguan, China), TaiDoc TD-7001 (TaiDoc Technology Co., New Taipei City, Taiwan), Vibralung® and HIFLO Miniheart Circulaire II (Westmed Medical Group, Purchase, USA), KEJIAN (Xuzhou Kejian Hi-Tech Co., Ltd., Xuzhou, China), YM- 252, P&S-T45 and P&S-360 (TEKCELEO, Valbonne, France), Maxwell YS-31 (Maxwell India, Jaipur, India), Kernmed® JLN-MB001 (Kernmed, Durmersheim, Germany).

[0198] Preferred are mesh nebulizers with a piezoelectric activation of the nebulization process, respectively vibrating mesh nebulizers.

[0199] Thus, in another aspect of the invention the present application relates to 5-amino-2,3-dihydro- 1 ,4-phthalazinedione or one of its pharmaceutically acceptable salts, a composition according to the invention or a combination according to the invention for use in the prophylaxis or treatment of an RNA virus infection in a formulation for inhalatory administration, with the proviso that said infection with an RNA virus does not include a coronaviral infection, wherein the inhalatory administration is carried out by means of a vibrating mesh nebulizer.

[0200] Mesh nebulizers can be classified into two groups according to patient interaction: Continuous mode devices and trigger-activated devices. In continuous mode mesh nebulizers the nebulized aerosol is continuously released into the mouth piece and the patient has to inhale the provided aerosol. In trigger-activated devices a defined amount of aerosol is released only upon an active and deep inspiratory breath. This way a far larger amount of active agent-containing aerosol is inhaled and reaches the lowest airways than with continuous mode devices. The latter lose a large amount of active agent-containing aerosol either to the surrounding or on the passage of the upper airways, as the aerosol release is not coupled to the respiratory cycle.

[0201] Therefore, trigger-activated mesh nebulizers are preferred, in particular vibrating mesh nebulizers.

[0202] Particularly preferred are trigger-activated mesh nebulizers with a piezoelectric activation of the nebulization process.

[0203] Preferred are the mesh nebulizer models PARI eFlow®rapid, Philips Respironics l-neb, Philips InnoSpire Go, M-neb® dose+mesh nebulizer inhalation MN-300 / 8, Hcmed Deepro HCM-86C and HCM860, OMRON MicroAir U100, Aerogen® Solo, KTMED NePlus NE-SM1 , Vectura Fox, Vectura Bayer Breelib™.

[0204] The most preferred vibrating mesh nebulizer models are high-end models such as PARI eFlow®rapid, PARI Velox, Philips Respironics l-neb, M-neb® dose+mesh nebulizer inhalation MN-300 / 8, Aerogen® Solo, Vectura Fox, Vectura Bayer Breelib™.

[0205] The mean droplet size is usually characterized as MMAD (median mass aerodynamic diameter). The individual droplet size is referred to as MAD (mass aerodynamic diameter). This value indicates the diameter of the nebulized particles (droplets) at which 50% are smaller or larger, respectively. Particles with a MMAD > 10 pm normally do not reach the lower airways, they often get stuck in the throat. Particles with a MMAD > 5 pm and < 10 pm usually reach the bronchi but not the alveoli. Particles between 100 nm and 1 pm MMAD do not deposit in the alveoli and are exhaled immediately. Therefore, the optimal range is between 1 pm and 5 pm MMAD. Recent publications even favor a narrower range between 3.0 pm and 4.0 pm (cf. Amirav et al. (2010) J Allergy Clin Immunol 25: 1206-1211 ; Haidl et al. (2012) Pneumologie 66: 356-360).

[0206] A further commonly accepted quality parameter is the percentage of the particles in the generated aerosol with a diameter in the range of 1 pm to 5 pm (FPM; fine particle mass). FPM is a measure for the particle distribution. It is calculated by subtracting the percentage of the particles in the generated aerosol with a diameter in the range < 1 pm from the overall percentage of the particles in the generated aerosol with a diameter in the range < 5 pm (FPF; fine particle fraction).

[0207] In another aspect of the invention the present application refers also to a method for producing an aerosol according to the invention for the prophylaxis or treatment of an RNA virus infection, with the proviso that said infection with an RNA virus does not include a coronaviral infection, comprising the following steps: a) filling 0.1 ml to 5 ml of an aqueous solution containing 5-amino-2,3-dihydro-1 ,4- phthalazinedione or one of its pharmaceutically acceptable salts, a composition according to the invention or a combination according to the invention and optionally at least one pharmaceutically acceptable excipient into the nebulization chamber of a mesh nebulizer, b) starting vibration of the mesh of the mesh nebulizer at a frequency of 80 kHz to 200 kHz, and c) discharging the generated aerosol at the side of the mesh of the mesh nebulizer opposite to the nebulization chamber.

[0208] The vibration frequency of vibrating mesh nebulizers is normally in the range of 80 kHz to 200 kHz, preferred 90 kHz to 180 kHz, more preferred 100 kHz to 160 kHz, most preferred 105 kHz to 130 kHz (cf. Chen, The Aerosol Society. DDL2019; Gardenshire et al. (2017) A Guide to Aerosol Delivery Devices for Respiratory Therapists, 4th ed.).

[0209] Thus, the aforementioned method is also disclosed with said vibration frequency ranges.

[0210] The method according to the invention is thus characterized in that at least 80 % in weight, preferred at least 85 % in weight, most preferred at least 90 % in weight of 5-amino-2,3- dihydro-1 ,4-phthalazinedione or one of its pharmaceutically acceptable salts, a composition according to the invention or a combination according to the invention contained in said aqueous solution are nebulized in the generated aerosol.

[0211] The method of the invention is particularly effective in nebulizing a high percentage of the pharmaceutically active agent(s) from the provided aqueous solution during a short time. This is an important feature for patient compliance. A considerable percentage of the patient population finds the inhalatory process to be uncomfortable, weary and physically demanding. On the other hand, the patient’s active cooperation is essential for an effective and targeted inhalatory application. Therefore, it is desirable that a therapeutically sufficient amount is applied during a period of time as short as possible. Surprisingly, it showed that during a three minutes time span 95 % of the substance provided in the aqueous solution could be nebulized. This is an ideal time span for a high patient compliance.

[0212] Therefore, the method according to the invention is thus characterized in that at least 80 % of the generated aerosol are produced during three minutes after starting nebulization in the mesh nebulizer, preferred at least 85 % and most preferred at least 90 %. While the pharmaceutically active agent is usually provided in a single dosage container for every nebulization procedure the nebulizer and / or the mouthpiece can be used over a certain period of time and have to be replaced at certain intervals. A cleaning of the nebulizer and the mouthpiece is recommended by default after each nebulization. But herein patient compliance cannot be reasonably taken for granted. But even after a meticulous cleaning there are always some deposits of the aerosol in the nebulization chamber, the outlet and / or the mouthpiece. As the aerosol is produced from an aqueous solution these depositions bear the risk of producing a bioburden of bacteria that might contaminate the inhaled aerosol. Deposits may also plug holes in the mesh membrane of the mesh nebulizer. In general, the nebulizer and / or the mouthpiece should be exchanged every one or two weeks. Therefore, it is convenient to offer the medication and the nebulizer as a combined product.

[0213] Thus, in another aspect of the invention the present application refers also to a kit comprising a mesh nebulizer and a pharmaceutically acceptable container with an aqueous solution containing an effective amount of 5-amino-2,3-dihydro-1 ,4-phthalazinedione or one of its pharmaceutically acceptable salts, a composition according to the invention or a combination according to the invention for the prophylaxis or treatment of an RNA virus infection, with the proviso that said infection with an RNA virus does not include a coronaviral infection, and optionally at least one pharmaceutically acceptable excipient.

[0214] In an alternative kit 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts, a composition according to the invention or a combination according to the invention is not provided in form of an aqueous solution but in two separated containers, one for a solid form for the active agent and the other for an aqueous solution. The final aqueous solution is freshly prepared by solving the active agent in the final solution. Thereupon the final aqueous solution is filled into the nebulization chamber of the mesh nebulizer. These two containers can be completely separated containers, e.g. two vials, or e.g. a dualchamber vial. For solving the active agent e.g., a membrane between the two chambers is perforated to allow for mixing of the content of both chambers.

[0215] Thus, the present application discloses also a kit, comprising a mesh nebulizer, a first pharmaceutically acceptable container with water for injection or physiological saline solution and a second pharmaceutically acceptable container with an effective dosage of a solid form of 5-amino-2,3-dihydro-1 ,4-phthalazinedione or one of its pharmaceutically acceptable salts, a composition according to the invention or a combination according to the invention for the prophylaxis or treatment of an RNA virus infection, with the proviso that said infection with an RNA virus does not include a coronaviral infection, wherein optionally at least one pharmaceutically acceptable excipient is contained in the first pharmaceutically acceptable container and / or the second pharmaceutically acceptable container. The aerosol generated by the method according to the invention is administered, respectively self-administered by means of a mouthpiece. Optionally, such a mouthpiece can be additionally included in the beforementioned kits.

[0216] A common way to transfer the provided aqueous solution or final aqueous solution into the nebulization chamber of the mesh nebulizer by means of a syringe equipped with an injection needle. First, the aqueous solution is drawn up into the syringe and then injected into the nebulization chamber. Optionally, such a syringe and / or injection needle can be additionally included in the beforementioned kits. Without being limiting, typical syringes made of polyethylene, polypropylene or cyclic olefin co-polymers can be used, and a typical gauge for a stainless-steel injection needle would be in the range of 14 to 27.

[0217] In yet another aspect of the invention 5-amino-2,3-dihydro-1 ,4-phthalazinedione or one of its pharmaceutically acceptable salts, a composition according to the invention or a combination according to the invention for use in the prophylaxis or treatment of an RNA virus infection, with the proviso that said infection with an RNA virus does not include a coronaviral infection, wherein said substance, composition or combination is provided as an additive to the ventilation air of a cardiopulmonary bypass device, a form of assisted ventilation. When the patient’s condition in intensive care unit worsens, they often need to be ventilated in such a device for an indefinite period of time until their own respiration would allow for a sufficient oxygen supply. Good results have been achieved when with an aerosol in a metered-dose inhaler combined with an inhalation chamber at the Y-piece. This can increase the applied dosage of bronchodilators by the factor 1 .5 to 4 (Fuller et al. (1994) Chest 105: 214-218). 38% of the pharmaceutically active agent could be delivered (Marik et al. (1999) Chest 115: 1653- 1657). Alternatively, a constant output mesh nebulizer yielded rates of 10 - 15%, as assessed in a scintigraphic study (Dugernier et al. (2016) Ann Intensive Care 6: 73). Vibrating mesh nebulizers delivered better results than ultrasonic or jet nebulizers for administration of antibiotics. When a constant output vibrating-mesh nebulizer is placed on the inspiratory limb at 10 cm of the Y-piece and specific ventilation parameters (tidal volume of 8 ml / kg, respiratory rate of 12 c / min, duty cycle of 50%, constant and low inspiratory flow rate inferior to 30 l / min and end inspiratory pause of 20%) are set, 63% of the administered drug (ceftazidime, amikacin) reach the inlet of the endotracheal tube, versus 37% extrapulmonary deposition (Lu et al. (2011 ) Am J RespirCrit Care Med 184: 106-115). Mostly, the administered drug is evenly distributed between both lungs. In pigs, the use of helium (He / 02) instead of nitrogen (N2 / O2) in inhaled gas was found to increase ceftazidime concentrations in subpleural lung specimens (Tonnelier et al. (2005) Anesthesiology 102: 995-1000). In these cases 5-amino-2,3-dihydro-1 ,4-phthalazinedione or one of its pharmaceutically acceptable salts can be added to the intubated ventilation air in solid form (dry powder) or in liquid form (in an aqueous solution or as a nebulized aerosol, as described before).

[0218] The present application discloses thus also 5-amino-2,3-dihydro-1 ,4-phthalazinedione or one of its pharmaceutically acceptable salts, a composition according to the invention or a combination according to the invention for use in the prophylaxis or treatment of an RNA virus infection, with the proviso that said infection with an RNA virus does not include a coronaviral infection, wherein said substance, composition or combination is added to the ventilation air of a cardiopulmonary bypass device.

[0219] In yet another aspect of the invention 5-amino-2,3-dihydro-1 ,4-phthalazinedione or one of its pharmaceutically acceptable salts, a composition according to the invention or a combination according to the invention for use in the prophylaxis or treatment of an RNA virus infection, with the proviso that said infection with an RNA virus does not include a coronaviral infection, wherein said substance, composition or combination is applied in form of liposomes, micelles, multilamellar vesicles or a cyclodextrin complex.

[0220] In yet another aspect of the invention the present application relates to 5-amino-2,3-dihydro-

[0221] 1 ,4-phthalazinedione or one of its pharmaceutically acceptable salts, a composition according to the invention or a combination according to the invention for use in the prophylaxis or treatment of an RNA virus infection, with the proviso that said infection with an RNA virus does not include a coronaviral infection, in a formulation for sublingual tablets.

[0222] In yet another aspect of the invention the present application relates to 5-amino-2,3-dihydro-

[0223] 1 ,4-phthalazinedione or one of its pharmaceutically acceptable salts, a composition according to the invention or a combination according to the invention for use in the prophylaxis or treatment of an RNA virus infection, with the proviso that said infection with an RNA virus does not include a coronaviral infection, in a liquid dosage form.

[0224] The present application discloses also the parenteral administration of 5-amino-2,3-dihydro-

[0225] 1 ,4-phthalazinedione or one of its pharmaceutically acceptable salts, a composition according to the invention or a combination according to the invention in the prophylaxis or treatment of an RNA virus infection, with the proviso that said infection with an RNA virus does not include a coronaviral infection, in the form of intravenous injection, intraarterial injection or intraperitoneal injection.

[0226] These liquid dosage forms comprise solutions, suspensions and emulsions. Examples are water and water / propylene glycol solutions for parenteral injections, or the addition of a sweetener or opacifier for oral solutions, suspensions and emulsions. These liquid dosage forms can be stored in vials, IV bags, ampoules, cartridges, and prefilled syringes. Suitable excipients include solubilizers, stabilizers, buffers, tonicity modifiers, bulking agents, viscosity enhancers / reducers, surfactants, chelating agents, and adjuvants.

[0227] In yet another aspect of the invention 5-amino-2,3-dihydro-1 ,4-phthalazinedione or one of its pharmaceutically acceptable salts, a composition according to the invention or a combination according to the invention for use in the prophylaxis or treatment of an RNA virus infection, with the proviso that said infection with an RNA virus does not include a coronaviral infection, wherein said substance, composition or combination is formulated as a lyophilizate. A lyophilizate can be reconstituted with water for injection or physiological saline or a water / ethanol solution and then be administered by injection.

[0228] Typical application forms for intravenous injections include infusion pumps, hypodermic needles, drip chambers, peripheral cannulas (peripheral venous catheters) and pressure bags.

[0229] In general, an aqueous solution or a physiological saline solution is preferred. In case of a poorly soluble pharmaceutical agent according to the invention also ethanol or ethanol / water mixtures can be used.

[0230] Further suitable liquid dosage forms include drops, eyedrops and eardrops.

[0231] RNA virus infections affect often first the pharynx / throat area. Only a minor percentage of these patients develops later a pulmonary infection and a pneumonia. While these pharyngeal infections cause usually only mild symptoms as in a cold these patients can be highly infectious for their environment. Therefore, there is a medical need to treat an RNA virus infection already when they are still in the pharyngeal stage, not only for treating such a patient but also for epidemiologic reasons to prevent the spreading of the viral infection. For patients with a pharyngeal infection only a systemic route of administration, e.g. intravenously or perorally, with a highly effective drug or drug combination that may also cause adverse side effects is not ideal. Thus, it is desirable to provide routes of administration that treat the infected pharyngeal tissue locally.

[0232] Therefore, in yet another aspect of the invention the present application relates to 5-amino- 2,3-dihydro-1 ,4-phthalazinedione or one of its pharmaceutically acceptable salts, a composition according to the invention or a combination according to the invention for use in the prophylaxis or treatment of an RNA virus infection in a formulation for pharyngeal administration, with the proviso that said infection with an RNA virus does not include a coronaviral infection. Administration of a medication to the pharynx can be effected by topical administrations, such as brushing of the throat / pharynx area with a suitable liquid dosage form as drops, a lotion or a tincture, or with a viscous dosage form such as a gel or hydrogel, gurgling with a mouthwash, a sublingual tablet, a lozenge, a throat spray or a posterior pharyngeal wall injection.

[0233] A lotion is a low-viscosity topical preparation intended for application to the skin or the mucosa. Lotions are applied to the skin or mucosa with bare hands, a brush, a clean cloth, or cotton wool.

[0234] An advantage of a lotion is that it may be spread thinly and may cover a large area of skin or mucosa. Typical drugs that can be administered in form of a lotion include antibiotics, antiseptics, antifungals, corticosteroids, anti-acne agents, soothing, smoothing, moisturizing or protective agents, or anti-allergens.

[0235] Most lotions are oil-in-water emulsions using a substance such as cetearyl alcohol to keep the emulsion together, but water-in-oil lotions are also formulated. The key components are the aqueous and oily phases, an emulgent to prevent separation of these two phases and the drug substance(s). A wide variety of excipients such as fragrances, glycerol, petroleum jelly, dyes, preservatives, proteins and stabilizing agents are commonly added to lotions.

[0236] Thickness, consistency and viscosity of the lotion can be adjusted during manufacturing. Manufacturing lotions can be carried out in two cycles: a) Emollients and lubricants are dispersed in oil with blending and thickening agents, b) Perfume, color and preservatives are dispersed in the water phase. Pharmaceutically active principles are broken up in both cycles depending on the raw materials involved and the desired properties of the lotion.

[0237] A tincture is typically an alcoholic extract or formulation. Solvent concentrations of 25-60% (or even 90%) are common. Other solvents for producing tinctures include vinegar, glycerin, diethyl ether and propylene glycol. Ethanol has the advantage of being an excellent solvent for both acidic and alkaline constituents. A tincture using glycerin is called a glycerite. Glycerin is generally a poorer solvent than ethanol. Vinegar, being acidic, is a better solvent for obtaining alkaloids but a poorer solvent for acidic components.

[0238] A gel is a colloid in which the solid disperse phase forms a network in combination with that of the fluid continuous phase, resulting in a viscous semirigid sol. Gel properties range from soft and weak to hard and tough. They are defined as a substantially dilute cross-linked system, which exhibits no flow in the steady-state. By weight, gels are mostly liquid, yet they behave like solids due to a three-dimensional cross-linked network within the liquid. It is the crosslinking within the fluid that gives a gel its consistency and contributes to the adhesive stick. Gels are a dispersion of molecules of a liquid within a solid medium. A hydrogel is a network of polymer chains that are hydrophilic, sometimes found as a colloidal gel in which water is the dispersion medium. A three-dimensional solid results from the hydrophilic polymer chains being held together by cross-links. Because of the inherent cross-links, the structural integrity of the hydrogel network does not dissolve from the high concentration of water. Hydrogels are highly absorbent (they can contain over 90% water) natural or synthetic polymeric networks. Hydrogels also possess a degree of flexibility very similar to natural tissue, due to their significant water content. In medicine, hydrogels can encapsulate chemical systems which upon stimulation by external factors such as a change of pH may cause specific pharmaceutically active agent(s) to be liberated to the environment, in most cases by a gel-sol transition to the liquid state.

[0239] Suitable gel formers can be selected from the group comprising, but not limited to, agar, algin, alginic acid, bentonite, carbomer, carrageenan, hectorite, hydroxyethyl cellulose, hydroxypropyl cellulose, polyvinyl alcohol, polyvinyl pyrrolidone, sodium carbomer.

[0240] A mouthwash is a liquid which is held in the mouth passively or swilled around the mouth by contraction of the perioral muscles and / or movement of the head, and may be gargled, where the head is tilted back and the liquid bubbled at the back of the mouth. An aqueous or alcoholic solution of 5-amino-2,3-dihydro-1 ,4-phthalazinedione or one of its pharmaceutically acceptable salts, a composition according to the invention or a combination according to the invention can thus be formulated and administered to the pharynx.

[0241] Sublingual drug delivery can be an alternative when compared to oral drug delivery as sublingually administered dosage forms bypass hepatic metabolism. A rapid onset of pharmacological effect is often desired for some drugs, especially those used in the treatment of acute disorders. Sublingual tablets disintegrate rapidly, and the small amount of saliva present is usually sufficient for achieving disintegration of the dosage form coupled with better dissolution and increased bioavailability.

[0242] The drug must be lipophilic enough to be able to partition through the lipid bilayer, but not so lipophilic such that once it is in the lipid bilayer, it will not partition out again. According to the diffusive model of absorption, the flux across the lipid bilayer is directly proportional to the concentration gradient. Therefore, lower salivary solubility results in lower absorption rates and vice versa. In general, a drug which has been formulated for sublingual should ideally have a molecular weight of less than 500 to facilitate its diffusion. The oral cavity has a narrow pH range which lies between 5.0 to 7.0. The inclusion of a suitable buffer during the formulation of an ionizable drug makes it possible to control the pH of aqueous saliva. For avoiding a possibly unpleasant taste or smell of the drug taste masking is needed. Sweeteners, flavors, and other taste-masking agents are essential components. Sugarbased excipients quickly dissolve in saliva and produce endothermic heat of dissolution. They create a pleasant feeling in the mouth and are most suitable for sublingual tablets along with other flavors.

[0243] Typical techniques for manufacturing sublingual tablets include direct compression, compression molding, freeze drying and hot melt extrusion (Khan et al. (2017) J Pharmaceut Res 16: 257-267).

[0244] When swallowing is avoided, an administration of a pharmaceutically active agent by means of a sublingual tablet can also reach the pharynx / throat topically. Absorption of the pharmaceutically active agent occurs to a good part via the pharyngeal mucosa.

[0245] A lozenge (troche) is a small, disc-shaped or rhombic body composed of solidifying paste containing an astringent, antiseptic, or demulcent drug, used for local treatment of the mouth or throat, the lozenge being held in the mouth until dissolved. The vehicle or base of the loze nge is usually sugar, made adhesive by admixture with acacia or tragacanth, fruit paste, made from black or red currants, confection of rose, or balsam of tolu.

[0246] In particular, the present application relates to 5-amino-2,3-dihydro-1 ,4-phthalazinedione or one of its pharmaceutically acceptable salts, a composition according to the invention or a combination according to the invention for use in the prophylaxis or treatment of an RNA virus infection, with the proviso that said infection with an RNA virus does not include a coronaviral infection, in a formulation for pharyngeal administration, wherein the pharyngeal administration is carried out by means of a throat spray.

[0247] A throat spray is a medicated liquid administered to the throat as a spray, typically for the treatment of a sore throat or cough.

[0248] A throat spray may typically contain a local anesthetic (e.g. lidocaine, benzocaine), an antiseptic (e.g. chlorhexidine, cetylpyridinium chloride), herbal extracts or a combination thereof. Whatever the formulation, it should not contain too much sugar or ethanol, which further irritates the mucosa. And finally, the user should not experience any unpleasant aftertaste.

[0249] The standard for throat sprays is currently a metering pump attached to a bottle containing between 10 to 30 ml of a liquid formulation. The formulation is filled into a glass or plastic bottle with the pump fixed by a screw closure, crimped on or simply snapped onto the bottle neck. Irrespective of the fixing option selected, the system should be tight, with no leakage observed during carrying or handling by the user. Usually, the container is made from glass or plastic.

[0250] Typically, a throat spray pump will deliver a dose in the range of 50 to 200 pl per actuation. For a targeted administration, the pump will be equipped with an actuator with a prolonged nozzle. The nozzle length may range from 30 to 70 mm. It is easier to target the affected area with such a long-fixed nozzle, but this can be too bulky for users to carry, which is why actuators with foldable or swivel-mounted nozzles are preferred.

[0251] Alternatively, devices utilize continuous valves. A continuous valve delivers a targeted treatment but not precise dosing, as the formulation will be aerosolized while the actuator is pressed down. One technical solution is a tin or aluminum can with pressurized head space. When actuating the valve, the elevated internal pressure will force the formulation out of the can as long as the valve stem is pressed down.

[0252] A related but more sophisticated system is the bag-on-valve (BOV) system. The product is placed inside a bag while a propellant (in most cases compressed air) is filled in the space between the bag and the outer can. The product is squeezed out of the bag by the compressed air when the continuous valve is actuated. A BOV system will work with any 360° orientation.

[0253] Care should be taken, as throat spray formulations may contain ingredients that are very aggressive and can lower the surface tension. A simple test for spray performance will ensure that the formulation can be aerosolized by the system and that the delivered spray pattern and particle size is appropriate for the intended use.

[0254] Spray pattern and droplet size distribution are the most important parameters for a throat spray. Spray pattern is a term used to describe the spray angle and the shape of the plume for a fully developed spray. The droplet size is characterized once the spray is fully developed using a laser diffraction method. Fine particles (droplets with less than 10 pm mean dynamic diameter) should be as low as possible to avoid droplet deposition in the lower airways.

[0255] Some carrageenan-based throat sprays have been developed, claiming protection to virus born upper respiratory infections. The first polymer of this platform is Carragelose®, a broadly active anti-viral compound for treating respiratory diseases. The compound prevents the binding of viruses on the mucosal cells, in addition to its moistening effect.

[0256] Alternatively, a portable nebulizer with a high output rate and a tuned droplet size for deposition in the upper airways can be used. Breathing through a face mask can deposit droplets on the mucosa of the whole upper airways (cf. Marx and Nadler (2018) Drug Development & Delivery).

[0257] In particular, the present application relates to 5-amino-2,3-dihydro-1 ,4-phthalazinedione or one of its pharmaceutically acceptable salts, a composition according to the invention or a combination according to the invention for use in the prophylaxis or treatment of an RNA virus infection, with the proviso that said infection with an RNA virus does not include a coronaviral infection, in a formulation for pharyngeal administration, wherein the pharyngeal administration is carried out by means of a posterior pharyngeal wall injection.

[0258] This technique is used for pharyngoplasty by injection of calcium hydroxyapatite and other methods in plastic surgery. However, also a local injection can be made into the pharyngeal tissue for administering a pharmaceutically active agent. The injection solution can be roughly the same as for intravenous or intramuscular injections. Preferred are aqueous solutions, physiological saline solutions or, in case of a rather lipophilic pharmaceutically active agent, an ethanol / water mixture.

[0259] In a further aspect of the invention the present application relates to 5-amino-2,3-dihydro-1 ,4- phthalazinedione or one of its pharmaceutically acceptable salts, a composition according to the invention or a combination according to the invention for use in the prophylaxis or treatment of an RNA virus infection in a formulation for nasal administration, with the proviso that said infection with an RNA virus does not include a coronaviral infection.

[0260] In particular, the nasal administration is carried out by means of a nasal spray or nose drops.

[0261] The common formulation types used for nasal spray products are solutions, suspensions, and emulsions. Nasal spray formulations may be aqueous, hydroalcoholic, or nonaqueousbased. Depending on the type of system, the formulation will include a range of functional excipients, including solvents and cosolvents; mucoadhesive agents; pH buffers; antioxidants; preservatives; osmolality and tonicity agents; penetration enhancers; suspending agents; and surfactants. The choice of formulation type and the excipients selected will be driven by the solubility and stability of 5-amino-2,3-dihydro-1 ,4- phthalazinedione or one of its pharmaceutically acceptable salts, as well as the concentration needed to deliver an efficacious dose in a typical 100 pl spray (cf. Kulkarni and Shaw (2016) in: Essential Chemistry for Formulators of Semisolid and Liquid Dosages, Elsevier). The aforementioned Carragelose® technique is used also for nasal sprays.

[0262] Nose drops are administered in a similar formulation but dropwise instead of a push on the dispenser. In particular, the present application relates to 5-amino-2,3-dihydro-1 ,4-phthalazinedione or one of its pharmaceutically acceptable salts, a composition according to the invention or a combination according to the invention for use in a formulation in the prophylaxis or treatment of an RNA virus infection, with the proviso that said infection with an RNA virus does not include a coronaviral infection, for nasal administration, wherein the nasal administration is carried out by means of a nasal spray or nose drops.

[0263] It is known that the eye mucosae are another entry point of RNA viruses to the organism e.g., a person carries the viruses on his hands while rubbing his eyes.

[0264] Therefore, the present application relates also to 5-amino-2,3-dihydro-1 ,4-phthalazinedione or one of its pharmaceutically acceptable salts, a composition according to the invention or a combination according to the invention, wherein the administration of 5-am i no-2, 3-d ihydro- 1 ,4-phthalazinedione or one of its pharmaceutically acceptable salts, a composition according to the invention or a combination according to the invention is carried out by means of eye drops.

[0265] Eye drops are mostly aqueous solutions containing a pharmaceutically active agent. The pH is usually adjusted to 7.1 to 7.5. Common buffers for eye drops are boric acid and monobasic sodium phosphate. The tonicity should be adjusted by 0.9 % saline (or another isotonizing agent such as potassium nitrate, boric acid, sodium acetate, sodium acetate phosphate buffer or mannitol) to an osmotic pressure isotonic to the cornea epithelium (225 - 430 mosm / kg). Suitable preservatives include thiomersal, organic mercury compounds such as phenylmercury, benzalkonium chloride, chlorhexidine and benzylic alcohol. For prolonging the contact time viscosity-increasing substances (thickening agents) such as cellulose derivatives (hypromellose, methylcellulose, hydroxypropyl methylcellulose), hyaluronic acid, cellulose acetate phthalate, polyethylene glycol, polyvinyl alcohols or poloxamers can be added. Wetting agents or surfactants such as benzalkonium chloride, polysorbate 20, polysorbate 80, dioctyl sodium sulphosuccinate can be included. Some amino acids, alone or in combination with sodium hyaluronate may be helpful in promoting tissue reconstitution, if needed. Suitable amino acids are glycine, leucine, lysine and proline (cf. EP 1940381 B1 ).

[0266] In a further aspect of the invention a method of treatment of an RNA virus infection is disclosed, with the proviso that said infection with an RNA virus does not include a coronaviral infection, in which an effective dose of 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts, a composition according to the invention or a combination according to the invention is administered to a patient in need thereof or to a healthy person in risk of being infected with an RNA virus. EXAMPLES

[0267] In all experiments, solutions containing 5-amino-2,3-dihydro-1 ,4-phthalazinedione sodium salt were prepared using the beforementioned anhydrous Form I of 5-amino-2,3-dihydro-1 ,4- phthalazinedione sodium salt (provided by MetrioPharm).

[0268] Example 1 : Microarray data prove that 5-amino-2,3-dihydro-1 ,4-phthalazinedione sodium salt triggers an interferon response in LPS-stimulated murine peritoneal macrophages

[0269] DNA microarray analysis is a major technology for gene expression studies since it allows to study the entire transcriptome (i.e. more than 30,000 estimated genes). It is increasingly used to identify changes in gene expression that occur upon exposure of cells to specific drugs. In this study, the effects of 5-amino-2,3-dihydro-1 ,4-phthalazinedione sodium salt on LPS-stimulated murine peritoneal macrophages (PM) were evaluated at different time-points.

[0270] For the isolation of PM, 6- 8 weeks female C57BI / 6 mice in the weight range of 22-24 g were purchased from Envigo (San Pietro al Natisone, Udine, Italy). The mice were kept under standard laboratory conditions (non-specific pathogen-free) with free access to food and water. The handling of the animals and the study protocol was in accordance with international guidelines and approved by the local Institutional Animal Care and Use Committee.

[0271] PM were isolated from three mice, 4 days after intraperitoneal injection of 4% thioglycolate medium and further purified by overnight adherence to plastic in the presence of 5% FCS (fetal calf serum). Cells were further cultivated in DMEM / 12 Medium supplemented with 10% FCS.

[0272] FCS, DMEM / F12 medium, Phosphate-Buffered Saline (PBS), Lipopolysaccharide (LPS, E. coli 055:B5), Thioglycolate Medium were purchased from Sigma Aldrich.

[0273] 5-amino-2,3-dihydro-1 ,4-phthalazinedione sodium salt was dissolved in water for injection (WFI; 1 mM) and administered by pipetting directly onto the cells. Prior to preparation, 5- amino-2,3-dihydro-1 ,4-phthalazinedione sodium salt was stored at room temperature (15°C to 25°C) in sealed containers (or Eppendorf tubes) and protected from light. Solutions were freshly prepared prior to the experiment and not further stored.

[0274] An Affymetrix GeneChip® Mouse Transcriptome Array 1 .0 (MTA 1 .0.) was used, which covers all known transcripts and allows the comprehensive and detailed analysis of coding and noncoding genes, exons, and splice variants.

[0275] The PM (0.5*106cells / well in 24-well plates with 1 ml total volume of medium were preincubated with a single dose of 5-amino-2,3-dihydro-1 ,4-phthalazinedione sodium salt (1.0 mM) for 1 h, before LPS (100 ng / ml) was added to the culture. Total RNA was extracted at 1 h, 3 h, 6 h and 24 h following LPS-stimulation. PM only stimulated with LPS were used as a reference control. Raw data were pre-processed and normalized using the Robust Multi-chip Average (RMA) algorithm, as per the manufacturer’s recommendation. Genes with a fold change <-2 or >2 in 5-amino-2,3-dihydro-1 ,4-phthalazinedione sodium salt-treated cells as compared to LPS-stimulated cells were considered as differentially expressed (DE) genes.

[0276] In these data, the results for interferon (IFN) -alpha and interferon-beta were analyzed. Interferon-alpha 4 showed an upregulation after 3 h. Interferon-beta 1 showed an upregulation after 1 h and 3h:

[0277] Further, the results for OAS 1 (2'-5'-oligoadenylate synthetase 1 ; 2-5 (A) synthetase) were analyzed. OAS1a, OAS1c and OAS1g were upregulated after 24 h:

[0278] Upon binding of a virion (in this case a virion from an RNA virus) to its specific receptor on the cell membrane and its internalization into the cell, RIG-I (retinoic acid-inducible gene I; a cytosolic pattern recognition receptor (PRR)) is stimulated. RIG-I is an ATP-dependent DExD / H box RNA helicase that is an essential molecule in the innate immune system for recognizing cells that have been infected with a virus. Via RIG-I, the expression of Type-I interferons (IFNs) such as IFN-alpha and IFN-beta is stimulated. Type-I IFNs have three main functions: to limit the virus from spreading to nearby cells, to promote an innate immune response, including inflammatory responses, and to help activate the adaptive immune system. Once the Type 1-IFNs leave the cell, they can bind to the IFN-alpha receptor (IFNAR) on the cell surface from which they came from, or other cells close by. This will upregulate the production of more Type 1-IFNs, thus creating an antiviral environment. They stimulate both macrophages and NK cells to elicit an anti-viral response, involving IRF3 / IRF7 antiviral pathways. They also activate the JAK-STAT pathway, leading to the production of IFN-stimulated genes (ISGs).

[0279] The binding of Type I interferons to the extracellular IFN-alpha receptor induces the gene expression of OAS1. With dsRNA as a co-factor, OAS1 catalyzes the conversion of ATP (adenosine triphosphate) to 2’-5’-oligoadenylate. 2’-5’-oligoadenylate is an activator of RNase L. Upon activation this ribonuclease degrades all cytosolic RNA into smaller compounds i.e., mainly viral RNA. RNase L is constitutively expressed i.e. , its expression is not modulated during a viral infection. But without the activator 2’-5’-oligoadenylate RNase L remains widely inactive.

[0280] This is the standard pathway how a cell reacts on an RNA-viral infection and finally degrades the RNA copies thus produced. This way the host cell used to get rid of the RNA virus infection (for review see Latarissa et al. (2021) Clin Pharmacol 13: 225-234).

[0281] As can be learnt from the microarray data, 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt is able to strongly enforce this natural defense mechanism of the cell. The induction of Type-I IFN expression can be seen shortly after the infection of the cell, and with a due delay, the induced expression of OAS1 after 24 h. Once OAS1 is upregulated, the activation of RNase L ensues automatically and therewith the degradation of the RNA-viral RNA, independently of which specific RNA virus infected the cell. Hence, this mechanism of - amino-2,3-dihydro-1 ,4-phthalazinedione holds true for all species of RNA viruses.

[0282] Example 2: 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt inhibits the replication of IAV in infected MDCKII cells in qRT-PCR qRT-PCR (quantitative real-time polymerase chain reaction) experiments were conducted. This method is a very sensitive method to determine quantitatively the number of IAV RNA copies of infective virions released from cells in the supernatant. MDCKII cells (Madin-Darby canine kidney cells) were received from Prof. Matthias Tenbusch, Institute of Clinical and Molecular Virology, University of Erlangen, Germany. They were maintained in Dulbecco’s Modified Eagle Medium (DMEM; Gibco Cat. No. 41965) containing 10% (v / v) inactivated FCS (fetal calf serum; Sigma Cat. No. F7524), 100 pg / ml penicillin, 100 pg / ml streptomycin (both from Sigma Cat. No. P4333) and 1 x GlutaMAX™ (glutamine supplement, Gibco Cat. No. 35050061 ). The isolate of Influenza virus A (IAV) subtype Puerto Rico / 8 / 34 (PR8) was also received from Prof. Matthias Tenbusch.

[0283] Treatment scheme:

[0284] Day 0:

[0285] Seeding of MDCKII cells in 24-well plates (5*105cells / well; use 500 pl medium per well)

[0286] Day 1 : Infection and treatment

[0287] - Infection of confluent monolayers of MDCKII cells with IAV PR8 for 30 min

[0288] - Discard medium - Add new medium with interventions (500 pl) for 48 h.

[0289] Day 3: Preparation of virion containing supernatants for qRT-PCR

[0290] - Take 200 pl supernatants in 1.5 ml Eppendorf reaction tubes

[0291] - Centrifuge at 6000 rpm for 5 minutes

[0292] - Transfer the supernatant in a new 1 .5 ml Eppendorf reaction tube Heat for 10 min at 95°C

[0293] - qRT-PCR analysis with 5 pl

[0294] Per experiment, each treatment was run three times. At harvest, respective supernatants will be pooled, corresponding to n=1. In total, a minimum of n = 3 was achieved.

[0295] Samples containing the released virions were quantified by real-time PCRGoTaq® Probe qPCR one steo Kit from Promega (Cat: A6120, Madison, Wisconsin, USA), allowing reverse transcription, cDNA synthesis and PCR amplification in a single step. Samples were analyzed by 7500 software v2.3 (Applied Biosystems, Waltham, Massachusetts, USA).

[0296] The PCR primers were purchased from Integrated DNA Technologies, Coralville, Iowa, USA) and contained parts of the IAV Matrix gene.

[0297] The following 5-amino-2,3-dihydro-1 ,4-phthalazinedione sodium salt doses were used as single substance treatment: 0.0625 mM - 0.125 mM - 0.25 mM - 0.5 mM - 1 mM.

[0298] 5-amino-2,3-dihydro-1 ,4-phthalazinedione sodium salt stock solutions were dissolved in water for injection (Wfl). Working solutions were diluted in cell culture media.

[0299] Amantadine (Sigma Cat. No. A1260) was used as a positive control. Amantadine is an inhibitor of the IAV M2 ion channel. It is a well-established drug for the treatment of IAV infections.

[0300] Statistical analysis was performed using a multiple comparison Kruskal-Wallis test (Anova) followed by Dunn's post hoc test.

[0301] Treatment with 5-amino-2,3-dihydro-1 ,4-phthalazinedione sodium salt led to a dose dependent reduction of virus replication. Thereby, the production of progeny virions was blocked by ca. 80 % at a concentration of 0.5 mM MP 1032. The IC50 was ca. 0.25 mM (Fig. 1 ).

[0302] This experiment shows clearly that 5-amino-2,3-dihydro-1 ,4-phthalazinedione sodium salt inhibits the replication of IAV with high significance in a dose-dependent manner.

[0303] Example 3: 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt does not affect cell viability of MDCKII cells at the tested concentrations For addressing the question whether 5-amino-2,3-dihydro-1 ,4-phthalazinedione sodium salt shows a cytotoxic effect in the abovementioned systems non-infected MDCKII were treated in parallel to qRT-PCR studies with increasing concentrations of 5-amino-2,3-dihydro-1 ,4- phthalazinedione sodium salt (0.0625 mM, 0.125 mM, 0.25 mM, 0.5 mM, 1 mM), Toxicity is assessed with a WST (water-soluble tetrazolium salt 1 ) assay. Herein viable cells with an intact mitochondrial succinate-tetrazolium dehydrogenase system effect an enzymatic conversion of the feebly red tetrazolium salt WST-1 (4-[3-(4-iodophenyl)-2-(4-nitrophenyl)- 2 / - / -5-tetrazolio]-1 ,3 benzene disulfonate) into dark red formazan. This color change can be measured photometrically in a spectrophotometer. Thus, the WST assay is a very sensitive method for measuring the toxicity of substances on the cell metabolism. The value for untreated cells was set to 100%.

[0304] It can be shown that 5-amino-2,3-dihydro-1 ,4-phthalazinedione sodium salt does not display any significant toxic effect in antivirally effective concentrations in MDCKII cells during an observation period of 3 days.

[0305] In Fig. 2 the percentage of viable cells is depicted in comparison to untreated cells. The value for untreated cells was set to 100%. 1 pM staurosporine (an indolocarbazole compound from Streptomyces staurosporeus, an apoptosis inducer) was used as positive control. Statistical analyses were performed using unpaired T Test with Welch’s correction; **p<0.01 , *p<0.05.

[0306] Thus, it can be stated that the antiviral effect of 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt is not due to unspecific cytotoxic effects.

[0307] Example 4: 5-amino-2,3-dihydro-1 ,4-phthalazinedione sodium salt inhibits the replication of HRSV in infected Hep-2 cells

[0308] Immunofluorescence experiments were conducted for determining quantitatively the number of HRSV virions released from cells in the supernatant. Hep-2 cells (human epithelioma-2 cells) were received from Prof. Matthias Tenbusch, Institute of Clinical and Molecular Virology, University of Erlangen, Germany. They were maintained in Dulbecco’s Modified Eagle Medium (DMEM; Gibco Cat. No. 41965) containing 10% / 2% without (v / v) inactivated FCS (fetal calf serum; Sigma Cat. No. F7524), 100 pg / ml penicillin, 100 pg / ml streptomycin (both from Sigma Cat. No P4333) and 1 x GlutaMAX™ (glutamine supplement, Gibco Cat. No. 35050061 ). The isolate of human respiratory syncytial virus (HRSV) subtype A2 was also received from Prof. Matthias Tenbusch. The cell counter was from Invitrogen Countess.

[0309] Treatment scheme: Day 0:

[0310] - Seeding of Hep-2 cells in 96-well plates (Greiner Bio-One Cat. No. 655 180) (1.2-104cells / well; use 100 pl medium per well)

[0311] Day 1 : Infection and pre-treatment

[0312] - Treatment of cells with 5-amino-2,3-dihydro-1 ,4-phthalazinedione sodium salt for 1 h in 100 pl DM EM (10% FCS)

[0313] Remove Medium

[0314] Infection of Hep-2 cells with HRSV (MOI (multiplicity of infection) 0.1 ) for 1 h in 100 pl DMEM (without FCS)

[0315] - Add new medium 1 :1 (DMEM with 2% FCS) with interventions for 48 h.

[0316] Day 3: Preparation of cells for immunofluorescence analysis

[0317] Remove supernatant

[0318] Fixation of cells with 1% PFA (paraformaldehyde; Carl Roth Cat. No. 0335.3) for 24 h at 4°C

[0319] Permeabilization of cells with PBS (phosphate-buffered saline; homemade) supplemented with 0.1% Triton X-100 (Carl Roth Cat. No. 3051.2) for 10 min at room temperature

[0320] Cells are blocked with 200 pl PBS supplemented with 1 % BSA (bovine serum albumin; Capricorn Scientific Cat. No. BSA-1T) for 1 h at 4°C.

[0321] The following 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt doses were used as single substance treatment: 0.125 mM - 0.25 mM - 0.5 mM - 1 mM - 2 mM.

[0322] 5-amino-2,3-dihydro-1 ,4-phthalazinedione sodium salt stock solutions were dissolved in water for injection (Wfl). Working solutions were diluted in cell culture media.

[0323] For immunofluorescence analysis, cells were stained with a goat polyclonal anti-HRSV antibody (1:1000) (Merck AB1128, Temecula, California, USA) for 2 h at room temperature. Plates were incubated for 45 min with donkey anti-goat IgG H&L (AlexaFlour® 488) (1 :1000) (Abeam, AB150129, Cambridge, UK). Cells were stained with DAPI (4',6-diamidino-2- phenylindole) for 10 min. Fluorescence output of AlexaFlour® 488 was quantitatively analyzed with a Perkin Elmer VictorX4. Pictures were taken using a CTL-ELISPOT reader.

[0324] As a positive control, lota-Carrageenan (Marinomed Biotech AG, Korneuburg, Austria) was used. 1.2 mg / ml lota-Carrageenan was prepared in 0.5% NaCI. lota-Carrageenan proved to be highly effective against infections with respiratory viruses such as HRSV (i.a., WO 2008 / 067982; WO 2009 / 027057) and SARS-CoV-2 (WO 2022 / 013113). Treatment with 5-amino-2,3-dihydro-1 ,4-phthalazinedione sodium salt led to a dosedependent reduction of HRSV replication. Thereby, the production of progeny virions was blocked by ca. 80 % at a concentration of 2 mM 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt. The IC50 was ca. 500 M.

[0325] Fig. 3A shows the immunostainings and Fig. 3B the quantitative evaluation of the immunostainings in a bar diagram.

[0326] Example 5: 5-amino-2,3-dihydro-1 ,4-phthalazinedione sodium salt does not affect cell viability of Hep-2 cells at the tested concentrations

[0327] In analogy to Example 3, the cell viability of Hep-2 cells was tested in parallel to the immunofluorescence analyses of Example 4 with increasing concentrations of 5-amino-2,3- dihydro-1 ,4-phthalazinedione sodium salt (0.125 mM, 0.25 mM, 0.5 mM, 1 mM, 2 mM; n = 3).

[0328] Also in this cell system 5-amino-2,3-dihydro-1 ,4-phthalazinedione sodium salt did not display any cytotoxic effects at the tested concentrations (Fig. 4). The antiviral effect of 5-amino-2,3- dihydro-1 ,4-phthalazinedione sodium salt is thus not due to unspecific cytotoxic effects.

[0329] FIGURES for all Figures: * = p < 0.05; ** = p < 0.01 ; *** = p < 0.0001 ; ns = not significant

[0330] Fig. 1 : bar diagram showing the effect of different concentrations of 5-amino-2,3- dihydro-1 ,4-phthalazinedione sodium salt on the number of RNA copies in lAV-infected MDCKII cells, determined by qRT-PCR untreated cells

[0331] 0.125 mM 5-amino-2,3-dihydro-1 ,4-phthalazinedione sodium salt 0.25 mM 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt 0.5 mM 5-amino-2,3-dihydro-1 ,4-phthalazinedione sodium salt 1 mM 5-amino-2,3-dihydro-1 ,4-phthalazinedione sodium salt amantadine (positive control)

[0332] Fig. 2: bar diagram showing the effect of different concentrations of 5-amino-2,3- dihydro-1 ,4-phthalazinedione sodium salt on the cell viability in non-infected MDCKII cells, determined by WST assay untreated cells

[0333] 0.125 mM 5-amino-2,3-dihydro-1 ,4-phthalazinedione sodium salt 0.25 mM 5-amino-2,3-dihydro-1 ,4-phthalazinedione sodium salt 0.5 mM 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt

[0334] 1 mM 5-amino-2,3-dihydro-1 ,4-phthalazinedione sodium salt staurosporine (positive control)

[0335] Fig. 3: A: immunofluorescence stainings of HRSV-infected Hep-2 cells with different concentrations of 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt [L] untreated cells

[0336] 0.125 mM 5-amino-2,3-dihydro-1 ,4-phthalazinedione sodium salt

[0337] 0.25 mM 5-amino-2,3-dihydro-1 ,4-phthalazinedione sodium salt

[0338] 0.5 mM 5-amino-2,3-dihydro-1 ,4-phthalazinedione sodium salt

[0339] 1 mM 5-amino-2,3-dihydro-1 ,4-phthalazinedione sodium salt

[0340] 2 mM 5-amino-2,3-dihydro-1 ,4-phthalazinedione sodium salt l-C (lota-Carrageenan; positive control)

[0341] B: bar diagrams quantifying the immunofluorescence stainings shown above

[0342] Fig. 4: bar diagram showing the effect of different concentrations of 5-amino-2,3- dihydro-1 ,4-phthalazinedione sodium salt on the cell viability in non-infected Hep-2 cells, determined by WST assay untreated cells

[0343] 0.125 mM 5-amino-2,3-dihydro-1 ,4-phthalazinedione sodium salt

[0344] 0.25 mM 5-amino-2,3-dihydro-1 ,4-phthalazinedione sodium salt

[0345] 0.5 mM 5-amino-2,3-dihydro-1 ,4-phthalazinedione sodium salt

[0346] 1 mM 5-amino-2,3-dihydro-1 ,4-phthalazinedione sodium salt

[0347] 2 mM 5-amino-2,3-dihydro-1 ,4-phthalazinedione sodium salt 4 mM 5-amino-2,3-dihydro-1 ,4-phthalazinedione sodium salt staurosporine (positive control)

Claims

Claims1. 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts for use in the prophylaxis or treatment of an infection with an RNA virus, with the proviso that said infection with an RNA virus does not include a coronaviral infection.

2. 5-amino-2,3-dihydro-1 ,4-phthalazinedione or one of its pharmaceutically acceptable salts for use according to Claim 1, wherein the pharmaceutically acceptable salt of 5- amino-2,3-dihydro-1 ,4-phthalazinedione is 5-amino-2,3-dihydro-1 ,4-phthalazinedione sodium salt3. 5-amino-2,3-dihydro-1 ,4-phthalazinedione or one of its pharmaceutically acceptable salts for use according to claim 2, wherein 5-amino-2,3-dihydro-1 ,4-phthalazinedione sodium salt is provided as one of crystalline anhydrate polymorph forms I, II or III characterized by crystallography values determined by means of x-ray powder diagrams: d values: 13.5; 6.9; 5.2; 4.6; 3.9; 3.5; 3.4; 3.3; 3.1; 3.0 and / or2-theta values: 6.5; 12.7; 16.9; 19.3; 22.8; 25.8; 26.6; 27.2; 28.7; 30.3 for Form I, d values: 12.9; 7.9; 7.1 ; 6.5; 5.3; 4.0; 3.7; 3.6; 3.3; 3.2 and / or2-theta values: 6.8; 11.2; 12.5; 13.7; 16.7; 22.4; 24.3; 24.9; 27.2; 27.8 for Form II, and d values: 13.131 ; 7.987; 7.186; 6.566; 6.512; 5.372; 3.994; 3.662; 3.406; 3.288;3.283; 3.222; 3.215; 3.127; 2.889 and / or2-theta values: 6.73; 11.07; 12.31 ; 13.48; 13.59; 16.49; 22.24; 24.29; 26.14; 27.10; 27.14; 27.67; 27,72; 28.52; 30.93 for Form III.

4. 5-amino-2,3-dihydro-1 ,4-phthalazinedione or one of its pharmaceutically acceptable salts for use according to any one of Claims 1 to 3, wherein said infection with an RNA virus is an infection with an influenza virus selected from the group consisting of I AV, IBV, ICV and IDV.

5. 5-amino-2,3-dihydro-1 ,4-phthalazinedione or one of its pharmaceutically acceptable salts for use according to any one of Claims 1 to 3, wherein said infection with an RNA virus is an infection with human respiratory syncytial virus.

6. 5-amino-2,3-dihydro-1 ,4-phthalazinedione or one of its pharmaceutically acceptable salts for use according to any one of Claims 1 to 3, wherein said infection with an RNA virus is selected from the group comprising an infection with RVs, PV, HMPV, HEV, RoV, RuV, TBEV, JEV, ZIKV, YFV, WNV, DENV, LASV, EBOV, MARV, HTNV, PUUV, DOBV, SEOV, SNV, ANDV and RABV.

7. Pharmaceutical composition for use in the prophylaxis or treatment of an infection with an RNA virus, with the proviso that said infection with an RNA virus does not include a coronaviral infection, wherein said composition contains 5-amino-2,3- dihydro-1 ,4-phthalazinedione or one of its pharmaceutically acceptable salts, a carrier and at least one pharmaceutically acceptable excipient.

8. Combination of 5-amino-2,3-dihydro-1 ,4-phthalazinedione or one of its pharmaceutically acceptable salts and at least one active agent selected from a group comprising steroidal and non-steroidal anti-inflammatory drugs, immunomodulators, immunosuppressive agents; anti-infective agents like antibiotics, antiretroviral agents, antiviral agents, antifungal agents and antiprotozoal agents, analgesics, anticoagulants, antiplatelet drugs, bronchodilators, pulmonary vasodilators, mucolytic agents, pulmonary surfactants, antioxidants, ENaC-activating agents, HMG-CoA reductase inhibitors or ATi receptor antagonists for use in the prophylaxis or treatment of an infection with an RNA virus, with the proviso that said infection with an RNA virus does not include a coronaviral infection.

9. 5-amino-2,3-dihydro-1 ,4-phthalazinedione or one of its pharmaceutically acceptable salts as defined in any one of claims 1 to 3, a composition as defined in claim 7 or a combination as defined in claim 8 for use in the prophylaxis or treatment of an infection with an RNA virus, with the proviso that said infection with an RNA virus does not include a coronaviral infection, wherein said substance, composition or combination is applied orally in the form of tablets, soft gelatin capsules, hard gelatin capsules, sugar-coated tablets, pills, powders, granulates, juices, syrups, drops, teas, solutions or suspensions in aqueous or non-aqueous liquids, edible foams, mousses, oil-in-water emulsions or water-in-oil emulsions.

10. 5-amino-2,3-dihydro-1 ,4-phthalazinedione or one of its pharmaceutically acceptable salts as defined in any one of claims 1 to 3, a composition as defined in claim 7 or a combination as defined in claim 8 for use in the prophylaxis or treatment of aninfection with an RNA virus, with the proviso that said infection with an RNA virus does not include a coronaviral infection, in a formulation for inhalatory administration.11 . 5-amino-2,3-dihydro-1 ,4-phthalazinedione or one of its pharmaceutically acceptable salts as defined in any one of claims 1 to 3, a composition as defined in claim 7 or a combination as defined in claim 8 for use in a formulation according to claim 10, wherein the inhalatory administration is carried out by means of a vibrating mesh nebulizer.

12. 5-amino-2,3-dihydro-1 ,4-phthalazinedione or one of its pharmaceutically acceptable salts as defined in any one of claims 1 to 3, a composition as defined in claim 7 or a combination as defined in claim 8 for use in the prophylaxis or treatment of an infection with an RNA virus, with the proviso that said infection with an RNA virus does not include a coronaviral infection, wherein said substance, composition or combination is added to the ventilation air of a cardiopulmonary bypass device.

13. 5-amino-2,3-dihydro-1 ,4-phthalazinedione or one of its pharmaceutically acceptable salts as defined in any one of claims 1 to 3, a composition as defined in claim 7 or a combination as defined in claim 8 for use in the prophylaxis or treatment of an infection with an RNA virus, with the proviso that said infection with an RNA virus does not include a coronaviral infection, in a formulation for sublingual tablets.

14. 5-amino-2,3-dihydro-1 ,4-phthalazinedione or one of its pharmaceutically acceptable salts as defined in any one of claims 1 to 3, a composition as defined in claim 7 or a combination as defined in claim 8 for use in the prophylaxis or treatment of an infection with an RNA virus, with the proviso that said infection with an RNA virus does not include a coronaviral infection, wherein the administration of 5-amino-2,3- dihydro-1 ,4-phthalazinedione or one of its pharmaceutically acceptable salts, said composition according to the invention or a combination according to the invention is carried out by means of a nose spray, nose drops or eye drops.

15. 5-amino-2,3-dihydro-1 ,4-phthalazinedione or one of its pharmaceutically acceptable salts as defined in any one of claims 1 to 3, a composition as defined in claim 7 or a combination as defined in claim 8 for use in the prophylaxis or treatment of an infection with an RNA virus, with the proviso that said infection with an RNA virus does not include a coronaviral infection, in a formulation according to claim 13, wherein the pharyngeal administration is carried out by means of a throat spray.

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