WO2022228652A1 - Moyen et méthodes de traitement d'infections virales - Google Patents

Moyen et méthodes de traitement d'infections virales Download PDF

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Publication number
WO2022228652A1
WO2022228652A1 PCT/EP2021/060836 EP2021060836W WO2022228652A1 WO 2022228652 A1 WO2022228652 A1 WO 2022228652A1 EP 2021060836 W EP2021060836 W EP 2021060836W WO 2022228652 A1 WO2022228652 A1 WO 2022228652A1
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Prior art keywords
virus
compound
pharmaceutical composition
composition according
pyruvate
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PCT/EP2021/060836
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English (en)
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Gerd Birkenmeier
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Gerd Birkenmeier
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Priority to PCT/EP2021/060836 priority Critical patent/WO2022228652A1/fr
Publication of WO2022228652A1 publication Critical patent/WO2022228652A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4706—4-Aminoquinolines; 8-Aminoquinolines, e.g. chloroquine, primaquine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses

Definitions

  • the present invention relates to a compound according to the general formula
  • the virus infection is a coronavirus infection.
  • a method for disinfecting a substrate against viruses comprising con tacting a substrate with at least a compound according to the general formula (I).
  • Viruses are small non-living particles consisting of DNA or RNA covered by membranes. Viruses due to specific membrane proteins are capable to enter host cells for replication. The steps of virus replication include membrane adsorption, host cell entry, production of viral constituents including protein and genetic material, followed by release of the virus out of the cells. Usually, antiviral agents interfere with the process of adsorption by interruption of ligand-receptors interaction. Other agents block tran scriptional machinery and/or nucleic acid multiplication. All are directed to inhibit the growth cycle of the virus within the host cell. In some cases the genome of the virus is persistently integrated into the genome of the host cells and expensive medical care must be applied to eliminate the integrated virus.
  • Viruses have either DNA or RNA genomes, invade the host cell and proliferate using the metabolic system in the host cell. The process common to all virus infections is adsorption, entry into viral host cells, synthesis of viral constituents, assembly of viral constituents (i.e., formation of virus particles), and release of the virus out of the cell (see also Fig. 1).
  • Viruses multiply only in living cells.
  • the host cell must provide the energy and synthetic machinery and the low molecular-weight precursors for the synthesis of viral proteins and nucleic acids. All this requires the energy-rich intermediate ATP.
  • Replica tion between viruses is greatly varied and depends on the virus type. Most DNA viruses assemble in the nucleus while most RNA viruses develop solely in cytoplasm. Through the generation of abundant copies of its own, the virus continues infecting new hosts.
  • Coronaviruses are the largest group of viruses belonging to the Nidovi- rales order, which includes Coronaviridae, Arteriviridae, and Roniviridae families.
  • the Coronavirinae comprise one of two subfamilies in the Coronaviridae family, with the other being the Torovirinae.
  • the Coronavirinae are further subdivided into four groups, the alpha, beta, gamma and delta coronaviruses.
  • Coronavirus virus particles contain four main structural proteins. These are the spike (S), membrane (M), envelope (E), and nucleocapsid (N) proteins.
  • the spike protein mediates attachment to the host receptor, which is suggested to be Angiotensin-Con verting Enzyme-2 (ACE-2) in case of SARS-CoV-2.
  • ACE-2 Angiotensin-Con verting Enzyme-2
  • the spike protein is cleaved by a host cell protease such as furin or Transmembrane prote ase, serine 2 (TMPRRS2). Proteolytic cleavage is a prerequisite for the entry of the virus into the cell.
  • Coronaviruses typically bind to cells with receptors for spike proteins, i.e., S protein sensitive cells.
  • S protein sensitive cells For the SARS virus, it has been shown that one of the cellular receptors is ACE-2.
  • the binding between the spike protein and the ACE-2 receptor re sults in a change in the three-dimensional structure of the spike protein.
  • the spike pro- tein becomes sensitive to certain cell-derived proteases.
  • a specific site of a loop in that protein is cleaved.
  • the terminal end having an affinity for the cell membrane is exposed, so that the virus particle is attracted to the cell in a dis tance where the virus membrane and the cell membrane can fuse. It is believed that the viral particle and the cell membrane subsequently fuse together and that then the core of the virus enters the cell.
  • the first protein made is a protease that shapes some of the enzymes neces sary for viral RNA synthesis and into an active form. Positive to negative RNAs are syn thesized using these enzymes. Negative RNA is synthesized in large quantities which functions as mRNA having various lengths. These mRNA molecules are necessary for the synthesis of viral structural proteins and positive RNA (genomic RNA) having full length, which is to be incorporated into viral particles. Next, the genomic RNA and the aggregate (shell) of the N protein recognize the viral membrane protein incorporated into the membrane of the rough endoplasmatic reticulum (RER) and force them towards the in side of the intracellular RER to produce virus particles.
  • RER rough endoplasmatic reticulum
  • RER being loaded with viral par- tides subsequently fuses with the Golgi apparatus, i.e., the intracellular excretion appa ratus.
  • the Golgi structures comprising the virus particles then migrate to the cell surface and fuse with the cell membrane to release internal viral particles to the outside of the cell.
  • the present invention addresses this need and provides a compound according to the general formula (I) for use as an antiviral agent; wherein X is O; and
  • the present inventor has surprisingly found that the above-mentioned de- picted compound is capable of inhibiting virus multiplication in host cells by inhibiting the supply of energy in metabolically activated cells.
  • Virus-activated cells but also tumor cells, LPS-activated immune cells and cells with a high rate of glycolysis are driven into suicide by the compound according to the present invention. This is due to the inhibition of glyoxalase-1 and the associated accumulation of cell-toxic methylglyoxal (MGO). Methylglyoxal induces apoptosis in the affected cells.
  • non-metaboli- cally activated cells such as normal, healthy body cells, and cells that are in a post-mitotic state, are not affected by this mechanism.
  • a further advantageous property of the compound of the present invention is that it is capable of inhibiting inflammation of virus-infected cells and tissues. During a virus infection, cells and tissue are typically destroyed, which triggers an inflammatory reaction. This reaction is further reinforced by humoral and cellular defense mecha nisms. The mediators of these mechanisms are primarily inflammatory cytokines such as TNF-alpha, IL-1, and IL-6.
  • the compound of the present invention is, advantageously, capable of inhibiting the release of inflammatory cytokines and thereby abolishes the damaging effects on lung tissue. This does not negatively affect the alveolar oxygen sup ply.
  • the compound of the present invention thus has a protective function for cells and tissues.
  • Another helpful and advantageous property of the compound of the present invention is its anti-viral neuroprotective effect.
  • Coronaviruses and, in particular, SARS- CoV-2 are assumed to reach the central nervous system (CNS) in a neuro-invasion pro cess, probably via the nasal mucosa and lungs.
  • CNS central nervous system
  • the virus causes different neuronal damages including changes in gait safety, and smell and taste distortions.
  • the compound of the present invention can overcome the blood-brain-barrier and is at the same time neuroprotective.
  • a further advantage of the compound of the present invention is its additional property to kill bacteria and other pathogens, such as fungi.
  • the fatal effects of a viral infection, in particular a coronavirus infection such as COVID-19 are more common in people with immunodeficiency, tumor diseases, diabetes, cardiovascular diseases and the elderly. In these cases, but also in infection scenarios, where the subject has no pre existing condition, bacterial superinfections may occur because of immunosuppression in the course of a viral infection.
  • the compound of the present is bactericidal and further eliminates pathogenic fungi.
  • non-pathogenic microbes such as Lacto bacilli are not affected.
  • Yet another extremely helpful feature of the compound of the present inven tion is its capability to preventing virus multiplication in the intestinal tract. Since coro navirus receptors, e.g., SARS-CoV-2 receptors, are also found in the intestinal mucosa, this tissue is a suitable site for virus replication, which can additionally contribute to viral spreading and may also increase the disease symptoms. Since the compound of the pre- sent invention can be formulated as oral composition and can be ingested, e.g., via drinking, it easily reaches the infected intestinal regions, thus attacking the virus there as well. [0020] An extremely useful further property of the compound of the present invention is its volatility.
  • the compound of the present invention can thus be advantageously applied to all areas of the respiratory tract in variable concentrations, e.g., by using a vaporizer through the nose and mouth.
  • R1 comprises 1 to 4 carbon atoms and R2 is H or comprises 1 to 4 carbon atoms. It is preferred that R1 and/or R2 is methyl, ethyl, propyl, isopropyl, butyl, or isobutyl.
  • the compound as defined above has a low IC50 to wards glyoxalase 1 and/or pyruvate kinase, preferably an IC50 towards glyoxalase 1 and/or pyruvate kinase of about 0.01 mM to about 15 mM.
  • said compound is an alkyl 2-oxo derivative.
  • the compound is ethyl 2-oxobutyrate, butyl py ruvate or ethyl pyruvate.
  • the compound as defined herein above is for use in the treatment and/or prophylaxis of a virus infection. It is particularly pre ferred that the virus infection is an infection in a mammal or an avian species.
  • the present invention relates to a prodrug of the compound of formula (I) as defined above, wherein said prodrug is a compound of the general for mula (II) or (III), wherein
  • X is O
  • R1 is a branched or non-branched alkyl, alkenyl, alkinyl or a cycloalkyl residue; and R2 is H or a branched or non-branched alkyl, alkenyl, or alkinyl residue.
  • the present invention relates to a method of treatment com prising administering a therapeutically effective amount of at least one compound ac cording to the general formula (I) wherein X is O;
  • R1 is a branched or non-branched alkyl, alkenyl, alkinyl or a cycloalkyl residue
  • R2 is H or a branched or non-branched alkyl, alkenyl, or alkinyl residue
  • the substituents of the compound used in the context of the method of treat ment as defined above (formula (I)) correspond to those of the compound (formula (I)) according to the present invention as defined above.
  • R1 of general formula (II) or (III) com- prises 1 to 8 carbon atoms and R2 of general formula (II) or (III) is H or comprises 1 to 8 carbon atoms.
  • R1 of general formula (II) or (III) comprises 1 to 4 carbon atoms and R2 of general formula (II) or (III) is H or comprises 1 to 4 carbon atoms.
  • R1 and/or R2 of general formula (II) or (III) is methyl, ethyl, propyl, isopropyl, butyl, or isobutyl.
  • the prodrug is ethyl lactate or propyl lac tate.
  • the compound is ethyl pyruvate and the prodrug is ethyl lactate. More preferably the compound and the prodrug are adminis tered in a proportion of 90:10, 80:20, 70:30, 60:40, 50:50, 40:60, 30:70, 20:80, or 10:90, more preferably in a proportion of 50:50.
  • the present invention relates to a pharmaceutical composi tion comprising at least a compound according to the general formula (I) wherein X is O;
  • R1 is a branched or non-branched alkyl, alkenyl, alkinyl or a cycloalkyl residue
  • R2 is H or a branched or non-branched alkyl, alkenyl, or alkinyl residue
  • R3 and R4 together 0; and/or a prodrug of the compound as described above, for use in the treatment and/or prophylaxis of a virus infection in a mammal or an avian species.
  • said prodrug is ethyl lactate or propyl lactate.
  • said pharma- ceutical composition comprises ethyl pyruvate and ethyl lactate. It is particularly pre ferred that ethyl pyruvate and ethyl lactate are comprised in a proportion of 90:10, 80:20, 70:30, 60:40, 50:50, 40:60, 30:70, 20:80, or 10:90, more preferably in a propor tion of 50:50.
  • the pharmaceutical compo- sition as defined above wherein said compound according to formula (I) and/or prodrug is present in a therapeutically effective concentration.
  • composition as used herein com prises one or more additional therapeutically active ingredients.
  • said additional therapeutically active ingredient is an antivi- ral compound, an antibacterial compound, an antifungal compound, an anti-protozoal compound, an anti-inflammatory compound, a protease inhibitor, an immune stimula tor, a vaccine or a repurposing drug.
  • the additional antiviral compound is an agent which interferes with the binding of the virus to a cellular receptor, an entry in hibitor, an uncoating inhibitor, a reverse transcriptase inhibitor, an integrase inhibitor, a protease inhibitor, a viral assembly inhibitor, a viral release inhibitor, or an agent which interferes with the furin and/or the TMBRSS2 binding site at S1/S2 and S2 ' cleavage site in a virus, preferably the SARS-CoV-2 virus, such as a reactive oxo-aldehyde or a protease inhibitor.
  • the additional antiviral compound is one or more of the group of Abacavir; Acyclovir; Adefovir; Amantadine; Ampligen; Amprenavir; Arbidol; Atazanavir; Atripla; ; Balavir; Baloxavir marboxil; Biktarvy; Boceprevir; Cidofovir; Cobicistat; Combivir; Daclatasvir; Darunavir; Delavirdine; Descovy; Didanosine; Docosa- nol; Dolutegravir; Doravirine; Ecoliever; Edoxudine; Efavirenz; Elvitegravir; Emtricita- bine; Enfuvirtide; Entecavir; Etravirine; Famciclovir; Fomivirsen; Fosamprenavir; Foscar- net; Fosfonet; Fusion inhibitor; Ganciclovir; Ibacitabine; Ibalizumab; Idox
  • the antibacterial agent is one or more of the group of penicillin, aminoglycoside, tetracycline, macrolide, fluoroquinolone, and sulfonamide.
  • the antifungal agent is one or more of the groups of miconazole, ketoconazole, nystatin, ciclopirox, oxiconazole, sertaconazole, efinaconazole, tavaborole, terbinafine, tolnaftate, clotrimazole, salicylic acid and buten- Bennette.
  • the anti-protozoal compound is chloro- quine or a derivative thereof.
  • the pharmaceutical composition as de fined above comprises one or more auxiliary compounds such as fillers, flavouring agents and stabilizers.
  • the pharmaceutical composition is provided in the form of a sustained release or controlled release galenic formulation.
  • the pharmaceutical composition is for topic or sys temic administration.
  • the pharmaceutical composition is for oral, intrave- nous, subcutaneous, intramuscular, intradermal, intraperitoneal, rectal, intranasal, epi dural, percutaneous, transdermal or pulmonary administration, or for administration as an aerosol, via mini-pumps, as mouth lavage, cream, ointment, lipstick, spray, gel, plas ter, and/or via microbubbles.
  • the pharmaceutical composition is ad- ministered via an inhaler device or a spraying device.
  • the present invention relates to a method for disinfecting a substrate against viruses, comprising contacting the substrate with at least a compound according to the invention or a composition as described above.
  • said method additionally comprises a step of ex- posing the substrate to the compound or composition, wherein the exposition time is about 0.5 to 6 h or more, preferably 0.5 to 30 min when inhaled, or at least 6 h when used as an ointment.
  • said virus in- fection is caused by a rapidly replicating virus.
  • Said virus may be a DNA or RNA virus.
  • the virus is a dsDNA virus.
  • said virus is a dsDNA virus belonging to the order of Caudovirales, Herpesvirales or Ligamenvirales, or belongs to the family of Adenoviri- dae, Ampullaviridae, Ascoviridae, Asfarviridae, Baculoviridae, Bicaudaviridae, Clavaviri- dae, Corticoviridae, Fuselloviridae, Globuloviridae, Guttaviridae, Hytrosaviridae, Iri- doviridae, Lavidaviridae, Marseilleviridae, Mimiviridae, Nimaviridae, Nudiviridae, Pan- doraviridae, Papillomaviridae, Phycodnaviridae, Plasmaviridae, Polydnaviruses, Poly- omaviridae, Poxviridae, Sphaerolipoviridae, Tectivi
  • said virus is a ssDNA virus.
  • said virus is a ssDNA virus belonging to the family of Anelloviridae, Bacilladnaviridae, Bidnaviridae, Circoviridae, Geminiviridae, Ge- nomoviridae, Inoviridae, Microviridae, Nanoviridae, Parvoviridae, Smacoviridae or Spiraviridae.
  • said virus is a dsRNA virus.
  • said virus is said virus is a dsRNA virus belonging to the family of Amalgaviridae, Birnaviridae, Chrysoviridae, Cystoviridae, Endornaviridae, Hypoviridae, Megabirnaviridae, Partitiviridae, Picobirnaviridae, Reoviridae, Totiviridae, Quadriviridae, Botybirnavirus, preferably a rotavirus.
  • said virus is a ssRNA virus.
  • said virus is a negative strand ssRNA virus.
  • said virus is said virus is a negative strand ssRNA virus belonging to the order of Muvirales, Serpentovirales, Jingchuvirales, Mononegavi- rales, Goujianvirales, Bunyavirales, Articulavirales.
  • the virus is a negative strand ssRNA virus belonging to the family of Filoviridae, Paramyx- oviridae, Pneumoviridae or Orthomyxoviridae.
  • the virus is an RSV, metapneumovirus, or an influenza virus.
  • said virus is a positive strand ssRNA virus.
  • said virus is a positive strand ssRNA virus belonging to the order of Nidovirales, Picornavirales orTymovirales.
  • said virus is a positive strand ssRNA virus belonging to the family of Coronaviridae, Picornaviridae, Caliciviridae, Flaviviridae or Togaviridae, preferably a rhinovirus, Norwalk-Virus, Echo-Virus or enterovirus.
  • said virus is a Coronavirus or belongs to the group of coronaviruses, or belongs to the group of alpha or beta coronaviruses, prefer ably a human or Microchiroptera (bat) coronavirus.
  • said virus is a causative agent of a viral res piratory tract infection.
  • said virus is a causative agent of MERS, SARS or COVID, preferably COVID-19, or a similar virally induced disease.
  • said virus is PHEV, FcoV, IBV, HCoV- OC43 and HcoV HKU1, JHMV, HCoV NL63, HCoV 229E, TGEV, PEDV, FIPV, CCoV, MHV, BCoV, SARS-CoV, MERS-CoV or SARS-CoV-2, or any mutational derivative thereof.
  • said virus is SARS-CoV-2.
  • said virus infection is or comprises a viral respiratory tract infection. It is particularly preferred that said virus infection is MERS, SARS or COVID, more preferably COVID-19.
  • said pharmaceutical composition is for the treatment and of a virus infection which is present in a mammal or avian species concomitant with a bacterial infection.
  • said bacterial infection is caused by a bacte rium belonging to the genus of Actinobacillus, Actinomyces, Bacteroides, Clostridium, Campylobacter, Enterobacter, Enterococcus, Eubacterium, Fusobacterium, Helicobac- ter, Peptostreptococcus, Pneumococcus, Porphyromonas, Prevotella, Pseudomonas, Spirochetes, Staphylococcus, Streptococcus, or Treponema.
  • said bacterial infection is due to a bacte rium which is resistant beta-lactamase antibiotics and/or to methicillin. It is particularly preferred that said bacterial infection is an MRSA or EHEC infection.
  • the pharmaceutical composition is for use in the treatment of a virus infection which is present in a mammal or avian species concomi tant with a fungal and/or a bacterial infection.
  • the pharmaceutical composition is for use in an immuno- suppressed or immunodeficient mammal or avian species. It is further preferred that said immunosuppression or immunodeficiency is associated with hereditary or acquired immuno-defects. In a particularly preferred embodiment said acquired immune defect is associated with HIV, organ transplantation, chemotherapy or exposure to radiation.
  • Figure 1 shows the mechanism of virus replication on mammalian host cells.
  • Figure 2 shows the inhibition of the enzymatic activity of glyoxalase I of yeast by ethyl pyruvate (EP).
  • Figure 3 shows the inhibition of the enzymatic activity of glyoxalase I of human erythrocytes by ethyl pyruvate (EP).
  • Figure 4 shows targets of ethyl pyruvate and derivatives in metabolically acti vated mammalian cells.
  • Figure 5 shows the effect of ethyl pyruvate on non-metabolically activated hu man skin fibroblasts.
  • Figure 6 shows the effect of ethyl pyruvate on metabolically activated human prostate cancer cells.
  • Figure 7 shows fingerprints of non-disinfected hands on blood agar containing ethyl pyruvate (middle) ethyl lactate (right) and medium (left).
  • the microbes displayed at the circumferences of the agar plates depict a selection of microbes investigated in the present study.
  • Figure 8 shows the inhibition of the growth of a fluconazole-resistant Candida isolates by ethyl pyruvate.
  • Figure 9 shows the effect of ethyl pyruvate on growth of yeast cells in the pres ence of glucose (glycolytic condition) or in the presence of glycerol/ethanol (gluconeo- genetic condition).
  • Figure 10 shows shows the decreasing size and number of plaques with increas ing concentration of ethyl pyruvate in the overlay medium indicating that ethyl pyruvate is capable to diminish the cytopathic effect of the virus.
  • Figure 11 shows inhibition of release of inflammatory cytokines by ethyl py ruvate (EP) and ethyl lactate in LPS-stimulated blood cells.
  • Figure 12 shows the effect of ethyl pyruvate and ethyl lactate on cellular ATP level in cells exhibiting a high glycolytic throughput.
  • the terms “about” and “approximately” denote an interval of accuracy that a person skilled in the art will understand to still ensure the technical effect of the feature in question.
  • the term typically indicates a de viation from the indicated numerical value of ⁇ 20 %, preferably ⁇ 15 %, more preferably ⁇ 10 %, and even more preferably ⁇ 5 %.
  • the terms relate to steps of a method or use there is no time or time interval coherence between the steps, i.e., the steps may be carried out simultaneously or there may be time intervals of seconds, minutes, hours, days, weeks etc. between such steps, unless otherwise indicated.
  • the present invention concerns in one aspect a com pound according to the general formula (I) for use as an antiviral agent; wherein X is O, wherein R1 is a branched or non-branched alkyl, branched or non-branched alkenyl, branched or non-branched alkinyl, alkoxyalkyl, or alkoxycarbonylalkyl, each preferably with a chain length of Cl to CIO, more preferably Cl to C8, more preferably Cl to C4, in particular Cl, C2, C3 or C4;or a cycloalkyl, cycloalkenyl, cycloa Ikinyl, aryl or a sugar resi due, each preferably with a chain length of C3 to CIO, more preferably C3 to C8, more preferably C3, C4, C5 or C6; and
  • the sugar in position R1 is substituted or non-substituted sugar.
  • R1 comprises 1 to 4 carbon atoms and R2 is H or comprises 1 or 2 carbon atoms.
  • R1 and/or R2 is methyl, ethyl, propyl, isopropyl, butyl, or isobutyl.
  • R2 is H
  • R1 is methyl, ethyl, propyl, isopropyl, butyl, or isobutyl.
  • Specific examples of compounds according to formula (I) comprise methyl py ruvate, ethyl pyruvate, propyl pyruvate, butyl pyruvate, pentyl pyruvate, hexyl pyruvate, octyl pyruvate, isobutyl pyruvate, isopentyl pyruvate, isohexyl pyruvate, isoheptyl pyrvate, isooctyl pyruvate, cyclopentyl pyruvate, cyclopentylmethyl pyruvate, cyclo hexyl pyruvate, cyclohexylmethyl pyruvate, butenyl pyruvate, hexenyl pyruvate, isobu- tenyl pyruvate, isohexenyl pyruvate, butinyl pyruvate,
  • [OIOS] Preferred examples of compounds according to the invention comprise methyl pyruvate, ethyl pyruvate, propyl pyruvate, butyl pyruvate, pentyl pyruvate, hexyl py ruvate, isopropyl pyruvate, isobutyl pyruvate, isopentyl pyruvate, isohexyl pyruvate, methyl-2-oxobutanoate, methyl-2-oxopentanoate, ethyl-2-oxobutanoate, butyl-2-oxo- butanoate, ethyl-2-oxopentanoate and cyclohexylmethyl pyruvate.
  • Particularly preferred compounds according to the present invention are me thyl pyruvate, ethyl pyruvate, propyl pyruvate, butyl pyruvate, isobutyl pyruvate, ethyl- 2-oxobutanoate, ethyl-2-oxopantanoate and cyclohexylmethyl pyruvate.
  • alkyl 2-oxo derivates are particularly preferred.
  • the compound according to the invention is not a pyruvate.
  • Even more preferred compounds according to the present invention are me- thyl pyruvate, ethyl pyruvate, butyl pyruvate, isobutyl pyruvate and ethyl-2-oxo-butyr- ate.
  • the most preferred compounds according to the present invention are ethyl 2- oxobutyrate, ethyl 2-oxobutyrate and ethyl pyruvate, which are also shown in the fol lowing Table 2. [0109] Table 2: Most preferred compounds for use as antiviral agents according to the invention.
  • the compound according to the present invention has a low IC50 towards glyoxalase 1 and/or pyruvate kinase.
  • IC50 as used herein relates to the half maximal inhibitory concentration of a compound, which is a measure of the potency of the compound in inhibiting a specific biological or biochemical function. IC50 is a quantitative measure that indicates how much of a par ticular inhibitory compound is needed to inhibit, in vitro, a given biological process or biological component by 50%.
  • the biological/bi ochemical process is the enzymatic activity of glyoxalase 1.
  • a further biological/bio chemical process which is inhibited by the compounds of the present invention is the activity of pyruvate kinase.
  • the IC50 value used in the context of the present invention relates to a value obtained from cell culture experiments with the mentioned enzymatic activities. Further details and protocols may be derived from the Examples.
  • Glyoxalase 1 is an enzyme that catalyzes the isomerization of hemithioacetal adducts, which are formed in a spontaneous reaction between a glutathionyl group and aldehydes such as methylglyoxal.
  • Glyoxalase 1 derives its name from its catalysis of the first step in the glyoxalase system, which is a two-step detoxification system for methyl glyoxal.
  • Glyoxalase 1 (GLOl, alternatively abbreviated as Gly 1,) is also known as (R)-S- lactoylglytythione methyl-glyoxal-lyase EC4.4.1.5).
  • the second detoxification step in which (R)-S-lactoylglutathione is split into glutathione and D-lactate, is carried out by glyoxalase 2, a hydrolase.
  • Glyoxalase 1 thus is responsible for the degradation of the side product of glycolysis, methylglyoxal. Methylglyoxal is cytotoxic (e.g. by the formation of adducts with cellular proteins and nucleic acids).
  • apoptotic cell death may be induced in a cell, e.g. a eukaryotic cell, preferably in a mammal cell or the cell of an avian species, which is in fected by a virus, more preferably in a human cell which is infected by a virus, in partic- ular a coronavirus or similar virus as defined herein.
  • a cell e.g. a eukaryotic cell, preferably in a mammal cell or the cell of an avian species, which is in fected by a virus, more preferably in a human cell which is infected by a virus, in partic- ular a coronavirus or similar virus as defined herein.
  • a further example of an enzyme, which can advantageously be inhibited by a compound of the present invention is pyruvate kinase.
  • Pyruvate kinase is an enzyme, which is involved in the last step of glycolysis. It catalyzes the transfer of a phosphate group from phosphoenolpyruvate (PEP) to adenosine diphosphate (ADP), yielding one molecule of pyruvate and one molecule of ATP.
  • PEP phosphoenolpyruvate
  • ADP adenosine diphosphate
  • An inhibition of pyruvate kinase leads to a slowing down of glycolysis and is assumed to reduce the availability of energy sources such as ATP in a cell.
  • a eukaryotic cell preferably a mammal cell or cell of an avian species, which is infected by a virus, more preferably a human cell which is infected by a coronavirus or similar virus as defined herein, will re- prise the virus induced viral replication due to a general shortage of biochemical energy sources.
  • compounds of the present invention such as ethyl pyruvate are capable of inhibiting at least glyoxalase 1 and pyruvate kinase. Inhibition of glyoxalases by compounds of the present invention thus inhibits the cellular detoxification of methylglyoxal and via various mechanisms leads to the inhibition of cell proliferation and to cell death.
  • com pounds of the invention inhibit such cells showing a clearly increased rate of glycolysis whereas the metabolism of cells with a normal rate of glycolysis is not or only slightly affected.
  • a compound as defined herein has a low IC50 value for the inhibition of the enzymatic activity of glyoxalase 1 and/or pyruvate kinase as obtained in an in vitro test, preferably as obtained in an in vitro test described herein. It is preferred that the IC50 towards glyoxalase 1 is of about 0.01 mM to about 15 mM.
  • the IC50 value for an enzyme involved in a detoxification system is between about 0.5 to 3 mM, more preferably between about 1 and 2 mM.
  • the IC50 value for an enzyme involved in a detoxification system is between about 5 to 9 mM, more preferably between about 7 and 8 mM.
  • the most preferred compounds i.e., ethyl 2-oxobutyrate.
  • the IC50 value for an enzyme involved in a detoxification system is between about 8 to 12 mM, more preferably between about 9.5 and 10.5 mM.
  • the present invention also relates to antiviral compounds which are indirect inhibitors, i.e. which work as prodrugs and require metabolic activation by the cellular enzymatic machinery.
  • Specific compounds ofthe general formula (II) and/or (III) may, for example, be methyl lactate, propyl lactate, butyl lactate, ethyl lactate, and ethyl-2-hydroxybuta- noate, which are transformed into, e.g. butyl pyruvate, ethyl pyruvate, or ethyl-2-oxo- butanoate, respectively.
  • R3 or R4 is OH
  • the invention encompasses the D-, L- enantiomer and the racemic mixture thereof.
  • equimolar as well as non-equimolar mixtures of corresponding enantio mers are to be considered as racemic mixtures.
  • the compounds of the invention are compounds with one or more chiral centers, for example ethyl lactate or butyl lactate
  • the corresponding D- and L-isomers can be used as well as racemic mixtures, for example ethyl D-lactate (DEL), ethyl L-lactate (LEL) or racemic mixtures of DEL and LEL, and butyl D-lactate (DBL), butyl L-lactate (LBL) or racemic mixtures of DBL and LBL, respectively.
  • DEL ethyl D-lactate
  • LEL ethyl L-lactate
  • DBL butyl L-lactate
  • Specific examples of compounds of the invention are listed in the following ta ble 3, however, it is to be understood that this is not a limiting list.
  • the D- or L- enantiomers orthe racemic mixtures thereof of the following com pounds are additionally envisaged in specific embodiments of the present invention: methyl lactate, ethyl lactate, propyl lactate, butyl lactate, pentyl lactate, hexyl lactate, octyl lactate, isobutyl lactate, isopentyl lactate, isohexyl lactate, isoheptyl lactate, isooc tyl lactate, cyclopentyl lactate, cyclopentylmethyl lactate, cyclohexyl lactate, cyclohex- ylmethyl lactate, butenyl lactate, hexenyl lactate, isobutenyl lactate, isohexenyl lactate, butinyl lactate, hexinyl lactate, methoxymethyl lactate, ethoxymethyl lactate, ethox- ycarbonylmethyl
  • the prodrug compounds according to the present invention for example ethyl lactate or propyl lactate, are transformed into ac tive compounds by NAD-dependent lactate dehydrogenases or similar enzymatic activi ties.
  • lactate and alkyl lactate are transported over the cell membrane by a lactate shuttle (mon- ocarboxylate transporters (MCT ' s)) in combination with a proton transporter.
  • MCT mono- ocarboxylate transporters
  • MCTs mitochondria mitochondrial MCTs are available.
  • Addition of lactate and its alkyl esters, respectively, to blood leads typically to slight alkalization due to the pro- ton-connected lactate transporters whereas the application of pyruvate and its alkyl es- ters, respectively, leads to an acidosis of blood, caused by enzymatic ester cleavage.
  • Lac tate and alkyl lactate may be transported stereo selectively and better through the membrane as compared to pyruvate and alkyl pyruvate. According to certain embodi ments, alkyl pyruvates administered to blood are most probably transformed into alkyl lactates before they can enter cells.
  • the present invention relates to the medical use of compounds of the inven tion, their use for the preparation of medicaments, pharmaceutical compositions com prising said compounds and methods of treatment comprising administering said com pounds or compositions.
  • a pharmaceutical composi tion comprising the compound as defined herein for use in the treatment and/or prophylaxis of a virus infection in a mammal or avian species.
  • a pharmaceutical composi tion comprises at least one compound of the invention as defined herein.
  • the pharmaceutical composition of the invention may comprise the compound according to the invention as the sole active ingredient. This does not exclude the presence of more than one compound of the present invention. This does also not exclude the presence of non-pharmaceutically active additives, i.e., substances which contribute to preparing a galenic formulation, such as fillers, flavour- ing agents, stabilizers, etc.
  • R3 or R4 is -OH like compounds of the general formula (II) and (III), e.g., ethyl lactate, (ethyl D- and/or L-lactate) may be provided in a pharmaceutical composition.
  • composition according to the invention can further com- prise one or more additional pharmaceutically or therapeutically active ingredients.
  • additional pharmaceutically or therapeutically active ingredients the low toxicity of the com pounds of the present invention as well as their metabolites is of particular advantage.
  • the additional therapeutically active ingredient is an antiviral compound, an antibacterial compound, an antifungal compound or an anti-protozoal compound, an anti-inflammatory compound, a protease inhibitor, an immune stimula tor, a vaccine or a repurposing drug.
  • Envisaged examples of additional antiviral compounds are agents which gener ally interfere with the virus' life cycle, replication and dispersal strategy.
  • the compound interferes with the binding of the virus to a cellular receptor.
  • the compound is an entry inhibitor, an uncoating inhibitor, a reverse tran scriptase inhibitor, an integrase inhibitor, a protease inhibitor, a viral assembly inhibitor, or a viral release inhibitor.
  • the antiviral compound is an agent which interferes with the furin and/or the TMBRSS2 binding site at S1/S2 and S2 ' cleav age site in a virus, preferably the SARS-CoV-2 virus.
  • agents include reactive oxo-aldehydes and protease inhibitors. Particularly preferred is methylglyoxal (MGO) and functional analogues thereof.
  • Preferred examples of additional antiviral compounds which may be used to gether with the compound(s) according to the present invention include one or more of the group of: Abacavir; Acyclovir; Adefovir; Amantadine; Ampligen; Amprenavir; Ar- bidol; Atazanavir; Atripla; Balavir; Baloxavir marboxil; Biktarvy; Boceprevir; Cidofovir; Cobicistat; Combivir; Daclatasvir; Darunavir; Delavirdine; Descovy; Didanosine; Docosa- nol; Dolutegravir; Doravirine; Ecoliever; Edoxudine; Efavirenz; Elvitegravir; Emtricita- bine; Enfuvirtide; Entecavir; Etravirine; Famciclovir; Fomivirsen; Fosamprenavir; Foscar- net; Fosfonet; Fusion inhibitor; Ganciclovir
  • antiviral plant ex tract relates to mixture plant extracts of plants which are known for their antiviral activity.
  • the group of plants includes 2, S, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or more or all of the following plants or plant extracts: Heracleum maximum, Plantago major Linn, P. asiatica Linn, Trifollium species, Pandanus, Amarylli- folius Roxb, Carissa edulis, Phyllanthus urinaria L., Astzragalus chinensis, Geranium san- guineum L., Elderberry extract, Boehmeria nivea L., Saxifraga melanocentra.
  • antibiotics comprising one or more selected from beta-lactam antibiotics (penicillins, ampicillins, carbenicillins, methicillin, ticarcillin, cephalosporin, imipenem, aztreonam), azithromy- cin, aminoglycosides (gentamycin, kanamycin, neomycin, netilmicin, streptomycin, to bramycin), tetracyclines (demeclocyclin, doxycyclin, minocyclin, oxytetracyclin), macro- lide (azithromycin, clarithromycin, clindamycin, erythromycin, lincomycin), quinolones and fluoroquinolones (cinoxacin, nalidixic acid, ciprofloxacin, enoxacin, norfloxacin, levofloxacin, lomefloxacin), sulfonamides (sulfiso
  • Suitable and envisaged examples of antifungal agents include one or more of the group of miconazole, ketoconazole, nystatin, ciclopirox, oxiconazole, sertaconazole, efinaconazole, tavaborole, terbinafine, tolnaftate, clotrimazole, salicylic acid and buten- antagoniste.
  • a suitable and envisaged example of an anti-protozoal compound is chloro- quine or a derivative thereof.
  • a suitable and envisaged example of an anti-inflammatory compound is ibu- profen, naproxen, diclofenac, diflunisal, etodolac, flurbiprofen, indomethacin, keto- profen, mefenamic acid, meloxicam, nabumetone, oxaprozin, piroxicam or sulindac.
  • a suitable and envisaged example of a protease inhibitor is atazanavir, da- runavir, fosamprenavir, indinavir, lopinavir/ritonavir, nelfinavir, ritonavir, saquinavir, tipranavir, atazanavir/cobicistat, darunavir/cobicistat.
  • immunosimulant relates to a non-specific immunosimulant.
  • a suitable and envisaged example of an immune stimulator is deoxycholic acid (DCA), imiquimod, resiquimod, glatiramer, pegademase, elapegademase, plerixafor, inter feron, interleukin, or colony stimulating factors.
  • a suitable and envisaged example of a vaccine is a vaccine against a coronavirus, preferably against SARS-CoV-2.
  • the vaccine may be a transcript or mRNA based or may be a vector based or protein-based vaccine.
  • the vaccine may be a vaccine produced and/or marketed by Biontech/Pfizer, John- son&Johnson, Moderna, AstraZeneca, Curvac, Biocad or any other company dedicated to the development of antiviral vaccines.
  • the term "repurposing drug" as used herein relates to a medicament for which a new therapeutic use or application is identified. It is preferred that this medicament's new use is associated with viral infections, preferably with the COVID disease or related diseases.
  • a suitable and envisaged example of a repurposing drug is remdesivir, astemi- zole, clofazimine, budesonide, tetrandrine.
  • corticosteroids e.g., glucocorticoids such as dexamethasone or budesonide.
  • Particularly preferred is the combination of compounds of the present inven tion, in particular ethyl pyruvate or the corresponding thioester, and oxamate, an inhib itor of lactate dehydrogenase. Also particularly preferred is the combination of com pounds of the present invention and an inhibitor of the glycerol aldehyde phosphate dehydrogenase, such as iodide acetate, and/or the lactate dehydrogenase inhibitor ox amate.
  • the pharmaceutical composition according to the present invention may com prise one or more compounds according to the present invention in combination with one or more additional agents, e.g., agents fulfilling different functions such as antibiot ics and antifungal agents, or different agents fulfilling the same function such as two or more different antibiotics etc.
  • additional agents e.g., agents fulfilling different functions such as antibiot ics and antifungal agents, or different agents fulfilling the same function such as two or more different antibiotics etc.
  • the present invention relates the use of com pounds of the present invention in combination with known or novel genetic methods like siRNA and antisense nucleotides for the targeted inhibition of enzymes or proteins.
  • the pharmaceutical composition or medicament can further comprise one or more auxiliary substances useful forthe galenic formulations of drugs, including, but not limited to, fillers, flavouring agents, stabilizers, and agents that prevent microbial growth in the pharmaceutical composition, propellants for inhalation, sequestering agents for stabilization of inhalation compositions, solvents or co-solvents etc.
  • auxiliary substances useful forthe galenic formulations of drugs including, but not limited to, fillers, flavouring agents, stabilizers, and agents that prevent microbial growth in the pharmaceutical composition, propellants for inhalation, sequestering agents for stabilization of inhalation compositions, solvents or co-solvents etc.
  • the pharmaceutical composition can be provided or used in any suitable ga- lenic formulation, depending on specific virus infection to be treated and the chosen route of administration.
  • the skilled person can readily select and prepare a suitable preparation based on common general knowledge.
  • Pharmaceutical compositions of the invention can be prepared according to known methods e.g., by mixing one or more effective substances with one or more carriers, and forming of e.g., aerosols or aerosol formulations, tablets, capsules, or liquid solutions. Where appropriate, solutions can, for example, be encapsulated in liposomes, microcapsules, or other forms of containment.
  • suitable formulations comprise aqueous solutions which can op tionally be buffered, water in oil emulsions, oil in water emulsions, creams, ointments and formulations comprising any of the foregoing.
  • the invention envisages a pharmaceutical composi tion prepared in the form of a sustained release or controlled release galenic formula tion.
  • Such formulations allow the targeted release in e.g., a certain location, such as a certain part of the stomach or intestine, or a certain tissue or organ, and/or allow the sustained release over a defined period of time.
  • an antiviral composition or pharmaceutical composition according to the present inven tion may be provided in the form of nasal drops, a spray, or an inhalant (droplet) form.
  • the antiviral composition or pharmaceutical composition according to the present invention may previously have been administered to, for example, the nasal cavity and the pharyngeal mucosa, and the lung.
  • the antiviral composition or pharma ceutical composition according to the present invention may accordingly be maintained at sufficiently high concentration around the cells of the pharyngeal mucosa and the lung.
  • For skin and mucous membrane viruses, patches, bandages, gauzes, nonwoven fabrics, gel-like patches, gelatinized patches, ointments, lipsticks enriched in the antivi ral composition or pharmaceutical composition according to the present invention may be provided.
  • Providing an antiviral composition or pharmaceutical composition accord ing to the present invention having the form of ointment or lotion makes it further pos- sible to maintain the antiviral compound or pharmaceutical composition at a sufficiently high concentration in the affected area.
  • the pharmaceutical composition accord ing to the present invention in the form of a composition suitable for inhalation or direct use in the respiratory tract of a subject, e.g., in the mouth, pharynx and lungs of a sub- ject.
  • the present invention envisages the formulation of the pharmaceutical composition as composition suitable for aerosol administration. It is particularly envis aged to use the pharmaceutical composition with pressurized metered dose inhalers (MDIs) suitable for aerosol administration. These MDI may use a propellant to expel droplets containing the pharmaceutical composition to the respiratory tract as an aero- sol.
  • MDIs pressurized metered dose inhalers
  • Suitable examples of such propellants include, for example, hydrofluoroalkanes (HFAs) such as 1,1,1,2-tetrafluoroethane (HFA 134a) or 1,1,1,2,3,3,3-heptafluoropro- pane (HFA 227) which have been acknowledged to be the best candidates for non-CFC propellants.
  • HFAs hydrofluoroalkanes
  • HFA 134a 1,1,1,2-tetrafluoroethane
  • HFA 227 1,1,1,2,3,3,3-heptafluoropro- pane
  • compositions to be used for inhalation according to the present invention may further contain excipients and in particular a low volatility com ponent in order to increase the mass median aerodynamic diameter (MMAD) of the aerosol particles on actuation of the inhaler.
  • MMAD mass median aerodynamic diameter
  • a pharmaceutical preparation can also be prepared by mixing ester components of the compounds of the invention under conditions at which compounds of the general formula (I) are formed.
  • the pharmaceutical prepara tion can also be prepared by assembling ester components of the compounds of the invention such that in the organism, for example in the acidic environment of the stom ach, the compounds of the general formula (I), (II) or (III) are formed.
  • Ester components are for example an alkanol like for example ethanol and an organic acid like for example lactic acid.
  • the pharmaceutical composition of the invention comprises at least one com pound of the invention in a therapeutically effective concentration or amount.
  • the skilled person can readily determine the therapeutically effective concentration or amount in standard in vitro or in vivo experiments.
  • the effective amount can be estimated based on an extrapolation from in vitro data, such as enzyme inhibition or cellular assays.
  • a dosage can be formulated in animal models which corresponds to the IC50 in cell culture experiments, e.g. as derivable from the Examples, infra.
  • the optimal dosage for the vertebrate to be treated can be deduced from animal experiments.
  • the amount of the agent to be administered naturally depends on the person to be treated, his body weight, his genetic and physical constitution, the disease state, the route of administra tion, the galenic formulation and other parameters.
  • dosage and the interval of administration may depend on the re spective clinical situation of the patient to guarantee a therapeutic effect.
  • useful effective concentrations i.e., concentrations to be achieved at the level of cellular exposure, may range from at least 0.05 mM up to 700 mM, e.g., including 1, 2, 3, 4, 5, 10, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 400, 450, 500, 550, 600,
  • the concentration typically depends on the route of administration, the tissue type and other factors and can accordingly be adapted or modified in line with the skilled person's common general knowledge.
  • the therapeutically effective concentration or amount of a pharmaceutical composition or of a compound according to the present invention may be specifically adapted to the preferred route of inhala tion.
  • the amount or concentration or active ingredient used for inhalation is higher than the amount to be used for other routes of administration. It is accordingly preferred to use a suitably defined concentration.
  • the optimal therapeutic concentration must be tested.
  • Useful effective concentrations i.e.
  • concentrations to be achieved at the site of cellular exposure range from at least 5 mM, preferably from 5 mM to 50 mM, more preferably from 5 to 200 mM, most preferably from 5 mM to 700 mM in the context of inhalation.
  • the effective concentrations to be applied may be different, preferably 1 mM to 20 mM, most preferably 1 mM to 100 mM, e.g., when given by infusion. In topic applications higher concentrations may be useful. Preferred are 0.2 to 200 mM, more preferred are 0.2 to 50 mM and 50 to 200 mM.
  • the concentrations above refer to desired blood and/or tissue concentrations, or local concentrations.
  • the invention relates to pharmaceutical preparations suitable to achieve such concentrations upon administration.
  • the pharmaceutical composition of the present invention is generally applied for several days or weeks as repeated bolus doses (e.g., injections, or inhalation) or continuous administration (e.g. infusion), or any time period required to achieve a therapeutic effect, at the respective therapeutically effective dos- age.
  • repeated bolus doses e.g., injections, or inhalation
  • continuous administration e.g. infusion
  • esters are of limited stability, which may require the use of higher and/or repeated doses for all kind of applications.
  • dosage and the interval of administration can be guided by the individual plasma concentrations of the agent that guarantee a therapeutic effect.
  • composition of the present invention can, in further em- bodiments, be administered topically or systemically.
  • a local administration to a selected site can be performed.
  • compositions comprising the compounds of the invention can be administered according to suitable or generally known method - including but not limited to oral, intravenous, intraarterial, subcutaneous, intramuscular, intradermal, in- traperitonal, intraauricular, rectal, intranasal, epidural, percutaneous, transdermal or pulmonary administration, or administration as an aerosol, nasal drops, via mini-pumps, as mouth lavage, gel, ointment, cream, spray, oil, lipstick, plaster, via microbubbles and/or pulmonary application (e.g. by inhalation or via an inhalator). It is particularly preferred to administer the pharmaceutical composition via inhalation as outlined above.
  • a spraying device e.g. as aerosol.
  • suitable literature sources such as Anthony J. Hickey, Sandro R. da Rocha, Pharmaceutical Inhalation Aerosol Technology, CRC Press, Third Edition, 2019.
  • the pharmaceutical composition is ad- ministered via the respiratory tract and/or the mouth. It is further particularly preferred to administer the pharmaceutical composition via an inhaler device or a spraying device.
  • Administration may, in further embodiments, be for example systemic, e.g., by single or repeated oral or parenteral application, or via methods wherein the medica ment is administered systemically in an inert vehicle and is only released at the desired location by respective manipulation. An example thereof is, amongst others, so called microbubbles.
  • the pharmaceutical composition can also be a provided as food supplement or beverage supplement.
  • food supplement or “beverage supplement” means a pharmaceutical composition that is administered to gether with the standard daily diet, or a special medical diet. It also means “health food”, i.e., food of a particular composition that is consumed by subjects without medical su pervision to achieve a prophylactic or therapeutic effect.
  • the pharmaceutical composition is formulated as drink or beverage, i.e., is mixed with water or other beverages and may then be orally administered.
  • the present invention relates to a method for disinfecting a substrate against viruses, comprising contacting the substrate with at least a compound according to the invention or a composition according to the invention, as described above.
  • the contacting may be performed in any suitable manner, e.g., by spraying, wet ting, production of aerosols and application thereof to the substrate etc.
  • the contacting may be performed with any suitable amount of the compound and in any suitable fre quency of application.
  • the substrate may be contacted once or more often with the compound or composition in order to achieve a disinfection effect.
  • the method additionally comprises a step of exposing the substrate to the com pound or composition as defined above for a certain period of time.
  • the exposure time may be between about 10 sec to 6 h or more, e.g. about 10 sec to 60 min, preferably between about 0.5 min to 30 min, more preferably between about 1 min to BO min, or for any other period of time, e.g. 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 0, 25, 30, 35, 4045 or more minutes, especially when inhaled, or, in a different embodi ment between 1 h to 6 h, especially when administered as an ointment.
  • a central aspect of the present invention is that the compound, pharmaceutical composition, medicament or method of treatment of the present invention is for the treatment of a virus infection in a subject, i.e., that the compound is used as antiviral compound.
  • the compound, pharmaceutical composition, me dicament or method of treatment of the present invention is for the prophylaxis of a virus infection in a subject.
  • a subject to be treated may be a mammal, in particular a human.
  • the mammals may be dogs, cats, swine, cattle, monkeys, goats, sheep, mice, rats and others. Also envisaged are other mammals.
  • non-mammalian animals may be treated, e.g., chicken or other types of birds etc. It is further preferred that the non-mammalian animal is an avian species. Envisaged exam- pies of avian species include poultry such as chicken, turkeys, ducks, geese, guinea fowls or pigeons.
  • treatment and/or prophylaxis of viral infections encompasses viri cidal and virostatic effects.
  • the treatment approach is via virus infected cells, i.e. the viricidal and virostatic effect are implemented by reducing or eliminating the viral repli- cation in a mammal cell or avian cell, e.g. in a human epithelial cell.
  • the pharmaceutical compositions or compounds of the present invention thus have no direct virus-destroy ing effect, but indirectly and significantly or completely abolish the viral replication in tissues which were treated.
  • a viral infection makes use of at least part of the cellular machinery and also the cellular energy resources during their replication and multiplication.
  • the cellular machinery is misused for viral activities which typically involves a high energy turnover.
  • the virus accordingly depends on energy gained by cellular mecha- nisms such as oxidizing glycerolaldehyde phosphate to pyruvate (glycolysis).
  • mam mal cells such as epithelial cells or avian cells utilize glycolysis, as well as detoxifying glyoxalases, it is suggested by this invention that the inhibition of glycolytic enzymes by compounds as defined above induce cell death or apoptosis and thereby reduce and ultimately eliminate the viral infection process.
  • the compound accord ing to the present invention is also capable of reducing bacterial or fungal infections, since bacteria and fungi also make use of glycolysis and thus are vulnerable to the inhi bition of glycolytic enzymes by compounds as defined above. This allows for a unique treatment of not only virus infections, but also additional bacterial and/or fungal infec tions, which may be present as additional complication during a virus infection.
  • virus infection encompasses viral infection of certain tissues, e.g., of the respiratory tract, the brain, the gastrointestinal tract, the liver or the mucosa as well as systemic infections, including infections of general tissues and organs.
  • Compounds of the invention are used for the treatment of mucosal (topic), respiratory tract or lung diseases and/or systemic diseases.
  • bacterial infection encompasses superficial colonisation by bacte ria, e.g., of the skin, intraauricular, respiratory tract or mucosa as well as systemic infec tions, including infections of blood, tissues and organs. Also encompassed are infections of the gastrointestinal tract.
  • Compounds of the invention may be used are used for the treatment of mucosal (topic) and/or systemic diseases.
  • the mucosal diseases can be caused by oral or vaginal infections.
  • the oral or vaginal infections are for example the consequence of AIDS, chemotherapy or an immune suppressive therapy or immune sup pressive conditions.
  • treatment encompasses the provision of pharmaceutical composi tions as defined herein to subjects suffering from any of various disease or virus infec tion stages or stages of virus and bacterial/fungal infection, such as acute or chronic infection, and may also encompass after-treatment as well as prophylaxis.
  • After-treat ment means a treatment following conventional therapy. Treatment concomitantly with conventional therapy (e.g., further antiviral treatment or treatment with antibiot ics) is also part of the present invention.
  • prophylaxis as used herein relates to the administration of a phar maceutical composition of the invention when a subject is at risk to develop a virus in fection or a combination of a virus and bacterial/fungal infection, or a disease/infection is suspected or is present sub-clinically, but said disease/infection has not fully evolved or has not been diagnosed.
  • the present invention relates to the treat ment or prophylaxis of a virus infection caused by a replicating virus, more preferably by a rapidly replicating virus.
  • replicating virus refers to the property of viruses to replicate by making use of the cellular machinery and thereby using the cells energy sources and mechanisms for generating energy, e.g., in the form of ATP.
  • the present invention is not directed to the treatment of dormant or sleeping or inactive viruses, since these viruses are not making cellular energy producing mecha nism, in particular those mechanisms which can be inhibited via the inhibition of glyox- alase 1 or pyruvate kinase.
  • said virus infection may be provoked or induced by any virus attacking a subject according to the present invention, e.g., a mammal or avian species, in particular a human being.
  • the virus infection may, for example, be caused by a DNA or RNA virus.
  • the DNA virus may be a dsDNA virus.
  • the dsDNA virus may, in fur ther embodiments, belong to the order of Caudovirales, Herpesvirales or Ligamen- virales, or belongs to the family of Adenoviridae, Ampullaviridae, Ascoviridae, Asfarviri- dae, Baculoviridae, Bicaudaviridae, Clavaviridae, Corticoviridae, Fuselloviridae, Globulo- viridae, Guttaviridae, Hytrosaviridae, Iridoviridae, Lavidaviridae, Marseilleviridae, Mim- iviridae, Nimaviridae, Nudiviridae, Pandoraviridae, Papillomaviridae, Phycodnaviridae, Plasmaviridae, Polydnaviruses, Polyomaviridae, Poxviridae, Sphaerolipoviridae, Tec- tiviridae,
  • the virus infection to be treated according to the pre sent invention may, for example, be caused by a ssDNA virus.
  • the ssDNA virus may, in further embodiments, belong to the family of Anelloviridae, Bacilladnaviridae, Bidnaviri- dae, Circoviridae, Geminiviridae, Genomoviridae, Inoviridae, Microviridae, Nanoviridae, Parvoviridae, Smacoviridae or Spiraviridae.
  • the virus infection to be treated according to the pre sent invention may, for example, be caused by a dsRNA virus.
  • the dsDNA virus may, in further embodiments, belong to the family of Amalgaviridae, Birnaviridae, Chrysoviri- dae, Cystoviridae, Endornaviridae, Hypoviridae, Megabirnaviridae, Partitiviridae, Pico- birnaviridae, Reoviridae, Totiviridae, Quadriviridae, Botybirnavirus.
  • it is a ro tavirus.
  • the virus infection to be treated according to the pre- sent invention may, for example, be caused by a ssRNA virus.
  • said virus may be a negative strand ssRNA virus.
  • the negative strand ssRNA virus may, in further embodiments, belong to the order of Muvirales, Serpentovirales, Jingchu- virales, Mononegavi rales, Goujianvirales, Bunyavirales or Articulavirales.
  • the virus is a negative strand ssRNA virus belonging to the family of Filoviridae, Paramyxoviridae, Pneumoviridae or Orthomyxoviridae.
  • the virus is an RSV, metapneumovirus, or an influenza virus.
  • the virus infection to be treated according to the present invention may, for example, be caused by a positive strand ssRNA virus.
  • Said positive strand ssRNA virus may, for example, belong to the order of Nidovirales, Picornavirales orTymovirales.
  • said virus is a pos itive strand ssRNA virus belonging to the family of Coronaviridae, Picornaviridae, Calici- viridae, Flaviviridae or Togaviridae. It is further preferred that virus is a rhinovirus, Nor- walk-Virus, Echo-Virus or enterovirus.
  • the virus infection to be treated according to the present invention may, for example, be caused by a virus belonging to the family of Coronaviridae.
  • a virus belonging to the family of Coronaviridae examples are Coronavirus ora member of the group of Coronavi ruses.
  • the group of Coronaviruses is typically divided into subgroups, i.e., alpha or beta coro- naviruses.
  • the present invention in very preferred embodiment, envisages the treat ment of a virus infection caused by a human coronavirus or a Microchiroptera (bat) coro navirus or a coronavirus obtained from wild an animal belonging to the group of pango lins or similar animals or belonging the Pholidota group.
  • bat Microchiroptera
  • the virus is a causative agent of a viral res- piratory tract infection. Accordingly, the virus may belong to any of the above men tioned groups, families, classes or orders and be known to the skilled person as causing a viral respiratory tract infection.
  • said virus is a causative agent of MERS, SARS or COVID.
  • the virus is a causative agent of COVID-19, or a similar virally induced disease.
  • said virus is PHEV, FcoV, IBV, HCoV- OC43 and HcoV HKU1, JHMV, HCoV NL63, HCoV 229E, TGEV, PEDV, FIPV, CCoV, MHV, BCoV, SARS-CoV, MERS-CoV or SARS-CoV-2, or any mutational derivative thereof.
  • the term "mutational derivative thereof" as used herein relates to virus variants, which do not have the same genomic sequence as the mentioned viruses but is derived therefrom by mutational events which are typical for this virus group. These events may lead to changes in the infectious behavior of the virus, but still allows for a classification of the virus, thus identification of the virus as belonging to the group of coronaviruses.
  • said virus is SARS-CoV-2.
  • the virus infection to be treated is or comprises a viral respiratory tract infection. It is particularly preferred that said virus infection is MERS, SARS or COVID, more preferably COVID-19.
  • MERS MERS
  • SARS SARS
  • COVID COVID-19.
  • the present invention relates to the treatment or prophylaxis of a virus infection in a mammal or avian species concomitant with a bacte rial infection.
  • the compound according to the present invention is not only capable of reducing or eliminating the viral replication in a mammalian or avian cell, it also is capable of killing bacterial cells. Accordingly, a virus infection as defined above together with a bacterial infection by a pathogenic bacterium may be treated. In specific embodiment, the concomitant bacterial infection may be caused by aerobic and/or anaerobic bacteria, or Gram-positive and/or Gram-negative bacteria.
  • the bacterial infection may be caused by the bacterium belonging to the genus of Actinobacillus, Actinomyces, Bacteroides, Clostridium, Campylobacter, Enterobacter, Enterococcus, Eubacterium, Fusobacterium, Helicobacter, Peptostrepto- coccus, Pneumococcus, Porphyromonas, Prevotella, Pseudomonas, Spirochetes, Staph ylococcus, Streptococcus, or Treponema.
  • the concomitant bacterial infection to be treated or prevented may be caused by one or more bacteria belonging to the genus Acrobacter, Borrelia, Bacillus, Brucella, Clamydia, Corynebacterium, Cryptococcus, Erythrobacter, gram-positiv cocci, Hemophilus, Legionella, Listeria, Mycobacteria, My coplasma, Neissaria, Pasteurella, Rickettsia, Salmonella, Vibrio, Yersinia, more specifi cally, Escherichia coli, Pneumocystis carinii, Helicobacter pylori or Borrelia burgdorferi.
  • the concomitant bacterial infection to be treated may be caused one or more bacteria of the group of Porphyromonas gingivalis, Prevotella intermedia, Actinomyces, Eubacterium nodatum, Peptostreptococcus mi cros, Peptostreptococcus anaerobius, Campylobacter rectur, Neisseria, Treponema denticola, Tannerella forsynthensis, Staphylococus aureus and Fusobacterium nuclea- tum.
  • the term "treating a bacterial infection” as used herein accordingly relates to the treatment of a clinically manifest bacterial infection associated disease. It is meant to encompass both cytotoxic and cytostatic effects on bacterial cells, thus lead ing to an inhibition of bacterial cells, which typically encompasses the inhibition of cell proliferation (bacteriostatic action) as well as the killing of the cells (bactericidal action). The killing of bacterial cells by necrosis or apoptosis is further encompassed by the in vention.
  • the terms "proliferation” and “growth” are used interchangeably in the context of this application.
  • the compound according to the invention is not ethyl pyruvate when the disease is lethal polymicrobial bacterial peritonitis.
  • the compound according to the present invention is not or does not comprise pyruvate.
  • the concomitant bacterial infection to be treated or prevented may be caused by a bacterium or bacterial strain that is re- sistant to conventional antibacterial agents.
  • the bacterium or bacterial strain may be resistant to one or more selected from the group comprising penicillins, aminoglycosides, tetracyclines, macrolide, fluoroquinolones, sulfonamides, vancomy cin, trimethoprim, ciprofloxacin, oxazolidinones, linezolid, isoniazid, rifampin, methicil- lins and/or exhibit resistance due to expression of beta-lactamase, antibiotics trans- porter molecules, RNA methylation, and/or that resistance is due to other genetic changes of the bacteria.
  • said concomitant bacterial infection may be due to a bacterium which is resistant to beta-lactamase antibiotics and/or
  • said concomitant bacterial in- fection to be treated according to the present invention may be due to an MRSA or EHEC infection.
  • the compounds of the present invention are capable of also inhibiting bacteria such as methicillin-resistant staphylococcus aureus (MRSA) or EHEC, which pose severe problems in the clinical setting, in particular in combination with virus infections as mentioned above.
  • MRSA methicillin-resistant staphylococcus aureus
  • EHEC methicillin-resistant staphylococcus aureus
  • the virus infection to be treated or pre vented may be present or may potentially develop in a mammal or avian species con comitant with a fungal infection.
  • the fungal infection may further be present or may potentially develop together with a bacterial infection as de scribed above.
  • a fungal infection as mentioned herein may, for example, be caused by one or more selected from group comprising Candida spp., Aspergillus spp., Cryptococcus spp., Pneumocystis spp., Zygomyces spp., Dermatophytes, Blastomyces spp., Histoplasma spp., Coccidoides spp., Sporothrix spp. Microsporidia spp., Malassezia spp. and Basidio- mycetes.
  • Some of the corresponding infectious diseases caused by said fungi may be an opportunistic infection, and/or may be characterized by antibiotic resistance.
  • Viral and bacterial and/or fungal infections further represent a significant prob lem in patients in an immunosuppressed state, and are amongst the leading cause of death, e.g., in transplant patients.
  • the pharmaceutical composition according to the present invention is for use in an immu- nosuppressed or immunodeficient mammal or avian species. Said immunosuppression or immunodeficiency is associated with hereditary or acquired immuno-defects. For ex ample, said acquired immune defect is associated with HIV, organ transplantation, chemotherapy or exposure to radiation.
  • the present invention relates to a method of treatment com prising administering a therapeutically effective amount of at least one compound ac cording to the present invention, i.e., as defined herein above, to a mammal or avian species, wherein said mammal or avian species is suffering from a virus infection, pref- erably a virus infection as defined herein, most preferably a coronavirus infection.
  • the method envisages the administration of a therapeutically suitable or effective amount of a compound or pharmaceutical composition as defined herein. Definitions of thera Bennettically effective concentrations or amounts are provided herein above.
  • the method envisages further an administration according to administration routes and approaches as defined herein. It is particularly preferred to use an administration via inhalation, e.g., into the respiratory tract, mouth and/or lungs.
  • the measurement was performed in 50 mM sodium phosphate buffer, pH 7.0.
  • 2 mM methylglyoxal and 2 mM reduced glutathione were incubated for 2 minutes at 30°C for the formation of the hemithioacetal.
  • 20 pi of a 1 to 1000 dilution of the glyoxalase I (Sigma, G- 4252) was added to 1 ml of the measuring reagent to start the reaction.
  • the erythrocyte lysate was prepared according to the instructions of Mannervik et al., Glyoxalase I from human erythrocytes. Methods Enzymol. 1982; 90 Pt E:535-41.
  • Glyoxalase activity (III) corresponds to the amount of enzyme forming 1 pmol of S-D-lactoyl-glutathione/min.
  • the culture was continued at 37°C, 5% C02 and 95% humidity for 24 hours. Thereafter the supernatants were removed and 100 pi of a 50 % thymol blue solution was added to the wells. After washing the cells with medium the unstained and stained cells were counted under the light optical microscope comprising a coordinate plane. Cells stained blue were assessed as avital, unstained cells as vital. The percentage of unstained cells of the total number of cells corresponds to the vitality of the cells.
  • LNCaP cells androgen dependent prostate carcinoma cells; DSMZ No ACC 256
  • DSMZ No ACC 256 were routinely cultured in 75 cm2 culture flasks in RPMI-1640 medium (Gibco; Nr. 21875-034), penicillin/streptomycin (100 units penicillin/ml; 100 pg streptomycin/ml; Gibco; Nr. 15140/122) in the presence of 10% fetal calf serum (Bio- chrom; Nr. S0113/5; RPMI-FKS).
  • the flasks were incubated at 37°C in a humidified at mosphere (relative humidity >95%) of 5% C02 in air.
  • the medium was removed and the adherent cells were washed twice with PBS (phosphate buffered sodium chloride; 50 mM sodium phosphate, 150 mM NaCI, pH 7,4). Thereafter, the cells were incubated with serum free RPMI-medium (RPMI-SF) comprising the ex perimental supplements in five flasks each (i.e., five replicates each). The culture was continued at 37°C, 5% C02 and 95% humidity for 24 hours. Thereafter the respective supernatants were removed, and the adherent cells were detached from the bottom of the plate by trypsin/EDTA (Gibco; No. 25300-054) and were pelleted.
  • PBS phosphate buffered sodium chloride
  • RPMI-SF serum free RPMI-medium
  • the culture was continued at 37°C, 5% C02 and 95% humidity for 24 hours. Thereafter the respective supernatants were removed, and the adherent cells were detached from the bottom of the plate by trypsin/ED
  • Non-disinfected hands were contacted with sterile blood agar plates contain- ing ethyl pyruvate (middle) ethyl lactate (right) and medium (left) and incubated for 48h at 37°C.
  • the microbes displayed at the circumferences of the agar plates depict a selec tion of microbes investigated in the present study.
  • Figure 6 demonstrates the extraordinary capacity of ethyl pyruvate in killing most pathogenic microbes. Ethyl lactate that differs only by two protons is not effective compared to its oxidized counterpart.
  • Figure 7 shows that ethyl pyruvate causes inhibition of the growth of a flucon azole-resistant Candida isolates which are metabolically activated.
  • S. cerevisiae (ATCC 24859) cells were cultured in a medium containing 0.6% yeast extract and standard salt buffer in the presence of 3% glycerol/ethanol (glucone- ogenetic condition) or 2% glucose (glycolytic condition) for 10 h at 37°C in the presence and absence of ethyl pyruvate/ethyl lactate.
  • Figure 8 clearly shows that ethyl pyruvate strongly inhibits growth of yeast cells only when cultured in presence of glucose (glycolytic condition). In contrast, there was no growth inhibitory effect when cells were cultured under gluconeogenetic condition. Furthermore, the effect of ethyl lactate on growth of yeast cells was negligible.
  • Human Lymphocytes were prepared according to standard procedure, washed and dispersed in 24-well plates in RPMI medium containing 5% calf serum. Cells were infected with Herpes simplex virus Type 1 viruses or growth stimulated by incubation with PHA in the absence or presence of increasing concentration of ethyl pyruvate. After optimum time of incubation, cells were fixed and stained with trypan blue, and finally counted under a microscope.
  • Figure 9 shows that ethyl pyruvate causes death of virus-infected cells. Further more, it induces death in cell which were metabolically activated by PHA. Consequently, ethyl pyruvate is capable to stop virus replication in cells.
  • Plaque assay was used to quantify the plaques formed in cells upon infection with the SARS-CoV2 virus (BavPatl/2020) isolate from an infected patient.
  • Vero E6 cells (Vero E6 cells (ATCC ® CRL-1586TM) were seeded into 24-well plates (lml/well) in the presence of DMEM without FCS. After adherence, the medium was removed, and the cells were washed with PBS. Then cells were inoculated with 500mI of respective and appropriated dilution of SARS-CoV-2 specimen. To non-infected wells medium was added only. The plates were shacked and incubated for 1 h at 37°C, 5% C02.
  • Virus inoculum was removed from cells followed by adding of 500mI DMEM medium containing 2% FCS, 10 mM HEPES and ethyl pyruvate at increasing concentra tion. Control wells contained medium without ethyl pyruvate.
  • 500 mI agarose-overlay medium was added and the plated were left until the agar becomes solid. The plates were incubated for 2 days at 37°C, 5% CO2. After that the agarose-overlay was cautiously removed followed by adding 500 mI of 70% ethanol to the wells for 15 min. After remov ing the ethanol, 200 mI crystal violet solution (1%) was added and incubated for 15 min. Finally, the plates were washed and air-dried. Plaques appeared as white circles (cyto- pathic effect) on colored monolayer of cells. The experiments were performed in dupli cates.
  • Figure 10 shows the decreasing size and number of plaques with increasing concentration of ethyl pyruvate in the overlay medium indicating that ethyl pyruvate is capable to diminish the cytopathic effect of the virus.
  • FIG. 11 shows that lipopolysaccharide (LPS)-stimulated blood cells are caused to release inflammatory cytokines.
  • LPS lipopolysaccharide
  • the release of these cytokines can be effec tively inhibited by ethyl pyruvate and ethyl lactate.
  • ethyl lactate acts as a prodrug that is enzymatically converted to ethyl pyruvate inside the cells.
  • THP-1 (ACCT TIB-202) cells were mixed with RPMI medium containing 5% calf serum, seeded to microtiter plates (5000 cells/well) and cultured in the presence of medium and increasing concentration of ethyl pyruvate (0-20 mM) and (B) ethyl lactate (0-20mM) for 6h and 24h, respectively.
  • Cellular ATP content was determined using CellTiter-Glo Luminescent Cell Viability Assay (PROMEGA, USA).
  • Figure 12 shows that ethyl pyruvate and ethyl lactate inhibit cellular ATP con- tent. It reveals, that ethyl pyruvate is more effective than ethyl lactate with respect to diminishing the ATP level and incubation time. It further displays that metabolically ac tive or activated cells are guided into cell death by ATP depletion.
  • Cold sores are caused by the herpes simplex virus.
  • the herpes simplex type 1 virus usually causes cold sores
  • the herpes simplex type 2 virus usually causes genital herpes.
  • the sores are contagious even when they are not visible. Cold sores are red, fluid-filled blisters that form near the mouth or on other areas of the face. Cold sores may persist for two weeks.
  • a water-free emulsion of zinc ointment (containing 10% Zinc oxide, vaseline, wool wax) was mixed with 150 mM ethyl pyruvate and 150 mM ethyl lactate. The oint ment was applied to the lips twice daily.
  • Patient U.B. (65 years, pre-existing cardiac disease) was infected by her grand daughter with SARS-CoV-2 and tested positive (PCR). The granddaughter was infected by her father, who was on a skiing holiday in Italy.
  • CoR-V19 consisting of a solution (50% ethyl pyruvate / 50% ethyl lactate), immediately after positive testing and upon experiencing first clinical symp toms. After adding the recommended amounts (drops) of CoR-V19 to 10 ml water, the mixture was placed in the nebuliser (MICRO DROP PRO). Inhalation was carried out 5 times a day for 20 minutes. It was breathed alternately through the mouthpiece and the nose. [0241] The concentration of CoR-V19 in the solutions was increased daily to achieve an optimal effect in the respiratory tract. 10 days after the positive PCR test, the pa tient's general condition was good, she had no symptoms such as fever, cough, diarrhea. Then, U.B. was advised to stop inhalation.
  • MICRO DROP PRO nebuliser
  • Healthy Individuals [0242] In a first cohort healthy individuals have been recruited (age range 12 to 65 years) to check any possible adverse effects and tolerability. In total, eight individuals (4 female, 4 male) have been selected according to current health status of non-previous medical histories for allergies or lung associated disease. Prior of recruitment all infor mation regarding the product, trials, and compensation in case of adverse effects has been communicated orally and written information consent signed bilaterally. Healthy individuals were given CoR-V19 by inhalation in a respective dosage and time. As the result, 100% tolerability was observed in healthy tested individuals and physiological parameters were found within normal range after treatment.
  • COVID-19 Patients [0243] A second cohort was comprised of 32 randomized COVID-19 patients. The in fection was confirmed by reverse transcriptase polymerase-chain-reaction (RT-PCR) as say and an oxygen saturation ( ⁇ 94%), radiological examination (X-Ray, CT), analysis of blood, and urine as well as recording typical symptoms such as fatigue, high body tem perature >38°C, headache, cough, chest pain and loss of taste and/or smell.
  • RT-PCR reverse transcriptase polymerase-chain-reaction
  • X-Ray, CT radiological examination
  • Analysis of blood, and urine as well as recording typical symptoms such as fatigue, high body tem perature >38°C, headache, cough, chest pain and loss of taste and/or smell.
  • Ambulatory patients (8 females, 9 males) who obtained neither anti-viral nor preventive antibiotics, except antipyretics in the first 2 days on need with record of slight to moderate symptoms, having no history of other associated chronic disease, were en rolled comprising the low

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Abstract

La présente invention concerne un composé selon la formule générale (I) destiné à être utilisé en tant qu'agent antiviral. L'invention envisage en outre une méthode de traitement consistant à administrer une quantité thérapeutiquement efficace d'au moins un composé selon la formule générale (I) à un mammifère ou à une espèce aviaire souffrant d'une infection virale, ainsi qu'une composition pharmaceutique comprenant au moins un composé selon la formule générale (I) destinée à être utilisée dans le traitement et/ou la prophylaxie d'une infection virale. Selon un mode de réalisation préféré, l'infection virale est une infection à coronavirus. L'invention envisage aussi un procédé de désinfection d'un substrat contre des virus consistant à mettre en contact un substrat avec au moins un composé selon la formule générale (I).
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