IT202000015817A1 - ADENOSINE FOR USE IN THE TREATMENT OF VIRAL INFECTIONS - Google Patents

Description

Title: ?ADENOSINE FOR USE IN THE TREATMENT OF VIRAL INFECTIONS?

Description

Field of the technique of the invention

The present invention relates to the antiviral treatment of COVID-19 infections by administering adenosine in combination with other therapeutically active substances.

State of art

The coronavirus infection disease SARS-CoV-2 (COVID-19) ? a recently started infection caused by severe acute respiratory syndrome. It is a new viral pathogen reported for the first time in Wuhan, a city Chinese, in December 2019. Isn't it? never been seen before in humans and yes ? then spread rapidly around the world, resulting in the classification of a pandemic by the World Health Organization? (WHO). Despite being placed in the same category as other viruses such as influenza viruses, the SARS-CoV-2 coronavirus displays distinctly different characteristics. They are currently being studied, but no vaccines are yet available, and oxygen therapy and mechanical ventilation are the main treatments for patients with respiratory insufficiency and a severe degree of the disease.

The Coronavirus infection induces effects such as anosmia and akinesia, symptoms that exactly follow those of patients with Parkinson's disease, while the difficulty of storage ? attributable to symptoms of Alzheimer's disease and coincide precisely with a series of problems attributable to various pathologies.

Has the present inventor realized that the need for Adenosine by COVID-19 increases in proportion to the pathogenicity? expressed by the virus. The possibility? to vary the length of the gene region defined as the poly-A tail? a peculiarity? of the Corona virus that through this ability? they can increase or decrease the efficiency of viral replication at will. This ability? varying the length of the poly-A tail allows them to improve binding to the protein PABP (Poly-A Binding Protein), which therefore directly affects the efficiency of viral translation and replication. The larger the poly-A tail size, the larger the poly-A tail will be. the efficiency of translation and viral replication.

The very strong need for Adenosine by COVID-19, necessary for the elongation of the poly-A chain, is the very cause of the majority of the pathological effects induced by the virus. The breakdown of nucleoside A at the intracellular level drastically reduces the levels of ATP (Adenosine Triphosphate) and cAMP (Cyclic Adenosine Monophosphate), compromising the correct functioning of all the molecules that act through receptors associated with G proteins.

So the virus can implement a different strategy from one host subject to another and vary it over time within the same organism. This feature can already alone describe all the different trends of the pathological state found in infected patients, from asymptomatic or with reduced symptoms, in which the virus remains latent and does not cause an evident immune reaction (possibility of prolonged absence of IgG), up to subjects which show a cyclical trend, which pass cio? from a contagious phase, with a feverish state, to a practically asymptomatic phase (dissemination of the contagion) and again to a rapid and very significant increase in symptoms, in a third phase. AND? just at this moment that in predisposed subjects the? increased ability? of viral replication follows real ?rush? which therefore lead to such a rapid and dramatic subtraction of ATP and therefore cyclic AMP such as to compromise the central functional antagonism in the functioning of the receptors associated with G proteins, the cyclic AMP being the second messenger of all the molecules that act using the receptors metabotropics. Where do the symptoms come from? serious and obvious, such as:

- vaso- and bronchoconstriction (histamine),

- platelet aggregation and deep vein thrombosis (plekstrin, thromboxane A2, loss of the inhibitory effects of cAMP),

- atrioventricular block (adenosine),

- vasoconstriction and inflammation (angiotensin 2 and IL-6),

- edema (vasopressin),

- bronchoconstriction - possible anaphylactic shock - platelet aggregation (leukotrienes-prostaglandinthromboaxane),

- loss of myocardial functions (inotropic, chronotropic, dromotropic, bathmotropic due to the synergistic effect of adrenergic, muscarinic, adenosinic, opioid receptors, etc.).

Furthermore, the G protein-coupled or metabotropic receptors are responsible for the release of various neurotransmitters such as: dopamine, serotonin, GABA, etc., important to complete the picture of rapidly noticeable symptoms: anosmia and akinesia (dopamine), loss of taste (receptor gustducina), worsening of night vision (rhodopsin), also impaired sensitivity? on insulin ? again mediated by many molecules.

In the light of the previous considerations, ? the administration of Adenosine has been tested in the clinic, with the aim? to counter its consumption by the corona virus. However, if this administration is proved useful in some patients, in others it complicated the clinical picture.

Can an explanation reside in the fact that the A1 receptors for Adenosine alone mediate these effects

- bronchoconstriction

- vasoconstriction

- platelet aggregation

- atrioventricular block

- inflammation with release of interleukin 6 (IL-6).

Summary of the invention

The present inventor has surprisingly discovered that, by administering Adenosine in combination with at least one inhibitor of the A1 and/or A3 adenosine receptors, ? It is possible to obtain a therapeutic effect without inducing the side effects induced by Adenosine.

An object of the present invention ? therefore Adenosine for use in the treatment of a Corona virus viral syndrome, in particular COVID-19, in which Adenosine is? administered in combination with at least one antagonistic A1 and/or A3 adenosine receptor inhibitor and optionally with at least one A2a and/or A2b adenosine receptor agonist, wherein the administration of Adenosine is following or simultaneously with the administration of said inhibitor.

A further object of the invention ? Adenosine for use in the treatment of a Corona virus viral syndrome, specifically COVID-19, in which Adenosine is administered in combination with at least one antagonistic inhibitor of A1 and/or A3 adenosine receptors and optionally with at least one agonist of A2a and/or A2b adenosine receptors and an anti-viral molecule comprising an adenine nucleus and in which the administration of Adenosine ? following or simultaneously with the administration of said adenosine receptor inhibitor and ? contemporary or prior to the administration of said anti-viral molecule.

A further object of the invention are pharmaceutical compositions comprising Adenosine and an antiviral molecule comprising an adenine nucleus and optionally at least one inhibitor of the A1 and/or A3 adenosine receptors and optionally at least one agonist of the A2a and/or A2b adenosine receptors.

Yet another object of invention? a molecule chosen from:

- 3?-deoxyadenosine,

- mono-di- or tri-phosphorylated 3?-deoxyadenosine, - (2R,3R,4S,5R)-2-(6-amino-9H-purine-9-yl)-5-(4-hydroxy-3- (hydroxymethyl)butyl),

- (2R,3R,4S,5R)-2-(6-amino-9H-purin-9-yl)-5-((1,3-dihydroxypropan-2-yl)oxymethyl),

- (2R,3R,4S,5R)-2-(6-amino-9H-purin-9-yl)-5-((2-hydroxyethoxy)methyl),

- (2R,3R,4S,5R)-2-(6-amino-9H-purin-9-yl)-5-((2-bis(acetyloxymethyl)) ethyl)

- (2R,3R,4S,5R)-2-(6-amino-9H-purin-9-yl)-5-(2-amino-3-methylbutanoyloxy-2-(1-hydroxymethyl)ethoxymethyl - (2R, 3R,4S,5R)-2-(6-amino-9H-purin-9-yl)-5--(2-amino-3-methylbutanoyloxy-2-ethoxymethyl),

their configurational isomers, diastereomers, enantiomers, racemes or mixtures thereof or salts thereof with pharmaceutically acceptable acids, for use in the treatment of a viral syndrome of Corona virus, in particular COVID-19, orthomyxovirus or poliovirus, in which said 3 ?-deoxyadenosine blocks transcription and replication of the virus.

Yet another object of invention? Adenosine for use in the treatment of neurodegenerative diseases, particularly Parkinson's disease and Alzheimer's disease, in which Adenosine is administered in combination with at least one antagonistic A1 and/or A3 adenosine receptor inhibitor and optionally with at least one A2a and/or A2b adenosine receptor agonist, wherein the administration of Adenosine is following or simultaneously with the administration of said inhibitor.

These and further objects, as outlined in the appended claims, will be described in the continuation of the description. The text of the claims must be considered included in the description for the purposes of assessing the sufficiency of the description.

Further characteristics and advantages of the invention will result from the following description of preferred embodiments, given by way of non-limiting example.

Detailed description of the invention

According to a first aspect, the present invention relates to Adenosine for use in the treatment of a viral syndrome caused by the Corona virus, in particular COVID-19, in which the Adenosine is? administered in combination with at least one antagonistic inhibitor of A1 and/or A3 receptors and optionally with at least one agonist of A2a and/or A2b adenosine receptors and in which the administration of Adenosine is following or simultaneously with the administration of said at least one adenosine receptor inhibitor.

Adenosine has the following chemical structure:

Adenosine? a nucleoside composed of a molecule of adenine linked to a ribose (or deoxyribose) through a ?-N9-glycosidic bond. It therefore has an extremely important function in the constitution of DNA and RNA.

The antagonist inhibitor of A1 and/or A3 receptors and the agonist of A2a and/or A2b adenosine receptors are preferably selected from inosine (A1 and A3 antagonist, A2A and A2B agonist), theophylline (A1 and A3 antagonist), doxofylline, 8 -cyclopentyl-1,3-dimethylxanthine (antagonist A1), 8-cyclopentyl-1,3-dipropylxanthine (antagonist A1) , 1-butyl-3-(3-hydroxypropyl)-8-(3-noradamantyl)xanthine (antagonist A1 ), caffeine (antagonist A1 and A3), 3-Ethyl-5-benzyl-2-methyl-4-phenylethynyl-6-phenyl-1,4-(?)-dihydropyiidin-3,5-dicarboxylate (antagonist A3), N-[9-Chloro-2-(2-furanyl)[1,2,4]-triazole[1,5-c]quinazolin-5-yi]benzene acetamide (antagonist A3), 1,4-Dihydro-2 -methyl-6-phenyl-4-(phenylethynyl)-3,5-pyridinedicarboxylic acid, 3-ethyl-5-[(3-nitrophenyl)methyl]ester (antagonist A3), 3-Propyl-6-ethyl-5- [(ethylthio)carbonyl]-2 phenyl-4-propyl-3pyridine carboxylate (antagonist A3), 2-phenoxy-6-(cyclohexylamino)purine hemioxalate (antagonist A3), N-[2-(2-Furanyl)-8- propyl-8H-pyrazole[4,3-e][1,2,4]triazole[1,5-c]pyrimidin-5-yl]-N'-(4-methoxyphenyl)urea (antagonist A3), 8- Ethyl-1,4,7,8-tetrahydro-4-methyl-2-(2,3,5-trichlorophenyl)-5H-imidazo[2,1-i]purin-5-one monohydrochloride (antagonist A3), ( 8R)-8-Ethyl-1,4,7,8-tetrahydro-4-5H-imidazo[2,1-i]purin-5-one hydrochloride (antagonist A3), N-(2-Methoxyphenyl)-N' -[2-(3-pyridinyl)-4-quinazolinyl]-urea (A3 antagonist), 3-methoxy-4-hydroxybenzyl riboside adenine (A2a agonist), 4-{3-[6-Amino-9-(5- ethylcarbamoyl-3,4-dihydroxy-tetrahydro-furan-2-yl)-9H-purin-2-yl]-prop-2-ynyl}-cyclohexanecarboxylic acid. methyl ester (A2a agonist), 3-(4-(2-((6-amino-9-((2R,3R,4S,5S)-5-(ethylcarbamoyl)-3,4-dihydroxytetrahydrofuran-2-yl) -9H-purin-2-yl)amino)ethyl)phenyl)propanoic acid (A2a agonist), regadenoson (A2a agonist), 2-[[6-Amino-3,5-dicyan-4-[4-(cyclopropylmethoxy) phenyl]-2-pyridinyl]thio]-acetamide (A2b agonist), 2-Amino-4-(3-hydroxyphenyl)-6-[(1H-imidazol-2-ylmethyl)thio]-3,5-pyridinecarbonitrile (agonist A2b), 2-Amino-4-(4-methoxyphenyl)-6-[(1H-imidazol-2-ylmethyl)thio]-3,5-pyridinecarbonitrile (A2b agonist) and 5'-N-ethylcarboxamidoadenosine (A2b agonist) .

These molecules are known and commercially available. Pi? preferably, the? inhibitor? antagonist of both A1 and A3 adenosine receptors.

even more preferably the antagonistic inhibitor of the A1 and A3 receptors? also agonist of adenosine A2a and A2b receptors. A particularly favorite inhibitor? inosine.

Theophylline has stimulating effects on the central nervous system, its main actions are:

- relaxation of bronchial smooth muscles (bronchodilator action);

- increased contractility? of the heart muscle (positive inotropic action);

- increased heart rate (positive chronotropic action);

- increased renal blood flow;

- anti-inflammatory type action (inhibition of leukotrienes);

- stimulating action of the central nervous system, in particular on the medullary respiratory center (inhibition of adenosinic A1 receptors).

Doxofylline? a molecule with bronchodilator action, derived from theophylline, from which it differs in containing a dioxolane group in position 7. In studies on animals and humans, doxofylline has shown efficacy comparable to that of theophylline, but a better tolerability profile, with significantly fewer side effects.

Inosine has the following chemical structure:

The inosine? a nucleoside composed of a molecule of hypoxanthine bonded to a ribose. ? the first intermediate provided with a purine nucleus in the de novo synthesis of these nucleotides and is produced in the metabolism of adenosine.

Without being bound by any theory, the use of Adenosine with its selective inhibitor, which is preferably ? simultaneously antagonist of the A1 and A3 receptors and agonist of the A2a and A2b receptors, leads to the stimulation of only the A2a and A2b receptors which stimulate the enzyme adenylate cyclase which leads to an increase in cyclic AMP, which in turn leads to a first but significant improvement of the conditions of the patients. Stimulation of adenylate cyclase removes ATP from poly-A polymerase. Indeed ? the ATP which releases the Adenosine nucleotides for the polymerization of the viral poly-A tail, so by preventing this mechanism the symptoms of the viral pathology and the mortality rate are reduced? of the virus. On the other hand, the inhibition of the A1 and A3 receptors avoids the occurrence of the side effects described above for the administration of Adenosine and which would aggravate the clinical picture of the patients.

The inosine also ? able to modulate the immune response, which alone? able to increase cytotoxicity? of Nk natural killer cells and the activity? and differentiation of T lymphocytes and their release of interleukin1 and 2. Therefore l? Inosine pu? exert an antiviral effect which, in the embodiments in which an antiviral molecule is also administered, how will it be? described below, can? synergistically add to the antiviral effect of the latter.

When the antagonistic inhibitor of the A1 and/or A3 adenosine receptors is not? also A2a and/or A2b receptor agonist, ? is it possible to administer one or more? A1 and A3 receptor antagonists and one or more A2a and/or A2b receptor agonists.

The fact that the A1 and/or A3 receptor inhibitor is administered before or simultaneously with Adenosine depends on various factors, but in particular on the form of administration of the active ingredients.

If the form of administration ? by injection, what will be? preferred in case of intervention on patients in serious clinical conditions, sar? It is necessary to administer the inhibitor first and then the Adenosine, so that the inhibitor can carry out its inhibitory action before the Adenosine enters the circulation. Preferably, when the inhibitor? inosine, the? Adenosine will come? injected in a variable time between 5 minutes and 15 hours, more? preferably between 10 minutes and 6 hours, from the administration of inosine.

If the form of administration ? orally, however, the inhibitor and Adenosine can also be administered simultaneously, for example in the same oral formulation, thanks to the different bioavailability? of the two molecules.

The inhibitor of A1 and/or A3 adenosine receptors? preferably administered in weight excess with respect to Adenosine. Preferably, the inhibitor will come? administered in a weight ratio between 1.2:1 and 2:1, plus? preferably between 1.2:1 and 1.7:1, with respect to Adenosine.

In a preferred form, the invention relates to Adenosine for use in the treatment of a Corona virus viral syndrome, in particular COVID-19, in which Adenosine is administered in combination with at least one antagonistic inhibitor of A1 and/or A3 receptors and optionally with at least one agonist of A2a and/or A2b adenosine receptors and with an anti-viral molecule comprising an adenine nucleus and in which the administration of Adenosine is following or simultaneously with the administration of said adenosine receptor inhibitor and ? contemporary or prior to the administration of said anti-viral molecule.

The antiviral molecule? preferably chosen from: - 3?-deoxyadenosine,

- mono-di- or tri-phosphorylated 3?-deoxyadenosine, - (2R,3R,4S,5R)-2-(6-amino-9H-purine-9-yl)-5-(4-hydroxy-3- (hydroxymethyl)butyl),

- (2R,3R,4S,5R)-2-(6-amino-9H-purin-9-yl)-5-((1,3-dihydroxypropan-2-yl)oxymethyl),

- (2R,3R,4S,5R)-2-(6-amino-9H-purin-9-yl)-5-((2-hydroxyethoxy)methyl),

- (2R,3R,4S,5R)-2-(6-amino-9H-purin-9-yl)-5-((2-bis(acetyloxymethyl)) ethyl)

- (2R,3R,4S,5R)-2-(6-amino-9H-purin-9-yl)-5-(2-amino-3-methylbutanoyloxy-2-(1-hydroxymethyl)ethoxymethyl) - (2R ,3R,4S,5R)-2-(6-amino-9H-purin-9-yl)-5--(2-amino-3-methylbutanoyloxy-2-ethoxymethyl),

their configurational isomers, diastereomers, enantiomers, racemes or mixtures thereof or salts thereof with pharmaceutically acceptable acids.

The molecules described above are known or can be synthesized with methods known to those skilled in the art, such as those used for the guanosine derivatives penciclovir, ganciclovir, aciclovir, famciclovir, valganciclovir and valaciclovir.

The antiviral molecule? preferably 3?-deoxyadenosine, having the following chemical structure:

The administration of this nucleoside analogue makes it possible to further reduce the availability of ATP for the virus. In fact, the 3?-deoxyadenosine has an affinity? much greater for the poly-A polymerase than all? Adenosine, then ? the molecule that the enzyme will prefer? use for viral RNA. Thanks to its different structure compared to Adenosine, only one of these molecules interrupts the polymerization of the poly-A tail, blocking the transcription and replication of the virus, functioning as a nucleoside analogue ?chain terminator? as for many other antiviral molecules.

The antiviral molecule, in particular 3?-deoxyadenosine, can be administered simultaneously or subsequently to Adenosine, for example potr? be contained in the same injectable formulation or otherwise.

Preferably, the antiviral molecule, in particular 3?-deoxyadenosine, can be administered in a weight ratio between 0.3:1 and 1:1, pi? preferably between 0.5:1 and 0.8:1, with respect to Adenosine.

Another object of the invention? the use of Adenosine, in combination with at least one A1 and/or A3 receptor antagonist inhibitor and optionally with at least one A2A and/or A2B adenosine receptor agonist, plus? preferably inosine, and optionally with an antiviral molecule comprising an adenine core, preferably 3?-deoxyadenosine, for the preparation of a medicament in the form of one or more? unit? separate dosage lines, for the treatment of corona virus infections, especially COVID-19.

A further object of the invention ? a formulation comprising Adenosine and an antiviral molecule comprising an adenine nucleus, preferably 3?-deoxyadenosine. Optionally, when the formulation is not ? injectable, it will be able also contain at least one inhibitor of the A1 and/or A3 adenosine receptors, preferably inosine.

In these formulations, the weight ratios between the various active ingredients are:

- antiviral molecule, preferably 3?-deoxyadenosine, between 0.3:1 and 1:1, more? preferably between 0.5:1 and 0.8:1, with respect to Adenosine;

- inhibitor, preferably inosine, between 1.2:1 and 2:1, more? preferably between 1.2:1 and 1.7:1, with respect to Adenosine.

Further objects of the invention are an antiviral molecule selected from:

- 3?-deoxyadenosine,

- mono-di- or tri-phosphorylated 3?-deoxyadenosine, - (2R,3R,4S,5R)-2-(6-amino-9H-purine-9-yl)-5-(4-hydroxy-3- (hydroxymethyl)butyl),

- (2R,3R,4S,5R)-2-(6-amino-9H-purin-9-yl)-5-((1,3-dihydroxypropan-2-yl)oxymethyl),

- (2R,3R,4S,5R)-2-(6-amino-9H-purin-9-yl)-5-((2-hydroxyethoxy)methyl),

- (2R,3R,4S,5R)-2-(6-amino-9H-purin-9-yl)-5-((2-bis(acetyloxymethyl)) ethyl)

- (2R,3R,4S,5R)-2-(6-amino-9H-purin-9-yl)-5-(2-amino-3-methylbutanoyloxy-2-(1-hydroxymethyl)ethoxymethyl - (2R, 3R,4S,5R)-2-(6-amino-9H-purin-9-yl)-5--(2-amino-3-methylbutanoyloxy-2-ethoxymethyl),

their configurational isomers, diastereomers, enantiomers, racemes or mixtures thereof or salts thereof with pharmaceutically acceptable acids,

for use in the treatment of a viral syndrome of Corona virus, in particular COVID-19, orthomyxovirus or poliovirus, in which said antiviral molecule blocks the process of viral translation, and a pharmaceutical formulation, injectable or for oral administration, containing said antiviral molecule for such use.

Corona viruses, orthomyxoviruses and polioviruses are mediated by a similar mechanism of action and were found to be sensitive to the administration of an antiviral molecule comprising an adenine nucleus.

Yet another object of invention? Adenosine for use in the treatment of neurodegenerative diseases, particularly Parkinson's disease and Alzheimer's disease, in which Adenosine is administered in combination with at least one antagonistic A1 and/or A3 adenosine receptor inhibitor and optionally with at least one A2a and/or A2b adenosine receptor agonist, wherein the administration of Adenosine is following or simultaneously with the administration of said inhibitor. Yet another object of invention? Adenosine for use in the treatment of neurodegenerative diseases, particularly Parkinson's disease and Alzheimer's disease, in which Adenosine is administered in combination with at least one antagonistic A1 and/or A3 adenosine receptor inhibitor and optionally with at least one A2a and/or A2b adenosine receptor agonist, wherein the administration of Adenosine is following or simultaneously with the administration of said inhibitor. The pharmaceutical formulations can be formulated in dosage forms for oral, buccal, parenteral, rectal or transdermal administration.

For oral administration, pharmaceutical formulations may be found, for example, in the form of tablets or capsules, hard or soft, prepared in the conventional manner with pharmaceutically acceptable excipients such as binding agents (e.g. pregelatinised corn starch, or hydroxypropyl methylcellulose). ; filling agents (e.g. lactose, microcrystalline cellulose or calcium hydrogen phosphate); lubricants (for example, magnesium stearate, talc or silica); disintegrants (for example potato starch or sodium starch glycolate); or inhibitory agents (e.g. sodium lauryl sulfate). The tablets can be coated by methods well known in the art. The liquid preparations for oral administration can be presented, for example, in the form of solutions, syrups or suspensions or they can be presented as lyophilized products to be reconstituted, before use, with water or other suitable vehicles. Such liquid preparations can be prepared by conventional methods with pharmaceutically acceptable additives such as suspending agents (for example sorbitol syrup, cellulose derivatives or edible hydrogenated fats); emulsifying agents (for example, lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oil esters, ethyl alcohol, or fractionated vegetable oils); and preservatives (e.g. methyl- or propylp-hydroxybenzoates or sorbic acid). The preparation can also suitably contain flavorings, colorings and sweetening agents.

Preparations for oral administration can be suitably formulated to allow controlled release of the active principle.

For buccal administration, the formulations can be in the form of tablets or lozenges formulated in the conventional way, suitable for absorption at the level of the buccal mucosa. Typical buccal formulations are tablets for sublingual administration.

The formulation of the invention can? be formulated for parenteral administration by injection. The formulations for injections can be presented in the form of a dose divided between the inhibitor and the other active molecules, dose to be administered, for example in vials, with an added preservative. The compositions can be in this form as suspensions, solutions or emulsions in oily or aqueous vehicles and can contain formulary agents such as suspending, stabilizing and/or dispersing agents. Alternatively, the active ingredient or active ingredients can be found in the form of a powder to be reconstituted, before use, with a suitable vehicle, for example with sterile water.

The formulation of the invention can? also be a rectal formulation such as suppositories or retention enemas, for example containing the basic components of common suppositories such as cocoa butter or other glycerides.

The preferred formulations for the purposes of the present invention are the oral and the injectable ones.

In particular, the oral forms will be preferred in the case of a preventive therapy or in cases of mild or asymptomatic infections.

The injectable forms will be preferred in the case of emergency therapy, such as first aid for patients in serious or critical conditions.

The oral formulations may comprise Adenosine and the antiviral analogue substance of Adenosine, preferably 3?-deoxyadenosine.

The oral formulations will include the A1 and A3 adenosine receptor inhibitor in a vial separate from the one containing Adenosine and, when used, the antiviral molecule.

According to the present invention, the dose of Adenosine proposed for administration to a man (with a body weight of about 70 kg) ranges from 3 mg to 15 mg or from 5 mg to 12 mg of Adenosine per unit. of dose, in the event that the chosen route of administration is the injectable one. For oral administration, higher doses may be used depending on the age, weight, physical and pathological condition and other factors affecting the patient. For example, for oral administration, the unit? of dose will contain? preferably from 50 mg to 150 mg of Adenosine. The dosage of the inhibitor, preferably inosine, and of the antiviral, preferably cordycepin, will be calculated on the basis of the previously indicated weight ratios.

The unit dose can? be administered, for example, 1 to 4 times a day. The dose will depend by the chosen route of administration. You will have to consider that it may be necessary to administer continuously for patients more? serious and make continuous changes in the dosage of gravity? of the clinical condition to be treated. The exact dose and route of administration will be finally at the discretion of the attending physician.

The formulations according to the invention can be prepared according to conventional methods, such as those described in Remington's Pharmaceutical Sciences Handbook, Mack Pub. Co., N.Y., USA, edition 2012.

A further object of the invention ? a kit, in particular a first aid kit, comprising a first container, for example a vial, containing an injectable solution of at least one antagonist inhibitor of the A1 and A3 receptors and at least one agonist of the A2A and/or A2B adenosine receptors, preferably inosine , and a second container, preferably a vial, containing an injectable solution of Adenosine together with an antiviral molecule comprising an adenine nucleus as defined above, preferably 3?-deoxyadenosine.

The invention will be now further described by means of the following formulation examples.

Examples of wording

Example 1 - Sustained release gastro-resistant tablet

Adenosine 100mg Inosine 130mg

3?-Deoxyadenosine 70 mg Microcrystalline cellulose 80 mg Glyceryl Dibehenate 150 mg Polyvinylpyrrolidone 30 mg Magnesium stearate 5 mg Silicon dioxide 5 mg Gastro-resistant coating 40 mg Example 2 - Acid-fast hard capsule Adenosine 130 mg Inosine 160 mg

3?-Deoxyadenosine 90 mg Magnesium Stearate 5 mg Capsule Hypromellose Acid Fast Size ?0? Example 3 - Water-dispersible single-dose granulated powder stick

Adenosine 140 mg Inosine 200 mg Glyceryl Dipalmitostearate 200 mg Polyvinylpyrrolidone 30 mg Sorbitol 180 mg Corn Dextrin 800 mg Poloxamer 188 EP 50 mg Polysorbate 80 15 mg Rebaudioside A (Stevia) E960 10 mg Natural Flavor 20 mg Dimethyl Polysiloxane 3 mg Example 4 - Stick water-dispersible single-dose granulated powder

Adenosine 130mg Inosine 200mg

3?-Deoxyadenosine 80 mg Glyceryl dipalmitostearate 200 mg Polyvinylpyrrolidone 30 mg Sorbitol 180 mg Corn dextrin 800 mg Poloxamer 188 EP 50 mg Polysorbate 80 15 mg Rebaudioside A (Stevia) E960 10 mg Natural flavor 20 mg Dimethyl polysiloxane 3 mg Example 5 - Tablet effervescent

Adenosine 100mg Inosine 180mg

3?-Deoxyadenosine 50 mg Glyceryl Dipalmitostearate 250 mg Potassium Bicarbonate 343 mg Potassium Carbonate Anhydrous 108 mg Citric Acid Anhydrous 384 mg Corn Dextrin 400 mg Sorbitol 200 mg Polysorbate 80 15 mg Rebaudioside A (Stevia) E960 10 mg Natural Flavor 20 mg Dimethyl Polysilo ssano 3 mg Example 6 - Sterile single-dose solution for intramuscular injection

Vial 1:

Inosine 15 mg Sodium Chloride 18 mg Potassium Monobasic Phosphate 0.5 mg Water 1920 mg Sodium hydrate solution 25% qs. at pH 7.0 Vial 2:

Adenosine 12 mg Sodium Chloride 15 mg Potassium Monobasic Phosphate 0.5 mg Water 1920 mg Sodium hydrate solution 25% qs. at pH 7.0 Example 7 - Sterile single-dose solution for intramuscular injection

Vial 1:

Inosine 15 mg Sodium Chloride 18 mg Potassium Monobasic Phosphate 0.5 mg Water 1920 mg Sodium hydrate solution 25% qs. at pH 7.0 Vial 2:

Adenosine 12 mg 3?-deoxyadenosine 8 mg Sodium chloride 15 mg Potassium monobasic phosphate 0.5 mg Water 1920 mg Sodium hydroxide solution 25% qs. at pH 7.0

Claims (13)

1. Adenosine for use in the treatment of a Corona virus viral syndrome, particularly COVID-19, in which Adenosine is administered in combination with at least one antagonistic inhibitor of A1 and/or A3 adenosine receptors and optionally in combination with at least one agonist of A2a and/or A2b adenosine receptors, and in which the administration of Adenosine is subsequent to the administration of said adenosine receptor inhibitor. 2. Adenosine for use according to claim 1, wherein said at least one inhibitor of the A1 and/or A3 adenosine receptors ? selected from theophylline, doxofylline, caffeine, inosine, 8-cyclopentyl-1,3-dimethylxanthine (antagonist A1), 8-cyclopentyl-1,3-dipropylxanthine (antagonist A1), 1-butyl-3-(3-hydroxypropyl)- 8-(3-noradamantyl)xanthine (antagonist A1), caffeine (antagonist A1 and A3), 3-Ethyl-5-benzyl-2-methyl-4-phenylethynyl-6-phenyl-1,4-(?)-diidropyiidin -3,5-dicarboxylate (antagonist A3), N-[9-Chloro-2-(2-furanyl)[1,2,4]-triazole[1,5-c]quinazolin-5-yi]benzene acetamide ( antagonist A3), 1,4-Dihydro-2-methyl-6-phenyl-4-(phenylethynyl)-3,5-pyridinedicarboxylic acid, 3-ethyl-5-[(3-nitrophenyl)methyl] ester (antagonist A3) , 3-Propyl-6-ethyl-5-[(ethylthio)carbonyl]-2 phenyl-4-propyl-3-pyridine carboxylate (antagonist A3), 2-phenoxy-6(cyclohexylamino)purine hemioxalate (antagonist A3), N -[2-(2-Furanyl)-8-propyl-8H-pyrazole[4,3-e][1,2,4]triazole[1,5-c]pyrimidin-5-yl]-N'-( 4-Methoxyphenyl)urea (antagonist A3), 8-Ethyl-1,4,7,8-tetrahydro-4-methyl-2-(2,3,5-trichlorophenyl)-5H-imidazo[2,1-i] purin-5-one monohydrochloride (A3 antagonist), (8R)-8-Ethyl-1,4,7,8-tetrahydro-4-5H-imidazo[2,1-i]purin-5-one hydrochloride (A3 antagonist ), N-(2-Methoxyphenyl)-N'-[2-(3-pyridinyl)-4-quinazolinyl]-urea (antagonist A3). 3. Adenosine for use according to claim 1 or 2, wherein said at least one agonist of the A2a and/or A2b adenosine receptors ? selected from 3-methoxy-4-hydroxybenzyl riboside adenine (A2a agonist), 4-{3-[6-Amino-9-(5-ethylcarbamoyl-3,4-dihydroxy-tetrahydro-furan-2-yl)-9H- purin-2-yl]-prop-2-ynyl}-cyclohexanecarboxylic acid. methyl ester (A2a agonist), 3-(4-(2-((6-amino-9-((2R,3R,4S,5S)-5-(ethylcarbamoyl)-3,4-dihydroxytetrahydrofuran-2-yl) -9H-purin-2-yl)amino)ethyl)phenyl)propanoic acid (A2a agonist), regadenoson (A2a agonist), 2-[[6-Amino-3,5-dicyan-4-[4-(cyclopropylmethoxy) phenyl]-2-pyridinyl]thio]-acetamide (A2b agonist), 2-Amino-4-(3-hydroxyphenyl)-6-[(1H-imidazol-2-ylmethyl)thio]-3,5-pyridinecarbonitrile (agonist A2b), 2-Amino-4-(4-methoxyphenyl)-6-[(1H-imidazol-2-ylmethyl)thio]-3,5-pyridinecarbonitrile (A2b agonist) and 5'-N-ethylcarboxamidoadenosine (A2b agonist) . 4. Adenosine for use according to any one of claims 1 to 3, wherein said antagonistic inhibitor of the A1 and A3 adenosine receptors ? an agonist of the adenosine A2a and A2b receptors and ? preferably inosine. 5. Adenosine for use according to any one of claims 1 to 4, wherein the adenosine is administered from 5 minutes to 15 hours, or from 10 minutes to 6 hours, after administration of said adenosine receptor inhibitor. 6. Adenosine for use according to any one of claims 1 to 5, wherein the adenosine receptor inhibitor/Adenosine weight ratio is ? between 1.2:1 and 2:1, or between 1.2:1 and 1.7:1. 7. Adenosine for use according to any one of claims 1 to 6, wherein the Adenosine is? administered in combination with said at least one inhibitor of the A1 and/or A3 adenosine receptors and of an anti-viral molecule comprising an adenine nucleus and in which the administration of Adenosine is following or simultaneously with the administration of said at least one inhibitor of the A1 and/or A3 adenosine receptors and ? contemporary or prior to the administration of said anti-viral molecule. 8. Adenosine for use according to claim 7, wherein the antiviral molecule is choice between: - 3?-deoxyadenosine, - mono-di- or tri-phosphorylated 3?-deoxyadenosine, - (2R,3R,4S,5R)-2-(6-amino-9H-purine-9-yl)-5-(4-hydroxy-3- (hydroxymethyl)butyl), - (2R,3R,4S,5R)-2-(6-amino-9H-purin-9-yl)-5-((1,3-dihydroxypropan-2-yl)oxymethyl), - (2R,3R,4S,5R)-2-(6-amino-9H-purin-9-yl)-5-((2-hydroxyethoxy)methyl), - (2R,3R,4S,5R)-2-(6-amino-9H-purin-9-yl)-5-((2-bis(acetyloxymethyl)) ethyl) - (2R,3R,4S,5R)-2-(6-amino-9H-purin-9-yl)-5-(2-amino-3-methylbutanoyloxy-2-(1-hydroxymethyl)ethoxymethyl - (2R, 3R,4S,5R)-2-(6-amino-9H-purin-9-yl)-5--(2-amino-3-methylbutanoyloxy-2-ethoxymethyl), their configurational isomers, diastereomers, enantiomers, racemes or mixtures thereof or salts thereof with pharmaceutically acceptable acids and ? preferably 3?-deoxyadenosine. 9. Adenosine for use according to claim 7 or 8, wherein the antiviral molecule/adenosine weight ratio is ? between 0.3:1 and 1:1, or between 0.5:1 and 0.8:1. 10. Adenosine for use according to any one of claims 1 to 9, wherein said adenosine, said at least one inhibitor of A1 and/or A3 adenosine receptors and said antiviral molecule are contained in an oral formulation or in injectable formulations. 11. Pharmaceutical formulation in the form of a unit? dosage for oral administration, including: - Adenosine - Antiviral molecule according to claim 8, preferably 3?-deoxyadenosine, in a weight ratio between 0.3:1 and 1:1, or between 0.5:1 and 0.8:1, with respect to Adenosine; - Inhibitor of A1 and/or A3 adenosinic receptors, preferably inosine, in a weight ratio between 1.1:1 and 2:1, or between 1.2:1 and 1.7:1, with respect to Adenosine. 12. Pharmaceutical formulation in the form of units? injectable dosage, including: - Adenosine; - an antiviral molecule according to claim 8, preferably 3?-deoxyadenosine, in a weight ratio between 0.3:1 and 1:1, or between 0.5:1 and 0.8:1, with respect to Adenosine; - optionally, at least one inhibitor of the A1 and/or A3 adenosine receptors, preferably inosine, in a weight ratio between 1.1:1 and 2:1, or between 1.2:1 and 1.7:1, with respect to Adenosine , in which the at least one inhibitor of A1 and/or A3 adenosine receptors ? contained in a unit? separate dosage. 13. Kit comprising a first container, preferably a vial, containing an injectable solution of at least one inhibitor of the A1 and/or A3 adenosine receptors, preferably inosine, and a second container, preferably a vial, containing an injectable solution of Adenosine together with a antiviral molecule comprising an adenine nucleus, preferably 3?-deoxyadenosine.