Cyclic sidofovir or a prodrug thereof for use in the treatment or prevention of African swine fever

Abstract

Cyclic cidofovir for use in the treatment of African swine fever (ASF) in animals, wherein the treatment comprises orally administering the cyclic cidofovir at a dose of 10.0 to 30.0 mg / kg, and in a first period of 1 to 4 consecutive days, at least one dose, for example one or two doses of cyclic cidofovir, is administered daily to the animal, and in a second period of 5 to 14 consecutive days, one dose of cyclic cidofovir is administered every other day or daily to the animal, and the average daily dose administered in the first period is higher than the average daily dose administered in the second period, is provided.

Description

Technical Field

[0001] Field of the Invention The present invention relates to a method for treating or preventing African swine fever and a composition for use therein.

Background Art

[0002] Background of the Invention Forty percent of the world's meat consumption is pork, and Europe is the second largest pork-producing country, raising approximately 150 million pigs. However, as a characteristic of the industrial system, a large number of livestock are mainly raised in a closed system, and the rapid replacement of the group in one place makes the meat industry vulnerable to the occurrence of viral diseases, leading to huge economic losses, threats to food security, and possible suffering of livestock.

[0003] In the past decade, African swine fever (ASF) has spread from the Caucasus region to European countries, affecting breeding pigs and wild boar populations. ASF is a highly contagious and fatal pig disease. More specifically, the mortality rate of ASF in breeding pigs reaches 100%, characterized by high fever, depression, loss of appetite, vomiting, and bleeding of the skin and internal organs.

[0004] Currently, there is no effective vaccine or treatment for ASF, and the invasion and spread of ASF into domestic pig farms can only be prevented by strictly observing management measures. Important management measures include livestock identification and farm records, pig containment to prevent direct or indirect contact between pigs and pigs and / or pigs and wild boars, and proper disposal of manure and carcasses. As a result, ASF poses a serious constraint on the development of small-scale farmers and industrial pig farming.

Summary of the Invention

[0005] Therefore, it is necessary to develop an effective means to prevent the spread of ASF.

[0006] Summary of the Invention The inventors have, for the first time to our knowledge, demonstrated the in vivo efficacy of nucleoside phosphonates, more particularly cidofovir cyclophosphate, in the treatment of African swine fever virus (ASFV)-infected animals, more particularly pigs (as defined herein to include the treatment and prevention of the disease). Further, the inventors have tested several dosing regimens and found specific dosage ranges and specific dosing regimens for cidofovir cyclophosphate or its prodrug that enable the treatment (including prevention of the disease) of ASFV-infected animals, more particularly pigs. More particularly, the inventors have found a dosing regimen comprising two successive periods where the dose and / or timing of the first period is different from the dose and / or timing of the second period, preferably where the average daily dose administered in the first period is higher than the average daily dose administered in the second period, and which allows for an acceptable toxicity of cidofovir cyclophosphate or the prodrug or no toxicity while reducing viral shedding and clinical signs of the disease and improving survival in pigs challenged with ASFV.

[0007] Thus, a first aspect provides cidofovir cyclophosphate for use in the treatment of African swine fever (ASF) in animals, wherein the treatment comprises oral administration of said cidofovir cyclophosphate at a dose of 10.0 to 30.0 mg / kg, wherein at least one dose, such as one or two doses, of cidofovir cyclophosphate is administered daily to said animal during a first period of 1 to 4 consecutive days and one dose of cidofovir cyclophosphate is administered every other day or daily to said animal during a second period of 5 to 14 consecutive days, and wherein the average daily dose administered in the first period is higher than the average daily dose administered in the second period. In certain embodiments, cidofovir cyclophosphate for use as contemplated herein has the formula (i):

Chemical formula

[0008] In some embodiments, the cyclic cidofovir for use according to the invention has the formula (I) or (II):

Chemical formula

[0009] In some embodiments, the cyclic cidofovir for use according to the present invention wherein L is selected from the group consisting of -(CR 2 R 3 ) n - and -CH(R 4 )-C(O)-; n is an integer selected from 1, 2, or 3; R 1 is selected from the group consisting of C 6-25 alkyl, -C(O)R 6 -, -CO 2 R 7 -, C 6-25 haloalkyl, C 6-25 alkenyl, and C 3-10 cycloalkyl; Each R 2 is independently selected from the group consisting of hydrogen, C 1-6 alkyl, and halogen; Each R 3 is independently selected from the group consisting of hydrogen, C 1-6selected from the group consisting of alkyl and halogen; each R 4 is independently hydrogen, C 1-6 alkyl, and halogen; each R 5 is independently hydrogen, C 1-6 alkyl, C 3-10 selected from the group consisting of cycloalkyl and halogen; each R 6 is independently C 1-6 alkyl, C 1-6 haloalkyl, and C 3-6 selected from the group consisting of cycloalkyl; each R 7 is independently C 1-6 alkyl, C 1-6 haloalkyl, and C 3-6 selected from the group consisting of cycloalkyl, has the structure of formula (I).

[0010] In some embodiments, the cyclic cidofovir for use according to the present invention is as follows: [Table 1] selected from the group consisting of.

[0011] In certain embodiments, during a first period of 3 consecutive days, 2 doses of cyclic cidofovir are administered daily to the animal, and during a second period of 5 - 14 consecutive days, preferably 5 - 7 consecutive days, 1 dose of cyclic cidofovir is administered daily to the animal.

[0012] In certain embodiments, during a first period of 3 consecutive days, 1 dose of cyclic cidofovir is administered daily to the animal, and during a second period of 5 - 14 consecutive days, preferably 5 - 7 consecutive days, 1 dose of cyclic cidofovir is administered to the animal every other day.

[0013] In certain embodiments, the cyclic cidofovir is included in a pharmaceutical composition, and preferably, the pharmaceutical composition is an aqueous solution.

[0014] In certain embodiments, the animal is a pig.

[0015] In certain embodiments, the animal is housed in an ASF surveillance area or a protected area.

[0016] In certain embodiments, the administration of the cyclic cidofovir prevents the spread of ASF within the animal population. BRIEF DESCRIPTION OF THE DRAWINGS

[0017]

Figure 1

Figure 2

Figure 3

Figure 4-1

Figure 4-2

Figure 5

Figure 6-1

Figure 6-2

Figure 7

Figure 8

[0018] Detailed Description of the Invention The term "about", when used in relation to a numerical value, has the meaning generally understood in the art. In certain embodiments, the term "about" may be omitted or may be interpreted to mean the numerical value + 10%; or + 5%; or + 2%; or + 1%.

[0019] As used herein in relation to percentages, w / w means weight / weight and w / v means weight / volume.

[0020] As used herein, the singular forms "a", "an", and "the" include both singular and plural referents unless the context clearly dictates otherwise.

[0021] As used herein, the terms "comprising", "comprises" and "comprised of" are synonymous with "including", "includes", or "containing", "contains", and are inclusive or open-ended terms and do not exclude additional members, elements or method steps not recited. With respect to the recited members, elements or method steps, the terms "comprising", "comprises" and "comprised of" also include embodiments "consisting of" the recited members, elements or method steps.

[0022] Further, in this specification and the claims, terms such as first, second, third, etc., are used for purposes of distinguishing among similar elements or steps and not necessarily for describing a sequential or chronological order. The terms so used are interchangeable under appropriate circumstances and it is to be understood that the embodiments described herein are operable in other orders than those described or illustrated herein.

[0023] As used throughout this specification, the term "one embodiment" or "an embodiment" means that a particular feature, structure, or characteristic described in connection with that embodiment is included in at least one embodiment contemplated by this specification. Thus, the appearances of the phrases "in one embodiment" or "in an embodiment" in various places throughout this specification are not necessarily all referring to the same embodiment (although they could be). Further, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments, as will be apparent to those skilled in the art from this disclosure. Additionally, some embodiments described herein include some features included in other embodiments but not others, and as will be understood by those skilled in the art, combinations of features of different embodiments are within the scope of the invention and form different embodiments. For example, in the following claims, any of the claimed embodiments can be used in any combination.

[0024] All references cited herein are hereby incorporated by reference as part of this specification.

[0025] The inventors have, for the first time to their knowledge, demonstrated the in vivo efficacy of nucleoside phosphonates in the treatment (as defined herein to include treatment and prophylaxis) of African swine fever virus (ASFV)-infected animals, more particularly pigs. Further, the inventors have tested several dosing regimens and have found specific dosage ranges and specific dosing regimens for cidofovir cyclic or its prodrugs that enable the treatment (including prevention of disease) of ASFV-infected animals, more particularly pigs. More specifically, the inventors have found a dosing regimen comprising two successive periods where the dose and / or timing of the first period is different from the dose and / or timing of the second period, preferably where the average daily dose administered in the first period is higher than the average daily dose administered in the second period, and which reduces viral shedding and clinical signs of disease and improves survival in pigs challenged with ASFV while allowing for acceptable or no toxicity of cidofovir cyclic or the prodrug.

[0026] Thus, the first aspect provides a cyclic cidofovir or a prodrug thereof for use in the treatment of African swine fever (ASF) in animals, said treatment comprising orally administering said cyclic cidofovir or a prodrug thereof at a dose of 10.0 to 30.0 mg / kg, preferably 15.0 to 25.0 mg / kg, such as about 20.0 mg / kg, and administering at least one dose, such as one dose or two doses, of said cyclic cidofovir to the animal daily during a first period of 1 to 4 consecutive days, and administering one dose of cyclic cidofovir to the animal every other day or daily during at least 5 consecutive days, such as a second period of 5 to 14 consecutive days, wherein the average daily dose administered during the first period is higher than the average daily dose administered during the second period. Here, "mg / kg" refers to the amount of cyclic cidofovir or a prodrug thereof per 1 kg of the animal's body weight. Further, the average daily dose takes into account the total dose administered during that period and the total number of days in that period. For example, in a period of 5 consecutive days where 20.0 mg / kg of cyclic cidofovir is administered to the animal once every other day and the period starts from the administration day, the average daily dose is 12.0 mg / kg (i.e., (20.0 mg / kg * × 3) / 5).

[0027] A further aspect provides a method of treating (as defined herein to include treatment and prevention) ASF in animals, said method comprising orally administering a cyclic cidofovir or a prodrug thereof at a dose of 10.0 to 30.0 mg / kg, and administering at least one dose, such as one dose or two doses, of cyclic cidofovir to the animal daily during a first period of 1 to 4 consecutive days, and administering one dose of cyclic cidofovir to the animal every other day or daily during at least 5 consecutive days, such as a second period of 5 to 14 consecutive days, wherein the average daily dose administered during the first period is higher than the average daily dose administered during the second period.

[0028] A further aspect provides the use of cyclic cidofovir or a prodrug thereof in the preparation of a medicament for the treatment (as defined herein to include treatment and prophylaxis) of ASF in animals, wherein the cyclic cidofovir or a prodrug thereof is orally administered at a dose of 10.0 to 30.0 mg / kg, with at least one dose, such as one or two doses of cyclic cidofovir, being administered daily to the animal during a first period of 1 to 4 consecutive days, and one dose of cyclic cidofovir being administered to the animal every other day or daily during a second period of at least 5 consecutive days, such as 5 to 14 consecutive days, and the average daily dose administered during the first period being higher than the average daily dose administered during the second period.

[0029] "Cyclic cidofovir", "cCDV", "cyclic (S)-HPMPC", or "cHPMPC", as used herein, refers to a compound having the structural formula:

Chemical formula

[0030] Thus, the terms "cyclic cidofovir", "cCDV", or "cHPMPC", as used herein, include isomers, solvates, tautomers, salts, esters, amidates, ester amidates or pharmaceutically acceptable salts of the compounds of formula (i) above or compounds in equilibrium with the above compounds. The phosphonic acid functional group of the nucleoside analog can be derivatized to enhance the activity, pharmacokinetic or pharmacodynamic profile. Accordingly, the terms "cyclic cidofovir", "cCDV", or "cHPMPC" also include phosphonic acid esters, amidates or ester amidates of the compounds of formula (i), wherein the phosphonic acid may be mono- or di-substituted. Examples of such esters include alkyl esters, alkenyl esters, alkynyl esters, alkoxyalkyl esters, alkoxyalkenyl esters such as octyl, tetracosyl, hexadecyloxypropyl, octadecyloxyethyl, oleoyloxypropyl, tetradecyloxypropyl, octadecyloxypropyl, oleoyloxyethyl, 1-O-octadecyl-2-O-benzyl-glyceryl, and the like. Cyclic cidofovir can be prepared by any method known in the art, such as those described in WO 95 / 07919, for example.

[0031] Further suitable examples of esters, amidates or ester amidates of the compounds of formula (i) include acyloxyalkyl esters, alkoxycarbonyloxyalkyl esters, alkoxyalkyl esters, or amidates such as phosphoramidates or phosphonamidates, also known as ProTides.

[0032] The term "prodrug", as used herein, refers to a drug or compound that is metabolized to a pharmacologically active compound when administered to a subject. Prodrugs may have the potential to improve how the pharmacologically active compound is absorbed, distributed, metabolized and excreted (ADME) by the subject's body. Cyclic cidofovir is thought to be a prodrug of HPMPC (cidofovir) itself.

[0033] However, additional prodrugs can still be considered. For example, prodrugs of cyclic cidofovir can be prodrugs of cyclic cidofovir as described in Pertusat F. et al., Medicinal Chemistry of Nucleoside Phosphonate Prodrugs for Antiviral Therapy, Antiviral Chemistry and Chemotherapy, 2012, such as phenyl or salicylic acid ester prodrugs of cyclic cidofovir or serine peptide phosphoesters or alkyloxycarbonylphenyl prodrugs of cyclic cidofovir, or peptide conjugates of cyclic cidofovir such as those described in International Publication No. WO 2006 / 014429.

[0034] In certain embodiments, cyclic cidofovir is selected from the group consisting of pivaloyloxymethyl cyclic cidofovir, isopropyloxycarbonyloxymethyl cyclic cidofovir, isopropyl cyclic cidofovir L-alaninate, isopropyl cyclic cidofovir L-valinate, 1-O-hexadecylpropanediol-3-cyclic cidofovir, 1-O-octadecylpropanediol-3-cyclic cidofovir, 1-O-octadecylethanediol-2-cyclic cidofovir, hexadecyloxypropyl cyclic cidofovir, octadecyloxyethyl cyclic cidofovir, oleoyloxypropyl cyclic cidofovir, octyloxypropyl cyclic cidofovir, dodecyloxypropyl cyclic cidofovir, oleoyloxyethyl cyclic cidofovir, 1-O-octadecyl-2-O-benzyl-glyceryl cyclic cidofovir, tetradecyloxypropyl cyclic cidofovir, eicosyl cyclic cidofovir, docosyl cyclic cidofovir, and hexadecyl cyclic cidofovir, and preferably, the cyclic cidofovir prodrug is selected from the group consisting of pivaloyloxymethyl cyclic cidofovir, isopropyloxycarbonyloxymethyl cyclic cidofovir, isopropyl cyclic cidofovir L-alaninate, and isopropyl cyclic cidofovir L-valinate.

[0035] In some embodiments, the cyclic sidofovir for use in accordance with the present invention has the formula (I) or (II):

Chemical formula

[0036] The term "halo" or "halogen" as a group or part of a group is a general term for fluoro, chloro, bromo, and iodo.

[0037] The term "alkyl" as a group or part of a group refers to a hydrocarbyl group of the formula -C n H 2n+1 where n is a number of 1 or more. The alkyl group can be straight-chain or branched and may be substituted as shown herein. Generally, the alkyl groups of the present invention comprise up to 25 carbon atoms, preferably up to 24 carbon atoms, preferably up to 23 carbon atoms, more preferably up to 22 carbon atoms, still more preferably up to 21 carbon atoms. When a subscript is used after a carbon atom herein, the subscript refers to the number of carbon atoms that the named group may contain. For example, "C 1-6 alkyl" includes any straight-chain or branched alkyl group having 1 to 6 carbon atoms and thus includes methyl, ethyl, n-propyl, i-propyl, butyl and its isomers (e.g., n-butyl, i-butyl and t-butyl); pentyl and its isomers, hexyl and its isomers. For example, "C 1-5"Alkyl" includes all straight-chain or branched alkyl groups having 1 to 5 carbon atoms, and thus includes methyl, ethyl, n-propyl, i-propyl, butyl and its isomers (e.g., n-butyl, i-butyl and t-butyl); pentyl and its isomers. For example, "C 1-4 "Alkyl" includes all straight-chain or branched alkyl groups having 1 to 4 carbon atoms, and thus includes methyl, ethyl, n-propyl, i-propyl, butyl and its isomers (e.g., n-butyl, i-butyl and t-butyl). For example, "C 1-3 "Alkyl" includes all straight-chain or branched alkyl groups having 1 to 3 carbon atoms, and thus includes methyl, ethyl, n-propyl, i-propyl.

[0038] When the term "alkyl" is used as a suffix following another term, such as "hydroxyalkyl", this is intended to refer to an alkyl group as defined above which is substituted with one or two (preferably one) substituents selected from the other specifically named groups as defined herein. Thus, the term "hydroxyalkyl" refers to an -Ra-OH group where Ra is an alkylene as defined herein. a The term "haloalkyl" as a group or part of a group refers to an alkyl group having the meaning as defined above, in which one or more hydrogen atoms are each substituted with a halogen as defined herein. Non-limiting examples of such haloalkyl groups include chloromethyl, 1-bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1,1,1-trifluoroethyl, trichloromethyl, tribromomethyl, etc.

[0039]

[0040] The term "cycloalkyl", as a group or part of a group, refers to a monovalent saturated hydrocarbyl group having one or more ring structures and containing 3 to 12 carbon atoms, more preferably 3 to 9 carbon atoms, more preferably 3 to 7 carbon atoms; more preferably 3 to 6 carbon atoms, which is a cyclic alkyl group. Cycloalkyl includes any saturated hydrocarbon group containing one or more rings, including monocyclic or bicyclic groups. The additional rings of polycyclic cycloalkyl may be condensed, bridged and / or linked via one or more spiro atoms. When a subscript is used after a carbon atom in this specification, the subscript refers to the number of carbon atoms that the named group may contain. For example, the term "C 3-8 cycloalkyl" refers to a cyclic alkyl group containing 3 to 8 carbon atoms. For example, the term "C 3-6 cycloalkyl" refers to a cyclic alkyl containing 3 to 6 carbon atoms. Examples of C 3-12 cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[2.2.1]heptan-2-yl, (1S,4R)-norbornan-2-yl, (1R,4R)-norbornan-2-yl, (1S,4S)-norbornan-2-yl, (1R,4S)-norbornan-2-yl, 1-adamantyl.

[0041] The term "halocycloalkyl", as a group or part of a group, refers to a cycloalkyl group having the meaning as defined above, in which one or more hydrogen atoms are each substituted with a halogen as defined herein.

[0042] The term "alkenyl", as a group or part of a group, refers to an unsaturated hydrocarbyl group which may be straight-chain or branched and contains one or more carbon-carbon double bonds. When a subscript is used after a carbon atom in this specification, the subscript refers to the number of carbon atoms that the named group may contain. For example, "C 2-6The term "alkenyl" can be straight-chain or branched, contains one or more carbon-carbon double bonds, and refers to an unsaturated hydrocarbyl group containing 2 to 6 carbon atoms. For example, C 2-4 Alkenyl includes any straight-chain or branched alkenyl group having 2 to 4 carbon atoms. C 2-6 Examples of alkenyl groups include ethenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl and its isomers, 2-hexenyl and its isomers, 2,4-pentadienyl, and the like.

[0043] The term "haloalkenyl" as a group or part of a group refers to an alkenyl group having the meaning defined above, wherein one or more hydrogen atoms are each substituted with a halogen as defined herein.

[0044] The compounds of the present invention can also exist in non-solvated and solvated forms. The term "solvate" is used herein to represent a molecular complex comprising a compound of the present invention and one or more pharmaceutically acceptable solvent molecules, such as ethanol. The term "hydrate" is used when the solvent is water.

[0045] The currently accepted classification system for organic hydrates defines isolated-site hydrates, channel hydrates, and metal-ion coordination hydrates. See Polymorphism in Pharmaceutical Solids by K. R. Morris (Ed. H. G. Britain, Marcel Dekker, 1995), which is incorporated herein by reference. Isolated-site hydrates are those in which water molecules are isolated from each other by intervening organic molecules so that they do not directly contact each other. In channel hydrates, water molecules are within lattice channels and are adjacent to other water molecules. In metal-ion coordination hydrates, water molecules are bound to metal ions.

[0046] When the solvent or water is strongly bound, the complex has a well-defined stoichiometry that is independent of humidity. However, when the solvent or water is weakly bound, such as in the case of channel solvates and hygroscopic compounds, the water / solvent content depends on humidity and drying conditions. In such cases, non-stoichiometry is common.

[0047] As used herein, unless otherwise indicated, the term "stereoisomer" refers to any different potential isomeric forms and conformational forms that the compounds of the structural formulas herein may have, particularly any potential stereochemical and conformational isomeric forms, any diastereomers, enantiomers, and / or conformers of the basic molecular structure. Some compounds of the present invention may exist in different tautomeric forms, and all of them are included within the scope of the present invention.

[0048] The present invention includes any possible stereoisomeric compounds of formula (I) and any subgroup thereof. When a compound is desired as a single enantiomer, such a compound can be obtained by stereospecific synthesis, by separation of the final product or any convenient intermediate, or by chiral chromatography methods, each of which is known in the art. The resolution of the final product, intermediate, or starting material can be carried out by any suitable method known in the art. See, for example, Stereochemistry of Organic Compounds by E. L. Eliel, S. H. Wilen, and L. N. Mander (Wiley-Interscience, 1994), which is incorporated herein by reference with respect to stereochemistry. Structural isomers are a type of isomer in which molecules with the same molecular formula have different bonding patterns and atomic constitutions. Tautomerism can occur when structural isomers are interconvertible via a low energy barrier. This can take the form of proton tautomerism in compounds of the present invention containing, for example, imino, keto, or oxime groups, or so-called valence tautomerism in compounds containing an aromatic moiety.

[0049] The compounds of the present invention may be in the form of salts, preferably pharmaceutically acceptable salts, as generally described below. Some preferred, non-limiting examples of suitable pharmaceutically acceptable organic and / or inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, acetic acid and citric acid, as well as other pharmaceutically acceptable acids known per se (reference is made to the prior art mentioned below for this).

[0050] When the compounds of the present invention contain an acidic group as well as a basic group, the compounds of the present invention can also form internal salts, and such compounds are also within the scope of the present invention. When the compounds of the present invention contain a hydrogen-donating heteroatom (e.g., NH), the present invention also encompasses salts and / or isomers formed by the transfer of said hydrogen atom to a basic group or atom within the molecule.

[0051] The pharmaceutically acceptable salts of the compounds of formula (I) and any subgroup thereof include acid addition salts and base addition salts. Suitable acid addition salts are formed from acids that form non-toxic salts. Examples include acetate, adipate, aspartate, benzoate, besylate, bicarbonate / carbonate, bisulfate / sulfate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulfate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogenphosphate / dihydrogenphosphate, pyroglutamate, saccharinate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate and xinafoate. Suitable base salts are formed from bases that form non-toxic salts. Examples include aluminum salts, arginine salts, benzathine salts, calcium salts, choline salts, diethylamine salts, diolamine salts, glycine salts, lysine salts, magnesium salts, meglumine salts, olamine salts, potassium salts, sodium salts, tromethamine salts and zinc salts. Hemisalts of acids and bases, such as hemisulfate and hemicalcium salts, can also be formed. For a general review of suitable salts, see Handbook of Pharmaceutical Salts: Properties, Selection, and Use by Stahl and Wermuth (Wiley-VCH, 2002), which is incorporated herein by reference.

[0052] The compounds of the present invention can exist in a continuous solid state ranging from completely amorphous to completely crystalline. The term "amorphous" refers to a state in which a material lacks long-range order at the molecular level and can exhibit the physical properties of a solid or a liquid depending on temperature. Generally, such materials do not show a characteristic X-ray diffraction pattern and thus, while exhibiting solid properties, are more formally represented as liquids. Heating causes a change in properties from solid to liquid, which is characterized by a state change, usually a second-order change ("glass transition"). The term "crystalline" refers to a solid phase in which a substance has a regular internal structure at the molecular level and shows a characteristic X-ray diffraction pattern with distinct peaks. Such materials also exhibit liquid properties when heated sufficiently, but the change from solid to liquid is characterized by a phase change, usually a first-order change ("melting point").

[0053] Pharmaceutically acceptable salts of the compounds of formula (I) can be prepared by the following methods: (i) reacting a compound of formula (I) with a desired acid; (ii) reacting a compound of formula (I) with a desired base; (iii) removing an acid- or base-labile protecting group from a suitable precursor of a compound of formula (I), or ring-opening a suitable cyclic precursor, such as a lactone or lactam, with a desired acid; or (iv) reacting with a suitable acid or converting one salt of a compound of formula (I) to another salt by means of a suitable ion-exchange column and can be prepared by one or more of the above.

[0054] All of these reactions are generally carried out in solution. The salt can be precipitated from the solution and recovered by filtration or by evaporation of the solvent. The degree of ionization of the salt can vary from fully ionized to hardly ionized at all.

[0055] Furthermore, generally with respect to the salts of the compounds of the present invention, pharmaceutically acceptable salts are preferred, but it should be noted that the present invention, in its broadest sense, also includes salts that are not pharmaceutically acceptable, for example, those that may be used in the isolation and / or purification of the compounds of the present invention.

[0056] In some embodiments, the cyclic cidofovir for use according to the present invention has the formula (I) as defined herein (wherein, A is selected from the group consisting of O and NH; L is selected from the group consisting of -(CR 2 R 3 ) n -, -CH(R 4 )-C(O)- and -C(O)-CH(R 5 )-; preferably, L is -(CR 2 R 3 ) n - or -CH(R 4 )-C(O)-; n is an integer selected from 1, 2, 3, 4 or 5; preferably, n is 1, 2, 3, or 4; preferably, n is 1, 2, or 3; R 1 is selected from the group consisting of C 6-25 alkyl, -C(O)R 6 , -CO 2 R 7 , C 6-25 haloalkyl, C 6-25 alkenyl, C 6-25 haloalkenyl, C 3-12 cycloalkyl and C 3-12 halocycloalkyl; preferably, R 1 is C 6-24 alkyl, -C(O)R 6 , -CO 2 R 7 , C 6-24 haloalkyl, C 6-25 alkenyl, C 6-24 haloalkenyl, C 3-12 cycloalkyl and C 3-12 halocycloalkyl; preferably, R 1is C 6-24 alkyl, -C(O)R 6 , -CO 2 R 7 , C 6-24 haloalkyl, C 6-24 alkenyl, C 6-24 haloalkenyl, C 3-10 cycloalkyl and C 3-10 halocycloalkyl; preferably, R 1 is C 6-23 alkyl, -C(O)R 6 , -CO 2 R 7 , C 6-23 haloalkyl, C 6-23 alkenyl, C 6-23 haloalkenyl, C 3-10 cycloalkyl and C 3-10 halocycloalkyl; preferably, R 1 is C 6-22 alkyl, -C(O)R 6 , -CO 2 R 7 , C 6-22 haloalkyl, C 6-22 alkenyl, C 6-22 haloalkenyl, C 3-12 cycloalkyl and C 3-12 halocycloalkyl; preferably, R 1 is C 6-21 alkyl, -C(O)R 6 , -CO 2 R 7 , C 6-21 haloalkyl, C 6-21 alkenyl, C 6-21 haloalkenyl, C 3-10 cycloalkyl and C 3-10 halocycloalkyl; preferably, R 1 is C 6-20 alkyl, -C(O)R 6 , -CO 2 R 7 , C 6-20 haloalkyl, C 6-20 alkenyl, C 6-20 haloalkenyl, C 3-12 cycloalkyl and C 3-12is a halocycloalkyl; preferably, R 1 is C 6-20 alkyl, -C(O)R 6 -CO 2 R 7 C 6-20 haloalkyl, C 6-20 alkenyl, C 6-20 haloalkenyl, C 3-10 cycloalkyl and C 3-10 halocycloalkyl; preferably, R 1 is C 6-20 alkyl, -C(O)R 6 -CO 2 R 7 C 6-20 haloalkyl, C 3-12 cycloalkyl and C 3-12 halocycloalkyl; preferably, R 1 is C 6-20 alkyl, -C(O)R 6 and -CO 2 R 7 ; preferably, R 1 is C 6-18 alkyl, -C(O)R 6 and -CO 2 R 7 ; each R 2 is independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 3-12 cycloalkyl and halogen; preferably, each R 2 is independently hydrogen, C 1-6 alkyl, C 3-10 cycloalkyl and halogen; preferably, each R 2 is independently hydrogen, C 1-6 alkyl, C 3-10 cycloalkyl, fluoro, chloro, iodo, and bromo; preferably, each R 2 is independently hydrogen, C 1-5 alkyl, C 3-10 cycloalkyl, fluoro, chloro, iodo, and bromo; preferably, each R 2 is independently hydrogen, C 1-5 alkyl, C 3-8Cycloalkyl, fluoro, chloro, iodo, and bromo; preferably, each R 2 is independently hydrogen and C 1-5 alkyl; each R 3 is independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 3-12 cycloalkyl, and halogen; preferably, each R 3 is independently hydrogen, C 1-6 alkyl, C 3-10 cycloalkyl, and halogen; preferably, each R 3 is independently hydrogen, C 1-6 alkyl, C 3-10 cycloalkyl, fluoro, chloro, iodo, and bromo; preferably, each R 3 is independently hydrogen, C 1-5 alkyl, C 3-10 cycloalkyl, fluoro, chloro, iodo, and bromo; preferably, each R 3 is independently hydrogen, C 1-5 alkyl, C 3-8 cycloalkyl, fluoro, chloro, iodo, and bromo; preferably, each R 3 is independently hydrogen and C 1-5 alkyl; each R 4 is independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 3-12 cycloalkyl, and halogen; preferably, each R 4 is independently hydrogen, C 1-6 alkyl, C 3-10 cycloalkyl, and halogen; preferably, each R 4 is independently hydrogen, C 1-6 alkyl, C 3-10 cycloalkyl, fluoro, chloro, iodo, and bromo; preferably, each R 4 is independently hydrogen, C 1-5 alkyl, C 3-10 cycloalkyl, fluoro, chloro, iodo, and bromo; preferably, each R 4 is independently hydrogen, C 1-5Alkyl, C 3-8 cycloalkyl, fluoro, chloro, iodo, and bromo; preferably, each R 4 is independently hydrogen, C 1-4 alkyl, and C 3-8 cycloalkyl; preferably, each R 4 is independently hydrogen, and C 1-5 alkyl; each R 5 is independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 3-12 cycloalkyl and halogen; preferably, each R 5 is independently hydrogen, C 1-6 alkyl, C 3-10 cycloalkyl and halogen; preferably, each R 5 is independently hydrogen, C 1-6 alkyl, C 3-10 cycloalkyl, fluoro, chloro, iodo, and bromo; preferably, each R 5 is independently hydrogen, C 1-5 alkyl, C 3-10 cycloalkyl, fluoro, chloro, iodo, and bromo; preferably, each R 5 is independently hydrogen, C 1-5 alkyl, C 3-8 cycloalkyl, fluoro, chloro, iodo, and bromo; preferably, each R 5 is independently hydrogen, and C 1-5 alkyl; each R 6 is independently selected from the group consisting of C 1-10 alkyl, C 1-10 haloalkyl, C 3-12 cycloalkyl, C 3-12 halocycloalkyl, C 2-10 alkenyl, and C 2-10 haloalkenyl; preferably, each R 6 is independently C 1-8 alkyl, C 1-8 haloalkyl, C 3-10 cycloalkyl, C 3-10 halocycloalkyl, C 2-8 alkenyl, and C2-8 is a haloalkenyl; preferably, each R 6 is independently C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, C 3-8 halocycloalkyl, C 2-6 alkenyl, and C 2-6 haloalkenyl; preferably, each R 6 is independently C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, and C 2-6 haloalkenyl; each R 7 is independently selected from the group consisting of C 1-10 alkyl, C 1-12 haloalkyl, C 3-12 cycloalkyl, C 3-12 halocycloalkyl, C 2-10 alkenyl, and C 2-10 haloalkenyl; preferably, each R 7 is independently C 1-8 alkyl, C 1-8 haloalkyl, C 3-10 cycloalkyl, C 3-10 halocycloalkyl, C 2-8 alkenyl, and C 2-8 haloalkenyl; preferably, each R 7 is independently C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, C 3-8 halocycloalkyl, C 2-6 alkenyl, and C 2-6 haloalkenyl; preferably, each R 7 is independently C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, and C 2-6 haloalkenyl) has the structure of or is a stereoisomer, tautomer, solvate, hydrate, pharmaceutically acceptable salt thereof.

[0057] In some embodiments, A is O. In some embodiments, L is -(CR 2 R 3 ) n -. In some embodiments, L is -CH(R 4 )-.

[0058] Particularly preferred compounds of the present invention are shown in the following table:

Table 2

[0059] The term "treatment" includes both therapeutic treatment of a disease or condition already occurred, such as treatment of already developed ASFV infection, and prophylactic or preventive measures aimed at preventing or reducing the occurrence of an undesired pathologic condition, such as prevention of the occurrence, onset and progression of ASFV infection. Beneficial or desired clinical results include, but are not limited to, alleviation of one or more symptoms or one or more biological markers, diminishment of extent of disease, stabilization of a disease state (i.e., non-worsening), delay or slowing of disease progression, amelioration or alleviation of a disease state, etc. "Treatment" also means prolonging survival as compared to expected survival if not receiving treatment. "Treatment" can also mean reducing the viral load of ASFV in an animal, thereby reducing infectivity, and / or reducing viral excretion in an animal, thereby reducing viral / disease transmission / spread.

[0060] Unless otherwise specified, the terms "animal", "subject", or "patient" can be used interchangeably and refer to an animal, preferably a warm-blooded animal, more preferably a vertebrate, even more preferably a mammal, still more preferably a member of the family Suidae, and still more preferably a member of the genus Sus. Preferred subjects are wild or domestic pigs or swine. A more preferred subject is the domestic pig (Sus domesticus). Non-limiting examples of members of the family Suidae include the golden babirusa, Sulawesi babirusa, Togian babirusa, giant forest hog, Javan warty pig, common warty pig, pygmy hog, bushpig, red river hog, bearded pig, wild boar, Vietnamese warty pig, Visayan warty pig, Celebes warty pig, Flores warty pig, Mindoro warty pig, Philippine warty pig, Javan warty pig, wild boar, and domestic pig.

[0061] The terms "subject" or "patient" include a subject in need of treatment, more particularly a subject who would benefit from treatment of a given medical condition, in particular an ASFV infection. Such subjects include, but are not limited to, subjects diagnosed with the medical condition, subjects predisposed to developing the medical condition, and / or subjects in whom the medical condition should be prevented.

[0062] In certain embodiments, the animal is a member of the family Suidae, a member of the genus Sus, preferably a domestic pig, wild pig, domestic swine or wild swine (i.e., wild boar).

[0063] The term "African swine fever" or "ASF" as used herein refers to a viral disease caused by infection with ASFV. ASFV is a large enveloped double-stranded DNA virus. Its genome consists of 170-193 kilobase pairs and has up to 167 open reading frames. ASFV is the only member of the family Asfarviridae and the only DNA virus known to be transmitted by arthropods, namely soft ticks of the genus Ornithodoros. Based on sequence variations in the C-terminal region of the B646L gene encoding the major capsid protein p72, 24 ASFV genotypes (I-XXIV) have been identified to date. ASF may be of any type, including ASF caused by any ASFV genotype or ASFV isolate such as the Georgia 2007 / 1 isolate, KAB6 / 2 isolate, BOT1 / 99 isolate, and Magadi w / hog 9 isolate.

[0064] In certain embodiments, cyclic cidofovir or a prodrug thereof can treat pan-genotypic ASFV.

[0065] In certain embodiments, cyclic cidofovir or a prodrug thereof is administered orally in the form of a powder, liquid, semi-liquid, pill, tablet, capsule, or granule.

[0066] Daily administration of a dose of cyclic cidofovir or a prodrug thereof to an animal can refer to administration of the entire dose of cyclic cidofovir or a prodrug thereof at a single point in time within a day (i.e., once a day). Daily administration of a dose of cyclic cidofovir or a prodrug thereof to an animal can also include administration of doses of cyclic cidofovir or a prodrug thereof dispersed over a long period of a day, such as continuous administration by allowing free access to a source of water and / or feed containing multiple points in time or adjusted doses within a day.

[0067] When two doses of cyclic cidofovir or a prodrug thereof are administered daily to an animal (wherein the daily dose of cyclic cidofovir or a prodrug thereof is twice the daily dose for administration of one dose of cyclic cidofovir or a prodrug thereof), each of these two doses can be administered to the animal at a given point in time of a day (e.g., twice a day as described elsewhere herein), or the administration of each dose can also be dispersed at multiple given time points of a day or over a long period of a day such as continuous administration or free intake.

[0068] In certain embodiments, cyclic cidofovir or a prodrug thereof is orally administered by mixing cyclic cidofovir or a prodrug thereof with the animal's feed or drinking water.

[0069] In certain embodiments, cyclic cidofovir or a prodrug thereof is administered to the animal at a dose of 10.0 - 30.0 mg (mg / kg) of cyclic cidofovir or a prodrug thereof per kg of the animal's body weight, 15.0 - 30.0 mg / kg, 20.0 - 30.0 mg / kg, or 25.0 - 30.0 mg / kg, preferably about 30.0 mg / kg of the cyclic cidofovir or prodrug.

[0070] Such a single or double dose of cidofovir or its prodrug can be administered to an animal per day. In certain embodiments, when a single dose of cidofovir or its prodrug is administered to an animal daily, the total daily dose or amount of cidofovir or its prodrug is 10.0 to 30.0 mg (mg / kg) of cidofovir or its prodrug per kg of the animal's body weight, 15.0 to 30.0 mg / kg, 20.0 to 30.0 mg / kg, or 25.0 to 30.0 mg / kg, preferably about 30.0 mg / kg of said cidofovir or its prodrug. In certain embodiments, when a double dose of cidofovir or its prodrug is administered to an animal daily, the total daily dose of cidofovir or its prodrug is 20.0 to 60.0 mg (mg / kg) of cidofovir or its prodrug per kg of the animal's body weight, 30.0 to 60.0 mg / kg, 40.0 to 60.0 mg / kg, or 50.0 to 60.0 mg / kg, preferably about 60.0 mg / kg of said cidofovir or its prodrug. Similarly, when three or more doses are administered, this corresponds to a total amount of three or more times 10.0 to 30.0 mg (mg / kg) of cidofovir or its prodrug per kg of the animal's body weight, 15.0 to 30.0 mg / kg, 20.0 to 30.0 mg / kg, or 25.0 to 30.0 mg / kg, preferably about 30.0 mg / kg of said cidofovir or its prodrug.

[0071] In certain embodiments, during a first period of 1 to 4 consecutive days (i.e., during that time), at least 1 dose, such as 1 dose or 2 doses, of cidofovir cyclic or a prodrug thereof is administered daily to an animal, and during a second period of 5 to 14 consecutive days, preferably 5 to 7 consecutive days, such as 5 consecutive days, 1 dose of cidofovir cyclic is administered to the animal every other day or daily. Thus, in certain embodiments, during a first period of 1 to 4 consecutive days, cidofovir cyclic or a prodrug thereof having a total daily dose of 10.0 to 60.0 mg / kg is administered daily to an animal, and during a second period of 5 to 14 consecutive days, preferably 5 to 7 consecutive days, such as 5 consecutive days, cidofovir cyclic or a prodrug thereof having a total daily dose of 10.0 to 30.0 mg / kg is administered to the animal every other day or daily.

[0072] In certain embodiments, the second dosing period is immediately after the first dosing period, which means that the first dosing period and the second dosing period are not separated by a third dosing period or a non-dosing period of cidofovir cyclic or a prodrug thereof.

[0073] In certain embodiments, administration comprises a first period of 1 to 4 consecutive days, such as 1, 2, 3, or 4 consecutive days, preferably 3 consecutive days, during which 2 doses of cidofovir cyclic or a prodrug thereof are administered daily to an animal.

[0074] In certain embodiments, administration comprises a first period of 1 to 4 consecutive days, such as 1, 2, 3, or 4 consecutive days, preferably 3 consecutive days, during which 1 dose of cidofovir cyclic or a prodrug thereof is administered daily to an animal.

[0075] In certain embodiments, administration comprises a second period of 5 to 14 consecutive days, such as 5 to 13 consecutive days, 5 to 12 consecutive days, 5 to 10 consecutive days, 5 to 8 consecutive days, 5 to 7 consecutive days, preferably 5 consecutive days, during which 1 dose of cidofovir cyclic or a prodrug thereof is administered daily to an animal.

[0076] In certain embodiments, the administration comprises a second period of 5 to 14 consecutive days, preferably 5 to 7 consecutive days, such as 5, 6, or 7 consecutive days, more preferably 5 consecutive days, or preferably 10 to 14 consecutive days, such as 10, 11, 12, 13, or 14 consecutive days, more preferably 13 consecutive days, in which a single dose of cidofovir cyclic or its prodrug is administered to the animal every other day.

[0077] In certain embodiments, a single dose of cidofovir cyclic is administered to the animal every other day or daily during a second period of 5 to 7 consecutive days, preferably 5 consecutive days.

[0078] In certain embodiments, the second period in which cidofovir cyclic or its prodrug is administered every other day begins on the administration (i.e., treatment) day.

[0079] In certain embodiments, the administration comprises a first period of 3 consecutive days in which two doses of cidofovir cyclic or its prodrug are administered to the animal daily, and a second period of 5 to 14 consecutive days, such as 5 to 12 consecutive days, 5 to 10 consecutive days, 5 to 8 consecutive days, 5 to 7 consecutive days, preferably 5 consecutive days, in which a single dose of cidofovir cyclic or its prodrug is administered to the animal daily.

[0080] In certain embodiments, a single dose of the cidofovir cyclic or its prodrug is administered to the animal daily during the first period of 3 consecutive days, and a single dose of the cidofovir cyclic or its prodrug is administered to the animal every other day during a second period of 5 to 14 consecutive days, preferably 5 to 7 consecutive days, such as 5, 6, or 7 consecutive days, more preferably 5 consecutive days, or preferably 10 to 14 consecutive days, such as 10, 11, 12, 13, or 14 consecutive days, more preferably 13 consecutive days.

[0081] The inventors have found that a dosing regimen comprising a first period in which two doses of cidofovir cyclic or a prodrug thereof are administered daily to an animal, and a second period in which one dose of cidofovir cyclic or a prodrug thereof is administered daily to the animal, as described elsewhere herein, is more preferred than a dosing regimen comprising administering one dose of cidofovir cyclic or a prodrug thereof daily to the animal during the first period and administering one dose of said cidofovir cyclic or a prodrug thereof every other day to the animal during the second period, as described elsewhere herein.

[0082] As described elsewhere herein, the dose of cidofovir cyclic or a prodrug thereof may be administered to all animals at a given point in time.

[0083] Thus, in certain embodiments, the administration comprises a first period of 1 to 4 consecutive days, such as 1, 2, 3, or 4 consecutive days, preferably 3 consecutive days, in which two doses of cidofovir cyclic or a prodrug thereof are administered daily to the animal, and each of said doses of cidofovir cyclic or a prodrug thereof may be administered to all animals at a given point in time. In such embodiments, the animal receives two administrations of one dose of cidofovir cyclic or a prodrug thereof twice a day, for a total of two doses per day.

[0084] When the animal receives two doses per day, each dose of cidofovir cyclic or a prodrug thereof is preferably the same and is from 10.0 to 30.0 mg / kg.

[0085] In certain embodiments, the administration comprises a first period of 1 to 4 consecutive days, such as 1, 2, 3, or 4 consecutive days, preferably 3 consecutive days, in which one dose of cidofovir cyclic or a prodrug thereof is administered once a day to the animal. Thus, in such embodiments, the full dose of cidofovir cyclic or a prodrug thereof is administered to the animal at a given point in time of the day.

[0086] In certain embodiments, the administration comprises a second period of 5 to 14 consecutive days, such as 5 to 12 consecutive days, 5 to 10 consecutive days, 5 to 8 consecutive days, 5 to 7 consecutive days, preferably 5 consecutive days, during which a single dose of cidofovir or a prodrug thereof is administered to the animal once daily. Thus, in such embodiments, the animal is administered the full dose of cidofovir or a prodrug thereof at a given point in time in a day.

[0087] In certain embodiments, the administration comprises a second period of 5 to 14 consecutive days, preferably 5 to 7 consecutive days, such as 5, 6 or 7 consecutive days, more preferably 5 consecutive days, or preferably 10 to 14 consecutive days, such as 10, 11, 12, 13 or 14 consecutive days, more preferably 13 consecutive days, during which a single dose of cidofovir or a prodrug thereof is administered to the animal once every other day. Thus, in such embodiments, the animal is administered the full dose of cidofovir or a prodrug thereof at a given point in time in a day.

[0088] In certain embodiments, the second period during which cidofovir or a prodrug thereof is administered once every other day begins on the treatment day.

[0089] In certain embodiments, the administration comprises a first period of 3 consecutive days during which each of two doses of cidofovir or a prodrug thereof is administered to the animal once daily (i.e., the animal receives a single dose of cidofovir or a prodrug thereof twice a day), and a second period of 5 to 14 consecutive days, such as 5 to 12 consecutive days, 5 to 10 consecutive days, 5 to 8 consecutive days, 5 to 7 consecutive days, preferably 5 consecutive days, during which a single dose of cidofovir or a prodrug thereof is administered to the animal once daily.

[0090] In certain embodiments, during a first period of three consecutive days, a single dose of cidofovir cyclic or a prodrug thereof is administered to an animal once a day, and during a second period of 5 to 14 consecutive days, preferably 5 to 7 consecutive days, such as 5, 6, or 7 consecutive days, more preferably 5 consecutive days, or preferably 10 to 14 consecutive days, such as 10, 11, 12, 13, or 14 consecutive days, more preferably 13 consecutive days, a single dose of cidofovir cyclic or a prodrug thereof is administered to the animal once every other day.

[0091] In certain embodiments, when the administration is performed daily, the dose of cidofovir cyclic or a prodrug thereof is preferably administered with an interval of 20 to 28 hours, preferably 22 to 26 hours, more preferably 24 hours between two administrations. In certain embodiments, when the administration is performed daily, the dose of cidofovir cyclic or a prodrug thereof is preferably administered at approximately the same time every day.

[0092] In certain embodiments, the administration of cidofovir cyclic or a prodrug thereof is the same as the feeding time of the animal.

[0093] In certain embodiments, when the administration is performed every other day, the dose of cidofovir cyclic or a prodrug thereof is preferably administered with an interval of 44 to 52 hours, preferably 46 to 50 hours, more preferably 48 hours between two administrations. In certain embodiments, when the administration is performed every other day, the dose of cidofovir cyclic or a prodrug thereof is preferably administered at approximately the same time every other day.

[0094] In certain embodiments, when two doses of cidofovir cyclic or a prodrug thereof are administered to an animal in one day, cidofovir cyclic or a prodrug thereof is preferably administered with an interval of 8 to 16 hours, preferably 10 to 14 hours, more preferably 12 hours between each of the two doses.

[0095] In certain embodiments, circular cidofovir or a prodrug thereof is administered to an animal when the animal is infected with ASFV or when ASFV infection in the animal is to be prevented.

[0096] In certain embodiments, circular cidofovir or a prodrug thereof is administered to an animal as soon as the animal is diagnosed with ASF, and the animal diagnosed with ASF is housed in an area within a radius of 3 km to 10 km from the same farm as the animal to be treated or the accommodation where the animal to be treated is housed.

[0097] When an animal is infected with ASF, various areas or regions surrounding the infected area (i.e., the area directly surrounding the infected facility or infected animal) may be designated to manage and monitor the outbreak. There may be an ASF buffer zone immediately surrounding the infected area. There may be an ASF surveillance zone immediately surrounding the buffer zone. However, different terms may be used by the governing authorities to refer to the area. For example, the infected area may also be called a containment area. Further, the buffer zone and / or the surveillance zone may be a protected area, i.e., an area where specific biosecurity and hygiene measures are implemented to prevent the entry of ASFV from neighboring countries or regions with different health statuses into countries or regions without restrictions.

[0098] In certain embodiments, the animal is housed in an ASF-infected area, a buffer zone, a surveillance zone, a protected area, or a containment area. The requirements for the ASF-infected area, buffer zone, surveillance zone, protected area, or containment area may be regulated by the governing authorities of each country or the World Organization for Animal Health (OIE). Preferably, the width of the area closest to the infected facility or infected animal is from a radius of 3 km to 20 km from the infected facility or infected animal. In certain embodiments, the area typically has a boundary at least 3 km from the boundary of the nearest infected facility or infected animal.

[0099] The inventors have found that cyclic cidofovir or its prodrug can reduce viremia and viral shedding in exposed pigs and can be used for prophylactic treatment of healthy pigs in the area where the infection has occurred. Thus, in certain embodiments, administration of said cyclic cidofovir or its prodrug prevents the spread of ASF in animal populations such as in subsequent ASF buffer zones, surveillance zones, and / or protected containment zones.

[0100] The compounds of the present invention may be used in combination with other therapeutic agents for the treatment or prevention of the infectious diseases or conditions shown above.

[0101] In certain embodiments, cyclic cidofovir or its prodrug is included in a pharmaceutical composition. The pharmaceutical composition may comprise a pharmaceutically acceptable carrier. Such pharmaceutical formulations or compositions may be included in a kit of parts.

[0102] As used herein, the term "pharmaceutically acceptable" is consistent with the art and means compatible with the other ingredients of the pharmaceutical composition and not harmful to its recipient.

[0103] As used herein, "carrier" or "excipient" includes any solvent, diluent, buffer (e.g., neutral buffered saline or phosphate buffered saline), solubilizer, colloid, dispersion medium, vehicle, bulking agent, chelating agent (e.g., EDTA or glutathione), amino acid (e.g., glycine), protein, disintegrant, binder, lubricant, wetting agent, emulsifier, sweetening agent, coloring agent, flavoring agent, fragrance, thickening agent, agent for achieving depot effect, coating agent, antifungal agent, preservative, antioxidant, tonicity adjuster, absorption delaying agent, etc. The use of such media and agents for pharmaceutical active substances is well known in the art. Their use in therapeutic compositions is contemplated, except when conventional media or agents are incompatible with the active substance.

[0104] For oral administration, for example, the pharmaceutical composition can be formulated in the form of powders, pills, tablets, lacquered tablets, coated (e.g., sugar-coated) tablets, granules, hard and soft gelatin capsules, aqueous solutions, alcoholic or oily solutions, syrups, emulsions or suspensions. In one example, without limitation, the preparation of an oral dosage form can be appropriately achieved by uniformly and tightly blending an appropriate amount of the cyclic cidofovir or its prodrug disclosed herein in powder form, optionally including one or more solid carriers that have been micronized, and formulating the blend into pills, tablets or capsules. Examples of solid carriers, which are not limiting, include calcium phosphate, magnesium stearate, talc, sugars (e.g., glucose, mannose, lactose or sucrose), sugar alcohols (e.g., mannitol), dextrin, starch, gelatin, cellulose, polyvinylpyrrolidine, low melting point waxes and ion exchange resins. Compressed tablets containing the pharmaceutical composition can be prepared by uniformly and tightly mixing the cyclic cidofovir or its prodrug disclosed herein with a solid carrier as described above to provide a mixture having the required compression properties, and then compressing the mixture with an appropriate machine into the desired shape and size. Molded tablets can be produced by molding a mixture of powder compounds moistened with an inert liquid diluent with an appropriate machine. Carriers suitable for soft gelatin capsules and suppositories are, for example, fats, waxes, semi-solids and liquid polyols, natural or hardened oils, and the like.

[0105] In certain embodiments, the cyclic cidofovir or its prodrug is included in the pharmaceutical composition, and preferably, the pharmaceutical composition is an aqueous solution.

[0106] In certain embodiments, the pH of the pharmaceutical composition is from 6.0 to 8.0. The pH can be neutralized by any method known in the art, such as including 3 NaHCO.

[0107] In certain embodiments, the pharmaceutical composition is an aqueous solution comprising 5 to 40 mg / ml, preferably 10 to 30 mg / ml, such as about 20 mg / ml of cidofovir or a prodrug thereof.

[0108] A further aspect provides an aqueous solution comprising water and cidofovir or a prodrug thereof. Those skilled in the art will understand that the concentration of cidofovir or prodrug in the aqueous solution can be adjusted according to the type of animal, the age and / or year of the animal, and / or the type of animal farm (e.g., breeding / nursing facility, weaning farm, fattening farm), as long as the final daily dose of cidofovir or prodrug ingested by the animal is as described elsewhere in this specification.

[0109] A further aspect provides a feed composition comprising feed and cidofovir or a prodrug thereof. Those skilled in the art will understand that the concentration of cidofovir or prodrug in the feed can be adjusted according to the type of animal, the age and / or year of the animal, and / or the type of animal farm (e.g., breeding / nursing facility, weaning farm, fattening farm), as long as the final daily dose of cidofovir or prodrug ingested by the animal is as described elsewhere in this specification.

[0110] In certain embodiments, the pharmaceutical composition, aqueous solution or feed composition provided herein has the formula (i):

Chemical formula

[0111] In further particular embodiments, the pharmaceutical composition, feed composition or water composition comprises its acyloxyalkyl ester, alkoxycarbonyloxyalkyl ester, alkoxyalkyl ester, or phosphoramidate or phosphonamidite.

[0112] In certain embodiments, the above composition is as follows: [Table 3] comprises one or more compounds selected from the group consisting of

[0113] In a further specific embodiment, the compound is selected from the group consisting of Compounds 2, 3, 4 and 5 above. The above compositions have been found to be particularly suitable for use in the treatment of animals, more particularly in the treatment of viremia in animals. In particular, these compositions have been found to be useful in the treatment of African swine fever (ASF) in animals.

[0114] The following examples are intended to illustrate the invention and should not be construed as limiting its scope. [Examples]

[0115] Example 1. Synthesis of cHPMPC [Chemical formula] To a solution of (S)-2-(4-amino-2-oxo-2H-pyrimidin-1-yl)-1-(hydroxymethyl)-ethoxymethyl]-phosphonic acid (140 g, 0.5 mol, 1.0 eq) in dimethylformamide (140 mL, 10 V) was added N,N'-dicyclohexyl-4-morpholinecarboxamidine (162 g, 1.1 eq) and N,N-dicyclohexylcarbodiimide (311 g, 3.0 eq) at 25 ± 5 °C. The resulting reaction mass was heated to 90 ± 5 °C and stirred at 90 ± 5 °C for 8 hours. After completion, the reaction mass was cooled to room temperature and the volatile substances were evaporated under reduced pressure. The crude product was diluted with water (14 V) and filtered. The filtrate was concentrated under reduced pressure. The crude product was diluted with a minimum amount of water and loaded onto a column in the 2 acetate form of DOWEX 1 * (20 w / w). Elution was carried out with a gradually increasing percentage of 1.0 M acetic acid in purified water. The desired product was recovered at 3 - 7% 1.0 M acetic acid in purified water. The product-containing fractions were concentrated and the product was obtained as an off-white solid. Yield: 93.3 g, 71%.

[0116] Example 2. Antiviral Activity of cHPMPC against Various ASFV Strains in vitro Primary peripheral blood mononuclear cells (PBMCs) were treated with serial dilutions of cidofovir and infected with Gludia 2007 / 1, KAB6 / 2, BOT 1 / 99, or Magadi w / hog 9 at 0.1 MOI for 72 hours. The progeny virus production rate (%) was measured by a hemadsorption assay. The EC 50 values were calculated by non-linear regression, and the mean EC 50 obtained from three independent experiments was reported with the standard deviation.

[0117] [Table 4]

[0118] Example 3. Cytotoxicity Purified peripheral blood mononuclear cells (PBMCs) were treated with serial dilutions of cidofovir for 72 hours, and cell viability was measured by the RealTime-Glo™ MT Cell Viability Assay or the CellTiter 96 Non-Radioactive Cell Proliferation Assay (MTT). The CC 50 values (50% cytotoxic concentration) were calculated by non-linear regression from the relative cell viability (%). Four independent experiments were performed in triplicate, and the values represent the mean and standard deviation.

[0119] [Table 5]

[0120] Example 4. Single-Dose Pharmacokinetic Study in Pigs Materials and Methods Test Substances The 20 mg / mL aqueous solution of cHPMPC (pH neutralized with NaHCO 3 is also referred to herein as "VV03-0035".

[0121] Outline of the Test Plan Three weaned piglets at 3 weeks and 5 days old were procured from a commercial pig unit. They were confirmed to be in good health upon arrival and ear tags were attached. The piglets were reared as a group on straw. After acclimatization for 7 days, the treatment was initiated.

[0122] On day 0, once it was confirmed that the animals were suitable for inclusion in the study, the body weights of all the animals were measured, blood was collected, and then each was administered the test substance via the intravenous route. After administration, blood samples were collected at 10 minutes (±2 minutes), 30 minutes (±2 minutes), 45 minutes (±2 minutes), 1 hour (±2 minutes), 2 hours (±2 minutes), 4 hours (±2 minutes), 6 hours (±2 minutes), 8 hours (±2 minutes), 12 hours (±2 minutes), and 24 hours (±2 minutes).

[0123] After the last blood collection, the animals were allowed to recover for 7 days. On day 8, the body weights of all the animals were measured, blood was collected, and then each was administered the test substance via the oral route. After administration, blood samples were collected at 30 minutes (±2 minutes), 1 hour (±2 minutes), 2 hours (±2 minutes), 3 hours (±2 minutes), 4 hours (±2 minutes), 5 hours (±2 minutes), 6 hours (±2 minutes), 8 hours (±2 minutes), 12 hours (±2 minutes), and 24 hours (±2 minutes).

[0124] Clinical observations were performed at approximately 1 hour and 4 hours after administration on day 0 and day 8 of administration, including an assessment of whether there was an appropriate injection site.

[0125] The study was completed on day 9. The outline of the study plan is shown in Table 3 below.

[0126]

Table 6

[0127] Results In this study, VV03-0035 had sufficient tolerance in pigs. Generally, the pigs showed no abnormal behavior, injury, or signs of illness during the test, and all pigs were considered to be in good health during the observations conducted 1 hour and 4 hours after the administration of VV03-0035. One hour after the intravenous administration of VV03-0035, erythema was observed at the injection site in all pigs. However, no injection site reaction was observed in the observations 4 hours after the intravenous administration. No other adverse events were recorded after the intravenous administration of VV03-0035 at 5 mg / kg or the oral administration at 25 mg / kg.

[0128] The results obtained in this study showed that after a single intravenous administration of VV03-0035 at a dose of 5 mg / kg or a single oral administration of VV03-0035 at a dose of 25 mg / kg, all animals except one pig (Pig #342008), which was 24 hours after oral administration, exhibited measurable concentrations of both VV03-0035 and cidofovir in plasma by 24 hours after administration (at the last sampling time). This indicates that Pig #342008 did not receive the full target dose of 25 mg / kg of VV03-0035, but the actual dose on the day of oral administration was about 21.7 mg / kg, so the dose was about 83,100 nmol / kg lower than that of the other two pigs at doses of 93,900 and 92,400 nmol / kg.

[0129] The average maximum plasma concentration (C max ) after the intravenous administration of VV03-0035 was 49,504 ± 18,300 nM, and after the oral administration of VV03-0035 it was 2,036 ± 1,340 nM. The latter was achieved 2 hours after oral administration. The average C max of cidofovir after the intravenous administration of VV03-0035 was 1,816 ± 86 nM, which was achieved 2 hours after administration in all three pigs. After the oral administration of VV03-0035, the C maxwas 221 ± 140 nM and was achieved in pigs within 3 - 8 hours. In VV03 - 0035, following intravenous administration, the exposure (expressed as area under the curve or AUC) was in the range of 58000 - 95400 nM·h, with an average of 71571 nM·h and a between - subject variability (%CV) of 29%. However, following oral administration, the exposure was in the range of 2320 - 23700 nM·h, with an average of 11573 nM·h and a between - subject variability of 91%CV. The exposure parameters of cidofovir were lacking in accuracy due to the absence of an apparent terminal elimination phase. The average exposure of cidofovir after intravenous administration of VV03 - 0035 was 12044 nM·h, and the exposure after oral administration of VV03 - 0035 was 3562 nM·h. The average half - life (t 1 / 2 ) of VV03 - 0035 was 3.31 hours after intravenous administration and 3.51 hours after oral administration, respectively. The average half - life (t 1 / 2 ) of cidofovir was 9.37 hours and 11.23 hours after intravenous and oral administration of VV03 - 0035, respectively.

[0130]

Table 7

[0131] Example 5. VV03-0035 Administration Test in Pigs Materials and Methods VV03 - 0035 was formulated as a 20 mg / ml aqueous solution (pH neutralized with NaHCO 3 ).

[0132] The ASFV Georgia 2007 / 1 strain is a field isolate of genotype II, isolated from an ASF outbreak in Georgia in 2007, and is part of the ASFV strain collection available at the Pirbright Institute where this study was conducted.

[0133] Test Plan Two groups, Group 1, the VV03-0035 treatment group (n = 6 pigs, 3 males and 3 females), and Group 2, the placebo group (n = 3 mixed males and females), were housed in one room. The pigs were assigned according to a randomized block design. The female piglets (n = 5) and male piglets (n = 4) were sorted from the heaviest to the lightest by body weight, and random numbers generated by commercial software (Excel) were assigned. Starting from the pair with the lightest body weight, the animal with the larger assigned random number was assigned to the VV03-0035 treatment group (Group 1), and the animal with the smaller random number was assigned to the control group (Group 2).

[0134] The animals were acclimatized for 7 days, and clinical scoring including body temperature was performed daily from 3 days before the start of the test until the end of the test. One day before, EDTA blood (1 ml) and serum (4 ml) were collected from each pig. Nasal, oral, and rectal swabs were also collected from each pig.

[0135] Next, VV03-0035 or placebo (physiological saline) was orally delivered twice a day for 3 days from -1 to +1 days after ASFV challenge (the challenge was performed on day 0) (30 mg / kg, 1.5 mL / kg, 12-hour interval). From day 2 to day 6, the drug was delivered once a day, always at approximately the same time in the morning. The pigs were maintained for an additional 21 days to observe clinical signs typical of ASFV or drug treatment. The volume of VV03-0035 for each pig was calculated daily based on body weight. The control pigs were given the same volume of placebo per kg.

[0136] On day 0, 30 to 60 minutes after the administration of VV03-0035 or placebo to Group 1 and Group 2 respectively, 10 3 HAD 50 (50% hemadsorption dose) of Gludia 2007 / 1 was administered intramuscularly in a volume of 1 ml.

[0137] The control pigs in Group 2 were expected to be euthanized by day 5 or day 6 for reasons of humane welfare.

[0138]

Table 8

[0139] ASFV DNA was measured in whole blood by quantitative qPCR using primers specific for the B646L ASFV gene encoding the VP72 protein, using the method described in King et al., Protection of European domestic pigs from virulent African isolates of African swine fever by experimental immunization, Vaccine 29 (2011):4593-4600 (hereinafter also referred to as "King et al. (2011)" in the present invention). The results were expressed as genome copies per ml of blood by comparison with the standard curve of the control plasmid.

[0140] ASFV DNA was measured in nasal, oral and rectal swabs by quantitative qPCR using primers specific for the ASFV gene B646L encoding the VP72 protein, using the method described in King et al. (2011). The virus was eluted from the swab samples with phosphate buffered saline. The results were expressed as genome copy numbers per 1 m by comparison with the standard curve of the control plasmid.

[0141] Results All control pigs in group 2 (n = 3) were humanely euthanized on day 6 because they reached a humane endpoint of moderate severity due to the onset of ASF.

[0142] Of the 6 VV03-0035-treated pigs, 2 were euthanized at a humane endpoint of moderate severity on day 6 after ASFV challenge showing reduction of ASF disease, 2 were euthanized at a humane endpoint of moderate severity on days 19 and 20 after ASFV challenge showing delay and reduction of ASF disease, and the remaining 2 survived until the end of the study (day 27 after ASFV challenge) without ASF disease (Figs. 1 and 2).

[0143] The inventors found a decrease in the ASFV genomic copies in the blood (Figure 3) and in the swab samples (Figure 4) of the treated pigs at the end date compared to the control pigs.

[0144] Example 6. VV03-0035 Administration Test in Pigs Materials and Methods VV03-0035 was formulated as a 20 mg / ml aqueous solution (pH neutralized with NaHCO 3 ).

[0145] The ASFV Georgia 2007 / 1 strain is a genotype II field isolate isolated from an ASFV outbreak in Georgia and is part of the ASFV strain collection available at the Pirbright Institute where this study was conducted.

[0146] Test Plan Two groups, Group 1, the VV03-0035 treatment group (n = 6 pigs, 3 males and 3 females) and Group 2, the placebo group (n = 6 pigs, 3 males and 3 females) were housed separately in two rooms. The pigs were assigned according to a randomized block design. Female piglets (n = 6) and male piglets (n = 6) were arranged in descending order of body weight and assigned random numbers generated by commercially available software (Excel). Starting from the pair of the same sex with the lowest body weight, the animal with the larger assigned random number was assigned to the VV03-0035 treatment group (Group 1), and the animal with the smaller random number was assigned to the control group (Group 2).

[0147] The animals were acclimatized for 7 days, and clinical scoring including body temperature was performed daily from 3 days before the start of the test until the end of the test. One day before, EDTA blood (1 ml) and serum (4 ml) were collected from each pig. Nasal, pharyngeal, and rectal swabs were also collected from each pig.

[0148] Next, VV03-0035 or placebo (physiological saline) was orally delivered once daily at -1 day (night), 0 day (30 - 60 minutes before ASFV challenge), 1 day (morning), and 2 days (morning) (30 mg / kg, 1.5 mL / kg). From day 2 to day 8, drugs or placebo were delivered every other day (on day 4 and day 6), at approximately the same time in the morning each day. Feed was provided after administration. The volume of VV03-0035 for each pig was calculated daily based on body weight. Control pigs were given the same volume of placebo per kg.

[0149] On day 0, 30 - 60 minutes after the administration of VV03-0035 or placebo to groups 1 and 2 respectively, 10 3 HAD 50 (50% hemadsorption dose) of Gueldia 2007 / 1 in a 1 ml volume was administered intramuscularly.

[0150] Control pigs in group 2 were expected to be euthanized at a moderate severity humane endpoint between day 4 and day 6 for reasons of humane welfare.

[0151] Tissue samples including spleen, lung, submandibular lymph nodes (SMLN), renal lymph nodes (RNL), and gastroduodenal lymph nodes (GHLN) were collected at necropsy and stored at -80 °C until processing. Nucleic acids were extracted from 20 mg of homogenized tissue, and ASFV genomic copies were determined by quantitative qPCR using primers specific to the B646L gene, compared to a standard control plasmid (King et al., 2011).

[0152] EDTA blood samples were collected from pigs in groups 1 and 2 at various time points before or after ASFV challenge. ASFV genomic copies per ml of blood were measured by quantitative qPCR (King et al., 2011) using primers specific to the B646L ASFV gene, compared to a standard curve of the control plasmid.

[0153]

Table 9

[0154] Results VV03-0035 improved the survival time of pigs administered with Georgia 2007 / 1. A significant difference was observed in the median death date. Pigs treated with VV03-0035 survived until day 8, while the median death date in negative control animals was 5.5 days. This difference was statistically significant as determined by the log-rank (Mantel-Cox) test and the Gehan-Breslow-Wilcoxon test, with p-values of 0.0010 and 0.0016, respectively (Figure 5).

[0155] Compared with the placebo group, VV03-0035 significantly reduced ASF virus genome copies in multiple organs such as the lung, spleen, and several lymph nodes as measured by quantification of the viral genome in tissues using quantitative qPCR. Significance was calculated by a nested t-test comparing control pigs and treated pigs (Figure 6).

[0156] VV03-0035 significantly reduced ASF viremia as measured by quantitative qPCR. Significance was calculated by a nested t-test comparing control pigs and treated pigs at each time point (Figure 7).

[0157] Example 7. Synthesis of cHMPC Derivatives Pivaloyloxymethyl Ester of cHPMPC (POM-cHPMPC, Compound 1) [Chemical formula] Tetrabutylammonium hydroxide (0.8 mL; 25% in methanol) was added dropwise to a stirred mixture of cHPMPC (200 mg; 0.766 mmol) in methanol (24 mL) under an inert atmosphere. The mixture was stirred for 10 minutes until solubilized. Next, the solvent was evaporated and the remaining methanol was removed with dioxane (2 × 6 mL). The residue was dissolved in dioxane (10 mL) and chloromethyl pivalate (0.13 mL; 1.2 equiv) was added. The mixture was stirred at 90 °C for 1 hour. The reaction was monitored by TLC. After cooling to room temperature, the volatile substances were evaporated. The residue was subjected to chromatography on a silica gel column and further purified by preparative HPLC and lyophilized to give the product as a white solid (30 mg; 11% yield) as a diastereomer mixture of approximately 5:2. 1H NMR (400 MHz, D2O) δ ppm: 7.51 and 7.45 (d, 1H); 5.98 - 5.85 (m, 1H); 5.78 - 5.55 (m, 2H); 4.60 - 3.70 (m, 7H); 1.16 and 1.15 (s, 9H). ES + MS m / z: 376.1 (M + 1).

[0158] Isopropyloxycarbonyloxymethyl Ester of cHPMPC (POC-cHPMPC, Compound 2) [Chemical formula] Tetrabutylammonium hydroxide (0.8 mL; 25% in methanol) was added dropwise to a stirred mixture of cHPMPC (200 mg; 0.766 mmol) in methanol (24 mL) under an inert atmosphere. The mixture was stirred for 10 minutes until solubilized. Next, the solvent was evaporated and the remaining methanol was removed with dioxane (2 × 6 mL). The residue was dissolved in dioxane (10 mL) and chloromethyl isopropyl carbonate (0.14 mL; 1.2 equiv) was added. The mixture was stirred at 90 °C for 1 hour. The reaction was monitored by TLC. After cooling to room temperature, the volatile substances were evaporated. The residue was subjected to chromatography on a silica gel column and further purified by preparative HPLC and lyophilized to give the product as a white solid (30 mg; 11% yield) as a diastereomer mixture of approximately 1:1.2. 11H NMR (400 MHz, D 2 2O) δ ppm: 7.53 and 7.47 (d, 1H); 6.00 - 5.85 (m, 1H); 5.80 - 5.60 (m, 2H); 4.98 - 4.85 (m, 1H); 4.60 - 3.68 (m, 7H); 1.28 and 1.26 (d, 6H). ES + MS m / z: 378.1 (M + 1).

[0159] Hexadecyloxypropyl Ester of cHPMPC (HDP-cHPMPC, Compound 3)

Chem.

[0160] Octadecyloxyethyl Ester of cHPMPC (ODE-cHPMPC, Compound 4)

Chem.

[0161] Isopropyl L-alanyl cHPMPC( Compound 5)

Chem.

[0162] Example 8. Comparative Test of Compounds 1-5 and cHPMPC Methods Compounds 1 - 5 and cHPMPC were diluted in PBS and added to triplicate wells of a 96 - well plate at final concentrations of A: 1.0 μM, B: 0.5 μM, C: 0.1 μM, D: 0.05 μM, E: 0.01 μM, F: 0.005 μM, G 0.001 μM to porcine bone marrow cells cultured in EBSS supplemented with 10% porcine serum and 1% penicillin - streptomycin.

[0163] These cells were infected with a recombinant ASFV genotype II virus, GeorgiaDMGFB, expressing mNeon Green fluorescent protein under the control of the ASFV early promoter p30 at a low multiplicity (0.1 MOI). This reporter gene was inserted in place of four non - essential genes belonging to the multigene families MGF360 and MGF505 (https: / / journals.asm.org / doi / 10.1128 / jvi.01899 - 21), but did not cause a decrease in virus replication or pathogenicity. As a control, uninfected cells without drug treatment were included.

[0164] Cells were visualized using IncuCyte S3 (Sartorius) 72 hours after infection, and the expression of the mNeon Green fluorescent protein was measured as an indicator of virus infection. As shown in Figures 8A and 8B, the expression of mNeon Green varied depending on the drug used in the treatment and also showed variation at different drug concentrations. Particularly interestingly, no mNeon Green expression was observed in cells treated with Compounds 3 and 4 at concentrations higher than 0.005 μM (rows F, lanes 4, 5, 6 (Compound 3) and 7, 8, 9 (Compound 4) in Figure 8A), whereas no expression was seen at concentrations higher than 0.05 μM for Compound cHPMPC (rows D, lanes 10, 11, 12 in Figure 8A). These results indicate a significant increase in the efficacy of Compounds 3 and 4 compared to cHPMPC. Fluorescence detected in cells infected in the presence of Compounds 1, 2, and 5 (Figure 8B) showed that these compounds have an efficacy intermediate between Compounds 3 and 4 and cHPMPC.

[0165] Compounds 3 and 4 are particularly notable and have CC values 50 equivalent to or lower than that of cHPMPC (47 + / - 13 or 59 + / - 19 μM in porcine kidney cells). This led to a dramatic increase in the selectivity index to the thousands range equivalent to that reported by (Lipka et al., 2023). Therefore, the prepared compounds can be expected to be effective at much lower doses.

Claims

1. Cyclic cidofovir for use in the treatment of African swine fever (ASF) in animals, wherein the treatment comprises oral administration of said cyclic cidofovir at a dose of 10.0 to 30.0 mg / kg, and in a first period of 1 to 4 consecutive days, at least one dose, for example one or two doses, of cyclic cidofovir is administered daily to said animal, and in a second period of 5 to 14 consecutive days, one dose of cyclic cidofovir is administered to said animal every other day or daily, and the average daily dose administered in the first period is higher than the average daily dose administered in the second period, cyclic cidofovir.

2. A compound of formula (i): 【Chemical 1】 or an ester, amidate or ester amidate thereof, more particularly an acyloxyalkyl ester, alkoxycarbonyloxyalkyl ester, alkoxyalkyl ester, or phosphoramidate or phosphonamidite thereof, cyclic cidofovir for use according to claim 1.

3. A compound of formula (I) or (II): 【Chemical 2】 [wherein, A is selected from the group consisting of O and NH; L is selected from the group consisting of -(CR ２ R ３ ), -CH(R ｎ ), -C(O)- and -C(O)-CH(R ４ ), -C(O)-; ５ and is selected from the group consisting of; n is an integer selected from 1, 2, 3, 4 or 5; R １ is C ６－２５ alkyl, -C(O)R ６ , -CO ２ R ７ , C ６－２５ haloalkyl, C ６－２５ alkenyl, C ６－２５ haloalkenyl, C ３－１２ cycloalkyl and C ３－１２ selected from the group consisting of halocycloalkyl; Each R ２ is independently selected from the group consisting of hydrogen, C １－６ alkyl, C ３－１２ cycloalkyl and halogen; Each R ３ is independently selected from the group consisting of hydrogen, C １－６ alkyl, C ３－１２ cycloalkyl and halogen; Each R ４ is independently selected from the group consisting of hydrogen, C １－６ alkyl, C ３－１２ cycloalkyl and halogen; Each R ５ is independently selected from the group consisting of hydrogen, C １－６ alkyl, C ３－１２ cycloalkyl and halogen; Each R ６ is independently selected from the group consisting of C １－１０ alkyl, C １－１０ haloalkyl, C ３－１２ cycloalkyl, C ３－１２ halocycloalkyl, C ２－１０ alkenyl, and C ２－１０ haloalkenyl; Each R ７ is independently selected from the group consisting of C １－１０ alkyl, C １－１２ haloalkyl, C ３－１２ cycloalkyl, C ３－１２ halocycloalkyl, C ２－１０ alkenyl, and C ２－１０ haloalkenyl]] having the structure of, or a stereoisomer, tautomer, solvate, hydrate, pharmaceutically acceptable salt thereof, cyclic cidofovir for use according to claim 1 or 2.

4. L is selected from the group consisting of -(CR ２ R ３ ), ｎ - and -CH(R ４ ), and -C(O)-; n is an integer selected from 1, 2, or 3; R １ is C ６－２５ alkyl, -C(O)R ６ , -CO ２ R ７ , C ６－２５ haloalkyl, C ６－２５ alkenyl, and C ３－１０ selected from the group consisting of cycloalkyl; Each R ２ is independently selected from the group consisting of hydrogen, C １－６ alkyl, and halogen; Each R ３ is independently selected from the group consisting of hydrogen, C １－６ alkyl, and halogen; Each R ４ is independently selected from the group consisting of hydrogen, C １－６ alkyl, and halogen; Each R ５ is independently selected from the group consisting of hydrogen, C １－６ alkyl, C ３－１０ cycloalkyl and halogen; Each R ６ is independently selected from the group consisting of C １－６ alkyl, C １－６ haloalkyl, and C ３－６ cycloalkyl; Each R ７ is independently selected from the group consisting of C １－６ alkyl, C １－６ haloalkyl, and C ３－６ cycloalkyl cyclic cidofovir for use according to claim 3.

5. Selected from the group consisting of the following: 【Table 1】 cyclic cidofovir for use according to any one of claims 3 to 4.

6. In a first period of 3 consecutive days, two doses of cyclic cidofovir are administered daily to said animal, and in a second period of 5 to 14 consecutive days, preferably 5 to 7 consecutive days, one dose of cyclic cidofovir is administered daily to said animal, cyclic cidofovir for use according to any one of claims 1 to 5.

7. In a first period of 3 days, one dose of cyclic cidofovir is administered daily to said animal, and in a second period of 5 to 14 consecutive days, preferably 5 to 7 consecutive days, one dose of cyclic cidofovir is administered to said animal every other day, cyclic cidofovir for use according to any one of claims 1 to 5.

8. The cyclic cidofovir is included in a pharmaceutical composition, and preferably, the pharmaceutical composition is an aqueous solution. The cyclic cidofovir for use according to any one of claims 1 to 7.

9. The cyclic cidofovir for use according to any one of claims 1 to 8, wherein the animal is a pig.

10. The cyclic cidofovir for use according to any one of claims 1 to 9, wherein the animal is housed in an ASF surveillance area or a protected area.

11. The cyclic cidofovir for use according to any one of claims 1 to 10, wherein administration of the cyclic cidofovir prevents the spread of ASF within an animal population.

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