Antiviral drugs containing steroid sulfatase inhibitors

Abstract

The invention relates to a steroid sulfatase inhibitor which is a safe substance without toxicity or adverse effects, with inhibitory activity against various viruses, and thus capable of effectively preventing, improving, or treating viral infections or diseases caused by viral infections.

Description

Antiviral pharmaceutical composition comprising a steroid sulfatase inhibitor

[0001] The present invention relates to the antiviral use of a steroid sulfatase inhibitor, and further to the use for preventing, improving or treating viral infections or infectious diseases.

[0002] Viruses have a genome composed of DNA or RNA and a protein-encapsulated structure. Viruses cannot reproduce independently and must replicate within host cells, proliferating through infection between cells. These tiny organisms possess characteristics of both living and non-living organisms, and can infect humans and cause viral diseases. Unlike bacteria, viruses cannot be inhibited by standard antibiotics. Therefore, viral infections are difficult to treat with conventional antibiotics. Antiviral agents, which inhibit viral replication, are required. Currently, antiviral agents are drugs developed to weaken the activity of viruses that have invaded the body or to treat viral infections. These include virus-neutralizing antibodies, which neutralize the virus's ability to infect host cells, and aphidicolin, which inhibits the activity of DNA polymerase α, which is involved in viral DNA synthesis. In addition to therapeutic strategies that inhibit viral invasion and replication, many strategies are being attempted to overcome viral infections by appropriately regulating the body's immune response, such as interferon.

[0003] Recently, because the development of new drugs requires a long time, a lot of money, and effort, in order to shorten this process as much as possible, drug repurposing research is being conducted mainly on drugs that inhibit the action of viral protein scissors or RNA polymerase among existing treatments for RNA viruses (such as the AIDS virus, Ebola virus, and influenza virus) to prevent viral replication. Efforts are being made to quickly find drugs that are safe for host cells and effective in treating viruses among other treatments currently used on patients or new drug candidates under development. However, there is currently a lack of drugs that are completely safe for host cells, have minimal side effects, and are effective.

[0004] The present inventors have confirmed that existing therapeutic drugs for the treatment of obesity and metabolic diseases, which have proven to be safe, have antiviral effects, and have discovered that they can be used as antiviral drugs that do not cause side effects in the human body, thereby completing the present invention.

[0005] One object of the present invention is to provide a composition having an antiviral effect against various viruses.

[0006] Another object of the present invention is to provide a composition for various uses that can prevent, improve or treat infection by a virus or various diseases caused by such infection.

[0007] Another object of the present invention is to provide a method for inhibiting the activity of various viruses and a method for preventing, improving or treating infection by viruses or various diseases caused by such infection.

[0008] However, the technical problems to be solved by the present invention are not limited to the problems mentioned above, and other problems not mentioned can be clearly understood by those skilled in the art from the description below.

[0009] Hereinafter, various embodiments described herein will be described with reference to the drawings. In the following description, various specific details, such as specific configurations, compositions, and processes, are set forth to provide a thorough understanding of the present invention. However, certain embodiments may be practiced without one or more of these specific details, or in conjunction with other known methods and configurations. In other instances, well-known processes and manufacturing techniques have not been described in specific detail so as not to unnecessarily obscure the present invention. Reference throughout this specification to "one embodiment" or "an embodiment" means that a particular feature, configuration, composition, or characteristic described in connection with the embodiment is included in one or more embodiments of the present invention. Thus, the appearances of "in one embodiment" or "an embodiment" in various places throughout this specification do not necessarily refer to the same embodiment of the present invention. Additionally, the particular features, configurations, compositions, or characteristics may be combined in any suitable manner in one or more embodiments.

[0010] Unless otherwise specifically defined herein, all scientific and technical terms used herein have the same meaning as commonly understood by those skilled in the art to which the present invention belongs.

[0011]

[0012] According to one embodiment of the present invention, the present invention relates to an antiviral pharmaceutical composition comprising a steroid sulfatase inhibitor as an active ingredient.

[0013] In the present invention, the "steroid sulfatase" plays a role in regulating the local production of estrogens and androgens from precursors in several tissues. This enzyme is known to play a catalytic role in the process of hydrolyzing the sulfate ester group of 3-hydroxy steroids, which correspond to the inactivated transporter or precursor form of activated 3-hydroxy steroids.

[0014] In the present invention, the above-mentioned "steroid sulfatase inhibitor" has the above-mentioned antiviral effect and thus plays a role in inhibiting the proliferation of viruses.

[0015] In the present invention, the steroid sulfatase inhibitors include irosustat, 2-(hydroxyphenyl) indole sulfate, 5-androstene-3,17-diol-3 sulfate, estrone-3-O-methylthiophosphonate (E1-3-MTP), estrone-3-O-sulfamate (EMATE), estradiol-3-O-sulfamate (E2MATE), 4-methylcoumarin 7-O-sulfamate (COUMATE), KW-2581, STX213, and morpholino. (morpholino) may be one or more selected from the group consisting of, for example, irosustat, but is not limited thereto.

[0016] In the present invention, the above-described sulfate may be represented by the structure of the following chemical formula 1, and the IUPAC name of the compound may be (6-oxo-8,9,10,11-tetrahydro-7H-cyclohepta[c]chromen-3-yl) sulfamate, and the CAS number may be 288628-05-7.

[0017] [Chemical Formula 1]

[0018]

[0019] The present invention may include a pharmaceutically acceptable salt form of a steroid sulfatase inhibitor, such as yroserstat. A pharmaceutically acceptable salt should have low toxicity to the human body and should not adversely affect the biological activity or physicochemical properties of the parent compound. The pharmaceutically acceptable salt may include, but is not limited to, a pharmaceutically acceptable free acid and an acid addition salt of the steroid sulfatase inhibitor, preferably yroserstat.

[0020] Preferred salt forms of the compound according to the present invention include salts with inorganic acids or organic acids. In this case, inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, perchloric acid, and hydrobromic acid can be used. In addition, organic acids such as acetic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, fumaric acid, maleic acid, malonic acid, phthalic acid, succinic acid, lactic acid, citric acid, citric acid, gluconic acid, tartaric acid, salicylic acid, malic acid, oxalic acid, benzoic acid, embonic acid, aspartic acid, and glutamic acid can be used. Organic bases that can be used for preparing organic base addition salts include tris(hydroxymethyl)methylamine and dicyclohexylamine. Amino acids that can be used for preparing amino acid addition salts include natural amino acids such as alanine and glycine. It will be apparent to those skilled in the art that other acids or bases may be used in addition to the inorganic acids, organic acids, organic bases and amino acids exemplified above.

[0021] In the present invention, the salt form can be prepared by a conventional method. For example, the above-mentioned steroid sulfatase inhibitor, such as isostat, can be prepared by dissolving it in a water-miscible solvent such as methanol, ethanol, acetone, or 1,4-dioxane, adding a free acid or free base, and then crystallizing the resulting solution.

[0022] Meanwhile, the compounds according to the present invention may also be included in the scope of the present invention in the form of a hydrate or solvate of a steroid sulfatase inhibitor, for example, iroserstat.

[0023] The composition of the present invention has an excellent antiviral effect against an individual infected with a virus, particularly a DNA or RNA virus, and thus can be used to prevent or treat viral infections.

[0024] In the present invention, the above-mentioned "subject" refers to a subject that has or is suspected of having symptoms of a viral infection and needs improvement or treatment of a viral infection or a disease caused by the infection, such as by suppressing viral activity, and all animals, including humans, that are already infected or can be infected with the virus.

[0025] In the present invention, the target virus exhibiting the antiviral effect may be a DNA virus or an RNA virus, and more preferably, an RNA virus. Among viruses, an RNA virus refers to a virus with single-stranded RNA or double-stranded RNA as its genetic material, and most RNA viruses have double-stranded RNA as their genetic material. A general term for viruses that have RNA as their genetic material, some viruses have (+) strand RNA that becomes mRNA, (-) strand RNA of a complementary chain, and double-stranded RNA as their genetic material within the viral particle. Some viruses have only one molecule of RNA, some viruses have two identical RNA molecules (retroviruses), and some viruses use eight different RNA molecules as their genetic material (influenza viruses). Usually, an RNA synthetase (DNA synthetase in the case of retroviruses) exists using RNA as a template. RNA viruses lack their own RNA repair mechanism, so errors are more likely to occur during the replication process. These errors can easily cause mutations in the genome. RNA viruses are one of the major causes of viral diseases.

[0026] In the present invention, the virus may be a DNA virus or an RNA virus, and in the present invention, the “RNA virus” means all viruses that use RNA as their genetic material. As an example of an RNA virus, it may be at least one species selected from the group consisting of Flaviviridae, Coronavirinae, Reoviridae, Picornaviridae, Caliciviridae, Togaviridae, Arenaviridae, Orthomyxoviridae, Paramyxoviridae, Bunyaviridae, Rhabdoviridae, Filoviridae, Astroviridae, Bornaviridae, and Arteriviridae, and more preferably, it may be Flaviviridae or Coronavirinae.

[0027] In the present invention, the virus of the Flaviviridae family is one of the enveloped positive-strand RNA virus families that mainly infect mammals and birds, and it is known that they are mainly transmitted through arthropod vectors (mainly ticks and mosquitoes). The flavus of yellow fever virus means "yellow" in Latin, and the name jaundice is given because of its tendency to cause jaundice in victims. The family contains 89 species divided into 4 genera, and diseases belonging to the genus Flaviviridae include viruses such as yellow fever, Japanese encephalitis, West Nile virus, Saint Louis encephalitis, tick-borne encephalitis virus, and dengue virus.

[0028] In the present invention, the dengue virus belongs to the Flaviviridae family and the Flavivirus genus, and is a positive-sense single-stranded RNA virus with serotypes of Dengue 1, 2, 3, and 4. Dengue virus is transmitted by mosquitoes infected with the dengue virus, and dengue virus infection is classified into dengue fever (DF), dengue hemorrhagic fever (DHF), dengue shock syndrome (DSS), etc. depending on the symptoms. Once infected, lifelong immunity is formed against the same dengue virus type, but re-infection with a different type not only does not establish immunity, but may actually worsen the symptoms. Dengue fever and dengue hemorrhagic fever are reported to occur in a wide range of tropical and subtropical regions such as Asia, Central and South America, and Africa, and hundreds of millions of people are infected annually. Moreover, as the habitat of mosquitoes, the vector, is increasing due to climate change and other factors, the possibility of infection in endemic areas is very high, increasing the possibility of infection occurrence and spread.

[0029] In the present invention, the virus of the Coronaviridae family has four genera (alpha, beta, gamma, and delta), and is known to cause respiratory and digestive infections in humans and animals as an RNA virus with a genetic size of 27 to 32 kb. It is easily infected mainly through mucosal transmission and droplet transmission, and although it generally causes mild respiratory infections in humans, it can rarely cause fatal infections, and it can cause diarrhea in cattle and pigs and respiratory diseases in chickens. Among the coronaviruses, coronaviruses that use humans as a host are classified into the classification in Table 1 below (Korea Centers for Disease Control and Prevention, 2020). Among the four genera, alpha and beta are reported to infect humans and animals, while gamma and delta are reported to infect only animals.

[0030] Genus Human-coronavirus Non-human coronavirus Alpha coronavirus 229, NL63 Porcine epidemic diarrhea virus (PEDV), transmissible gastroenteritis virus (TGEV), canine coronavirus (CCoV), feline coronavirus (FCoV), Miniopterus bat coronavirus 1, Miniopterus bat coronavirus HKU8, Rhinolophus bat coronavirus HKU2, Scotophilus bat coronavirus 512 Beta coronavirus OC43, HKU1, SARS-CoV, SARS-CoV2, MERS-CoV Porcine hemagglutinating encephalomyelitis virus (PHEV), bovine coronavirus (BCoV), equine coronavirus (EqCoV), murine coronavirus (CCoV) MuCoV), Tylonycteris bat coronavirus HKU4, Pipistrellus bat coronavirus HKU5, Rousettus bat coronavirus HKU9, Gamma coronavirus-Avian coronavirus, Beluga whale-coronavirus SW1, Delta coronavirus-Bulbul-coronavirus HKU11, Thrush-coronavirus HKU12, Munia-coronavirus HKU13

[0031] In particular, there are currently seven types of coronaviruses that are infectious to humans, as shown in Table 2 below, and they are divided into types that cause colds (229E, OC43, NL63, HKU1) and types that cause severe pneumonia (SARS-CoV, SARS-CoV-2, MERS-CoV).

[0032] Virus nameGenusHostSymptomHCoV-229EAlphaHumanMild respiratory symptomsHCoV-NL63AlphaHumanMild respiratory symptomsSARS-CoVBetaHumanSevere respiratory symptomsMERS-CoVBetaHumanSevere respiratory symptomsHCoV-OC43BetaHumanMild respiratory symptomsHCoV-HKU1BetaHumanPneumonia symptomsSARS-CoV-2BetaHumanMild respiratory symptomsSevere cases may cause breathing difficulties

[0033] In the present invention, the "beta coronavirus" is one of four genera of coronaviruses in the coronavirus family and corresponds to a zoonotic infectious disease. Examples of beta coronaviruses are known to include severe acute respiratory syndrome virus (SARS; SARS-CoV), severe acute respiratory syndrome-2 virus (Severe Acute Respiratory Syndrome virus-2; SARS-CoV-2), Middle East respiratory syndrome virus (MERS; MERS-CoV), human coronavirus OC43 (HCoV-OC43), or human coronavirus HKU1 (HCoV-HKU1). In the present invention, the "severe acute respiratory syndrome-2 virus (SARS-CoV-2)" corresponds to an enveloped, positive-polarity single-stranded RNA beta coronavirus belonging to the coronavirus family. Historically, coronaviruses that have infected humans have been severe common cold viruses, including hCoV-OC43, HKU, and 229E5. Analysis of the sequence of SARS-CoV-2 isolates reveals that the 30-kb genome encodes 14 open-reading frames (ORFs), 13 of which at the 3' end of the viral genome are encoded by nine predicted subgenomic RNAs that encode four structural proteins: spike (S), envelope (E), membrane (M), and nucleocapsid (N), and nine putative additional elements. The nucleocapsid protein comprises N1, N2, and N3 segments.

[0034] In the present invention, the coronavirus includes a mutant that has been mutated naturally or artificially.

[0035] In the present invention, the infectious disease caused by the coronavirus may be coronavirus enteritis, coronavirus diarrhea, severe acute respiratory syndrome coronavirus (SARS), Middle East respiratory syndrome coronavirus (MERS), or a combination thereof, but any disease that can be caused by the coronavirus infection may be included without limitation.

[0036] In the present invention, the infectious disease may be a respiratory disease, hepatitis, gastroenteritis, or encephalitis caused by the viral infection.

[0037] The composition of the present invention can be used alone or in combination with a conventional antiviral agent, or can be used in combination with a biological agent such as an antiserum.

[0038]

[0039] According to another embodiment of the present invention, the present invention relates to a composition for preventing, improving or treating a viral infection or infectious disease, comprising a steroid sulfatase inhibitor as an active ingredient.

[0040] The composition of the present invention can be used as a pharmaceutical composition, a food composition, a food additive composition, a feed composition, or a feed additive composition, but is not particularly limited thereto.

[0041] In the present invention, “prevention” means any act of delaying the progression of infection or proliferation of a virus by administering the composition of the present invention.

[0042] In the present invention, the compound or pharmaceutical composition may be characterized as being in the form of a capsule, tablet, granule, injection, ointment, powder or beverage, and the pharmaceutical composition may be characterized as being for human use.

[0043] The pharmaceutical composition of the present invention is not limited to these, but can be formulated and used in the form of oral dosage forms such as powders, granules, capsules, tablets, aqueous suspensions, etc., external preparations, suppositories, and sterile injectable solutions, respectively, according to conventional methods. The pharmaceutical composition of the present invention may include a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers may include binders, lubricants, disintegrants, excipients, solubilizers, dispersants, stabilizers, suspending agents, coloring agents, fragrances, etc. for oral administration, and buffers, preservatives, analgesics, solubilizers, isotonic agents, stabilizers, etc. for injections. In the case of topical administration, bases, excipients, lubricants, preservatives, etc. can be used. The formulation of the pharmaceutical composition of the present invention can be prepared in various ways by mixing with the pharmaceutically acceptable carriers described above. For example, for oral administration, it can be manufactured in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, etc., and for injections, it can be manufactured in the form of unit dose ampoules or multiple doses. In addition, it can be formulated in the form of solutions, suspensions, tablets, capsules, sustained-release preparations, etc.

[0044] Meanwhile, examples of carriers, excipients, and diluents suitable for formulation include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, malditol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate, or mineral oil. In addition, fillers, anticoagulants, lubricants, wetting agents, fragrances, emulsifiers, preservatives, and the like may be additionally included.

[0045] Routes of administration of the compound or pharmaceutical composition according to the present invention include, but are not limited to, oral, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, intracardiac, transdermal, subcutaneous, intraperitoneal, intranasal, enteral, topical, sublingual, or rectal. Oral or parenteral administration is preferred.

[0046] "Parenteral" in the present invention includes subcutaneous, intradermal, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intralesional, and intracranial injection or infusion techniques. The pharmaceutical composition of the present invention may also be administered in the form of a suppository for rectal administration.

[0047] The compound or pharmaceutical composition of the present invention may vary depending on various factors including the activity of the specific compound used, age, body weight, general health, sex, diet, administration time, administration route, excretion rate, drug combination, and severity of the specific disease to be prevented or treated, and the dosage of the pharmaceutical composition may vary depending on the patient's condition, body weight, degree of disease, drug form, administration route, and period, but may be appropriately selected by those skilled in the art, and may be administered at 0.0001 to 50 mg / kg or 0.001 to 50 mg / kg per day. The administration may be administered once a day or divided into several times. The above dosage does not limit the scope of the present invention in any way. The pharmaceutical composition according to the present invention may be formulated as a pill, a dragee, a capsule, a liquid, a gel, a syrup, a slurry, or a suspension.

[0048] In the present invention, the food composition can be manufactured in the form of various foods, such as beverages, gum, tea, vitamin complexes, powders, granules, tablets, capsules, confectionery, rice cakes, bread, etc. In addition, it can also be used as a food additive composition necessary for manufacturing the food composition.

[0049] In the present invention, when the compound included as an active ingredient is included in a food composition, the amount may be added at a ratio of 0.1 to 50% of the total weight. Here, when the food composition is manufactured in the form of a beverage, there is no special limitation other than containing the food composition at the indicated ratio, and various flavoring agents or natural carbohydrates, etc. may be contained as additional ingredients like a typical beverage. That is, as a natural carbohydrate, it may include a monosaccharide such as glucose, a disaccharide such as fructose, a polysaccharide such as sucrose, a dextrin, a cyclodextrin, and a typical sugar such as dextrin, a cyclodextrin, and a sugar alcohol such as xylitol, sorbitol, and erythritol. As the flavoring agent, there may be mentioned a natural flavoring agent (thaumatin, stevia extract (e.g., rebaudioside A, glycyrrhizin, etc.)) and a synthetic flavoring agent (saccharin, aspartame, etc.).

[0050] In addition, the food composition or food composition additive of the present invention may contain various nutrients, vitamins, minerals (electrolytes), flavoring agents such as synthetic flavoring agents and natural flavoring agents, coloring agents, pectic acid and its salts, alginic acid and its salts, organic acids, protective colloid thickeners, pH regulators, stabilizers, preservatives, glycerin, alcohol, carbonating agents used in carbonated beverages, etc.

[0051] These ingredients can be used independently or in combination. The proportions of these additives are not particularly critical, but are typically selected within the range of 0.1 to about 50 parts by weight per 100 parts by weight of the food composition of the present invention.

[0052] When the compound of the present invention is contained and used in a feed composition or feed additive composition, the composition may be a highly concentrated solution of 20 to 90% or may be manufactured in the form of a powder or granules. The feed additive may additionally include one or more of organic acids such as citric acid, fumaric acid, adipic acid, lactic acid, and malic acid; phosphates such as sodium phosphate, potassium phosphate, acid pyrophosphate, and polyphosphate (polyphosphate); and natural antioxidants such as polyphenol, catechin, alpha-tocopherol, rosemary extract, vitamin C, green tea extract, licorice extract, chitosan, tannic acid, and phytic acid.

[0053] In the present invention, when the compound is used as a feed, the composition may be formulated in the form of a conventional feed and may contain conventional feed ingredients. The feed additives and feed may further include grains such as ground or crushed wheat, oats, barley, corn, and rice; plant-based protein feeds such as feeds mainly composed of rapeseed, soybeans, and sunflower; animal-based protein feeds such as blood meal, meat meal, bone meal, and fish meal; dry ingredients composed of sugars and dairy products such as various types of milk powder and whey powder, and may further include nutritional supplements, digestion and absorption enhancers, growth promoters, and the like.

[0054] In the present invention, when the compound is used as a feed additive, it may be administered to animals alone or in combination with other feed additives in an edible carrier. In addition, the feed additive can be easily administered to animals as a top dressing, by mixing them directly into animal feed, or in an oral formulation separate from the feed. When the feed additive is administered separately from animal feed, it can be prepared as an immediate-release or sustained-release formulation by combining it with a pharmaceutically acceptable edible carrier, as is well known in the art. Such edible carriers can be solid or liquid, such as corn starch, lactose, sucrose, soybean flakes, peanut oil, olive oil, sesame oil, and propylene glycol. When a solid carrier is used, the feed additive can be a tablet, capsule, powder, troche, or saccharide tablet, or a top dressing in a microdispersible form. When a liquid carrier is used, the feed additive can be in the form of a gelatin soft capsule, or a syrup, suspension, emulsion, or solution. The feed may comprise any protein-containing organic grain meal commonly used to satisfy the dietary needs of animals. Such protein-containing grain meal typically comprises corn, soybean meal, or a corn / soybean meal mix. The feed composition or feed additive composition may also contain, for example, preservatives, stabilizers, wetting or emulsifying agents, and solution promoters. The feed additive composition may also be added to animal feed by immersion, spraying, or mixing.

[0055] In the composition for preventing, improving or treating viral infection or infectious disease of the present invention, the definitions of the steroid sulfatase inhibitor, isostat, virus classification, pharmaceutically acceptable salts, etc. are omitted below to avoid excessive complexity of the specification as they overlap with those described in the antiviral pharmaceutical composition.

[0056]

[0057] According to another embodiment of the present invention, there is provided a method for inhibiting the activity of a virus, comprising administering to a subject in need of administration a composition comprising a steroid sulfatase inhibitor as an active ingredient in a pharmaceutically effective amount.

[0058] According to another embodiment of the present invention, there is provided a method for preventing or treating a viral infection or infectious disease, comprising administering to a subject in need of administration a composition comprising a steroid sulfatase inhibitor as an active ingredient in a pharmaceutically effective amount.

[0059] The steroid sulfatase inhibitors of the present invention include irosustat, 2-(hydroxyphenyl) indole sulfate, 5-androstene-3,17-diol-3 sulfate, estrone-3-O-methylthiophosphonate (E1-3-MTP), estrone-3-O-sulfamate (EMATE), estradiol-3-O-sulfamate (E2MATE), 4-methylcoumarin 7-O-sulfamate (COUMATE), KW-2581, STX213, and morpholino. (morpholino) may be one or more selected from the group consisting of, for example, irosustat, but is not limited thereto.

[0060] In the present invention, the description of the steroid sulfatase inhibitor, isostat, virus, viral infection or infectious disease, etc. is the same as that described in the antiviral pharmaceutical composition, and thus is omitted to avoid excessive complexity of the present specification.

[0061] In the present invention, the term “administration” means providing a predetermined compound of the present invention to a subject by any appropriate method.

[0062] In the present invention, the "subject" requiring the administration may include both mammals and non-mammals. Here, examples of mammals include, but are not limited to, humans, non-human primates such as chimpanzees, other apes, or monkey species; livestock animals such as cows, horses, sheep, goats, and pigs; domesticated animals such as rabbits, dogs, or cats; and laboratory animals such as rodents such as rats, mice, or guinea pigs. In addition, examples of non-mammals in the present invention may include, but are not limited to, birds or fish.

[0063] In the present invention, the formulation of the compound administered as described above is not particularly limited, and may be administered as a solid formulation, a liquid formulation, or an aerosol formulation for inhalation, and may be administered as a solid formulation intended to be converted into a liquid formulation for oral or parenteral administration immediately before use, and may be administered by being formulated in the form of, for example, oral formulations such as powders, granules, capsules, tablets, and aqueous suspensions, external preparations, suppositories, and sterile injectable solutions, but is not limited thereto.

[0064] In addition, in the present invention, a pharmaceutically acceptable carrier may be additionally administered together with the compound of the present invention during the above administration. Here, the pharmaceutically acceptable carrier may include a binder, a lubricant, a disintegrant, an excipient, a solubilizer, a dispersant, a stabilizer, a suspending agent, a pigment, a fragrance, etc. for oral administration, and may include a mixture of a buffer, a preservative, an analgesic, a solubilizer, an isotonic agent, a stabilizer, etc. for injections, and may include a base, an excipient, a lubricant, a preservative, etc. for topical administration. The formulation of the compound of the present invention may be prepared in various ways by mixing it with the pharmaceutically acceptable carrier described above. For example, the formulation may be prepared in the form of a tablet, troche, capsule, elixir, suspension, syrup, wafer, etc. for oral administration, and the formulation may be prepared in the form of a unit dosage ampoule or a multiple dosage form for injections. It can be formulated as a solution, suspension, tablet, capsule, sustained-release preparation, etc.

[0065] Meanwhile, examples of carriers, excipients, and diluents suitable for formulation include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, malditol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate, or mineral oil. In addition, fillers, anticoagulants, lubricants, wetting agents, fragrances, emulsifiers, preservatives, and the like may be additionally included.

[0066] Routes of administration of the compounds of the present invention include, but are not limited to, oral, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, intracardiac, transdermal, subcutaneous, intraperitoneal, intranasal, enteral, topical, sublingual, or rectal. Oral or parenteral administration is preferred.

[0067] In the present invention, "parenteral" includes subcutaneous, intradermal, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intralesional, and intracranial injection or infusion techniques. The pharmaceutical composition of the present invention may also be administered in the form of a suppository for rectal administration.

[0068] As used herein, a "pharmaceutically effective amount" refers to a sufficient amount of an agent to produce a desired biological result. This result may be a reduction and / or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration in a biological system. For example, an "effective amount" for therapeutic use is the amount of a compound disclosed herein required to produce a clinically significant reduction in a disease. The appropriate "effective" amount in any individual case can be determined by one skilled in the art using routine experimentation. Accordingly, the expression "effective amount" generally refers to an amount of an active agent that produces a therapeutic effect. In the present invention, the active agent is a steroid sulfatase inhibitor and an inhibitor of viral activity.

[0069] The compound of the present invention may vary depending on several factors including the activity of the specific compound used, age, body weight, general health, sex, diet, time of administration, route of administration, excretion rate, drug combination, and severity of the specific disease to be prevented or treated, and the dosage of the compound may vary depending on the patient's condition, body weight, degree of disease, drug form, route of administration, and period of time, but may be appropriately selected by those skilled in the art, and may be administered at 0.0001 to 100 mg / kg or 0.001 to 100 mg / kg per day. The administration may be administered once a day or divided into several times. The above dosage does not limit the scope of the present invention in any way. The compound according to the present invention may be formulated as a pill, a dragee, a capsule, a liquid, a gel, a syrup, a slurry, or a suspension.

[0070] The compounds of the present invention may be used alone or in combination with methods using surgery, radiation therapy, hormone therapy, chemotherapy, and biological response modifiers.

[0071]

[0072] According to another embodiment of the present invention, there is provided a method for preventing, improving or treating a viral infection or infectious disease, comprising administering to a subject a steroid sulfatase inhibitor.

[0073] In the present invention, the above-mentioned "subject" refers to a subject that has symptoms of or is suspected of being infected with a virus, and needs to improve or treat a virus infection or a disease caused by the infection by suppressing viral activity, etc., and all animals, including humans, that are already infected or can be infected with the virus.

[0074] In the method for preventing, improving or treating a viral infection or infectious disease of the present invention, the definitions of the steroid sulfatase inhibitor, isostat, virus classification, pharmaceutically acceptable salts, etc. are omitted below to avoid excessive complexity of the specification as they overlap with those described in the composition for preventing, improving or treating a viral infection or infectious disease.

[0075]

[0076] According to another embodiment of the present invention, the present invention relates to a disinfecting or cleaning composition having an inhibitory activity against viruses, which comprises a steroid sulfatase inhibitor as an active ingredient.

[0077] According to another embodiment of the present invention, there is provided a method for disinfecting or cleaning a virus, comprising the step of contacting a target object with a steroid sulfatase inhibitor.

[0078] In the present invention, the term "disinfection" refers to inactivating or killing a pathogenic microorganism or pathogenic virus. Inactivating includes inhibiting infection, survival, proliferation, transmission, or a combination thereof of the pathogenic microorganism or pathogenic virus.

[0079] In the present invention, the term "cleaning" refers to a method used to facilitate or assist in removing contaminants, bleaching, reducing microbial or viral populations, rinsing, and any combination thereof.

[0080] In the present invention, the “object” includes all living or non-living objects (apparatus, devices, clothing, tableware, etc.) or their hard surfaces that must be prevented from being infected by a virus.

[0081] Since the steroid sulfatase inhibitor of the present invention has a specific killing ability against viruses, the disinfecting composition or cleaning composition containing the inhibitor of the present invention can be usefully used as a disinfectant and cleaning agent for hospitals and health care to prevent hospital infections, and can be used for disinfecting and cleaning various items such as general household disinfectants and cleaning agents, tableware, food preparation equipment, building interiors, drinking water, vehicles, aircraft, and ships.

[0082] When the composition of the present invention is used as a disinfecting composition or a cleaning composition, it is of course possible to include a pharmacologically, veterinarily or agriculturally acceptable carrier or diluent.

[0083] Additionally, the compound or composition of the present invention can be prepared in any phase, such as a liquid phase, a solid phase, or a gas phase.

[0084] The compound or composition of the present invention can be applied to the human body itself or various devices or apparatuses used by humans, and when applied to the human body, can be administered in any manner such as orally or parenterally. In addition, the compound or composition can be formulated into various forms that can be effectively applied to the human body itself or various devices or apparatuses, and examples thereof include pharmaceutical formulations for oral administration such as tablets, pills, capsules, and powder preparations, or external preparations such as sprays, cleansing gels, liquids, creams, and ointments, or formulations applicable to devices and apparatuses.

[0085] In the present invention, the "contact" as a method of applying the compound or composition to a subject is appropriately selected according to the properties of the subject, the surrounding environment, etc., by a known disinfectant or detergent application method, and may include forms such as wiping, dipping, immersing, or spraying, and preferably may be in the form of spraying, but is not limited thereto.

[0086] In the disinfecting or cleaning composition of the present invention, definitions of the steroid sulfatase inhibitor, isostat, virus classification, pharmaceutically acceptable salts, etc. are omitted below to avoid excessive complexity of the specification as they overlap with those described above.

[0087] The composition comprising a steroid sulfatase inhibitor provided in the present invention is a safe substance without toxicity or side effects and has various virus inhibitory activities, so that it can effectively prevent, improve or treat infections caused by viruses or diseases caused by infections.

[0088] FIG. 1 is a diagram showing the results of measuring the mRNA expression level of Ifnb1, a type 1 interferon, through real-time qPCR analysis according to one embodiment of the present invention.

[0089] FIG. 2 is a diagram showing the results of measuring the mRNA expression levels of antiviral genes Mx1 and Mx2, which exhibit the key effects of type 1 interferon, through real-time qPCR analysis according to one embodiment of the present invention.

[0090] FIG. 3 is a diagram showing the results of measuring the antiviral potency through viral RNA extraction during an in vitro dengue virus infection experiment according to one embodiment of the present invention.

[0091] FIG. 4 is a diagram showing the results of measuring the antiviral potency through viral RNA extraction during an in vivo severe acute respiratory syndrome virus infection experiment according to one embodiment of the present invention.

[0092] FIG. 5 and FIG. 6 are diagrams showing the results of staining lung tissue of a mouse using the H & E stain method according to one embodiment of the present invention, observing the stained lung tissue under an optical microscope, and calculating the pathology score for inflammation findings in the lung.

[0093] One embodiment of the present invention relates to an antiviral pharmaceutical composition comprising a steroid sulfatase inhibitor as an active ingredient.

[0094] Another embodiment of the present invention relates to a method for inhibiting the activity of a virus, comprising administering to a subject in need of administration a composition comprising a steroid sulfatase inhibitor as an active ingredient in a pharmaceutically effective amount.

[0095] Another embodiment of the present invention relates to a pharmaceutical composition for preventing or treating a viral infection or infectious disease, comprising a steroid sulfatase inhibitor as an active ingredient.

[0096] Another embodiment of the present invention relates to a method for preventing or treating a viral infection or infectious disease, comprising administering to a subject in need of administration a composition comprising a steroid sulfatase inhibitor as an active ingredient in a pharmaceutically effective amount.

[0097] Another embodiment of the present invention relates to a food or food additive composition for preventing or improving viral infection or infectious disease, comprising a steroid sulfatase inhibitor as an active ingredient.

[0098] Another embodiment of the present invention relates to a feed or feed additive composition for preventing or improving viral infection or infectious disease, comprising a steroid sulfatase inhibitor as an active ingredient.

[0099] Another embodiment of the present invention relates to a disinfecting or cleaning composition having an inhibitory activity against viruses, comprising a steroid sulfatase inhibitor as an active ingredient.

[0100] Another embodiment of the present invention relates to a method for preventing or treating a viral infection or infectious disease, comprising administering a steroid sulfatase inhibitor to a subject other than a human.

[0101] Another embodiment of the present invention relates to a method for disinfecting or cleaning a virus, comprising the step of contacting a target with a steroid sulfatase inhibitor.

[0102] Hereinafter, the present invention will be described in more detail through examples. These examples are intended solely to illustrate the present invention more specifically, and it will be apparent to those skilled in the art that the scope of the present invention is not limited by these examples, in accordance with the gist of the present invention.

[0103]

[0104] Preparation Example 1: Preparation of Irosustat

[0105] The compound (6-oxo-8,9,10,11-tetrahydro-7H-cyclohepta[c]chromen-3-yl) sulfamate represented by the following chemical formula 1 (hereinafter referred to as 'Irosustat') was purchased and prepared:

[0106] [Chemical Formula 1]

[0107]

[0108]

[0109] Preparation Example 2: Mouse Production

[0110] The inventors of the present invention purchased 8-week-old C57BL / 6 male mice from the Central Laboratory Animal Center and used them in the experiments below. They were acclimatized to a laboratory environment under conditions of 21±2℃, 50±10% humidity, and 12-hour / 12-hour (dark / light cycle) conditions by sufficiently providing food and water for 1 week. More specifically, 8-week-old C57BL / 6 mice were orally administered the control group (vehicle) or Irosustat 10 mg / kg once daily for 2 weeks, and then sacrificed, and their livers were removed and used in the experiments below.

[0111]

[0112] Example 1: Confirmation of antiviral effect

[0113] In the following experiment, to confirm the antiviral effect of Irosustat, livers were extracted from the group administered Irosustat to mice and the control group, and the livers were pulverized with TissueLyser II (Qiagen), and total RNA was isolated using the RNeasy mini kit (Qiagen). Reverse transcription (RT) was performed using 2 µg of RNA using the RevertAid RT Kit (EP0441, Thermo Fisher Scientific), and qRT-PCR was performed using the SensiFAST SYBR Hi-ROX kit (BIO-92020, Bioline, London, UK) for real-time qPCR. The qPCR results were used to quantify the target gene through the housekeeping gene Gapdh.

[0114] As a result, as shown in Fig. 1, the mRNA expression level of Ifnb1 (interferon beta), a type 1 interferon, increased, and as shown in Fig. 2, the mRNA expression levels of genes Mx1 and Mx2, which express Mx1 (MX Dynamin Like GTPase 1) and Mx2 (MX Dynamin Like GTPase 2), proteins that exhibit a wide range of antiviral effects, were confirmed to increase.

[0115] Type I interferons (IFNs) mentioned above are proteins mainly secreted from virus-infected cells, and the most representative type I interferons in humans are IFN-α and IFN-β, which are known to exhibit a wide range of antiviral effects (Nat Rev Immunol. 2015 Feb;15(2):87-103.). In addition, both Mx1 (Interferon-induced GTP-binding protein Mx1) and Mx2 (Interferon-induced GTP-binding protein MX2) proteins are induced by type I interferons, and interferon-induced Mx proteins are markers known to accumulate in the cytoplasm in humans and bind to invading viruses to induce viral death (Trends Microbiol. 2015 Mar;23(3):154-63., Microbiol Mol Biol Rev. 2013 Dec;77(4):551-66.).

[0116] Therefore, the above results imply that when Iroserstat is administered during a viral infection, an antiviral effect is observed, and it suggests that Iroserstat, which has already been proven to be safe as a treatment for metabolic diseases, can also be used to effectively prevent, improve, or treat viral infections or diseases caused by infections.

[0117]

[0118] Example 2: Confirmation of antiviral effect through in vitro experiments

[0119] To confirm the antiviral effect of Irosustat in vitro, additional experiments were conducted in which Vero cells were infected with dengue virus. Irosustat was pretreated at concentrations of 0 μM, 20 μM, or 40 μM 16 hours prior to virus infection, and the cell culture medium containing the drug was replaced 1 hour later. Forty-eight hours after virus infection, dengue virus viral RNA was measured in the cell culture medium using qRT-PCR, and the results are shown in Figure 3.

[0120] As a result of the experiment, when comparing the control group (vehicle) and the Iroserstat treatment group, it was confirmed that the viral RNA of the dengue virus decreased in a concentration-dependent manner of Iroserstat, and when treated at a concentration of 40 μM, the virus titer was reduced by approximately 50% or more.

[0121]

[0122] Example 3: Confirmation of antiviral effect through in vivo experiments

[0123] To confirm the antiviral effect of Iroserstat in vivo, 9-week-old K18-ACE2 TG mice were used in the experiment. They were acclimatized for 1 week under laboratory conditions of 21±2℃ temperature, 50±10% humidity, and 12 h / 12 ​​h (dark / light cycle) with sufficient food and water. Starting one day before infection with Severe Acute Respiratory Syndrome virus (SARS; SARS-CoV-2), vehicle or Iroserstat 10 mg / kg was administered orally once daily.

[0124] 3.1 Measurement of viral titer 1 day after viral infection

[0125] One day after virus infection, three vehicle mice and four Irosert-treated mice were sacrificed to obtain lung tissues, and the virus titer in the lung tissues was measured using plaque assay, which is shown in Fig. 4.

[0126] The experimental results showed that the virus titer in the lung tissue was approximately 77% lower in the Iroserstart-treated group one day after virus infection.

[0127] 3.2 Calculation of inflammation score and edema score 7 days after viral infection

[0128] Seven days after virus infection, mice were sacrificed, lung tissues were collected, fixed in 10% neutral formalin, and stained with H&E stain. The stained lung tissues were observed under an optical microscope, and pathological scores for lung inflammation findings were calculated, which are shown in Figures 5 and 6.

[0129] The experimental results showed that the number of inflammatory cells was significantly reduced in the Iroserstat-treated group in lung tissue findings 7 days after viral infection, and both the calculated inflammation score and edema score were confirmed to be lower. These results indicate that the drug Iroserstat improved the symptoms of pneumonia caused by the severe acute respiratory syndrome virus (SARS-CoV-2), and thus, it can be applied to the treatment of coronavirus infection or diseases caused by infection.

[0130]

[0131] In summary, the inventors of the present invention have verified the antiviral effect of the drug Irosert through various virus infection experiments, and it is expected that it can be used as a treatment for infections or infectious diseases caused by various viruses as well as coronaviruses.

[0132]

[0133] While specific aspects of the present invention have been described in detail above, it should be apparent to those skilled in the art that these specific descriptions are merely preferred implementation examples and do not limit the scope of the present invention. Therefore, the substantial scope of the present invention is defined by the appended claims and their equivalents.

[0134] The composition of the present invention has inhibitory activity against various viruses, and thus can effectively prevent, improve, or treat infections caused by viruses or diseases caused by infections.

Claims

1. An antiviral pharmaceutical composition comprising a steroid sulfatase inhibitor as an active ingredient.

2. In paragraph 1, The above steroid sulfatase inhibitors include irosustat, 2-(hydroxyphenyl) indole sulfate, 5-androstene-3,17-diol-3 sulfate, estrone-3-O-methylthiophosphonate (E1-3-MTP), estrone-3-O-sulfamate (EMATE), estradiol-3-O-sulfamate (E2MATE), 4-methylcoumarin 7-O-sulfamate (COUMATE), KW-2581, STX213, and morpholino. A composition comprising at least one member selected from the group consisting of (morpholino).

3. In paragraph 1, The composition comprises a salt, hydrate or solvate form of a steroid sulfatase inhibitor.

4. In paragraph 1, A composition wherein the virus is a DNA virus or an RNA virus.

5. In paragraph 4, A composition wherein the virus is at least one species selected from the group consisting of Flaviviridae, Coronavirinae, Reoviridae, Picornaviridae, Caliciviridae, Togaviridae, Arenaviridae, Orthomyxoviridae, Paramyxoviridae, Bunyaviridae, Rhabdoviridae, Filoviridae, Astroviridae, Bornaviridae, and Arteriviridae.

6. In paragraph 5, The composition wherein the virus is from the Flaviviridae family or Coronavirinae family.

7. A pharmaceutical composition for preventing or treating viral infection or infectious disease, comprising a steroid sulfatase inhibitor as an active ingredient.

8. In paragraph 7, The above steroid sulfatase inhibitors include irosustat, 2-(hydroxyphenyl) indole sulfate, 5-androstene-3,17-diol-3 sulfate, estrone-3-O-methylthiophosphonate (E1-3-MTP), estrone-3-O-sulfamate (EMATE), estradiol-3-O-sulfamate (E2MATE), 4-methylcoumarin 7-O-sulfamate (COUMATE), KW-2581, STX213, and morpholino. A composition comprising at least one member selected from the group consisting of (morpholino).

9. In paragraph 7, The composition comprises a salt, hydrate or solvate form of a steroid sulfatase inhibitor.

10. In paragraph 7, A composition wherein the virus is a DNA virus or an RNA virus.

11. In paragraph 10, A composition wherein the virus is at least one species selected from the group consisting of Flaviviridae, Coronavirinae, Reoviridae, Picornaviridae, Caliciviridae, Togaviridae, Arenaviridae, Orthomyxoviridae, Paramyxoviridae, Bunyaviridae, Rhabdoviridae, Filoviridae, Astroviridae, Bornaviridae, and Arteriviridae.

12. In paragraph 11, The composition wherein the virus is from the Flaviviridae family or Coronavirinae family.

13. A food or food additive composition for preventing or improving viral infection or infectious disease, comprising a steroid sulfatase inhibitor as an active ingredient.

14. In paragraph 13, The above steroid sulfatase inhibitors include irosustat, 2-(hydroxyphenyl) indole sulfate, 5-androstene-3,17-diol-3 sulfate, estrone-3-O-methylthiophosphonate (E1-3-MTP), estrone-3-O-sulfamate (EMATE), estradiol-3-O-sulfamate (E2MATE), 4-methylcoumarin 7-O-sulfamate (COUMATE), KW-2581, STX213, and morpholino. A composition comprising at least one member selected from the group consisting of (morpholino).

15. In paragraph 13, The composition comprises a salt, hydrate or solvate form of a steroid sulfatase inhibitor.

16. A feed or feed additive composition for preventing or improving viral infection or infectious disease, comprising a steroid sulfatase inhibitor as an active ingredient.

17. In paragraph 16, The above steroid sulfatase inhibitors include irosustat, 2-(hydroxyphenyl) indole sulfate, 5-androstene-3,17-diol-3 sulfate, estrone-3-O-methylthiophosphonate (E1-3-MTP), estrone-3-O-sulfamate (EMATE), estradiol-3-O-sulfamate (E2MATE), 4-methylcoumarin 7-O-sulfamate (COUMATE), KW-2581, STX213, and morpholino. A composition comprising at least one member selected from the group consisting of (morpholino).

18. In paragraph 16, The composition comprises a salt, hydrate or solvate form of a steroid sulfatase inhibitor.

19. A disinfecting or cleaning composition having an inhibitory activity against viruses, comprising a steroid sulfatase inhibitor as an active ingredient.

20. In paragraph 19, The above steroid sulfatase inhibitors include irosustat, 2-(hydroxyphenyl) indole sulfate, 5-androstene-3,17-diol-3 sulfate, estrone-3-O-methylthiophosphonate (E1-3-MTP), estrone-3-O-sulfamate (EMATE), estradiol-3-O-sulfamate (E2MATE), 4-methylcoumarin 7-O-sulfamate (COUMATE), KW-2581, STX213, and morpholino. A composition comprising at least one member selected from the group consisting of (morpholino).

21. In paragraph 19, The composition comprises a salt, hydrate or solvate form of a steroid sulfatase inhibitor.

22. A method for preventing or treating a viral infection or infectious disease, comprising the step of administering a steroid sulfatase inhibitor to a subject other than a human.

23. In paragraph 22, The above steroid sulfatase inhibitors include irosustat, 2-(hydroxyphenyl) indole sulfate, 5-androstene-3,17-diol-3 sulfate, estrone-3-O-methylthiophosphonate (E1-3-MTP), estrone-3-O-sulfamate (EMATE), estradiol-3-O-sulfamate (E2MATE), 4-methylcoumarin 7-O-sulfamate (COUMATE), KW-2581, STX213, and morpholino. A method comprising at least one selected from the group consisting of (morpholino).

24. A method for disinfecting or cleaning a virus, comprising the step of contacting a target with a steroid sulfatase inhibitor.

25. In paragraph 24, The above steroid sulfatase inhibitors include irosustat, 2-(hydroxyphenyl) indole sulfate, 5-androstene-3,17-diol-3 sulfate, estrone-3-O-methylthiophosphonate (E1-3-MTP), estrone-3-O-sulfamate (EMATE), estradiol-3-O-sulfamate (E2MATE), 4-methylcoumarin 7-O-sulfamate (COUMATE), KW-2581, STX213, and morpholino. A method comprising at least one selected from the group consisting of (morpholino).

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