WO2022080577A1 - Composition comprising pmca inhibitor for prevention of coronavirus infection or infectious diseases or for disinfection - Google Patents
Composition comprising pmca inhibitor for prevention of coronavirus infection or infectious diseases or for disinfection Download PDFInfo
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- WO2022080577A1 WO2022080577A1 PCT/KR2020/016942 KR2020016942W WO2022080577A1 WO 2022080577 A1 WO2022080577 A1 WO 2022080577A1 KR 2020016942 W KR2020016942 W KR 2020016942W WO 2022080577 A1 WO2022080577 A1 WO 2022080577A1
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Images
Classifications
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/553—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
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- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
- A01N43/48—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with two nitrogen atoms as the only ring hetero atoms
- A01N43/58—1,2-Diazines; Hydrogenated 1,2-diazines
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- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
- A01N43/48—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with two nitrogen atoms as the only ring hetero atoms
- A01N43/60—1,4-Diazines; Hydrogenated 1,4-diazines
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- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
- A01N43/90—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having two or more relevant hetero rings, condensed among themselves or with a common carbocyclic ring system
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
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- A23K20/00—Accessory food factors for animal feeding-stuffs
- A23K20/10—Organic substances
- A23K20/116—Heterocyclic compounds
- A23K20/137—Heterocyclic compounds containing two hetero atoms, of which at least one is nitrogen
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
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- A—HUMAN NECESSITIES
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/50—Pyridazines; Hydrogenated pyridazines
- A61K31/5025—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with heterocyclic ring systems
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
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- A—HUMAN NECESSITIES
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- A23V2250/00—Food ingredients
- A23V2250/30—Other Organic compounds
Definitions
- the present invention relates to a composition that can effectively prevent a coronavirus infection or a disease caused by the infection, including a PMCA inhibitor, and a composition for disinfection or cleaning in addition.
- Coronavirus is a representative virus that causes lethal infectious diseases in modern civilization.
- Severe Acute Respiratory Syndrome also known as SARS
- MERS Middle East Respiratory Syndrome
- COVID-19 coronavirus
- SARS Severe acute respiratory syndrome coronavirus 2
- -CoV-2 Severe acute respiratory syndrome coronavirus 2
- Coronavirus Infectious Disease-19 is transmitted when droplets (saliva) of an infected person penetrate the respiratory tract or the mucous membranes of the eyes, nose, and mouth. After infection, after an incubation period of about 2 to 14 days (estimated), the main symptoms are fever (37.5 degrees), respiratory symptoms such as cough or shortness of breath, and pneumonia. reach
- One object of the present invention is to provide a composition for various uses that can prevent infection by coronavirus or various diseases caused by the infection.
- Another object of the present invention is to provide a composition for disinfection or cleaning having inhibitory activity against coronavirus.
- N-(2-(2-butyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl) represented by the following formula (1) Ethyl)-3-(2-ethyl-1H-imidazol-1-yl)propanamide (N-(2-(2-butyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H) )-yl)ethyl)-3-(2-ethyl-1H-imidazol-1-yl)propanamide) and 4-(imidazo[1,2-b]pyridazin-6-yl) represented by Formula 2 below -N-(3-methoxyphenethyl)piperazine-1-carboxamide(4-(imidazo[1,2-b]pyridazin-6-yl)-N-(3-methoxyphenethyl)piperazine-1-carboxamide ) at least one
- N- (2- (2-butyl-2,3-dihydrobenzo [f] [1,4] oxazepine-4 (5H) - yl)ethyl)-3-(2-ethyl-1H-imidazol-1-yl)propanamide
- N-(2-(2-butyl-2,3-dihydrobenzo[f][1,4]oxazepin-4) (5H)-yl)ethyl)-3-(2-ethyl-1H-imidazol-1-yl)propanamide
- it relates to a method for preventing
- the pharmaceutically acceptable salts are salts generally considered by those skilled in the art to be suitable for medical applications (eg, since such salts are not harmful to the subject to be treated with the salts), or each salts that cause acceptable side effects within the treatment of
- the pharmaceutically acceptable salt is a salt considered acceptable by a regulatory authority such as the U.S. Food and Drug Administration (FDA), the European Medicines Agency (EMA), or the Pharmaceutical and Medical Devices Agency (PMDA) of the Ministry of Health, Labor and Welfare of Japan. .
- the present invention in principle provides an intermediate, for example in the preparation of a compound according to the invention or a physiologically functional derivative thereof, or a pharmaceutically acceptable salt of a compound according to the invention or a physiologically functional derivative thereof
- an intermediate for example in the preparation of a compound according to the invention or a physiologically functional derivative thereof, or a pharmaceutically acceptable salt of a compound according to the invention or a physiologically functional derivative thereof
- salts of the compounds according to the invention which are not themselves pharmaceutically acceptable.
- Said salts include water-insoluble salts, particularly water-soluble salts.
- a particular compound according to the invention or a physiologically functional derivative thereof is capable of forming salts, ie whether said compound according to the invention or a physiologically functional derivative thereof is, for example, For example, it can be easily determined whether or not a group has a chargeable group such as an amino group, a carboxylic acid group, and the like.
- Exemplary salts of the compounds of the present invention are acid addition salts or salts with bases, particularly pharmaceutically acceptable inorganic and organic acid addition salts and salts with bases commonly used in pharmaceuticals, which are water-insoluble or particularly water-soluble acid addition salts. is salt Depending on the substituents of the compounds of the present invention, salts with bases may also be suitable.
- Acid addition salts can be prepared, for example, by combining a solution of a compound of the present invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid. It can be formed by mixing.
- pharmaceutically acceptable base addition salts include alkali metal salts (eg, sodium or potassium salts); alkaline earth metal salts (eg, calcium or magnesium salts); and salts formed with suitable organic ligands (eg, ammonium, quaternary ammonium and amines formed with counter anions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, alkyl sulfonates and aryl sulfonates). cations) may be included.
- alkali metal salts eg, sodium or potassium salts
- alkaline earth metal salts eg, calcium or magnesium salts
- suitable organic ligands eg, ammonium, quaternary ammonium and amines formed with counter anions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, alkyl sulfonates and aryl sulfonates
- Illustrative examples of pharmaceutically acceptable salts include acetate, adipate, alginate, arginate, ascorbate, aspartate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium edetate, camphorate, camphorsulfonate, camsylate, carbonate, chloride, citrate, digluconate, dihydrochloride, dodecylsulfate, edetate, edisylate, ethanesulfonate, Formate, fumarate, galactate, galacturonate, gluconate, glutamate, glycerophosphate, hemisulphate, heptanoate, hexanoate, hexylresorcinate, hydrobromide, hydrochloride, hydroiodide , 2-hydroxy-ethanesulfonate, hydroxynaphthoate
- Salts which are not pharmaceutically acceptable in the present invention and which, for example, can be obtained as process products during the preparation of the compounds according to the invention on an industrial scale, are also included in the invention and, if desired, are known to the person skilled in the art. It can be converted into a pharmaceutically acceptable salt by a method.
- the virus may be an RNA virus.
- the “RNA virus” refers to any virus using RNA as a genetic material.
- the RNA virus is Coronaviridae, Amalgaviridae, Birnaviridae, Chrysoviridae, Cystoviridae, Endornaviridae ( Endornaviridae), Hypoviridae, Megabirnaviridae, Partitiviridae, Picobirnaviridae, Reoviridae, Totiviridae, Quadriviridae, Arteriviridae, Mesoniviridae, Roniviridae, Dicistroviridae, Iflaviridae, Marnaviridae Marnaviridae, Picornaviridae, Secoviridae, Alphaflexiviridae, Betaflexiviridae, Gammaflexiviridae, Tymoviridae ), Bornaviridae, Filoviridae, Paramyx
- the "coronavirus (Coronavirus)” has four genera (alpha, beta, gamma, delta) in the coronavirus subfamily (Coronavirinae) of the coronaviridae, and is an RNA virus with a gene size of 27 to 32 kb. It is known to cause respiratory and digestive system infections in animals. It is easily transmitted mainly through mucosal transmission and droplet transmission. Humans usually cause mild respiratory infections, but rarely fatal infections. Diarrhea in cattle and pigs, and respiratory diseases in chickens. Among coronaviruses, coronaviruses that have humans as hosts are divided into classifications in Table 1 below (Centers for Disease Control and Prevention, 2020). Among the four genera, alpha and beta infect humans and animals, and gamma and delta are reported to infect only animals.
- coronaviruses there are seven types of coronaviruses in Table 2 below that currently infect humans, the types that cause colds (229E, OC43, NL63, HKU1) and the types that cause severe pneumonia (SARS-CoV, SARS-CoV-2) , MERS-CoV).
- Virus name Genus host Symptom HCoV-229E Alpha Human mild respiratory symptoms HCoV-NL63 Alpha Human mild respiratory symptoms SARS-CoV Beta Human severe respiratory symptoms MERS-CoV Beta Human severe respiratory symptoms HCoV-OC43 Beta Human mild respiratory symptoms HCoV-HKU1 Beta Human Pneumonia symptoms SARS-CoV-2 Beta Human Mild respiratory symptoms Severe cases can cause shortness of breath
- beta coronavirus corresponds to a zoonotic infection as one of four genera of coronaviruses in the subfamily Coronavirus.
- beta coronaviruses include Severe Acute Respiratory Syndrome virus (SARS; SARS-CoV), Severe Acute Respiratory Syndrome virus-2 (SARS-CoV-2), Middle East Respiratory Syndrome virus (SARS-CoV) Middle East Respiratory Syndrome virus (MERS; MERS-CoV), human coronavirus OC43 (HCoV-OC43), or human coronavirus HKU1 (HCoV-HKU1) are known to exist.
- the "Severe Acute Respiratory Syndrome virus-2 (SARS-CoV-2)" is an enveloped, positive-polar single-stranded RNA beta coronavirus belonging to the Coronaviridae family. .
- the coronaviruses that historically infect humans are severe common cold viruses, including hCoV-OC43, HKU and 229E5.
- nucleocapsid protein includes N1, N2 and N3 fragments.
- the coronavirus includes naturally or artificially mutated variants.
- the infectious disease caused by the coronavirus is coronavirus enteritis, coronavirus diarrhea, severe acute respiratory syndrome coronavirus (SARS), Middle East respiratory syndrome (MERS), or their It may be a combination, but may be included without limitation as long as it is a disease that can be caused by the coronavirus infection.
- coronavirus enteritis coronavirus diarrhea
- severe acute respiratory syndrome coronavirus SARS
- MERS Middle East respiratory syndrome
- the infectious disease may be a respiratory disease, hepatitis, gastroenteritis or encephalitis caused by the viral infection.
- the respiratory disease may be one that causes Severe Acute Respiratory Syndrome (SARS).
- SARS Severe Acute Respiratory Syndrome
- the severe acute respiratory syndrome is a disease that can cause infection of the upper or lower respiratory tract, which can cause sudden fever, cough, and shortness of breath, and can progress to pneumonia and even lead to death.
- composition of the present invention may be used alone or in combination with conventional antiviral agents, or may be used in combination with biological agents such as antiserum.
- composition of the present invention may 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.
- prevention means any action that delays the progress of virus infection or proliferation by administration of the composition of the present invention.
- the compound or pharmaceutical composition may be characterized in the form of capsules, tablets, granules, injections, ointments, powders or drinks, and the pharmaceutical composition may be characterized in that it is targeted to humans.
- the pharmaceutical composition of the present invention is not limited thereto, but each can be formulated in the form of oral dosage forms such as powders, granules, capsules, tablets, aqueous suspensions, external preparations, suppositories, and sterile injection solutions 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, colorants, fragrances, etc., in the case of oral administration, and in the case of injections, buffers, preservatives, pain relief A topical agent, solubilizer, isotonic agent, stabilizer, etc.
- the dosage form of the pharmaceutical composition of the present invention can be prepared in various ways by mixing with a pharmaceutically acceptable carrier as described above.
- a pharmaceutically acceptable carrier as described above.
- it can be prepared in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, etc., and in the case of injections, it can be prepared in the form of unit dose ampoules or multiple doses. there is.
- it can be formulated as a solution, suspension, tablet, capsule, sustained release formulation, and the like.
- suitable carriers, excipients and diluents 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, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate or mineral oil may be used.
- it may further include a filler, an anti-agglomeration agent, a lubricant, a wetting agent, a flavoring agent, an emulsifier, a preservative, and the like.
- the route of administration of the compound or pharmaceutical composition according to the present invention is, but not limited to, oral, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, intracardiac, transdermal, subcutaneous, intraperitoneal, intranasal, intestinal , topical, sublingual or rectal. Oral or parenteral administration is preferred.
- 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.
- the compound or pharmaceutical composition of the present invention may be determined by several factors including the activity of the specific compound used, age, weight, general health, sex, formula, administration time, administration route, excretion rate, drug formulation, and the severity of the specific disease to be prevented or treated.
- 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 from 0.0001 to 0.0001 per day It may be administered at 50 mg/kg or 0.001 to 50 mg/kg. Administration may be administered once a day, or may be administered in several divided doses. 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 pills, dragees, capsules, solutions, gels, syrups, slurries, and suspensions.
- the term "individual” means a subject who has or is suspected of having a virus infection and needs to prevent virus infection or a disease caused by the infection by suppressing virus activity, etc., which is already infected or can be infected with the virus means all animals, including humans.
- the "administration" of the present invention means the process of introducing the active ingredient of the present invention to an individual by any suitable method, and the administration method in the preventive method of the present invention is through various routes such as oral or parenteral. may be administered.
- a specific pharmaceutically effective amount for a target subject includes the type and extent of the reaction to be achieved, the specific composition comprising the active ingredient, including whether other agents are used in some cases, the age of the patient, Body weight, general health status, sex and diet, administration time, administration route and secretion rate of a composition containing the active ingredient, treatment period, various factors including drugs used or used together with a specific composition and well-known in the pharmaceutical field It is preferable to apply differently depending on similar factors.
- the food composition may be prepared in the form of various foods, for example, beverages, gum, tea, vitamin complexes, powders, granules, tablets, capsules, confectionery, rice cakes, bread, and the like.
- it may be used as a food additive composition necessary for the preparation of the food composition.
- the amount may be added in a proportion of 0.1 to 50% of the total weight.
- the food composition is prepared in the form of a beverage, there is no particular limitation other than containing the food composition in the indicated ratio, and it may contain various flavoring agents or natural carbohydrates as additional ingredients like a conventional beverage. That is, as natural carbohydrates, monosaccharides such as glucose, disaccharides such as fructose, polysaccharides such as sucrose, and common sugars such as dextrin and cyclodextrin, and sugar alcohols such as xylitol, sorbitol and erythritol are included. can do.
- flavoring agent examples include natural flavoring agents (taumatin, stevia extract (eg, rebaudioside A, glycyrrhizin, etc.) and synthetic flavoring agents (saccharin, aspartame, etc.).
- natural flavoring agents taumatin, stevia extract (eg, rebaudioside A, glycyrrhizin, etc.)
- synthetic flavoring agents sacharin, aspartame, etc.
- the food composition or food composition additive of the present invention includes various nutrients, vitamins, minerals (electrolytes), synthetic flavors and natural flavors such as flavoring agents, coloring agents, pectic acid and its salts, alginic acid and its salts, organic acids, protective colloidal thickeners, pH adjusting agents, stabilizers, preservatives, glycerin, alcohols, carbonation agents used in carbonated beverages, and the like.
- These components may be used independently or in combination.
- the proportion of these additives is not so important, but is generally selected in the range of 0.1 to about 50 parts by weight per 100 parts by weight of the food composition of the present invention.
- the composition may be 20 to 90% highly concentrated or may be prepared in powder or granular form.
- the feed additive is an organic acid such as citric acid, humic acid, adipic acid, lactic acid, malic acid, or phosphate such as sodium phosphate, potassium phosphate, acid pyrophosphate, polyphosphate (polyphosphate), polyphenol, catechin, alpha-tocopherol, rosemary Extract, vitamin C, green tea extract, licorice extract, chitosan, tannic acid, any one or more of natural antioxidants such as phytic acid may be further included.
- organic acid such as citric acid, humic acid, adipic acid, lactic acid, malic acid, or phosphate such as sodium phosphate, potassium phosphate, acid pyrophosphate, polyphosphate (polyphosphate), polyphenol, catechin, alpha-tocopherol, rosemary Extract, vitamin C, green tea extract, licorice extract, chitosan, tannic acid, any one or
- the composition when the compound represented by Formula 1 or 2 is used as feed, the composition may be formulated in a conventional feed form, and may include common feed ingredients together.
- the feed additive and feed include grains such as milled or crushed wheat, oats, barley, corn and rice; plant protein feeds, for example feeds based on rape, soybean and sunflower; animal protein feeds such as blood meal, meat meal, bone meal and fish meal; Sugar and dairy products, for example, may further include dry ingredients made of various types of milk powder and whey powder, and in addition, may further include nutritional supplements, digestion and absorption enhancers, growth promoters, and the like.
- the compound represented by Formula 1 or 2 when used as the feed additive, it may be administered to an animal alone or in combination with other feed additives in an edible carrier.
- the feed additives can be easily administered to the animal as a top dressing or directly mixed with the animal feed, or in an oral formulation separate from the feed.
- a pharmaceutically acceptable edible carrier as well known in the art to prepare an immediate release or sustained release formulation.
- Such edible carriers may be solid or liquid, for example corn starch, lactose, sucrose, soy flakes, peanut oil, olive oil, sesame oil and propylene glycol.
- the feed additive may be a tablet, capsule, powder, troche or sugar-containing tablet or top dressing in microdispersed form.
- the feed additive may be in the form of a gelatin soft capsule, or a syrup or suspension, emulsion, or solution.
- the feed may comprise any protein-containing organic flour conventionally used to meet the dietary needs of animals. Such protein-containing flour typically consists of corn, soy flour, or a corn/soy flour mix.
- the feed composition or feed additive composition may contain, for example, a preservative, a stabilizer, a wetting or emulsifying agent, a solution accelerator, and the like.
- the feed additive composition may be used by adding to the animal feed by immersion, spraying, or mixing.
- the definitions of the virus and pharmaceutically acceptable salts overlap with those described above and are omitted below to avoid excessive complexity of the specification.
- the "disinfection” means to lose or kill the activity of a pathogenic microorganism or a pathogenic virus. Losing activity includes inhibiting infection, survival, proliferation, transmission, or a combination thereof of a pathogenic microorganism or pathogenic virus.
- cleaning refers to a method used to facilitate or assist in removing contaminants, bleaching, reducing microbial or viral populations, rinsing, and any combination thereof.
- the "subject” includes all living or non-living objects (devices, devices, clothing, tableware, etc.) or hard surfaces thereof that must prevent virus infection.
- the disinfecting composition or cleaning composition comprising the compound in the present invention is used in hospitals and public health to prevent hospital infection. It can be usefully used as a disinfectant and a cleaning agent, and can be used for disinfection and cleaning of various articles such as general household disinfectants and cleaners, tableware, food cooking equipment, inside buildings, drinking water, vehicles, aircraft, and ships.
- composition of the present invention when used as a disinfecting composition or a cleaning composition, a pharmacologically, veterinarily or agriculturally acceptable carrier or diluent may be included together.
- the compound or composition of the present invention may be prepared in any phase, such as a liquid phase, a solid phase, and a gas phase.
- the compound or composition of the present invention may be applied to the human body itself or to various instruments or devices used by humans, and when applied to the human body, it may be administered in any manner, such as oral or parenteral.
- the compound or composition may be formulated in various forms that can be effectively applied to the human body itself or various instruments or devices, for example, pharmaceutical formulations for oral administration such as tablets, pills, capsules, powders, or sprays. ,Cleaner L gel, liquid, cream, ointment, etc., or a formulation applicable to instruments and devices.
- the "contact" refers to a known disinfection or cleaning agent application method appropriately selected according to the nature of the subject, the surrounding environment, etc., but wiping, dipping, immersion (immersing) or may include the form of spraying, preferably in the form of spraying, but is not limited thereto.
- composition provided in the present invention has a coronavirus inhibitory activity, and can effectively prevent infection or disease caused by coronavirus as well as disinfection or cleaning effect on coronavirus.
- Figure 3 shows the results of confirming the change in the expression level of ACE2 after treating Vero cells with the compound of Formula 2 in Experimental Example 3.
- N-(2-(2-butyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl) represented by the following formula (1) Ethyl)-3-(2-ethyl-1H-imidazol-1-yl)propanamide (N-(2-(2-butyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H) )-yl)ethyl)-3-(2-ethyl-1H-imidazol-1-yl)propanamide) and 4-(imidazo[1,2-b]pyridazin-6-yl) represented by Formula 2 below -N-(3-methoxyphenethyl)piperazine-1-carboxamide(4-(imidazo[1,2-b]pyridazin-6-yl)-N-(3-methoxyphenethyl)piperazine-1-carboxamide ) at least one
- RT-25] (IVD approved) kit was used to quantitatively detect N1, N2 and N3 fragments derived from the nucleocapsid (N) gene, which plays an important role in the proliferation of Sars-CoV-2 virus, through real-time RT assay. .
- the assay was performed at 25° C. for 2 minutes; 15 min at 50 °C; 2 min at 95 °C; 3 seconds at 95 °C; 45 cycles were performed at 55° C. for 30 seconds, and a BioRad CFX96 instrument was used.
- N1, N2 and N3 obtained by amplifying the RNA sample obtained from the Sars-CoV-2 infected Vero cells pretreated with the compound represented by Formula 2 with the obtained kit were analyzed.
- the Cq values of these virus targets (N1, N2, N3) were normalized to an internal control (Delta Ct), and the multiples of the virus targets (N1, N2, N3) were calculated for the vehicle CTR-treated cells, and the result was calculated 1 is shown.
- cells not infected with the Sars-CoV-2 virus and cells treated with the vehicle were used as controls.
- the assay was performed at 25° C. for 2 minutes; 15 min at 50 °C; 2 min at 95 °C; 3 seconds at 95 °C; 45 cycles were performed at 55° C. for 30 seconds, and a BioRad CFX96 instrument was used.
- the amplification plots of N1, N2 and N3 obtained by amplifying the RNA sample obtained from the Sars-CoV-2 infected Vero cells pretreated with the compound represented by Formula 2 with the obtained kit were analyzed.
- the Cq values of these viral targets are shown in Table 3 below, which were normalized to an internal control (Delta Ct), and the viral targets (N1, N2, N3) with respect to vehicle CTR-treated cells Calculate the multiple of , and the results are shown in FIG. 2 . However, cells not infected with the Sars-CoV-2 virus and cells treated with the vehicle were used as controls.
- Vero cells 5.0 X 10 5 cells were treated with 1 mM of the compound of formula 2 for 15 hours, and then anti-ACE antibody (Ab15348) and anti-PMCA antibody (F3) sc-271917 were used for total protein lysate.
- the expression level of ACE2 was determined by immunoblot analysis. The results are shown in FIG. 3 .
- valproic acid was used as a control here.
- the present invention relates to a composition for various uses that can effectively prevent a coronavirus infection or a disease caused by the infection, and a disinfecting or sterilizing composition having inhibitory activity against the coronavirus.
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Abstract
By using the compound represented by chemical formula 1 or 2, the present invention can not only exhibit disinfective or killing effects on coronavirus, but also can effectively prevent coronavirus infection or diseases caused by the infection through the inhibitory activity of the compounds against coronavirus.
Description
본 발명은 PMCA 억제제를 포함하여 코로나바이러스 감염 또는 상기 감염에 의한 질환을 효과적으로 예방할 수 있는 조성물과, 그 외에 소독용 또는 세정용 조성물에 관한 것이다. The present invention relates to a composition that can effectively prevent a coronavirus infection or a disease caused by the infection, including a PMCA inhibitor, and a composition for disinfection or cleaning in addition.
코로나바이러스는 현대 문명에서 치명적인 감염병을 일으키는 대표적인 바이러스로 2003년 4월에는 중증급성호흡기증후군(Severe Acute Respiratory Syndrome; SARS), 일명 사스가 유행해 사망률 9.6%를 기록하며 많은 사람이 사망했으며, 2015년에는 중동 호흡기 증후군(Middle East Respiratory Syndrome; MERS), 일명 메르스가 중동에서 전 세계로 퍼지면서 사망률 약 36%로써 사망자가 다수 발생한 바 있다. 또한, 코로나바이러스감염증-19(Coronavirus disease 19; COVID-19)는 2019년 12월 처음 발생하여 전세계로 확산된 새로운 유형의 코로나바이러스인 중증급성호흡기증후군 코로나바이러스 2(Severe acute respiratory syndrome coronavirus 2; SARS-CoV-2)에 의한 호흡기 감염질환이다. 코로나바이러스감염증-19는 감염자의 비말(침방울)이 호흡기나 눈·코·입의 점막으로 침투될 때 전염된다. 감염되면 약 2~14일(추정)의 잠복기를 거친 뒤 발열(37.5도) 및 기침이나 호흡곤란 등 호흡기 증상, 폐렴이 주증상으로 나타나고 치사율도 2020년 3월까지 집계된 자료에 따르면 5.6%에 달한다. Coronavirus is a representative virus that causes lethal infectious diseases in modern civilization. In April 2003, Severe Acute Respiratory Syndrome (SARS), also known as SARS, broke out and recorded a mortality rate of 9.6%, killing many people. Middle East Respiratory Syndrome (MERS), also known as MERS, spread from the Middle East to the world, resulting in a death rate of about 36%. In addition, Coronavirus disease 19 (COVID-19) is a new type of coronavirus that first occurred in December 2019 and spread worldwide, Severe acute respiratory syndrome coronavirus 2 (SARS). -CoV-2) is a respiratory infection. Coronavirus Infectious Disease-19 is transmitted when droplets (saliva) of an infected person penetrate the respiratory tract or the mucous membranes of the eyes, nose, and mouth. After infection, after an incubation period of about 2 to 14 days (estimated), the main symptoms are fever (37.5 degrees), respiratory symptoms such as cough or shortness of breath, and pneumonia. reach
신변종 바이러스의 유행은 인류에게 크나큰 문제를 야기하고 있으나, 지금까지 코로나바이러스에 대한 치료제 개발이 추진되고 있음에도, 마땅한 예방 및 치료를 위한 조성물은 완성되지 않은 상황이다. 따라서 코로나바이러스 감염 또는 감염 질환을 효과적으로 예방 또는 치료할 수 있는 조성물이 요구된다.The epidemic of new strains of viruses is causing great problems for mankind, but even though the development of therapeutic agents for coronaviruses is being promoted so far, the composition for proper prevention and treatment is not complete. Therefore, there is a need for a composition that can effectively prevent or treat coronavirus infection or infectious disease.
본 발명의 일 목적은 코로나바이러스에 의한 감염 또는 상기 감염에 의해 유발된 다양한 질환을 예방할 수 있는 다양한 용도의 조성물을 제공하자 한다. One object of the present invention is to provide a composition for various uses that can prevent infection by coronavirus or various diseases caused by the infection.
본 발명의 다른 목적은 코로나바이러스에 대한 억제 활성을 갖는 소독용 또는 세정용 조성물을 제공하자 한다. Another object of the present invention is to provide a composition for disinfection or cleaning having inhibitory activity against coronavirus.
그러나, 본 발명이 이루고자 하는 기술적 과제는 이상에서 언급한 과제에 제한되지 않으며, 언급되지 않은 또 다른 과제들은 아래의 기재로부터 당업계에서 통상의 지식을 가진 자에게 명확하게 이해될 수 있을 것이다.However, the technical problem to be achieved by the present invention is not limited to the above-mentioned problems, and other problems not mentioned will be clearly understood by those of ordinary skill in the art from the following description.
이하, 본원에 기재된 다양한 구체예가 도면을 참조로 기재된다. 하기 설명에서, 본 발명의 완전한 이해를 위해서, 다양한 특이적 상세사항, 예컨대, 특이적 형태, 조성물 및 공정 등이 기재되어 있다. 그러나, 특정의 구체예는 이들 특이적 상세 사항 중 하나 이상 없이, 또는 다른 공지된 방법 및 형태와 함께 실행될 수 있다. 다른 예에서, 공지된 공정 및 제조 기술은 본 발명을 불필요하게 모호하게 하지 않게 하기 위해서, 특정의 상세사항으로 기재되지 않는다. "한 가지 구체예" 또는 "구체예"에 대한 본 명세서 전체를 통한 참조는 구체예와 결부되어 기재된 특별한 특징, 형태, 조성 또는 특성이 본 발명의 하나 이상의 구체예에 포함됨을 의미한다. 따라서, 본 명세서 전체에 걸친 다양한 위치에서 표현된 "한 가지 구체예에서" 또는 "구체예"의 상황은 반드시 본 발명의 동일한 구체예를 나타내지는 않는다. 추가로, 특별한 특징, 형태, 조성, 또는 특성은 하나 이상의 구체예에서 어떠한 적합한 방법으로 조합될 수 있다.Hereinafter, various embodiments described herein are described with reference to the drawings. In the following description, various specific details are set forth, such as specific forms, compositions and processes, and the like, for 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 forms. In other instances, well-known processes and manufacturing techniques have not been described in specific detail in order not to unnecessarily obscure the present invention. Reference throughout this specification to “one embodiment” or “an embodiment” means that a particular feature, form, composition, or characteristic described in connection with the embodiment is included in one or more embodiments of the invention. Thus, references to "in one embodiment" or "an embodiment" in various places throughout this specification do not necessarily refer to the same embodiment of the invention. Additionally, the particular features, forms, compositions, or properties may be combined in any suitable way in one or more embodiments.
본 발명 내 특별한 정의가 없으면 본 명세서에 사용된 모든 과학적 및 기술적인 용어는 본 발명이 속하는 기술분야에서 당업자에 의하여 통상적으로 이해되는 것과 동일한 의미를 가진다.Unless specifically defined in the present invention, all scientific and technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
본 발명의 일 구현 예에 따르면, 하기 화학식 1로 표시되는 N-(2-(2-부틸-2,3-디하이드로벤조[f][1,4]옥사제핀-4(5H)-일)에틸)-3-(2-에틸-1H-이미다졸-1-일)프로판아마이드(N-(2-(2-butyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)ethyl)-3-(2-ethyl-1H-imidazol-1-yl)propanamide) 및 하기 화학식 2로 표시되는 4-(이미다조[1,2-b]피리다진-6-일)-N-(3-메톡시페네틸)피페라진-1-카복사마이드(4-(imidazo[1,2-b]pyridazin-6-yl)-N-(3-methoxyphenethyl)piperazine-1-carboxamide) 중 적어도 하나; 또는 이의 약학적으로 허용 가능한 염을 유효 성분으로 포함하는, 바이러스 감염 또는 감염 질환의 예방용 조성물에 관한 것이다.According to an embodiment of the present invention, N-(2-(2-butyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl) represented by the following formula (1) Ethyl)-3-(2-ethyl-1H-imidazol-1-yl)propanamide (N-(2-(2-butyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H) )-yl)ethyl)-3-(2-ethyl-1H-imidazol-1-yl)propanamide) and 4-(imidazo[1,2-b]pyridazin-6-yl) represented by Formula 2 below -N-(3-methoxyphenethyl)piperazine-1-carboxamide(4-(imidazo[1,2-b]pyridazin-6-yl)-N-(3-methoxyphenethyl)piperazine-1-carboxamide ) at least one of; Or it relates to a composition for the prevention of viral infection or infectious disease comprising a pharmaceutically acceptable salt thereof as an active ingredient.
[화학식 1][Formula 1]
[화학식 2][Formula 2]
본 발명의 다른 구현 예에 따르면, 개체에게 상기 화학식 1로 표시되는 N-(2-(2-부틸-2,3-디하이드로벤조[f][1,4]옥사제핀-4(5H)-일)에틸)-3-(2-에틸-1H-이미다졸-1-일)프로판아마이드(N-(2-(2-butyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)ethyl)-3-(2-ethyl-1H-imidazol-1-yl)propanamide) 및 상기 화학식 2로 표시되는 4-(이미다조[1,2-b]피리다진-6-일)-N-(3-메톡시페네틸)피페라진-1-카복사마이드(4-(imidazo[1,2-b]pyridazin-6-yl)-N-(3-methoxyphenethyl)piperazine-1-carboxamide) 중 적어도 하나; 또는 이의 약학적으로 허용 가능한 염을 투여하는 단계를 포함하는, 바이러스 감염 또는 감염 질환의 예방 방법에 관한 것이다.According to another embodiment of the present invention, N- (2- (2-butyl-2,3-dihydrobenzo [f] [1,4] oxazepine-4 (5H) - yl)ethyl)-3-(2-ethyl-1H-imidazol-1-yl)propanamide (N-(2-(2-butyl-2,3-dihydrobenzo[f][1,4]oxazepin-4) (5H)-yl)ethyl)-3-(2-ethyl-1H-imidazol-1-yl)propanamide) and 4-(imidazo[1,2-b]pyridazine-6- yl)-N-(3-methoxyphenethyl)piperazine-1-carboxamide(4-(imidazo[1,2-b]pyridazin-6-yl)-N-(3-methoxyphenethyl)piperazine-1 -carboxamide); Or it relates to a method for preventing a viral infection or infectious disease, comprising administering a pharmaceutically acceptable salt thereof.
본 발명에서 상기 약학적으로 허용되는 염은, 의학적 적용에 적합한 것으로 당업자에 의해 일반적으로 간주되는 염(예를 들어 이러한 염이 상기 염으로 치료될 수 있는 대상체에게 유해하지 않기 때문임), 또는 각각의 치료 내에서 허용 가능한 부작용을 야기하는 염이다. 일반적으로, 상기 약학적으로 허용되는 염은 미국 식품 의약국(FDA), 유럽 의약청(EMA), 또는 일본 후생성의 의약품 의료기기 종합기구(PMDA)와 같은 규제 당국에 의해 허용되는 것으로 간주되는 염이다. 그러나, 본 발명은 원칙적으로, 예를 들어 본 발명에 따른 화합물 또는 그의 생리학적으로 작용성인 유도체의 제조에서의 중간체, 또는 본 발명에 따른 화합물의 약학적으로 허용되는 염 또는 그의 생리학적으로 작용성인 유도체의 제조에서의 중간체로서, 그 자체로는 약학적으로 허용되지 않는 본 발명에 따른 화합물의 염을 또한 포함한다. 상기 염은 수불용성 염을 포함하고, 특히, 수용성 염을 포함한다.In the present invention, the pharmaceutically acceptable salts are salts generally considered by those skilled in the art to be suitable for medical applications (eg, since such salts are not harmful to the subject to be treated with the salts), or each salts that cause acceptable side effects within the treatment of In general, the pharmaceutically acceptable salt is a salt considered acceptable by a regulatory authority such as the U.S. Food and Drug Administration (FDA), the European Medicines Agency (EMA), or the Pharmaceutical and Medical Devices Agency (PMDA) of the Ministry of Health, Labor and Welfare of Japan. . However, the present invention in principle provides an intermediate, for example in the preparation of a compound according to the invention or a physiologically functional derivative thereof, or a pharmaceutically acceptable salt of a compound according to the invention or a physiologically functional derivative thereof Also included as intermediates in the preparation of derivatives are salts of the compounds according to the invention which are not themselves pharmaceutically acceptable. Said salts include water-insoluble salts, particularly water-soluble salts.
각각의 경우에, 당업자는 본 발명에 따른 특정 화합물 또는 그의 생리학적으로 작용성인 유도체가 염을 형성할 수 있는지 여부, 즉, 상기 본 발명에 따른 화합물 또는 그의 생리학적으로 작용성인 유도체가, 예를 들어 아미노 기, 카르복실산 기 등과 같은 전하를 띨 수 있는 기를 가지는지 여부를 쉽게 결정할 수 있다.In each case, the person skilled in the art will know whether a particular compound according to the invention or a physiologically functional derivative thereof is capable of forming salts, ie whether said compound according to the invention or a physiologically functional derivative thereof is, for example, For example, it can be easily determined whether or not a group has a chargeable group such as an amino group, a carboxylic acid group, and the like.
본 발명의 화합물의 예시적인 염은 산 부가 염 또는 염기와의 염, 특히 약학적으로 허용되는 무기산 및 유기산 부가 염 및 약학에서 통상적으로 사용되는 염기와의 염이며, 이는 수불용성 또는 특히 수용성 산 부가 염이다. 본 발명의 화합물의 치환기에 따라 염기와의 염이 또한 적합할 수 있다. 산 부가 염은, 예를 들어, 본 발명의 화합물의 용액을 염산, 황산, 푸마르산, 말레산, 석신산, 아세트산, 벤조산, 시트르산, 타르타르산, 탄산 또는 인산과 같은 약학적으로 허용되는 산의 용액과 혼합함으로써 형성될 수 있다. 마찬가지로, 약학적으로 허용되는 염기 부가 염은 알칼리 금속염(예를 들어, 나트륨 또는 칼륨 염); 알칼리 토금속 염(예를 들어, 칼슘 또는 마그네슘 염); 및 적합한 유기 리간드로 형성된 염(예를 들어, 할라이드, 하이드록사이드, 카복실레이트, 설페이트, 포스페이트, 니트레이트, 알킬 설포네이트 및 아릴 설포네이트와 같은 반대 음이온을 사용하여 형성된 암모늄, 4차 암모늄 및 아민 양이온)을 포함할 수 있다. 약학적으로 허용되는 염의 예시적인 예로는 아세테이트, 아디페이트, 알기네이트, 아르기네이트, 아스코르베이트, 아스파테이트, 벤젠설포네이트, 벤조에이트, 바이카르보네이트, 바이설페이트, 바이타르트레이트, 보레이트, 브로마이드, 부티레이트, 칼슘 에데테이트, 캄포레이트, 캄포설포네이트, 캄실레이트, 카르보네이트, 클로라이드, 시트레이트, 디글루코네이트, 디하이드로클로라이드, 도데실설페이트, 에데테이트, 에디실레이트, 에탄설포네이트, 포르메이트, 푸마레이트, 갈락테이트, 갈락투로네이트, 글루코네이트, 글루타메이트, 글리세로포스페이트, 헤미설페이트, 헵타노에이트, 헥사노에이트, 헥실레소르시네이트, 하이드로브로마이드, 하이드로클로라이드, 하이드로요오다이드, 2-하이드록시-에탄설포네이트, 하이드록시나프토에이트, 요오다이드, 이소부티레이트, 이소티오네이트, 락테이트, 라우레이트, 라우릴 설페이트, 말레이트, 말레에이트, 말로네이트, 만델레이트, 메탄설포네이트(메실레이트), 메틸설페이트, 2-나프탈렌설포네이트, 니코티네이트, 니트레이트, 올레에이트, 옥살레이트, 팔미테이트, 판토테네이트, 펙티네이트, 퍼설페이트, 3-페닐프로피오네이트, 포스페이트/디포스페이트, 프탈레이트, 피크레이트, 피발레이트, 폴리갈락투로네이트, 프로피오네이트, 살리실레이트, 스테아레이트, 설페이트, 수베레이트, 석시네이트, 탄네이트, 타르트레이트, 토실레이트, 운데카노에이트, 발레레이트 등이 포함되지만 이로 한정되지 않는다.Exemplary salts of the compounds of the present invention are acid addition salts or salts with bases, particularly pharmaceutically acceptable inorganic and organic acid addition salts and salts with bases commonly used in pharmaceuticals, which are water-insoluble or particularly water-soluble acid addition salts. is salt Depending on the substituents of the compounds of the present invention, salts with bases may also be suitable. Acid addition salts can be prepared, for example, by combining a solution of a compound of the present invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid. It can be formed by mixing. Likewise, pharmaceutically acceptable base addition salts include alkali metal salts (eg, sodium or potassium salts); alkaline earth metal salts (eg, calcium or magnesium salts); and salts formed with suitable organic ligands (eg, ammonium, quaternary ammonium and amines formed with counter anions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, alkyl sulfonates and aryl sulfonates). cations) may be included. Illustrative examples of pharmaceutically acceptable salts include acetate, adipate, alginate, arginate, ascorbate, aspartate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium edetate, camphorate, camphorsulfonate, camsylate, carbonate, chloride, citrate, digluconate, dihydrochloride, dodecylsulfate, edetate, edisylate, ethanesulfonate, Formate, fumarate, galactate, galacturonate, gluconate, glutamate, glycerophosphate, hemisulphate, heptanoate, hexanoate, hexylresorcinate, hydrobromide, hydrochloride, hydroiodide , 2-hydroxy-ethanesulfonate, hydroxynaphthoate, iodide, isobutyrate, isothionate, lactate, laurate, lauryl sulfate, maleate, maleate, malonate, mandelate, methane Sulfonate (mesylate), methylsulfate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pantothenate, pectinate, persulfate, 3-phenylpropionate, phosphate /diphosphate, phthalate, picrate, pivalate, polygalacturonate, propionate, salicylate, stearate, sulfate, suberate, succinate, tannate, tartrate, tosylate, undecanoate, Valerate and the like are included, but are not limited thereto.
본 발명에서 약학적으로 허용되지 않으며, 예를 들어, 산업적 규모로 본 발명에 따른 화합물을 제조하는 동안 공정 생성물로서 수득될 수 있는 염이 또한 본 발명에 포함되고, 요망되는 경우, 이는 당업자에게 알려진 방법에 의해 약학적으로 허용되는 염으로 전환될 수 있다.Salts which are not pharmaceutically acceptable in the present invention and which, for example, can be obtained as process products during the preparation of the compounds according to the invention on an industrial scale, are also included in the invention and, if desired, are known to the person skilled in the art. It can be converted into a pharmaceutically acceptable salt by a method.
본 발명에서 상기 바이러스는 RNA 바이러스일 수 있다. 본 발명에서, 상기 “RNA 바이러스”는 RNA를 유전물질로 사용하는 모든 바이러스를 의미한다. 예를 들어, 상기 RNA 바이러스는 코로나비리대 (Coronaviridae), 아말가비리대 (Amalgaviridae), 비르나비리대 (Birnaviridae), 크리소비리대 (Chrysoviridae), 시스토비리대 (Cystoviridae), 엔도르나비리대 (Endornaviridae), 하이포비리대 (Hypoviridae), 메가비르나비리대 (Megabirnaviridae), 파르티티비리대 (Partitiviridae), 피코비르나비리대 (Picobirnaviridae), 레오비리대 (Reoviridae), 토티비리대 (Totiviridae), 콰드리비리대 (Quadriviridae), 아르테리비리대 (Arteriviridae), 메소니비리대 (Mesoniviridae), 로니비리대 (Roniviridae), 디시스트로비리대 (Dicistroviridae), 이플라비리대 (Iflaviridae), 마르나비리대 (Marnaviridae), 피코르나비리대 (Picornaviridae), 세코비리대 (Secoviridae), 알파플렉시비리대 (Alphaflexiviridae), 베타플렉시비리대 (Betaflexiviridae), 감마플렉시비리대 (Gammaflexiviridae), 티모비리대 (Tymoviridae), 보르나비리대 (Bornaviridae), 필로비리대 (Filoviridae), 파라믹소비리대 (Paramyxoviridae), 랍도비리대 (Rhabdoviridae), 니아미비리대 (Nyamiviridae), 칼리시비리대 (Caliciviridae), 플라비비리대 (Flaviviridae), 루테오비리대 (Luteoviridae), 토가비리대 (Togaviridae), 뉴모바라대 (Pneumoviridae), 아레나비리대 (Arenaviridae), 델타비리대 (Deltavirus), 또는 오르토믹스비리대 (Orthomyxoviridae) 바이러스일 수 있으나, 바람직하게는 코로나비리대일 수 있으며, 보다 바람직하게는 코로나비리대에 속하는 코로나바이러스일 수 있다. In the present invention, the virus may be an RNA virus. In the present invention, the “RNA virus” refers to any virus using RNA as a genetic material. For example, the RNA virus is Coronaviridae, Amalgaviridae, Birnaviridae, Chrysoviridae, Cystoviridae, Endornaviridae ( Endornaviridae), Hypoviridae, Megabirnaviridae, Partitiviridae, Picobirnaviridae, Reoviridae, Totiviridae, Quadriviridae, Arteriviridae, Mesoniviridae, Roniviridae, Dicistroviridae, Iflaviridae, Marnaviridae Marnaviridae, Picornaviridae, Secoviridae, Alphaflexiviridae, Betaflexiviridae, Gammaflexiviridae, Tymoviridae ), Bornaviridae, Filoviridae, Paramyxoviridae, Rhabdoviridae, Nyamiviridae, Caliciviridae, Placa Flaviviridae, Luteoviridae, Togaviridae, Pneumoviridae, Arenaviridae, Deltavirus, or Orthomyxviridae ( Orthomyxoviridae), but may be a virus, preferably Coronaviridae, and more preferably a nose belonging to Coronaviridae. It could be a navirus.
본 발명에서 상기 "코로나바이러스(Coronavirus)"는 코로나바이러스과(Coronaviridae)의 코로나바이러스아과(Coronavirinae)에 4개의 속(알파, 베타, 감마, 델타)이 있으며, 유전자 크기 27 내지 32kb의 RNA 바이러스로 사람과 동물의 호흡기와 소화기계 감염을 유발하는 것으로 알려져 있다. 주로 점막 전염, 비말 전파로 쉽게 감염되며, 사람은 일반적으로 경미한 호흡기 감염을 일으키지만 드물게 치명적인 감염을 일으키기도 하며, 소와 돼지는 설사, 닭은 호흡기 질환이 발생하기도 한다. 코로나바이러스 중에서 사람을 숙주로 하는 코로나바이러스는 하기 표 1의 분류로 나뉜다(질병관리본부, 2020). 4개의 속 중에서 알파와 베타는 사람과 동물에게 감염이 되며, 감마와 델타는 동물에게만 감염되는 것으로 보고되고 있다.In the present invention, the "coronavirus (Coronavirus)" has four genera (alpha, beta, gamma, delta) in the coronavirus subfamily (Coronavirinae) of the coronaviridae, and is an RNA virus with a gene size of 27 to 32 kb. It is known to cause respiratory and digestive system infections in animals. It is easily transmitted mainly through mucosal transmission and droplet transmission. Humans usually cause mild respiratory infections, but rarely fatal infections. Diarrhea in cattle and pigs, and respiratory diseases in chickens. Among coronaviruses, coronaviruses that have humans as hosts are divided into classifications in Table 1 below (Centers for Disease Control and Prevention, 2020). Among the four genera, alpha and beta infect humans and animals, and gamma and delta are reported to infect only animals.
속(genus)genus | 사람-코로나바이러스person-coronavirus | 사람 외 감염 코로나바이러스non-human coronavirus |
알파 코로나바이러스alpha coronavirus | 229, NL63229, NL63 | 돼지 유행성 설사 바이러스(porcine epidemic diarrhea virus; PEDV), (돼지)전염성 위장염 바이러스 (transmissible gastroenteritis virus; TGEV), 개코로나바이러스(canine coronavirus; CCoV), 고양이 코로나바이러스 (feline coronavirus;FCoV), Miniopterus bat(박쥐) coronavirus1, Miniopterus bat(박쥐) coronavirus HKU8, Rhinolophus bat(박쥐) coronavirus HKU2, Scotophilus bat(박쥐) coronavirus 512porcine epidemic diarrhea virus (PEDV), (porcine) transmissible gastroenteritis virus (TGEV), canine coronavirus (CCoV), feline coronavirus (FCoV), Miniopterus bat ( bat) coronavirus1, Miniopterus bat coronavirus HKU8, Rhinolophus bat coronavirus HKU2, Scotophilus bat coronavirus 512 |
베타 코로나바이러스beta coronavirus | OC43, HKU1, SARS-CoV, SARS-CoV2, MERS-CoVOC43, HKU1, SARS-CoV, SARS-CoV2, MERS-CoV | 돼지 혈구 응집성뇌척수염 바이러스(porcine hemagglutinating encephalomyelitis virus; PHEV), 우코로나바이러스(bovine coronavirus; BCoV), 말코로나바이러스(equine coronavirus; EqCoV), 쥐코로나바이러스(murine coronavirus; MuCoV), Tylonycteris bat(박쥐) coronavirus HKU4, Pipistrellus bat(박쥐) coronavirus HKU5, Rousettus bat(박쥐) coronavirus HKU9porcine hemagglutinating encephalomyelitis virus (PHEV), bovine coronavirus (BCoV), equine coronavirus (EqCoV), murine coronavirus (MuCoV), Tylonycteris bat coronavirus HKU4, Pipistrellus bat (bat) coronavirus HKU5, Rousettus bat (bat) coronavirus HKU9 |
감마 코로나바이러스gamma coronavirus | -- | 새코로나바이러스(Avian coronavirus), 흰색 돌고래(Beluga whale)-코로나바이러스 SW1Avian coronavirus, Beluga whale - coronavirus SW1 |
델타 코로나바이러스delta coronavirus | -- | 제주직박구리(Bulbul)-코로나바이러스 HKU11, 개똥지빠귀(Thrush)-코로나바이러스 HKU12, 킨바라(Munia)-코로나바이러스 HKU13Bulbul-coronavirus HKU11, Thrush-coronavirus HKU12, Kinbara (Munia)-coronavirus HKU13 |
특히, 현재 사람에 감염력이 있는 코로나바이러스로는 하기 표 2의 7종이 존재하며, 감기를 일으키는 유형(229E, OC43, NL63, HKU1)과 중증 폐렴을 일으키는 유형(SARS-CoV, SARS-CoV-2, MERS-CoV)으로 나뉜다. In particular, there are seven types of coronaviruses in Table 2 below that currently infect humans, the types that cause colds (229E, OC43, NL63, HKU1) and the types that cause severe pneumonia (SARS-CoV, SARS-CoV-2) , MERS-CoV).
바이러스명Virus name | 속(Genus)Genus | 숙주(host)host | 증상Symptom |
HCoV-229EHCoV-229E | AlphaAlpha | HumanHuman | 가벼운 호흡기 증상mild respiratory symptoms |
HCoV-NL63HCoV-NL63 | AlphaAlpha | HumanHuman | 가벼운 호흡기 증상mild respiratory symptoms |
SARS-CoVSARS-CoV | BetaBeta | HumanHuman | 심각한 호흡기 증상severe respiratory symptoms |
MERS-CoVMERS-CoV | BetaBeta | HumanHuman | 심각한 호흡기 증상severe respiratory symptoms |
HCoV-OC43HCoV-OC43 | BetaBeta | HumanHuman | 가벼운 호흡기 증상mild respiratory symptoms |
HCoV-HKU1HCoV-HKU1 | BetaBeta | HumanHuman | 폐렴 증상Pneumonia symptoms |
SARS-CoV-2SARS-CoV-2 | BetaBeta | HumanHuman | 가벼운 호흡기 증상 심한 경우 호흡곤란 유발Mild respiratory symptoms Severe cases can cause shortness of breath |
본 발명에서 상기 "베타 코로나바이러스(Beta coronavirus)"는 코로나바이러스아과의 네 속의 코로나바이러스 중 하나로 인수공통 감염증에 해당한다. 베타 코로나바이러스의 예로는 중증 급성 호흡기 증후군 바이러스(Severe Acute Respiratory Syndrome virus; SARS; SARS-CoV), 중증 급성 호흡기 증후군-2 바이러스(Severe Acute Respiratory Syndrome virus-2; SARS-CoV-2), 중동 호흡기 증후군 바이러스(Middle East Respiratory Syndrome virus; MERS; MERS-CoV), 인간 코로나바이러스 OC43(HCoV-OC43) 또는 인간 코로나바이러스 HKU1(HCoV-HKU1) 등이 존재하는 것으로 알려져 있다.In the present invention, the "beta coronavirus" corresponds to a zoonotic infection as one of four genera of coronaviruses in the subfamily Coronavirus. Examples of beta coronaviruses include Severe Acute Respiratory Syndrome virus (SARS; SARS-CoV), Severe Acute Respiratory Syndrome virus-2 (SARS-CoV-2), Middle East Respiratory Syndrome virus (SARS-CoV) Middle East Respiratory Syndrome virus (MERS; MERS-CoV), human coronavirus OC43 (HCoV-OC43), or human coronavirus HKU1 (HCoV-HKU1) are known to exist.
본 발명에서 상기 "중증 급성 호흡기 증후군-2 바이러스(Severe Acute Respiratory Syndrome virus-2; SARS-CoV-2)"는 코로나비리대 패밀리에 속하는 외피로 둘러싸인, 양성-극성 외가닥 RNA 베타 코로나바이러스에 해당한다. 역사적으로 인간을 감염시키는 코로나바이러스는 중증 공통의 감기 바이러스로, hCoV-OC43, HKU 및 229E5 등을 포함한다. SARS-CoV-2 분리체의 서열을 분석하면, 30-kb 게놈은 14개의 오픈 리딩 프레임(open-reading frames; ORFs)을 코딩하는 것으로 알려져 있고, 바이러스 게놈의 3’말단에서 13개의 ORF는 9개의 예측되는 서브-게놈 RNA로부터 발현되며, 이들은 4개의 구조 단백질인, 스파이크(spike; S), 외피(envelope; E), 막(membrane; M) 및 뉴클레오캡시드(nucleocapsid; N)와, 9개의 추정적 부가 요소로부터 발현된다. 여기서, 상기 뉴클레오캡시드 단백질은 N1, N2 및 N3 절편을 포함한다.In the present invention, the "Severe Acute Respiratory Syndrome virus-2 (SARS-CoV-2)" is an enveloped, positive-polar single-stranded RNA beta coronavirus belonging to the Coronaviridae family. . The coronaviruses that historically infect humans are severe common cold viruses, including hCoV-OC43, HKU and 229E5. Sequence analysis of the SARS-CoV-2 isolate showed that the 30-kb genome is known to encode 14 open-reading frames (ORFs), and 13 ORFs at the 3' end of the viral genome are 9 Expressed from canine predicted sub-genomic RNAs, these are four structural proteins, spike (S), envelope (E), membrane (M) and nucleocapsid (N), 9 It is expressed from putative additional elements of the dog. Here, the nucleocapsid protein includes N1, N2 and N3 fragments.
본 발명에서, 상기 코로나바이러스는 자연적으로 또는 인공적으로 돌연변이가 발생한 변이체를 포함한다. In the present invention, the coronavirus includes naturally or artificially mutated variants.
본 발명에서 상기 코로나바이러스에 의한 감염 질환은 코로나바이러스성 장염, 코로나바이러스성 설사, 중증 급성 호흡기 증후군(severe acute respiratory syndrome coronavirus: SARS), 중동 호흡기 증후군(Middle East respiratory syndrome: MERS), 또는 이들의 조합일 수 있으나, 상기 코로나바이러스 감염에 의해 유발될 수 있는 질환이라면 제한없이 포함될 수 있다.In the present invention, the infectious disease caused by the coronavirus is coronavirus enteritis, coronavirus diarrhea, severe acute respiratory syndrome coronavirus (SARS), Middle East respiratory syndrome (MERS), or their It may be a combination, but may be included without limitation as long as it is a disease that can be caused by the coronavirus infection.
본 발명에서, 상기 감염 질환은 상기 바이러스 감염에 기인한 호흡기 질환, 간염, 위장염 또는 뇌염일 수 있다.In the present invention, the infectious disease may be a respiratory disease, hepatitis, gastroenteritis or encephalitis caused by the viral infection.
본 발명에서, 상기 호흡기 질환은 중증급성호흡기증후군(Severe Acute Respiratory Syndrome; SARS)을 유발하는 것일 수 있다. 상기 중증급성호흡증후군은 상기도 또는 하기도 감염을 유발하여 갑작스러운 발열, 기침, 호흡곤란을 일으킬 수 있고, 폐렴으로 진행돼 죽음에 이를 수도 있는 질환이다.In the present invention, the respiratory disease may be one that causes Severe Acute Respiratory Syndrome (SARS). The severe acute respiratory syndrome is a disease that can cause infection of the upper or lower respiratory tract, which can cause sudden fever, cough, and shortness of breath, and can progress to pneumonia and even lead to death.
본 발명의 조성물은 단독으로, 혹은 종전의 항바이러스제를 혼합하여 사용할 수 있고, 혹은 항혈청과 같은 생물학적 제제와 병용하여 사용할 수 있다.The composition of the present invention may be used alone or in combination with conventional antiviral agents, or may be used in combination with biological agents such as antiserum.
본 발명의 조성물은 약학적 조성물, 식품 조성물, 식품 첨가제 조성물, 사료 조성물 또는 사료 첨가제 조성물의 용도로 사용될 수 있으나, 특별히 제한되지는 않는다. The composition of the present invention may 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.
본 발명에서 "예방"은 본 발명의 조성물의 투여로 바이러스의 감염 또는 증식을 진행을 지연시키는 모든 행위를 의미한다. In the present invention, "prevention" means any action that delays the progress of virus infection or proliferation by administration of the composition of the present invention.
본 발명에 있어서, 상기 화합물 또는 약학적 조성물은 캡슐, 정제, 과립, 주사제, 연고제, 분말 또는 음료 형태임을 특징으로 할 수 있으며, 상기 약학적 조성물은 인간을 대상으로 하는 것을 특징으로 할 수 있다. In the present invention, the compound or pharmaceutical composition may be characterized in the form of capsules, tablets, granules, injections, ointments, powders or drinks, and the pharmaceutical composition may be characterized in that it is targeted to humans.
본 발명의 약학적 조성물은 이들로 한정되는 것은 아니지만, 각각 통상의 방법에 따라 산제, 과립제, 캡슐, 정제, 수성 현탁액 등의 경구형 제형, 외용제, 좌제 및 멸균 주사용액의 형태로 제형화하여 사용될 수 있다. 본 발명의 약학적 조성물은 약제적으로 허용 가능한 담체를 포함할 수 있다. 약학적으로 허용되는 담체는 경구 투여 시에는 결합제, 활탁제, 붕해제, 부형제, 가용화제, 분산제, 안정화제, 현탁화제, 색소, 향료 등을 사용할 수 있으며, 주사제의 경우에는 완충제, 보존제, 무통화제, 가용화제, 등장제, 안정화제 등을 혼합하여 사용할 수 있으며, 국소투여용의 경우에는 기제, 부형제, 윤활제, 보존제 등을 사용할 수 있다. 본 발명의 약학적 조성물의 제형은 상술한 바와 같은 약학적으로 허용되는 담체와 혼합하여 다양하게 제조될 수 있다. 예를 들어, 경구 투여시에는 정제, 트로키, 캡슐, 엘릭서(elixir), 서스펜션, 시럽, 웨이퍼 등의 형태로 제조할 수 있으며, 주사제의 경우에는 단위 투약 앰플 또는 다수회 투약 형태로 제조할 수 있다. 기타, 용액, 현탁액, 정제, 캡슐, 서방형 제제 등으로 제형할 수 있다.The pharmaceutical composition of the present invention is not limited thereto, but each can be formulated in the form of oral dosage forms such as powders, granules, capsules, tablets, aqueous suspensions, external preparations, suppositories, and sterile injection solutions according to conventional methods. can 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, colorants, fragrances, etc., in the case of oral administration, and in the case of injections, buffers, preservatives, pain relief A topical agent, solubilizer, isotonic agent, stabilizer, etc. can be mixed and used, and in the case of topical administration, a base, excipient, lubricant, preservative, etc. can be used. The dosage form of the pharmaceutical composition of the present invention can be prepared in various ways by mixing with a pharmaceutically acceptable carrier as described above. For example, in the case of oral administration, it can be prepared in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, etc., and in the case of injections, it can be prepared in the form of unit dose ampoules or multiple doses. there is. In addition, it can be formulated as a solution, suspension, tablet, capsule, sustained release formulation, and the like.
한편, 제제화에 적합한 담체, 부형제 및 희석제의 예로는, 락토즈, 덱스트로즈, 수크로즈, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말디톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로즈, 메틸 셀룰로즈, 미정질 셀룰로즈, 폴리비닐피롤리돈, 물, 메틸하이드록시벤조에이트, 프로필하이드록시벤조에이트, 탈크, 마그네슘 스테아레이트 또는 광물유 등이 사용될 수 있다. 또한, 충진제, 항응집제, 윤활제, 습윤제, 향료, 유화제, 방부제 등을 추가로 포함할 수 있다.Meanwhile, examples of suitable carriers, excipients and diluents 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, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate or mineral oil may be used. In addition, it may further include a filler, an anti-agglomeration agent, a lubricant, a wetting agent, a flavoring agent, an emulsifier, a preservative, and the like.
본 발명에 따른 화합물 또는 약학적 조성물의 투여 경로는 이들로 한정되는 것은 아니지만 구강, 정맥 내, 근육 내, 동맥 내, 골수 내, 경막 내, 심장 내, 경피, 피하, 복강 내, 비강 내, 장관, 국소, 설하 또는 직장이 포함된다. 경구 또는 비경구 투하가 바람직하다. The route of administration of the compound or pharmaceutical composition according to the present invention is, but not limited to, oral, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, intracardiac, transdermal, subcutaneous, intraperitoneal, intranasal, intestinal , topical, sublingual or rectal. Oral or parenteral administration is preferred.
본 발명에서, "비경구"는 피하, 피내, 정맥내, 근육내, 관절내, 활액낭내, 흉골내, 경막내, 병소내 및 두개골내 주사 또는 주입기술을 포함한다. 본 발명의 약학적 조성물은 또한 직장 투여를 위한 좌제의 형태로 투여될 수 있다.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.
본 발명의 화합물 또는 약학적 조성물은 사용된 특정 화합물의 활성, 연령, 체중, 일반적인 건강, 성별, 정식, 투여 시간, 투여 경로, 배출율, 약물 배합 및 예방 또는 치료될 특정 질환의 중증을 포함한 여러 요인에 따라 다양하게 변할 수 있고, 상기 약학적 조성물의 투여량은 환자의 상태, 체중, 질병의 정도, 약물 형태, 투여 경로 및 기간에 따라 다르지만 당업자에 의해 적절하게 선택될 수 있고, 1일 0.0001 내지 50mg/kg 또는 0.001 내지 50mg/kg으로 투여할 수 있다. 투여는 하루에 한번 투여할 수도 있고, 수회 나누어 투여할 수도 있다. 상기 투여량은 어떠한 면으로든 본 발명의 범위를 한정하는 것은 아니다. 본 발명에 따른 의약 조성물은 환제, 당의정, 캡슐, 액제, 겔, 시럽, 슬러리, 현탁제로 제형될 수 있다.The compound or pharmaceutical composition of the present invention may be determined by several factors including the activity of the specific compound used, age, weight, general health, sex, formula, administration time, administration route, excretion rate, drug formulation, and the severity of the specific disease to be prevented or treated. 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 from 0.0001 to 0.0001 per day It may be administered at 50 mg/kg or 0.001 to 50 mg/kg. Administration may be administered once a day, or may be administered in several divided doses. 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 pills, dragees, capsules, solutions, gels, syrups, slurries, and suspensions.
본 발명에서 상기 "개체"란 바이러스 감염 증상이 있거나 의심되어, 바이러스 활성을 억제하는 등으로 바이러스 감염 또는 상기 감염에 기인하여 유발된 질환을 예방이 필요한 대상체로, 상기 바이러스에 이미 감염되었거나 감염될 수 있는 인간을 포함한 모든 동물을 의미한다. In the present invention, the term "individual" means a subject who has or is suspected of having a virus infection and needs to prevent virus infection or a disease caused by the infection by suppressing virus activity, etc., which is already infected or can be infected with the virus means all animals, including humans.
본 발명의 상기 "투여"란, 임의의 적절한 방법으로 개체에게 본 발명의 유효성분을 도입하는 과정을 의미하는 것으로서, 본 발명의 상기 예방 방법에서 투여 방법은 경구 또는 비경구 등의 다양한 경로를 통해 투여될 수 있다.The "administration" of the present invention means the process of introducing the active ingredient of the present invention to an individual by any suitable method, and the administration method in the preventive method of the present invention is through various routes such as oral or parenteral. may be administered.
본 발명의 목적상, 목적하는 개체에 대한 구체적인 약학적 유효량은 달성하고자 하는 반응의 종류와 정도, 경우에 따라 다른 제제가 사용되는지의 여부를 비롯한 구체적 상기 유효성분을 포함하는 조성물, 환자의 연령, 체중, 일반 건강 상태, 성별 및 식이, 투여 시간, 투여 경로 및 상기 유효성분을 포함하는 조성물의 분비율, 치료기간, 구체적 조성물과 함께 사용되거나 동시 사용되는 약물을 비롯한 다양한 인자와 의약 분야에 잘 알려진 유사 인자에 따라 다르게 적용하는 것이 바람직하다.For the purposes of the present invention, a specific pharmaceutically effective amount for a target subject includes the type and extent of the reaction to be achieved, the specific composition comprising the active ingredient, including whether other agents are used in some cases, the age of the patient, Body weight, general health status, sex and diet, administration time, administration route and secretion rate of a composition containing the active ingredient, treatment period, various factors including drugs used or used together with a specific composition and well-known in the pharmaceutical field It is preferable to apply differently depending on similar factors.
본 발명에서 식품 조성물은 각종 식품류, 예를 들어, 음료, 껌, 차, 비타민 복합제, 분말, 과립, 정제, 캡슐, 과자, 떡, 빵 등의 형태로 제조될 수 있다. 또한 상기 식품 조성물의 제조에 필요한 식품 첨가제 조성물로도 이용될 수 있다.In the present invention, the food composition may be prepared in the form of various foods, for example, beverages, gum, tea, vitamin complexes, powders, granules, tablets, capsules, confectionery, rice cakes, bread, and the like. In addition, it may be used as a food additive composition necessary for the preparation of the food composition.
본 발명에서 유효 성분으로 포함되는 상기 화학식 1 또는 2로 표시되는 화합물이 식품 조성물에 포함될 때 그 양은 전체 중량의 0.1 내지 50%의 비율로 첨가할 수 있다. 여기서, 상기 식품 조성물이 음료 형태로 제조되는 경우 지시된 비율로 상기 식품 조성물을 함유하는 것 외에 특별한 제한점은 없으며 통상의 음료와 같이 여러가지 향미제 또는 천연 탄수화물 등을 추가 성분으로서 함유할 수 있다. 즉, 천연 탄수화물로서 포도당 등의 모노사카라이드, 과당 등의 디사카라이드, 슈크로스 등의 및 폴리사카라이드, 덱스트린, 시클로덱스트린 등과 같은 통상적인 당 및 자일리톨, 소르비톨, 에리트리톨 등의 당알콜 등을 포함할 수 있다. 상기 향미제로서는 천연 향미제(타우마틴, 스테비아 추출물(예를 들어 레바우디오시드 A, 글리시르히진등) 및 합성 향미제(사카린, 아스파르탐 등) 등을 들 수 있다.When the compound represented by Formula 1 or 2 included as an active ingredient in the present invention is included in the food composition, the amount may be added in a proportion of 0.1 to 50% of the total weight. Here, when the food composition is prepared in the form of a beverage, there is no particular limitation other than containing the food composition in the indicated ratio, and it may contain various flavoring agents or natural carbohydrates as additional ingredients like a conventional beverage. That is, as natural carbohydrates, monosaccharides such as glucose, disaccharides such as fructose, polysaccharides such as sucrose, and common sugars such as dextrin and cyclodextrin, and sugar alcohols such as xylitol, sorbitol and erythritol are included. can do. Examples of the flavoring agent include natural flavoring agents (taumatin, stevia extract (eg, rebaudioside A, glycyrrhizin, etc.) and synthetic flavoring agents (saccharin, aspartame, etc.).
그 외 본 발명의 식품 조성물 또는 식품 조성물 첨가제는 여러 가지 영양제, 비타민, 광물(전해질), 합성 풍미제 및 천연 풍미제 등의 풍미제, 착색제, 펙트산 및 그의 염, 알긴산 및 그의 염, 유기산, 보호성 콜로이드 증점제, pH 조절제, 안정화제, 방부제, 글리세린, 알콜, 탄산 음료에 사용되는 탄산화제 등을 함유할 수 있다.In addition, the food composition or food composition additive of the present invention includes various nutrients, vitamins, minerals (electrolytes), synthetic flavors and natural flavors such as flavoring agents, coloring agents, pectic acid and its salts, alginic acid and its salts, organic acids, protective colloidal thickeners, pH adjusting agents, stabilizers, preservatives, glycerin, alcohols, carbonation agents used in carbonated beverages, and the like.
이러한 성분은 독립적으로 또는 조합하여 사용할 수 있다. 이러한 첨가제의 비율은 그렇게 중요하진 않지만 본 발명의 식품 조성물 100 중량부 당 0.1 내지 약 50 중량부의 범위에서 선택되는 것이 일반적이다.These components may be used independently or in combination. The proportion of these additives is not so important, but is generally selected in the range of 0.1 to about 50 parts by weight per 100 parts by weight of the food composition of the present invention.
본 발명의 상기 화학식 1 또는 2로 표시되는 화합물이 사료 조성물 또는 사료 첨가제 조성물에 함유되어 이용될 경우, 상기 조성물은 20 내지 90% 고농축액이거나 분말 또는 과립형태로 제조될 수 있다. 상기 사료 첨가제는 구연산, 후말산, 아디픽산, 젖산, 사과산 등의 유기산이나 인산나트륨, 인산칼륨, 산성 피로인산염, 폴리인산염(중합인산염) 등의 인산염이나, 폴리페놀, 카테킨, 알파-토코페롤, 로즈마리 추출물, 비타민 C, 녹차 추출물, 감초 추출물, 키토산, 탄닌산, 피틴산 등의 천연 항산화제 중 어느 하나 또는 하나 이상을 추가로 포함할 수 있다. When the compound represented by Formula 1 or 2 of the present invention is contained in a feed composition or feed additive composition, the composition may be 20 to 90% highly concentrated or may be prepared in powder or granular form. The feed additive is an organic acid such as citric acid, humic acid, adipic acid, lactic acid, malic acid, or phosphate such as sodium phosphate, potassium phosphate, acid pyrophosphate, polyphosphate (polyphosphate), polyphenol, catechin, alpha-tocopherol, rosemary Extract, vitamin C, green tea extract, licorice extract, chitosan, tannic acid, any one or more of natural antioxidants such as phytic acid may be further included.
본 발명에서, 상기 화학식 1 또는 2로 표시되는 화합물이 사료로 이용될 경우, 상기 조성물은 통상의 사료 형태로 제제화될 수 있으며, 통상의 사료 성분을 함께 포함할 수 있다. 상기 사료 첨가제 및 사료는 곡물, 예를 들면 분쇄 또는 파쇄된 밀, 귀리, 보리, 옥수수 및 쌀; 식물성 단백질 사료, 예를 들면 평지, 콩 및 해바라기를 주성분으로 하는 사료; 동물성 단백질 사료, 예를 들면 혈분, 육분, 골분 및 생선분; 당분 및 유제품, 예를 들면 각종 분유 및 유장 분말로 이루어지는 건조 성분 등을 더 포함할 수 있으며, 이외에도 영양 보충제, 소화 및 흡수 향상제, 성장 촉진제 등을 더 포함할 수 있다. In the present invention, when the compound represented by Formula 1 or 2 is used as feed, the composition may be formulated in a conventional feed form, and may include common feed ingredients together. The feed additive and feed include grains such as milled or crushed wheat, oats, barley, corn and rice; plant protein feeds, for example feeds based on rape, soybean and sunflower; animal protein feeds such as blood meal, meat meal, bone meal and fish meal; Sugar and dairy products, for example, may further include dry ingredients made of various types of milk powder and whey powder, and in addition, may further include nutritional supplements, digestion and absorption enhancers, growth promoters, and the like.
본 발명에서, 상기 화학식 1 또는 2로 표시되는 화합물이 상기 사료 첨가제로 사용될 경우에는 동물에게 단독으로 투여하거나 식용 담체 중에서 다른 사료 첨가제와 조합하여 투여할 수도 있다. 또한, 상기 사료 첨가제는 탑 드레싱으로서 또는 이들을 동물 사료에 직접 혼합하거나 또는 사료와 별도의 경구 제형으로 용이하게 동물에게 투여할 수 있다. 상기 사료 첨가제를 동물 사료와 별도로 투여할 경우, 당해 기술분야에 잘 알려진 바와 같이 약제학적으로 허용 가능한 식용 담체와 조합하여, 즉시 방출 또는 서방성 제형으로 제조할 수 있다. 이러한 식용 담체는 고체 또는 액체, 예를 들어 옥수수 전분, 락토오스, 수크로오스, 콩 플레이크, 땅콩유, 올리브유, 참깨유 및 프로필렌글리콜일 수 있다. 고체 담체가 사용될 경우, 사료 첨가제는 정제, 캡슐제, 산제, 트로키제 또는 함당정제 또는 미분산성 형태의 탑 드레싱일 수 있다. 액체 담체가 사용될 경우, 사료 첨가제는 젤라틴 연질 캡슐제, 또는 시럽제나 현탁액, 에멀젼제, 또는 용액제의 제형일 수 있다. 상기 사료는 동물의 식이 욕구를 충족시키는데 통상적으로 사용되는 임의의 단백질-함유 유기 곡분을 포함할 수 있다. 이러한 단백질-함유 곡분은 통상적으로 옥수수, 콩 곡분, 또는 옥수수/콩 곡분 믹스로 구성되어 있다. 또한 사료 조성물 또는 사료 첨가제 조성물은 예를 들어 보존제, 안정화제, 습윤제 또는 유화제, 용액 촉진제 등을 함유할 수 있다. 또한 사료 첨가제 조성물은 침지, 분무 또는 혼합하여 동물의 사료에 첨가하여 이용될 수 있다.In the present invention, when the compound represented by Formula 1 or 2 is used as the feed additive, it may be administered to an animal alone or in combination with other feed additives in an edible carrier. In addition, the feed additives can be easily administered to the animal as a top dressing or directly mixed with the animal feed, or in an oral formulation separate from the feed. When the feed additive is administered separately from the animal feed, it may be combined with a pharmaceutically acceptable edible carrier as well known in the art to prepare an immediate release or sustained release formulation. Such edible carriers may be solid or liquid, for example corn starch, lactose, sucrose, soy flakes, peanut oil, olive oil, sesame oil and propylene glycol. When a solid carrier is used, the feed additive may be a tablet, capsule, powder, troche or sugar-containing tablet or top dressing in microdispersed form. When a liquid carrier is used, the feed additive may be in the form of a gelatin soft capsule, or a syrup or suspension, emulsion, or solution. The feed may comprise any protein-containing organic flour conventionally used to meet the dietary needs of animals. Such protein-containing flour typically consists of corn, soy flour, or a corn/soy flour mix. In addition, the feed composition or feed additive composition may contain, for example, a preservative, a stabilizer, a wetting or emulsifying agent, a solution accelerator, and the like. In addition, the feed additive composition may be used by adding to the animal feed by immersion, spraying, or mixing.
본 발명의 또 다른 구현 예에 따르면, 상기 화학식 1로 표시되는 N-(2-(2-부틸-2,3-디하이드로벤조[f][1,4]옥사제핀-4(5H)-일)에틸)-3-(2-에틸-1H-이미다졸-1-일)프로판아마이드(N-(2-(2-butyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)ethyl)-3-(2-ethyl-1H-imidazol-1-yl)propanamide) 및 상기 화학식 2로 표시되는 4-(이미다조[1,2-b]피리다진-6-일)-N-(3-메톡시페네틸)피페라진-1-카복사마이드(4-(imidazo[1,2-b]pyridazin-6-yl)-N-(3-methoxyphenethyl)piperazine-1-carboxamide) 중 적어도 하나; 또는 이의 약학적으로 허용 가능한 염을 유효 성분으로 포함하는, 바이러스에 대한 억제 활성을 갖는 소독용 또는 세정용 조성물에 관한 것이다.According to another embodiment of the present invention, N-(2-(2-butyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl represented by Formula 1) )ethyl)-3-(2-ethyl-1H-imidazol-1-yl)propanamide (N-(2-(2-butyl-2,3-dihydrobenzo[f][1,4]oxazepin-4( 5H)-yl)ethyl)-3-(2-ethyl-1H-imidazol-1-yl)propanamide) and 4-(imidazo[1,2-b]pyridazin-6-yl represented by Formula 2) )-N-(3-methoxyphenethyl)piperazine-1-carboxamide(4-(imidazo[1,2-b]pyridazin-6-yl)-N-(3-methoxyphenethyl)piperazine-1- carboxamide); Or it relates to a composition for disinfection or cleaning having inhibitory activity against viruses, comprising as an active ingredient a pharmaceutically acceptable salt thereof.
본 발명의 또 다른 구현 예에 따르면, 대상체에 상기 화학식 1로 표시되는 N-(2-(2-부틸-2,3-디하이드로벤조[f][1,4]옥사제핀-4(5H)-일)에틸)-3-(2-에틸-1H-이미다졸-1-일)프로판아마이드(N-(2-(2-butyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)ethyl)-3-(2-ethyl-1H-imidazol-1-yl)propanamide) 및 상기 화학식 2로 표시되는 4-(이미다조[1,2-b]피리다진-6-일)-N-(3-메톡시페네틸)피페라진-1-카복사마이드(4-(imidazo[1,2-b]pyridazin-6-yl)-N-(3-methoxyphenethyl)piperazine-1-carboxamide) 중 적어도 하나; 또는 이의 약학적으로 허용 가능한 염을 접촉시키는 단계를 포함하는, 바이러스에 대한 소독 또는 세정 방법에 관한 것이다.According to another embodiment of the present invention, N-(2-(2-butyl-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H) represented by Formula 1 above in the subject) -yl)ethyl)-3-(2-ethyl-1H-imidazol-1-yl)propanamide (N-(2-(2-butyl-2,3-dihydrobenzo[f][1,4]oxazepin- 4(5H)-yl)ethyl)-3-(2-ethyl-1H-imidazol-1-yl)propanamide) and 4-(imidazo[1,2-b]pyridazine-6 represented by Formula 2) -yl)-N-(3-methoxyphenethyl)piperazine-1-carboxamide(4-(imidazo[1,2-b]pyridazin-6-yl)-N-(3-methoxyphenethyl)piperazine- 1-carboxamide); Or it relates to a disinfection or cleaning method for a virus, comprising the step of contacting a pharmaceutically acceptable salt thereof.
본 발명에서 상기 바이러스 및 약학적으로 허용 가능한 염에 대한 정의는 앞서 기재된 바와 중복되어 명세서의 과도한 복잡을 방지하기 위하여 이하 생략한다.In the present invention, the definitions of the virus and pharmaceutically acceptable salts overlap with those described above and are omitted below to avoid excessive complexity of the specification.
본 발명에서 상기 "소독(disinfection)"은 병원 미생물 또는 병원 바이러스의 활성을 잃게 하거나 죽이는 것을 의미한다. 활성을 잃게 하는 것은 병원 미생물 또는 병원 바이러스의 감염, 생존, 증식, 전파, 또는 이들의 조합을 저해하는 것을 포함한다.In the present invention, the "disinfection" means to lose or kill the activity of a pathogenic microorganism or a pathogenic virus. Losing activity includes inhibiting infection, survival, proliferation, transmission, or a combination thereof of a pathogenic microorganism or pathogenic virus.
본 발명에서 상기 "세정"은 오염물 제거, 표백, 미생물 또는 바이러스 집단 감소, 헹굼 및 임의의 이들의 조합을 용이하게 하거나 돕는 데 사용되는 방법을 지칭한다.As used herein, "cleaning" refers to a method used to facilitate or assist in removing contaminants, bleaching, reducing microbial or viral populations, rinsing, and any combination thereof.
본 발명에서 상기 "대상체"는 바이러스의 감염을 저지하여야 하는 생물체 또는 비생물체(기구, 장치, 의류,식기 등) 또는 이들의 경질 표면을 모두 포함한다. In the present invention, the "subject" includes all living or non-living objects (devices, devices, clothing, tableware, etc.) or hard surfaces thereof that must prevent virus infection.
본 발명의 상기 화학식 1 또는 2로 표시되는 화합물은 바이러스에 특이적 사멸능을 가지므로, 본 발명에서의 상기 화합물을 포함하는 소독용 조성물 또는 세정용 조성물은 병원 감염을 막기 위한 병원 및 보건용의 소독제 및 세정제로 유용하게 사용될 수 있고 일반 생활 소독제 및 세정제, 식기, 식품 조리 설비, 건물 내부, 음수, 차량, 항공기 및 선박 등의 각종 용품의 소독 및 세정 등에 사용될 수 있다.Since the compound represented by Chemical Formula 1 or 2 of the present invention has a specific killing ability against viruses, the disinfecting composition or cleaning composition comprising the compound in the present invention is used in hospitals and public health to prevent hospital infection. It can be usefully used as a disinfectant and a cleaning agent, and can be used for disinfection and cleaning of various articles such as general household disinfectants and cleaners, tableware, food cooking equipment, inside buildings, drinking water, vehicles, aircraft, and ships.
본 발명의 조성물을 소독용 조성물 또는 세정용 조성물로 사용되는 경우, 약리학적, 수의학적 또는 농학적으로 허용 가능한 담체 또는 희석제를 함께 포함할 수 있음은 물론이다.Of course, when the composition of the present invention is used as a disinfecting composition or a cleaning composition, a pharmacologically, veterinarily or agriculturally acceptable carrier or diluent may be included together.
또한, 본 발명의 화합물 또는 조성물은 액체상,고체상 및 기체상 등 임의의 상으로 제조될 수 있다.In addition, the compound or composition of the present invention may be prepared in any phase, such as a liquid phase, a solid phase, and a gas phase.
본 발명의 상기 화합물 또는 조성물은 인체 자체 또는 인간이 사용하는 각종 기구나 장치에 적용될 수 있으며,인체에 적용되는 경우 경구, 비경구 등 임의의 방식으로 투여될 수 있다. 또한, 상기 화합물 또는 조성물은 인체 자체 또는 각종 기구나 장치에 효과적으로 적용될 수 있는 다양한 형태로 제형화 될 수 있으며,예로서, 정제, 환제,캡술제, 분체제제 등과 같은 경구 투여용 약학 제형, 또는 분무제,세정거 L 겔제, 액제,크림제,연고제 등과 같은 외용제 또는 기구 및 장치에 적용 가능한 제형을 들 수 있다. The compound or composition of the present invention may be applied to the human body itself or to various instruments or devices used by humans, and when applied to the human body, it may be administered in any manner, such as oral or parenteral. In addition, the compound or composition may be formulated in various forms that can be effectively applied to the human body itself or various instruments or devices, for example, pharmaceutical formulations for oral administration such as tablets, pills, capsules, powders, or sprays. ,Cleaner L gel, liquid, cream, ointment, etc., or a formulation applicable to instruments and devices.
본 발명에서 상기 화합물 또는 조성물을 대상체에 적용하는 방법으로 상기 "접촉"은 공지의 소독 또는 세정제 적용 방법을 대상체의 성질,주변 환경 등에 따라 적절히 선택하되, 닦음질(wiping), 침액(dipping), 침지(immersing) 또는 분무의 형태를 포함할 수 있으며, 바람직하게는 분무의 형태일 수 있으나, 이에 제한되는 것은 아니다.In the present invention, as a method of applying the compound or composition to a subject, the "contact" refers to a known disinfection or cleaning agent application method appropriately selected according to the nature of the subject, the surrounding environment, etc., but wiping, dipping, immersion (immersing) or may include the form of spraying, preferably in the form of spraying, but is not limited thereto.
본 발명에서 제공하는 조성물은 코로나바이러스 억제 활성을 가져, 코로나바이러스에 대한 소독 또는 세정 효과뿐만 아니라, 코로나바이러스에 의한 감염 또는 상기 감염에 의한 질환을 효과적으로 예방할 수 있다. The composition provided in the present invention has a coronavirus inhibitory activity, and can effectively prevent infection or disease caused by coronavirus as well as disinfection or cleaning effect on coronavirus.
도 1은 실험예 1에서 화학식 2의 화합물로 처리된 베로 세포를 Sars-CoV-2 바이러스로 감염시킨 뒤 N1, N2 및 N3 유전자의 발현 수준의 변화를 확인한 결과를 그래프로 나타낸 것이다. 1 is a graph showing the results of confirming the change in the expression level of the N1, N2 and N3 gene after infecting Vero cells treated with the compound of Formula 2 in Experimental Example 1 with Sars-CoV-2 virus.
도 2는 실험예 2에서 베로 세포를 Sars-CoV-2 바이러스로 감염시킨 뒤 화학식 1의 화합물 및 화학식 2의 화합물로 처리한 후 N1, N2 및 N3 유전자의 발현 수준의 변화를 확인한 결과를 그래프로 나타낸 것이다. 2 is a graph showing the results of confirming the change in the expression level of the N1, N2 and N3 genes after the Vero cells were infected with the Sars-CoV-2 virus in Experimental Example 2 and treated with the compound of Formula 1 and the compound of Formula 2; it has been shown
도 3은 실험예 3에서 베로 세포에 화학식 2의 화합물로 처리한 후 ACE2의 발현 수준의 변화를 확인한 결과를 나타낸 것이다. Figure 3 shows the results of confirming the change in the expression level of ACE2 after treating Vero cells with the compound of Formula 2 in Experimental Example 3.
본 발명의 일 구현 예에 따르면, 하기 화학식 1로 표시되는 N-(2-(2-부틸-2,3-디하이드로벤조[f][1,4]옥사제핀-4(5H)-일)에틸)-3-(2-에틸-1H-이미다졸-1-일)프로판아마이드(N-(2-(2-butyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)ethyl)-3-(2-ethyl-1H-imidazol-1-yl)propanamide) 및 하기 화학식 2로 표시되는 4-(이미다조[1,2-b]피리다진-6-일)-N-(3-메톡시페네틸)피페라진-1-카복사마이드(4-(imidazo[1,2-b]pyridazin-6-yl)-N-(3-methoxyphenethyl)piperazine-1-carboxamide) 중 적어도 하나; 또는 이의 약학적으로 허용 가능한 염을 유효 성분으로 포함하는, 바이러스 감염 또는 감염 질환의 예방용 조성물에 관한 것이다.According to an embodiment of the present invention, N-(2-(2-butyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl) represented by the following formula (1) Ethyl)-3-(2-ethyl-1H-imidazol-1-yl)propanamide (N-(2-(2-butyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H) )-yl)ethyl)-3-(2-ethyl-1H-imidazol-1-yl)propanamide) and 4-(imidazo[1,2-b]pyridazin-6-yl) represented by Formula 2 below -N-(3-methoxyphenethyl)piperazine-1-carboxamide(4-(imidazo[1,2-b]pyridazin-6-yl)-N-(3-methoxyphenethyl)piperazine-1-carboxamide ) at least one of; Or it relates to a composition for the prevention of viral infection or infectious disease comprising a pharmaceutically acceptable salt thereof as an active ingredient.
[화학식 1][Formula 1]
[화학식 2][Formula 2]
본 발명의 다른 구현 예에 따르면, 상기 화학식 1로 표시되는 N-(2-(2-부틸-2,3-디하이드로벤조[f][1,4]옥사제핀-4(5H)-일)에틸)-3-(2-에틸-1H-이미다졸-1-일)프로판아마이드(N-(2-(2-butyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)ethyl)-3-(2-ethyl-1H-imidazol-1-yl)propanamide) 및 상기 화학식 2로 표시되는 4-(이미다조[1,2-b]피리다진-6-일)-N-(3-메톡시페네틸)피페라진-1-카복사마이드(4-(imidazo[1,2-b]pyridazin-6-yl)-N-(3-methoxyphenethyl)piperazine-1-carboxamide) 중 적어도 하나; 또는 이의 약학적으로 허용 가능한 염을 유효 성분으로 포함하는, 바이러스에 대한 억제 활성을 갖는 소독용 또는 세정용 조성물에 관한 것이다.According to another embodiment of the present invention, N-(2-(2-butyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl) represented by Formula 1 above Ethyl)-3-(2-ethyl-1H-imidazol-1-yl)propanamide (N-(2-(2-butyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H) )-yl)ethyl)-3-(2-ethyl-1H-imidazol-1-yl)propanamide) and 4-(imidazo[1,2-b]pyridazin-6-yl) represented by Formula 2 above -N-(3-methoxyphenethyl)piperazine-1-carboxamide(4-(imidazo[1,2-b]pyridazin-6-yl)-N-(3-methoxyphenethyl)piperazine-1-carboxamide ) at least one of; Or it relates to a composition for disinfection or cleaning having inhibitory activity against viruses, comprising as an active ingredient a pharmaceutically acceptable salt thereof.
이하, 본 발명을 하기의 실시예에 의해 상세히 설명한다. 단, 하기 실시예는 본 발명을 예시하는 것일 뿐, 본 발명의 내용이 하기 실시예에 의해 한정되는 것은 아니다. Hereinafter, the present invention will be described in detail with reference to the following examples. However, the following examples are only illustrative of the present invention, and the content of the present invention is not limited by the following examples.
실시예Example
[준비예 1 및 2] 화합물의 준비[Preparation Examples 1 and 2] Preparation of compounds
하기 화학식 1로 표시되는 N-(2-(2-부틸-2,3-디하이드로벤조[f][1,4]옥사제핀-4(5H)-일)에틸)-3-(2-에틸-1H-이미다졸-1-일)프로판아마이드(N-(2-(2-butyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)ethyl)-3-(2-ethyl-1H-imidazol-1-yl)propanamide)와, 하기 화학식 2로 표시되는 4-(이미다조[1,2-b]피리다진-6-일)-N-(3-메톡시페네틸)피페라진-1-카복사마이드(4-(imidazo[1,2-b]pyridazin-6-yl)-N-(3-methoxyphenethyl)piperazine-1-carboxamide)의 화합물을 준비하였다:N-(2-(2-butyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)ethyl)-3-(2-ethyl) represented by the following formula (1) -1H-imidazol-1-yl)propanamide (N-(2-(2-butyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)ethyl)-3- (2-ethyl-1H-imidazol-1-yl)propanamide) and 4-(imidazo[1,2-b]pyridazin-6-yl)-N-(3-methoxy A compound of phenethyl)piperazine-1-carboxamide (4-(imidazo[1,2-b]pyridazin-6-yl)-N-(3-methoxyphenethyl)piperazine-1-carboxamide) was prepared:
[화학식 1][Formula 1]
[화학식 2][Formula 2]
[실험예 1] 화합물의 코로나바이러스 억제 효과(1)[Experimental Example 1] Coronavirus inhibitory effect of the compound (1)
베로(Vero) 세포와 COVID19 양성 환자에 사용된 동결된 스왑으로부터 얻어진 Sars-CoV-2 바이러스 입자를 이용하여 코로나바이러스 감염의 예방 효과를 확인하였다. 구체적으로는 베로 세포 6.0 X 105 세포에 화학식 2로 표시되는 화합물(PMCA inhibitor #8) 1 mM을 처리한 뒤 20분이 경과하였을 때, COVID19 양성 환자에 사용된 동결된 스왑으로부터 얻어진 Sars-CoV-2 바이러스 입자를 0.01 MOI로 세포에 감염시켰다. 감염 후 12시간이 경과하였을 때, 베로 세포를 용혈시킨 뒤 RNA를 추출하였다. 이후 "CLONIT quanty COVID-19" [Ref. RT-25](IVD approved) 키트를 사용하여 실시간 RT 어쎄이를 통해 Sars-CoV-2 바이러스의 증식에 중요한 역할을 하는 뉴클레오캡시드(N) 유전자 유래의 N1, N2 및 N3 절편을 정량적으로 검출하였다. 상기 어쎄이는 25 ℃에서 2분; 50 ℃에서 15분; 95 ℃에서 2분; 95 ℃에서 3초; 55 ℃에서 30초의 조건으로 45회 사이클 수행하였고, BioRad CFX96 기기를 사용하였다. 이처럼 화학식 2로 표시되는 화합물로 전처리된, Sars-CoV-2 감염 베로 세포로부터 얻어진 RNA 시료를 상기 얻어진 키트로 증폭하여 얻어진 N1, N2 및 N3의 증폭 플롯을 분석하였다. 여기서 이들 바이러스 타겟(N1, N2, N3)의 Cq 값은 내부 대조군(Delta Ct)로 정규화 하였고, 비히클 CTR 처리된 세포에 대하여 상기 바이러스 타겟(N1, N2, N3)의 배수를 계산하여 그 결과를 도 1에 나타내었다. 단, Sars-CoV-2 바이러스에 의해 감염되지 않은 세포와 감염된 세포에 비히클을 처리한 경우를 대조군으로 사용하였다.The preventive effect of coronavirus infection was confirmed using Sars-CoV-2 virus particles obtained from Vero cells and frozen swabs used in COVID19-positive patients. Specifically, when Vero cells 6.0 X 10 5 cells were treated with 1 mM of the compound represented by Formula 2 (PMCA inhibitor #8), 20 minutes elapsed, Sars-CoV- obtained from frozen swabs used in COVID19-positive patients 2 Virus particles were infected into cells at an MOI of 0.01. 12 hours after infection, Vero cells were lysed and RNA was extracted. Since "CLONIT quantitative COVID-19" [Ref. RT-25] (IVD approved) kit was used to quantitatively detect N1, N2 and N3 fragments derived from the nucleocapsid (N) gene, which plays an important role in the proliferation of Sars-CoV-2 virus, through real-time RT assay. . The assay was performed at 25° C. for 2 minutes; 15 min at 50 °C; 2 min at 95 °C; 3 seconds at 95 °C; 45 cycles were performed at 55° C. for 30 seconds, and a BioRad CFX96 instrument was used. As such, the amplification plots of N1, N2 and N3 obtained by amplifying the RNA sample obtained from the Sars-CoV-2 infected Vero cells pretreated with the compound represented by Formula 2 with the obtained kit were analyzed. Here, the Cq values of these virus targets (N1, N2, N3) were normalized to an internal control (Delta Ct), and the multiples of the virus targets (N1, N2, N3) were calculated for the vehicle CTR-treated cells, and the result was calculated 1 is shown. However, cells not infected with the Sars-CoV-2 virus and cells treated with the vehicle were used as controls.
도 1에서 보는 바와 같이, 화학식 2로 표시되는 화합물로 전처리된 베로 세포에 Sars-CoV-2를 감염시킨 결과, 대조군에 비하여 N1, N2 및 N3 유전자 절편의 발현 수준이 현저히 감소하였고, 특히 Sars-CoV-2 비감염 세포의 수준으로 감소한 것을 확인할 수 있었다. As shown in FIG. 1 , as a result of infecting Vero cells pretreated with the compound represented by Formula 2 with Sars-CoV-2, the expression levels of N1, N2, and N3 gene segments were significantly reduced compared to the control group, particularly Sars- It was confirmed that it was reduced to the level of CoV-2 non-infected cells.
[실험예 2] 화합물의 코로나바이러스 억제 효과(2)[Experimental Example 2] Coronavirus inhibitory effect of the compound (2)
24 멀티웰에 베로 세포를 8.5 X 104 세포로 분주한 뒤, COVID19 양성 환자에 사용된 동결된 스왑으로부터 얻어진 Sars-CoV-2 바이러스 입자를 0.09 MOI로 세포에 감염시켰다. 24시간 경과 후 화학식 1로 표시되는 화합물(PMCA inhibitor #7) 또는 화학식 2로 표시되는 화합물(PMCA inhibitor #8)을 1 mM의 양으로 처리하였다. 처리 후 24시간 경과하였을 때 베로 세포를 용혈시킨 뒤 RNA를 추출하였다. 이후 "CLONIT quanty COVID-19" [Ref. RT-25](IVD approved) 키트를 사용하여 실시간 RT 어쎄이를 통해 Sars-CoV-2 뉴클레오캡시드(N) 유전자 유래의 N1, N2 및 N3 절편을 정량적으로 검출하였다. 상기 어쎄이는 25 ℃에서 2분; 50 ℃에서 15분; 95 ℃에서 2분; 95 ℃에서 3초; 55 ℃에서 30초의 조건으로 45회 사이클 수행하였고, BioRad CFX96 기기를 사용하였다. 이처럼 화학식 2로 표시되는 화합물로 전처리된, Sars-CoV-2 감염 베로 세포로부터 얻어진 RNA 시료를 상기 얻어진 키트로 증폭하여 얻어진 N1, N2 및 N3의 증폭 플롯을 분석하였다. 여기서 이들 바이러스 타겟(N1, N2, N3)의 Cq 값을 하기 표 3에 나타내었고, 이를 내부 대조군(Delta Ct)로 정규화 하였으며, 비히클 CTR 처리된 세포에 대하여 상기 바이러스 타겟(N1, N2, N3)의 배수를 계산하여 그 결과를 도 2에 나타내었다. 단, Sars-CoV-2 바이러스에 의해 감염되지 않은 세포와 감염된 세포에 비히클을 처리한 경우를 대조군으로 사용하였다.After dividing Vero cells into 8.5 X 10 4 cells in 24 multiwells, Sars-CoV-2 virus particles obtained from frozen swabs used in COVID19-positive patients were infected with the cells at MOI of 0.09. After 24 hours, the compound represented by Formula 1 (PMCA inhibitor #7) or the compound represented by Formula 2 (PMCA inhibitor #8) was treated in an amount of 1 mM. After 24 hours of treatment, Vero cells were lysed and RNA was extracted. Since "CLONIT quantitative COVID-19" [Ref. RT-25] (IVD approved) kit was used to quantitatively detect N1, N2 and N3 fragments derived from the Sars-CoV-2 nucleocapsid (N) gene through real-time RT assay. The assay was performed at 25° C. for 2 minutes; 15 min at 50 °C; 2 min at 95 °C; 3 seconds at 95 °C; 45 cycles were performed at 55° C. for 30 seconds, and a BioRad CFX96 instrument was used. As such, the amplification plots of N1, N2 and N3 obtained by amplifying the RNA sample obtained from the Sars-CoV-2 infected Vero cells pretreated with the compound represented by Formula 2 with the obtained kit were analyzed. Here, the Cq values of these viral targets (N1, N2, N3) are shown in Table 3 below, which were normalized to an internal control (Delta Ct), and the viral targets (N1, N2, N3) with respect to vehicle CTR-treated cells Calculate the multiple of , and the results are shown in FIG. 2 . However, cells not infected with the Sars-CoV-2 virus and cells treated with the vehicle were used as controls.
시료sample | 타겟target | Cq(평균)Cq (average) |
비감염된 베로 세포Uninfected Vero cells | N1N1 | 25.7249972425.72499724 |
N2N2 | 25.6886650225.68866502 | |
N3N3 | 25.6385761525.63857615 | |
INT CTRINT CTR | 23.8103934423.81039344 | |
비히클 CTR 처리된 Sars-CoV-2 바이러스 감염 베로 세포Sars-CoV-2 virus-infected Vero cells treated with vehicle CTR | N1N1 | 9.8272834889.827283488 |
N2N2 | 5.7281777845.728177784 | |
N3N3 | 5.8003942625.800394262 | |
INT CTRINT CTR | 18.7245719118.72457191 | |
화학식 1로 표시된 화합물이 처리된 Sars-CoV-2 바이러스 감염 베로 세포Sars-CoV-2 virus-infected Vero cells treated with the compound represented by |
N1N1 | 19.8776184419.87761844 |
N2N2 | 20.1546860620.15468606 | |
N3N3 | 20.2455974120.2459741 | |
INT CTRINT CTR | 21.9888975321.98889753 | |
화학식 2로 표시된 화합물이 처리된 Sars-CoV-2 바이러스 감염 베로 세포Sars-CoV-2 virus-infected Vero cells treated with the compound represented by |
N1N1 | 20.2761053220.27610532 |
N2N2 | 20.5805956520.58059565 | |
N3N3 | 21.317129221.3171292 | |
INT CTRINT CTR | 21.3660811921.36608119 |
상기 표 3 및 도 2에서 보는 바와 같이, Sars-CoV-2로 감염시킨 베로 세포에 화학식 1 또는 2로 표시되는 화합물을 처리한 결과, 대조군에 비하여 N1, N2 및 N3 유전자 절편의 발현 수준이 현저히 감소하였고, 특히 Sars-CoV-2 비감염 세포의 수준으로 감소한 것을 확인할 수 있었다. As shown in Table 3 and FIG. 2, as a result of treating Vero cells infected with Sars-CoV-2 with the compound represented by Formula 1 or 2, the expression levels of N1, N2 and N3 gene segments were significantly higher than that of the control group. decreased, and in particular, it was confirmed that it decreased to the level of Sars-CoV-2 non-infected cells.
[실험예 3] 화합물과 ACE2 사이의 상관 관계 분석[Experimental Example 3] Correlation analysis between the compound and ACE2
베로 세포 5.0 X 105 세포를 화학식 2로 표시되는 화합물 1 mM으로 15 시간 동안 처리한 뒤, 단백질 총 용혈물에 대하여 항-ACE 항체(Ab15348), 항-PMCA 항체(F3) sc-271917를 사용해 이뮤노블롯 분석으로 ACE2의 발현 수준을 측정하였다. 그 결과는 도 3에 나타내었다. 단, 여기서 대조군으로 발프로산(Valproic acid)을 사용하였다. Vero cells 5.0 X 10 5 cells were treated with 1 mM of the compound of formula 2 for 15 hours, and then anti-ACE antibody (Ab15348) and anti-PMCA antibody (F3) sc-271917 were used for total protein lysate. The expression level of ACE2 was determined by immunoblot analysis. The results are shown in FIG. 3 . However, valproic acid was used as a control here.
도 3에서 보는 바와 같이, 화합물 2의 처리 시 비히클을 처리한 대조군에 비하여 ACE2 단백질의 발현 수준이 80% 정도 현저히 감소한 것을 확인할 수 있었다. As shown in FIG. 3 , it was confirmed that the expression level of the ACE2 protein was significantly reduced by about 80% compared to the vehicle-treated control group when the compound 2 was treated.
이상으로 본 발명의 특정한 부분을 상세히 기술하였는 바, 당업계의 통상의 지식을 가진 자에게 있어서 이러한 구체적인 기술은 단지 바람직한 구현 예일 뿐이며, 이에 본 발명의 범위가 제한되는 것이 아닌 점은 명백하다. 따라서, 본 발명의 실질적인 범위는 첨부된 청구항과 그의 등가물에 의하여 정의된다고 할 것이다. As described above in detail a specific part of the present invention, for those of ordinary skill in the art, this specific description is only a preferred embodiment, and it is clear that the scope of the present invention is not limited thereto. Accordingly, the substantial scope of the present invention will be defined by the appended claims and their equivalents.
본 발명은 코로나바이러스 감염 또는 상기 감염에 의한 질환을 효과적으로 예방할 수 있는 다양한 용도의 조성물과, 코로나바이러스에 대한 억제 활성을 갖는 소독용 또는 살균용 조성물에 관한 것이다. The present invention relates to a composition for various uses that can effectively prevent a coronavirus infection or a disease caused by the infection, and a disinfecting or sterilizing composition having inhibitory activity against the coronavirus.
Claims (18)
- 하기 화학식 1로 표시되는 화합물 및 하기 화학식 2로 표시되는 화합물 중 적어도 하나; 또는 이의 약학적으로 허용 가능한 염을 유효 성분으로 포함하는, 바이러스 감염 또는 감염 질환의 예방용 약학적 조성물:at least one of a compound represented by the following formula (1) and a compound represented by the following formula (2); Or a pharmaceutical composition for the prevention of viral infection or infectious disease comprising a pharmaceutically acceptable salt thereof as an active ingredient:[화학식 1][Formula 1][화학식 2][Formula 2]
- 제1항에 있어서,According to claim 1,상기 바이러스는 코로나바이러스(coronavirus)인, 약학적 조성물.The virus is a coronavirus (coronavirus), pharmaceutical composition.
- 제2항에 있어서,3. The method of claim 2,상기 코로나바이러스는 인간 코로나바이러스 229E(HCoV-229E), 인간 코로나바이러스 OC43(HCoV-OC43), 인간 코로나바이러스 HKU1(HCoV-HKU1), 인간 코로나바이러스 NL63(HCoV-NL63), 중증 급성 호흡기 증후군 코로나바이러스(SARS-CoV), 중증 급성 호흡기 증후군-2 바이러스(Severe Acute Respiratory Syndrome virus-2; SARS-CoV-2), 중동 호흡기 증후군 코로나바이러스(MERS-CoV), 돼지 전염성 설사 바이러스(porcine epidemic diarrhea virus; PEDV), 전염성 위장염 바이러스(transmissible gastroenteritis virus; TGEV), 돼지 혈구 응집성뇌척수염 바이러스(porcine hemagglutinating encephalomyelitis virus; PHEV), 우 코로나바이러스(bovine coronavirus; BCoV), 말 코로나바이러스(equine coronavirus; EqCoV), 쥐 코로나바이러스(murine coronavirus; MuCoV), 개코로나바이러스(canine coronavirus; CCoV), 고양이 코로나바이러스 (feline coronavirus; FCoV), 박쥐 코로나바이러스-1(Miniopterus bat coronavirus1), 박쥐 코로나바이러스 HKU8(Miniopterus bat coronavirus HKU8), 박쥐 코로나바이러스 HKU2(Rhinolophus bat coronavirus HKU2), 박쥐 코로나바이러스 512(Scotophilus bat coronavirus 512), 박쥐 코로나바이러스 HKU4(Tylonycteris bat coronavirus HKU4), 박쥐 코로나바이러스 HKU5(Pipistrellus bat coronavirus HKU5), 박쥐 코로나바이러스 HKU9(Rousettus bat coronavirus HKU9), 새 코로나바이러스(Avian coronavirus), 흰색 돌고래 코로나바이러스 SW1(Beluga whale coronavirus SW1), 제주직박구리 코로나바이러스 HKU11(Bulbul coronavirus HKU11), 개똥지빠귀 코로나바이러스 HKU12(Thrush coronavirus HKU12) 및 킨바라 코로나바이러스 HKU13(Munia coronavirus HKU13)로 이루어진 군에서 선택된 1종 이상인, 약학적 조성물. Said coronaviruses include human coronavirus 229E (HCoV-229E), human coronavirus OC43 (HCoV-OC43), human coronavirus HKU1 (HCoV-HKU1), human coronavirus NL63 (HCoV-NL63), severe acute respiratory syndrome coronavirus (SARS-CoV), Severe Acute Respiratory Syndrome virus-2 (SARS-CoV-2), Middle East Respiratory Syndrome Coronavirus (MERS-CoV), porcine epidemic diarrhea virus; PEDV), transmissible gastroenteritis virus (TGEV), porcine hemagglutinating encephalomyelitis virus (PHEV), bovine coronavirus (BCoV), equine coronavirus (EqCoV), murine coronavirus Virus (murine coronavirus; MuCoV), canine coronavirus (CCoV), feline coronavirus (FCoV), bat coronavirus-1 (Miniopterus bat coronavirus1), bat coronavirus HKU8 (Miniopterus bat coronavirus HKU8), Rhinolophus bat coronavirus HKU2 (HKU2), Scotophilus bat coronavirus 512 (Scotophilus bat coronavirus 512), Tylonycteris bat coronavirus HKU4 (HKU4), Pipistrellus bat coronavirus HKU5 (HKU5), bat coronavirus HKU9 (Rousettus) bat coronavirus HKU9), novel coronavirus (A) vian coronavirus), Beluga whale coronavirus SW1 (SW1), Bulbul coronavirus HKU11 (HKU11), Thrush coronavirus HKU12 (HKU12) and Kinbara coronavirus HKU13 (Munia coronavirus HKU13) At least one selected from the group, a pharmaceutical composition.
- 하기 화학식 1로 표시되는 화합물 및 하기 화학식 2로 표시되는 화합물 중 적어도 하나; 또는 이의 약학적으로 허용 가능한 염을 유효 성분으로 포함하는, 바이러스 감염 또는 감염 질환의 예방용 식품 또는 식품 첨가제 조성물:at least one of a compound represented by the following formula (1) and a compound represented by the following formula (2); Or a food or food additive composition for the prevention of viral infection or infectious disease comprising a pharmaceutically acceptable salt thereof as an active ingredient:[화학식 1] [Formula 1][화학식 2][Formula 2]
- 제4항에 있어서,5. The method of claim 4,상기 바이러스는 코로나바이러스(coronavirus)인, 식품 또는 식품 첨가제 조성물.The virus is a coronavirus (coronavirus), food or food additive composition.
- 제5항에 있어서,6. The method of claim 5,상기 코로나바이러스는 인간 코로나바이러스 229E(HCoV-229E), 인간 코로나바이러스 OC43(HCoV-OC43), 인간 코로나바이러스 HKU1(HCoV-HKU1), 인간 코로나바이러스 NL63(HCoV-NL63), 중증 급성 호흡기 증후군 코로나바이러스(SARS-CoV), 중증 급성 호흡기 증후군-2 바이러스(Severe Acute Respiratory Syndrome virus-2; SARS-CoV-2), 중동 호흡기 증후군 코로나바이러스(MERS-CoV), 돼지 전염성 설사 바이러스(porcine epidemic diarrhea virus; PEDV), 전염성 위장염 바이러스(transmissible gastroenteritis virus; TGEV), 돼지 혈구 응집성뇌척수염 바이러스(porcine hemagglutinating encephalomyelitis virus; PHEV), 우 코로나바이러스(bovine coronavirus; BCoV), 말 코로나바이러스(equine coronavirus; EqCoV), 쥐 코로나바이러스(murine coronavirus; MuCoV), 개코로나바이러스(canine coronavirus; CCoV), 고양이 코로나바이러스 (feline coronavirus; FCoV), 박쥐 코로나바이러스-1(Miniopterus bat coronavirus1), 박쥐 코로나바이러스 HKU8(Miniopterus bat coronavirus HKU8), 박쥐 코로나바이러스 HKU2(Rhinolophus bat coronavirus HKU2), 박쥐 코로나바이러스 512(Scotophilus bat coronavirus 512), 박쥐 코로나바이러스 HKU4(Tylonycteris bat coronavirus HKU4), 박쥐 코로나바이러스 HKU5(Pipistrellus bat coronavirus HKU5), 박쥐 코로나바이러스 HKU9(Rousettus bat coronavirus HKU9), 새 코로나바이러스(Avian coronavirus), 흰색 돌고래 코로나바이러스 SW1(Beluga whale coronavirus SW1), 제주직박구리 코로나바이러스 HKU11(Bulbul coronavirus HKU11), 개똥지빠귀 코로나바이러스 HKU12(Thrush coronavirus HKU12) 및 킨바라 코로나바이러스 HKU13(Munia coronavirus HKU13)로 이루어진 군에서 선택된 1종 이상인, 식품 또는 식품 첨가제 조성물. Said coronaviruses include human coronavirus 229E (HCoV-229E), human coronavirus OC43 (HCoV-OC43), human coronavirus HKU1 (HCoV-HKU1), human coronavirus NL63 (HCoV-NL63), severe acute respiratory syndrome coronavirus (SARS-CoV), Severe Acute Respiratory Syndrome virus-2 (SARS-CoV-2), Middle East Respiratory Syndrome Coronavirus (MERS-CoV), porcine epidemic diarrhea virus; PEDV), transmissible gastroenteritis virus (TGEV), porcine hemagglutinating encephalomyelitis virus (PHEV), bovine coronavirus (BCoV), equine coronavirus (EqCoV), murine coronavirus Virus (murine coronavirus; MuCoV), canine coronavirus (CCoV), feline coronavirus (FCoV), bat coronavirus-1 (Miniopterus bat coronavirus1), bat coronavirus HKU8 (Miniopterus bat coronavirus HKU8), Rhinolophus bat coronavirus HKU2 (HKU2), Scotophilus bat coronavirus 512 (Scotophilus bat coronavirus 512), Tylonycteris bat coronavirus HKU4 (HKU4), Pipistrellus bat coronavirus HKU5 (HKU5), bat coronavirus HKU9 (Rousettus) bat coronavirus HKU9), novel coronavirus (A) vian coronavirus), Beluga whale coronavirus SW1 (SW1), Bulbul coronavirus HKU11 (HKU11), Thrush coronavirus HKU12 (HKU12) and Kinbara coronavirus HKU13 (Munia coronavirus HKU13) At least one selected from the group, food or food additive composition.
- 하기 화학식 1로 표시되는 화합물 및 하기 화학식 2로 표시되는 화합물 중 적어도 하나; 또는 이의 약학적으로 허용 가능한 염을 유효 성분으로 포함하는, 바이러스 감염 또는 감염 질환의 예방용 사료 또는 사료 첨가제 조성물:at least one of a compound represented by the following formula (1) and a compound represented by the following formula (2); Or a feed or feed additive composition for the prevention of viral infection or infectious disease, comprising a pharmaceutically acceptable salt thereof as an active ingredient:[화학식 1] [Formula 1][화학식 2][Formula 2]
- 제7항에 있어서,8. The method of claim 7,상기 바이러스는 코로나바이러스(coronavirus)인, 사료 또는 사료 첨가제 조성물.The virus is a coronavirus (coronavirus), feed or feed additive composition.
- 제8항에 있어서,9. The method of claim 8,상기 코로나바이러스는 인간 코로나바이러스 229E(HCoV-229E), 인간 코로나바이러스 OC43(HCoV-OC43), 인간 코로나바이러스 HKU1(HCoV-HKU1), 인간 코로나바이러스 NL63(HCoV-NL63), 중증 급성 호흡기 증후군 코로나바이러스(SARS-CoV), 중증 급성 호흡기 증후군-2 바이러스(Severe Acute Respiratory Syndrome virus-2; SARS-CoV-2), 중동 호흡기 증후군 코로나바이러스(MERS-CoV), 돼지 전염성 설사 바이러스(porcine epidemic diarrhea virus; PEDV), 전염성 위장염 바이러스(transmissible gastroenteritis virus; TGEV), 돼지 혈구 응집성뇌척수염 바이러스(porcine hemagglutinating encephalomyelitis virus; PHEV), 우 코로나바이러스(bovine coronavirus; BCoV), 말 코로나바이러스(equine coronavirus; EqCoV), 쥐 코로나바이러스(murine coronavirus; MuCoV), 개코로나바이러스(canine coronavirus; CCoV), 고양이 코로나바이러스 (feline coronavirus; FCoV), 박쥐 코로나바이러스-1(Miniopterus bat coronavirus1), 박쥐 코로나바이러스 HKU8(Miniopterus bat coronavirus HKU8), 박쥐 코로나바이러스 HKU2(Rhinolophus bat coronavirus HKU2), 박쥐 코로나바이러스 512(Scotophilus bat coronavirus 512), 박쥐 코로나바이러스 HKU4(Tylonycteris bat coronavirus HKU4), 박쥐 코로나바이러스 HKU5(Pipistrellus bat coronavirus HKU5), 박쥐 코로나바이러스 HKU9(Rousettus bat coronavirus HKU9), 새 코로나바이러스(Avian coronavirus), 흰색 돌고래 코로나바이러스 SW1(Beluga whale coronavirus SW1), 제주직박구리 코로나바이러스 HKU11(Bulbul coronavirus HKU11), 개똥지빠귀 코로나바이러스 HKU12(Thrush coronavirus HKU12) 및 킨바라 코로나바이러스 HKU13(Munia coronavirus HKU13)로 이루어진 군에서 선택된 1종 이상인, 사료 또는 사료 첨가제 조성물.Said coronaviruses include human coronavirus 229E (HCoV-229E), human coronavirus OC43 (HCoV-OC43), human coronavirus HKU1 (HCoV-HKU1), human coronavirus NL63 (HCoV-NL63), severe acute respiratory syndrome coronavirus (SARS-CoV), Severe Acute Respiratory Syndrome virus-2 (SARS-CoV-2), Middle East Respiratory Syndrome Coronavirus (MERS-CoV), porcine epidemic diarrhea virus; PEDV), transmissible gastroenteritis virus (TGEV), porcine hemagglutinating encephalomyelitis virus (PHEV), bovine coronavirus (BCoV), equine coronavirus (EqCoV), murine coronavirus Virus (murine coronavirus; MuCoV), canine coronavirus (CCoV), feline coronavirus (FCoV), bat coronavirus-1 (Miniopterus bat coronavirus1), bat coronavirus HKU8 (Miniopterus bat coronavirus HKU8), Rhinolophus bat coronavirus HKU2 (HKU2), Scotophilus bat coronavirus 512 (Scotophilus bat coronavirus 512), Tylonycteris bat coronavirus HKU4 (HKU4), Pipistrellus bat coronavirus HKU5 (HKU5), bat coronavirus HKU9 (Rousettus) bat coronavirus HKU9), novel coronavirus (A) vian coronavirus), Beluga whale coronavirus SW1 (SW1), Bulbul coronavirus HKU11 (HKU11), Thrush coronavirus HKU12 (HKU12) and Kinbara coronavirus HKU13 (Munia coronavirus HKU13) At least one selected from the group, feed or feed additive composition.
- 하기 화학식 1로 표시되는 화합물 및 하기 화학식 2로 표시되는 화합물 중 적어도 하나; 또는 이의 약학적으로 허용 가능한 염을 유효 성분으로 포함하는, 바이러스에 대한 억제 활성을 갖는 소독용 또는 세정용 조성물:at least one of a compound represented by the following formula (1) and a compound represented by the following formula (2); Or a composition for disinfection or cleaning having inhibitory activity against viruses, comprising as an active ingredient a pharmaceutically acceptable salt thereof:[화학식 1] [Formula 1][화학식 2][Formula 2]
- 제10항에 있어서,11. The method of claim 10,상기 바이러스는 코로나바이러스(coronavirus)인, 소독용 또는 세정용 조성물.The virus is a coronavirus (coronavirus), disinfecting or cleaning composition.
- 제11항에 있어서,12. The method of claim 11,상기 코로나바이러스는 인간 코로나바이러스 229E(HCoV-229E), 인간 코로나바이러스 OC43(HCoV-OC43), 인간 코로나바이러스 HKU1(HCoV-HKU1), 인간 코로나바이러스 NL63(HCoV-NL63), 중증 급성 호흡기 증후군 코로나바이러스(SARS-CoV), 중증 급성 호흡기 증후군-2 바이러스(Severe Acute Respiratory Syndrome virus-2; SARS-CoV-2), 중동 호흡기 증후군 코로나바이러스(MERS-CoV), 돼지 전염성 설사 바이러스(porcine epidemic diarrhea virus; PEDV), 전염성 위장염 바이러스(transmissible gastroenteritis virus; TGEV), 돼지 혈구 응집성뇌척수염 바이러스(porcine hemagglutinating encephalomyelitis virus; PHEV), 우 코로나바이러스(bovine coronavirus; BCoV), 말 코로나바이러스(equine coronavirus; EqCoV), 쥐 코로나바이러스(murine coronavirus; MuCoV), 개코로나바이러스(canine coronavirus; CCoV), 고양이 코로나바이러스 (feline coronavirus; FCoV), 박쥐 코로나바이러스-1(Miniopterus bat coronavirus1), 박쥐 코로나바이러스 HKU8(Miniopterus bat coronavirus HKU8), 박쥐 코로나바이러스 HKU2(Rhinolophus bat coronavirus HKU2), 박쥐 코로나바이러스 512(Scotophilus bat coronavirus 512), 박쥐 코로나바이러스 HKU4(Tylonycteris bat coronavirus HKU4), 박쥐 코로나바이러스 HKU5(Pipistrellus bat coronavirus HKU5), 박쥐 코로나바이러스 HKU9(Rousettus bat coronavirus HKU9), 새 코로나바이러스(Avian coronavirus), 흰색 돌고래 코로나바이러스 SW1(Beluga whale coronavirus SW1), 제주직박구리 코로나바이러스 HKU11(Bulbul coronavirus HKU11), 개똥지빠귀 코로나바이러스 HKU12(Thrush coronavirus HKU12) 및 킨바라 코로나바이러스 HKU13(Munia coronavirus HKU13)로 이루어진 군에서 선택된 1종 이상인, 소독용 또는 세정용 조성물.Said coronaviruses include human coronavirus 229E (HCoV-229E), human coronavirus OC43 (HCoV-OC43), human coronavirus HKU1 (HCoV-HKU1), human coronavirus NL63 (HCoV-NL63), severe acute respiratory syndrome coronavirus (SARS-CoV), Severe Acute Respiratory Syndrome virus-2 (SARS-CoV-2), Middle East Respiratory Syndrome Coronavirus (MERS-CoV), porcine epidemic diarrhea virus; PEDV), transmissible gastroenteritis virus (TGEV), porcine hemagglutinating encephalomyelitis virus (PHEV), bovine coronavirus (BCoV), equine coronavirus (EqCoV), murine coronavirus Virus (murine coronavirus; MuCoV), canine coronavirus (CCoV), feline coronavirus (FCoV), bat coronavirus-1 (Miniopterus bat coronavirus1), bat coronavirus HKU8 (Miniopterus bat coronavirus HKU8), Rhinolophus bat coronavirus HKU2 (HKU2), Scotophilus bat coronavirus 512 (Scotophilus bat coronavirus 512), Tylonycteris bat coronavirus HKU4 (HKU4), Pipistrellus bat coronavirus HKU5 (HKU5), bat coronavirus HKU9 (Rousettus) bat coronavirus HKU9), novel coronavirus (A) vian coronavirus), Beluga whale coronavirus SW1 (SW1), Bulbul coronavirus HKU11 (HKU11), Thrush coronavirus HKU12 (HKU12) and Kinbara coronavirus HKU13 (Munia coronavirus HKU13) At least one selected from the group, disinfecting or cleaning composition.
- 개체에게 하기 화학식 1로 표시되는 화합물 및 하기 화학식 2로 표시되는 화합물 중 적어도 하나; 또는 이의 약학적으로 허용 가능한 염을 투여하는 단계를 포함하는, 바이러스 감염 또는 감염 질환의 예방 방법:At least one of a compound represented by the following formula (1) and a compound represented by the following formula (2) to an individual; Or a method for preventing a viral infection or infectious disease comprising administering a pharmaceutically acceptable salt thereof:[화학식 1] [Formula 1][화학식 2][Formula 2]
- 제13항에 있어서,14. The method of claim 13,상기 바이러스는 코로나바이러스(coronavirus)인, 방법.wherein the virus is a coronavirus.
- 제14항에 있어서,15. The method of claim 14,상기 코로나바이러스는 인간 코로나바이러스 229E(HCoV-229E), 인간 코로나바이러스 OC43(HCoV-OC43), 인간 코로나바이러스 HKU1(HCoV-HKU1), 인간 코로나바이러스 NL63(HCoV-NL63), 중증 급성 호흡기 증후군 코로나바이러스(SARS-CoV), 중증 급성 호흡기 증후군-2 바이러스(Severe Acute Respiratory Syndrome virus-2; SARS-CoV-2), 중동 호흡기 증후군 코로나바이러스(MERS-CoV), 돼지 전염성 설사 바이러스(porcine epidemic diarrhea virus; PEDV), 전염성 위장염 바이러스(transmissible gastroenteritis virus; TGEV), 돼지 혈구 응집성뇌척수염 바이러스(porcine hemagglutinating encephalomyelitis virus; PHEV), 우 코로나바이러스(bovine coronavirus; BCoV), 말 코로나바이러스(equine coronavirus; EqCoV), 쥐 코로나바이러스(murine coronavirus; MuCoV), 개코로나바이러스(canine coronavirus; CCoV), 고양이 코로나바이러스 (feline coronavirus; FCoV), 박쥐 코로나바이러스-1(Miniopterus bat coronavirus1), 박쥐 코로나바이러스 HKU8(Miniopterus bat coronavirus HKU8), 박쥐 코로나바이러스 HKU2(Rhinolophus bat coronavirus HKU2), 박쥐 코로나바이러스 512(Scotophilus bat coronavirus 512), 박쥐 코로나바이러스 HKU4(Tylonycteris bat coronavirus HKU4), 박쥐 코로나바이러스 HKU5(Pipistrellus bat coronavirus HKU5), 박쥐 코로나바이러스 HKU9(Rousettus bat coronavirus HKU9), 새 코로나바이러스(Avian coronavirus), 흰색 돌고래 코로나바이러스 SW1(Beluga whale coronavirus SW1), 제주직박구리 코로나바이러스 HKU11(Bulbul coronavirus HKU11), 개똥지빠귀 코로나바이러스 HKU12(Thrush coronavirus HKU12) 및 킨바라 코로나바이러스 HKU13(Munia coronavirus HKU13)로 이루어진 군에서 선택된 1종 이상인, 방법.Said coronaviruses include human coronavirus 229E (HCoV-229E), human coronavirus OC43 (HCoV-OC43), human coronavirus HKU1 (HCoV-HKU1), human coronavirus NL63 (HCoV-NL63), severe acute respiratory syndrome coronavirus (SARS-CoV), Severe Acute Respiratory Syndrome virus-2 (SARS-CoV-2), Middle East Respiratory Syndrome Coronavirus (MERS-CoV), porcine epidemic diarrhea virus; PEDV), transmissible gastroenteritis virus (TGEV), porcine hemagglutinating encephalomyelitis virus (PHEV), bovine coronavirus (BCoV), equine coronavirus (EqCoV), murine coronavirus Virus (murine coronavirus; MuCoV), canine coronavirus (CCoV), feline coronavirus (FCoV), bat coronavirus-1 (Miniopterus bat coronavirus1), bat coronavirus HKU8 (Miniopterus bat coronavirus HKU8), Rhinolophus bat coronavirus HKU2 (HKU2), Scotophilus bat coronavirus 512 (Scotophilus bat coronavirus 512), Tylonycteris bat coronavirus HKU4 (HKU4), Pipistrellus bat coronavirus HKU5 (HKU5), bat coronavirus HKU9 (Rousettus) bat coronavirus HKU9), novel coronavirus (A) vian coronavirus), Beluga whale coronavirus SW1 (SW1), Bulbul coronavirus HKU11 (HKU11), Thrush coronavirus HKU12 (HKU12) and Kinbara coronavirus HKU13 (Munia coronavirus HKU13) At least one selected from the group, the method.
- 대상체에 하기 화학식 1로 표시되는 화합물 및 하기 화학식 2로 표시되는 화합물 중 적어도 하나; 또는 이의 약학적으로 허용 가능한 염을 접촉시키는 단계를 포함하는, 바이러스의 소독 또는 세정 방법:at least one of a compound represented by the following formula (1) and a compound represented by the following formula (2) to a subject; Or a method for disinfecting or cleaning a virus, comprising the step of contacting a pharmaceutically acceptable salt thereof:[화학식 1] [Formula 1][화학식 2][Formula 2]
- 제16항에 있어서,17. The method of claim 16,상기 바이러스는 코로나바이러스(coronavirus)인, 방법.wherein the virus is a coronavirus.
- 제17항에 있어서,18. The method of claim 17,상기 코로나바이러스는 인간 코로나바이러스 229E(HCoV-229E), 인간 코로나바이러스 OC43(HCoV-OC43), 인간 코로나바이러스 HKU1(HCoV-HKU1), 인간 코로나바이러스 NL63(HCoV-NL63), 중증 급성 호흡기 증후군 코로나바이러스(SARS-CoV), 중증 급성 호흡기 증후군-2 바이러스(Severe Acute Respiratory Syndrome virus-2; SARS-CoV-2), 중동 호흡기 증후군 코로나바이러스(MERS-CoV), 돼지 전염성 설사 바이러스(porcine epidemic diarrhea virus; PEDV), 전염성 위장염 바이러스(transmissible gastroenteritis virus; TGEV), 돼지 혈구 응집성뇌척수염 바이러스(porcine hemagglutinating encephalomyelitis virus; PHEV), 우 코로나바이러스(bovine coronavirus; BCoV), 말 코로나바이러스(equine coronavirus; EqCoV), 쥐 코로나바이러스(murine coronavirus; MuCoV), 개코로나바이러스(canine coronavirus; CCoV), 고양이 코로나바이러스 (feline coronavirus; FCoV), 박쥐 코로나바이러스-1(Miniopterus bat coronavirus1), 박쥐 코로나바이러스 HKU8(Miniopterus bat coronavirus HKU8), 박쥐 코로나바이러스 HKU2(Rhinolophus bat coronavirus HKU2), 박쥐 코로나바이러스 512(Scotophilus bat coronavirus 512), 박쥐 코로나바이러스 HKU4(Tylonycteris bat coronavirus HKU4), 박쥐 코로나바이러스 HKU5(Pipistrellus bat coronavirus HKU5), 박쥐 코로나바이러스 HKU9(Rousettus bat coronavirus HKU9), 새 코로나바이러스(Avian coronavirus), 흰색 돌고래 코로나바이러스 SW1(Beluga whale coronavirus SW1), 제주직박구리 코로나바이러스 HKU11(Bulbul coronavirus HKU11), 개똥지빠귀 코로나바이러스 HKU12(Thrush coronavirus HKU12) 및 킨바라 코로나바이러스 HKU13(Munia coronavirus HKU13)로 이루어진 군에서 선택된 1종 이상인, 방법.Said coronaviruses include human coronavirus 229E (HCoV-229E), human coronavirus OC43 (HCoV-OC43), human coronavirus HKU1 (HCoV-HKU1), human coronavirus NL63 (HCoV-NL63), severe acute respiratory syndrome coronavirus (SARS-CoV), Severe Acute Respiratory Syndrome virus-2 (SARS-CoV-2), Middle East Respiratory Syndrome Coronavirus (MERS-CoV), porcine epidemic diarrhea virus; PEDV), transmissible gastroenteritis virus (TGEV), porcine hemagglutinating encephalomyelitis virus (PHEV), bovine coronavirus (BCoV), equine coronavirus (EqCoV), murine coronavirus Virus (murine coronavirus; MuCoV), canine coronavirus (CCoV), feline coronavirus (FCoV), bat coronavirus-1 (Miniopterus bat coronavirus1), bat coronavirus HKU8 (Miniopterus bat coronavirus HKU8), Rhinolophus bat coronavirus HKU2 (HKU2), Scotophilus bat coronavirus 512 (Scotophilus bat coronavirus 512), Tylonycteris bat coronavirus HKU4 (HKU4), Pipistrellus bat coronavirus HKU5 (HKU5), bat coronavirus HKU9 (Rousettus) bat coronavirus HKU9), novel coronavirus (A) vian coronavirus), Beluga whale coronavirus SW1 (SW1), Bulbul coronavirus HKU11 (HKU11), Thrush coronavirus HKU12 (HKU12) and Kinbara coronavirus HKU13 (Munia coronavirus HKU13) At least one selected from the group, the method.
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JP2015513557A (en) * | 2012-03-09 | 2015-05-14 | レクシコン ファーマシューティカルズ インコーポレイテッド | Inhibition of adapter-related kinase 1 for the treatment of pain |
WO2014039714A2 (en) * | 2012-09-06 | 2014-03-13 | Plexxikon Inc. | Compounds and methods for kinase modulation, and indications therefor |
KR20180018683A (en) * | 2015-06-15 | 2018-02-21 | 글락소스미스클라인 인털렉츄얼 프로퍼티 디벨로프먼트 리미티드 | NRF2 modulator |
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