Cold medicines and antiviral drugs

Abstract

To provide a novel cold remedy or antiviral agent. A cold remedy including a compound represented by general formula (1) or a pharmaceutically acceptable salt thereof.

Description

Technical Field

[0001] Inventions related to cold remedies and antiviral agents are disclosed.

Background Art

[0002] Colds generally include the common cold, often referred to as "flu," and epidemic ones with sometimes severe symptoms such as Severe Acute Respiratory Syndrome (SARS) and Middle East Respiratory Syndrome (MERS). The common cold is an infection caused by four types of coronaviruses: HCoV-229E, HCoV-OC43, HCoV-NL63, and HCoV-HKU1. It is also known that SARS and MERS are caused by infections with coronaviruses SARS-CoV and MERS-CoV, respectively. Infections caused by new types of viruses such as SARS and MERS sometimes trigger a global pandemic, having a great impact on humanity. In particular, in early 2020, the so-called coronavirus disease (COVID-19) caused a pandemic, resulting in a large number of deaths and still continuing to cause great damage to humanity. Not only limited to epidemic and severe colds, for the treatment of colds, drugs that suppress symptoms such as antipyretics and antitussives are exclusively prescribed.

Prior Art Documents

Patent Documents

[0003]

Patent Document 1

Summary of the Invention

Problems to be Solved by the Invention

[0004] One problem is to provide a new cold remedy or antiviral agent.

Means for Solving the Problems

[0005] In order to solve the problems including the above-mentioned problem, extensive research has been conducted. As a result, it has been found that the compound disclosed in Patent Document 1 as a compound having an LPL activating action has antiviral activity. Based on such findings and further research, the inventions represented by the following are provided.

[0006] Item 1 An anti-cold agent comprising a compound represented by the following general formula (1) or a pharmaceutically acceptable salt thereof:

Chemical formula

[0007] Term A1 A method for treating the common cold, comprising administering a compound represented by the following general formula (1) or a pharmaceutically acceptable salt thereof to a patient in need: [ka] (In the formula, R 1 This is a pyridyl group having two substituents selected from the group consisting of halogen atoms and halogen-substituted C1-C6 alkyl groups. R 2 , R 5 and R 6 It is a hydrogen atom, R 3 These are C1-C6 alkoxy groups or halogen atoms. R 4 This is a pyridyl group having a halogen atom as a substituent, R 6 It is substituted on only one of the nitrogen atoms at position 1 and position 3 of the imidazole skeleton, and if the bond between the nitrogen atom at position 3 and the carbon atom at position 2 of the imidazole skeleton is a double bond, then R 6 If the N at position 1 is substituted and the bond between the N at position 3 and the C at position 2 is a single bond, then R 6 It is replaced with N in the 3rd position, R 7 It is a halogen atom. A is a C1-C6 alkylene group, If the bond between the nitrogen at position 3 and the carbon at position 2 of the imidazole skeleton is a double bond, then the bond between the carbon at position 2 and the nitrogen at position 1 is a single bond. Conversely, if the bond between the nitrogen at position 3 and the carbon at position 2 is a single bond, then the bond between the carbon at position 2 and the nitrogen at position 1 is a double bond. Term A2 R 4 The method according to item A1, wherein the group is a 6-halogenopyridine-3-yl group. Section A3 R 1 The method according to item A1 or A2, wherein the pyridine-2-yl group has a halogen-substituted C1-C6 alkyl group at the 3rd position and a halogen atom at the 5th position. Section A4 The method according to any one of items A1 to A3, wherein A is a methylene group. Section A5 R 1 However, it is a 3-fluoro-5-(trifluoromethyl)pyridine-2-yl group, R 4 The method according to any of items A1 to A4, wherein the group is a 6-fluoropyridine-3-yl group. Section A6 The method according to any one of items A1 to A5, wherein the compound is one of the following. ·2-[[4-(5-bromo-2-(6-fluoropyridine-3-yl)-1H-imidazole-4-yl)-3-methoxyphenoxy]methyl]-3-fluoro-5-(trifluoromethyl)pyridine ·2-[[4-(5-chloro-2-(6-fluoropyridine-3-yl)-1H-imidazole-4-yl)-3-methoxyphenoxy]methyl]-3-fluoro-5-(trifluoromethyl)pyridine ·2-[[3-chloro-4-(5-chloro-2-(6-fluoropyridine-3-yl)-1H-imidazole-4-yl)phenoxy]methyl]-3-fluoro-5-(trifluoromethyl)pyridine Section A7 A method for treating a viral infection, comprising administering a compound represented by the following general formula (1) or a pharmaceutically acceptable salt thereof to a patient in need: [ka] (In the formula, R 1 This is a pyridyl group having two substituents selected from the group consisting of halogen atoms and halogen-substituted C1-C6 alkyl groups. R 2 , R 5 and R 6 It is a hydrogen atom, R 3 These are C1-C6 alkoxy groups or halogen atoms. R 4 This is a pyridyl group having a halogen atom as a substituent, R 6 It is substituted on only one of the nitrogen atoms at position 1 and position 3 of the imidazole skeleton, and if the bond between the nitrogen atom at position 3 and the carbon atom at position 2 of the imidazole skeleton is a double bond, then R 6 If the N at position 1 is substituted and the bond between the N at position 3 and the C at position 2 is a single bond, then R 6 It is replaced with N in the 3rd position, R 7 It is a halogen atom. A is a C1-C6 alkylene group, If the bond between the nitrogen at position 3 and the carbon at position 2 of the imidazole skeleton is a double bond, then the bond between the carbon at position 2 and the nitrogen at position 1 is a single bond. Conversely, if the bond between the nitrogen at position 3 and the carbon at position 2 is a single bond, then the bond between the carbon at position 2 and the nitrogen at position 1 is a double bond. Section A8 R 4 The method according to item A7, wherein the group is a 6-halogenopyridine-3-yl group. Section A9 R 1 The method according to item A7 or A8, wherein the pyridine-2-yl group has a halogen-substituted C1-C6 alkyl group at the 3rd position and a halogen atom at the 5th position. Section A10 The method according to any one of items A7 to A9, wherein A is a methylene group. Section A11 R 1 However, it is a 3-fluoro-5-(trifluoromethyl)pyridine-2-yl group, R 4The method according to any of items A7 to A10, wherein the group is a 6-fluoropyridine-3-yl group. Section A12 The method according to any one of items A7 to A11, wherein the compound is one of the following. ·2-[[4-(5-bromo-2-(6-fluoropyridine-3-yl)-1H-imidazole-4-yl)-3-methoxyphenoxy]methyl]-3-fluoro-5-(trifluoromethyl)pyridine ·2-[[4-(5-chloro-2-(6-fluoropyridine-3-yl)-1H-imidazole-4-yl)-3-methoxyphenoxy]methyl]-3-fluoro-5-(trifluoromethyl)pyridine ·2-[[3-chloro-4-(5-chloro-2-(6-fluoropyridine-3-yl)-1H-imidazole-4-yl)phenoxy]methyl]-3-fluoro-5-(trifluoromethyl)pyridine Section A13 The method described in sections A7-A12, wherein the virus is a coronavirus.

[0008] Term B1 Use of a compound represented by the following general formula (1) or a pharmaceutically acceptable salt thereof for the manufacture of cold medicines: [ka] (In the formula, R 1 This is a pyridyl group having two substituents selected from the group consisting of halogen atoms and halogen-substituted C1-C6 alkyl groups. R 2 , R 5 and R 6 It is a hydrogen atom, R 3 These are C1-C6 alkoxy groups or halogen atoms. R 4 This is a pyridyl group having a halogen atom as a substituent, R 6It is substituted on only one of the nitrogen atoms at position 1 and position 3 of the imidazole skeleton, and if the bond between the nitrogen atom at position 3 and the carbon atom at position 2 of the imidazole skeleton is a double bond, then R 6 If the N at position 1 is substituted and the bond between the N at position 3 and the C at position 2 is a single bond, then R 6 It is replaced with N in the 3rd position, R 7 It is a halogen atom. A is a C1-C6 alkylene group, If the bond between the nitrogen at position 3 and the carbon at position 2 of the imidazole skeleton is a double bond, then the bond between the carbon at position 2 and the nitrogen at position 1 is a single bond. Conversely, if the bond between the nitrogen at position 3 and the carbon at position 2 is a single bond, then the bond between the carbon at position 2 and the nitrogen at position 1 is a double bond. Term B2 R 4 However, the use described in item B1 is a 6-halogenopyridine-3-yl group. Term B3 R 1 However, the use described in item B1 or B2 is a pyridine-2-yl group having a halogen-substituted C1-C6 alkyl group at the 3rd position and a halogen atom at the 5th position. Section B4 Use as described in any of items B1 to B3, wherein A is a methylene group. Section B5 R 1 However, it is a 3-fluoro-5-(trifluoromethyl)pyridine-2-yl group, R 4 However, the use described in any of items B1 to B4 is a 6-fluoropyridine-3-yl group. Section B6 The use described in any of items B1 to B5, wherein the compound is one of the following. ·2-[[4-(5-bromo-2-(6-fluoropyridine-3-yl)-1H-imidazole-4-yl)-3-methoxyphenoxy]methyl]-3-fluoro-5-(trifluoromethyl)pyridine ·2-[[4-(5-chloro-2-(6-fluoropyridine-3-yl)-1H-imidazole-4-yl)-3-methoxyphenoxy]methyl]-3-fluoro-5-(trifluoromethyl)pyridine ·2-[[3-chloro-4-(5-chloro-2-(6-fluoropyridine-3-yl)-1H-imidazole-4-yl)phenoxy]methyl]-3-fluoro-5-(trifluoromethyl)pyridine Section B7 Use of compounds represented by the following general formula (1) or pharmaceutically acceptable salts thereof for the manufacture of antiviral agents: [ka] (In the formula, R 1 This is a pyridyl group having two substituents selected from the group consisting of halogen atoms and halogen-substituted C1-C6 alkyl groups. R 2 , R 5 and R 6 It is a hydrogen atom, R 3 These are C1-C6 alkoxy groups or halogen atoms. R 4 This is a pyridyl group having a halogen atom as a substituent, R 6 It is substituted on only one of the nitrogen atoms at position 1 and position 3 of the imidazole skeleton, and if the bond between the nitrogen atom at position 3 and the carbon atom at position 2 of the imidazole skeleton is a double bond, then R 6 If the N at position 1 is substituted and the bond between the N at position 3 and the C at position 2 is a single bond, then R 6 It is replaced with N in the 3rd position, R 7 It is a halogen atom. A is a C1-C6 alkylene group, If the bond between the nitrogen at position 3 and the carbon at position 2 of the imidazole skeleton is a double bond, then the bond between the carbon at position 2 and the nitrogen at position 1 is a single bond. Conversely, if the bond between the nitrogen at position 3 and the carbon at position 2 is a single bond, then the bond between the carbon at position 2 and the nitrogen at position 1 is a double bond. Section B8 R 4 However, the use described in item B7 is a 6-halogenopyridine-3-yl group. Section B9 R 1However, the use described in item B7 or B8 is a pyridine-2-yl group having a halogen-substituted C1-C6 alkyl group at the 3rd position and a halogen atom at the 5th position. Section B10 Use as described in any of sections B7 to B9, wherein A is a methylene group. Section B11 R 1 However, it is a 3-fluoro-5-(trifluoromethyl)pyridine-2-yl group, R 4 However, the use described in any of items B7 to B10 is a 6-fluoropyridine-3-yl group. Section B12 The use described in any of items B7 to B11, wherein the compound is one of the following: ·2-[[4-(5-bromo-2-(6-fluoropyridine-3-yl)-1H-imidazole-4-yl)-3-methoxyphenoxy]methyl]-3-fluoro-5-(trifluoromethyl)pyridine ·2-[[4-(5-chloro-2-(6-fluoropyridine-3-yl)-1H-imidazole-4-yl)-3-methoxyphenoxy]methyl]-3-fluoro-5-(trifluoromethyl)pyridine ·2-[[3-chloro-4-(5-chloro-2-(6-fluoropyridine-3-yl)-1H-imidazole-4-yl)phenoxy]methyl]-3-fluoro-5-(trifluoromethyl)pyridine Section B13 The virus is a coronavirus, as described in sections B7-B12. [Effects of the Invention]

[0009] A new and effective treatment for the common cold will be provided. [Brief explanation of the drawing]

[0010] [Figure 1] The structures of the compounds used in the pharmacological tests of the examples are shown. [Figure 2] The results of pharmacological test 1 of the example are shown. [Figure 3] The results of pharmacological test 2 for the example are shown. [Figure 4] The results of pharmacological test 3 for the example are shown. [Modes for carrying out the invention]

[0011] 1. Compounds of general formula (1) Halogen atoms include, for example, fluorine, chlorine, bromine, and iodine.

[0012] C1-C6 alkyl groups include, for example, linear or branched alkyl groups having 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, 1-methylethyl, tert-butyl, and 2-methylbutyl groups.

[0013] C1-C6 alkoxy groups include, for example, linear or branched alkoxy groups with 1 to 6 carbon atoms, such as methoxy, ethoxy, n-propoxy, n-butoxy, n-pentyloxy, n-hexyloxy, 1-methylethoxy, tert-butoxy, and 2-methylbutoxy groups.

[0014] C1-C6 alkylene groups include, for example, linear or branched alkylene groups with 1-6 carbon atoms, such as methylene, ethylene, ethylidene, trimethylene, tetramethylene, pentamethylene, and hexamethylene groups.

[0015] Halogenated C1-C6 alkyl groups include halogenoalkyl groups having a halogen atom selected from the group consisting of fluorine, chlorine, bromine, and iodine atoms as a substituent, and the alkyl portion being a linear or branched alkyl group having 1 to 6 carbon atoms. Preferred halogenated C1-C6 alkyl groups are perhalogenoalkyl groups, and more preferably perfluoroalkyl groups. Specific halogenated C1-C6 alkyl groups include trifluoromethyl, pentafluoroethyl, heptafluoropropyl, nonafluorobutyl, undecafluoropentyl, tridecafluorohexyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl, 5,5,5-trifluoropentyl, and 6,6,6-trifluorohexyl groups.

[0016] Examples of "pyridyl groups having two groups selected from the group consisting of halogen atoms and halogen-substituted C1-C6 alkyl groups as substituents" include 3,4-ditrifluoromethyl-2-pyridyl, 3,5-ditrifluoromethyl-2-pyridyl, 3,6-ditrifluoromethyl-2-pyridyl, 2,4-ditrifluoromethyl-3-pyridyl, 2,5-ditrifluoromethyl-3-pyridyl, 2,6-ditrifluoromethyl-3-pyridyl, and 2,3-ditrifluoromethyl-2-pyridyl. Lifluoromethyl-3-pyridyl, 3,5-dipentafluoroethyl-2-pyridyl, 3,5-diheptafluoropropyl-2-pyridyl, 3,5-dinonafluorobutyl-2-pyridyl, 3,5-diundecafluoropentyl-2-pyridyl, 3,5-ditridecafluorohexyl-2-pyridyl, 5-bromo-3-fluoro-2-pyridyl, 5-chloro-3-fluoro-2-pyridyl, 3-fluoro-5-iodo-2-pyridyl, 5-bromo-3- Chloro-2-pyridyl, 5-bromo-3-iodo-2-pyridyl, 3-bromo-5-fluoro-2-pyridyl, 3-chloro-5-fluoro-2-pyridyl, 5-fluoro-3-iodo-2-pyridyl, 3-bromo-5-chloro-2-pyridyl, 3-bromo-5-iodo-2-pyridyl, 3-fluoro-5-trifluoromethyl-2-pyridyl, 5-fluoro-3-trifluoromethyl-2-pyridyl, 3-chloro-5-trifluoromethyl-2-pyridyl Examples include 3-bromo-5-trifluoromethyl-2-pyridyl, 3-iodo-5-trifluoromethyl-2-pyridyl, 3-fluoro-5-pentafluoroethyl-2-pyridyl, 3-fluoro-5-heptafluoropropyl-2-pyridyl, 3-fluoro-5-nonafluorobutyl-2-pyridyl, 3-fluoro-5-undecafluoropentyl-2-pyridyl, and 3-fluoro-5-tridecafluorohexyl-2-pyridyl groups. Thus, the two groups selected from the group consisting of a halogen atom and a halogen-substituted C1-C6 alkyl group may be the same or different.

[0017] In one embodiment, a preferred "pyridyl group having two groups selected from the group consisting of a halogen atom and a halogen-substituted C1-C6 alkyl group as substituents" is a "pyridin-2-yl group having a halogen-substituted C1-C6 alkyl group at the 3 position and a halogen atom at the 5 position," and preferred examples include 3-fluoro-5-trifluoromethyl-2-pyridyl, 3-bromo-5-trifluoromethyl-2-pyridyl, 3-fluoro-5-pentafluoroethyl-2-pyridyl, 3-fluoro-5-heptafluoropropyl-2-pyridyl, 3-fluoro-5-nonafluorobutyl-2-pyridyl, 3-fluoro-5-undecafluoropentyl-2-pyridyl, and 3-fluoro-5-tridecafluorohexyl-2-pyridyl groups, with 3-fluoro-5-trifluoromethyl-2-pyridyl being more preferred.

[0018] Examples of "pyridyl groups having a halogen atom as a substituent" include 3-fluoro-2-pyridyl, 4-fluoro-2-pyridyl, 5-fluoro-2-pyridyl, 6-fluoro-2-pyridyl, 2-fluoro-3-pyridyl, 4-fluoro-3-pyridyl, 5-fluoro-3-pyridyl, 6-fluoro-3-pyridyl, 2-fluoro-4-pyridyl, 3-fluoro-4-pyridyl, 6-chloro-3-pyridyl, 6-bromo-3-pyridyl, and 6-iodo-3-pyridyl groups. Of these, 6-halogenopyridine-3-yl groups such as 6-fluoro-3-pyridyl, 6-chloro-3-pyridyl, 6-bromo-3-pyridyl, and 6-iodo-3-pyridyl groups are preferred, and 6-fluoro-3-pyridyl groups are more preferred.

[0019] In one embodiment, as shown in (1-1) below, the bond between the nitrogen at position 3 and the carbon at position 2 of the imidazole skeleton of general formula (1) is a double bond, and the bond between the carbon at position 2 and the nitrogen at position 1 is a single bond. In another embodiment, as shown in (1-2) below, the bond between the nitrogen at position 3 and the carbon at position 2 of the imidazole skeleton of general formula (1) is a single bond, and the bond between the carbon at position 2 and the nitrogen at position 1 is a double bond.

[0020] [ka]

[0021] Preferred specific examples of compounds represented by general formula (1) include the following compounds. ·2-[[4-(5-bromo-2-(6-fluoropyridine-3-yl)-1H-imidazole-4-yl)-3-methoxyphenoxy]methyl]-3-fluoro-5-(trifluoromethyl)pyridine ·2-[[4-(5-chloro-2-(6-fluoropyridine-3-yl)-1H-imidazole-4-yl)-3-methoxyphenoxy]methyl]-3-fluoro-5-(trifluoromethyl)pyridine ·2-[[3-chloro-4-(5-chloro-2-(6-fluoropyridine-3-yl)-1H-imidazole-4-yl)phenoxy]methyl]-3-fluoro-5-(trifluoromethyl)pyridine

[0022] The compound represented by general formula (1) may also be a pharmaceutically acceptable salt thereof. A pharmaceutically acceptable salt is not particularly limited and may be, for example, at least one selected from the group consisting of hydrochloride, nitrate, sulfate, hydrobromide, phosphate, carbonate, sulfonate, acetate, lactate, and citrate. These acid addition salts can be prepared by conventional methods.

[0023] Compounds represented by general formula (1) may have optical isomers with the carbon atom as the chiral center. Compounds represented by general formula (1) encompass both racemates, which are mixtures of such optical isomers, and optically active compounds, which are each of the optical isomers. Optical isomers can be separated using various known resolution methods.

[0024] 2. Manufacturing method The compound represented by general formula (1) can be produced according to the manufacturing method described in Patent Document 1.

[0025] 3. Formulation and method of administration Compounds represented by general formula (1) or pharmaceutically acceptable salts thereof have excellent infection-inhibiting and viral replication-inhibiting effects. Therefore, compounds represented by general formula (1) or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing them, can be used as cold remedies, antiviral agents, viral infection inhibitors, and preventive or therapeutic agents for viral infections.

[0026] The types of viruses and viral infections are not particularly limited. Examples of viral infections include gastrointestinal viral infections (e.g., enterovirus, cytomegalovirus), respiratory viral infections (e.g., infections caused by respiratory viruses such as influenza virus, rhinovirus, coronavirus, parainfluenza virus, RSV, adenovirus, and reovirus), herpes zoster caused by herpesvirus, diarrhea caused by rotavirus, viral hepatitis, and AIDS. In one embodiment, the virus is preferably a coronavirus (including SARS-CoV-2).

[0027] A pharmaceutical composition is provided comprising a compound represented by general formula (1) or a pharmaceutically acceptable salt thereof. The pharmaceutical composition may be in the form of a general pharmaceutical formulation. In addition to the compound represented by general formula (1) or a pharmaceutically acceptable salt thereof, the pharmaceutical composition may also contain any pharmaceutically acceptable carrier. Examples of pharmaceutically acceptable carriers include fillers, bulking agents, binders, humectants, disintegrants, surfactants, lubricants, and diluents. These can be appropriately selected depending on the dosage unit form of the resulting pharmaceutical composition.

[0028] The above-mentioned pharmaceutical preparations can be administered in various forms, depending on the therapeutic purpose. Typical dosage forms include tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, injections (liquids, suspensions, etc.), inhalants, and ointments.

[0029] When forming the tablets, the above-mentioned pharmaceutically acceptable carriers include, for example, excipients such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid, and potassium phosphate; binders such as water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, hydroxypropylcellulose, methylcellulose, and polyvinylpyrrolidone; sodium carboxymethylcellulose, calcium carboxymethylcellulose, low-substituted hydroxypropylcellulose, dried starch, sodium alginate, agar powder, At least one of the following can be used: disintegrants such as laminarin powder, sodium bicarbonate, and calcium carbonate; surfactants such as polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, and monoglyceride stearate; disintegration inhibitors such as sucrose, stearin, cocoa butter, and hydrogenated oil; absorption enhancers such as quaternary ammonium bases and sodium lauryl sulfate; humectants such as glycerin and starch; adsorbents such as starch, lactose, kaolin, bentonite, and colloidal silicic acid; and lubricants such as purified talc, stearate, boric acid powder, and polyethylene glycol. Furthermore, the tablets may be coated with a conventional coating as needed, such as sugar-coated tablets, gelatin-coated tablets, enteric-coated tablets, film-coated tablets, or double or multi-layered tablets.

[0030] When forming the product into pill form, at least one of the following can be used as a pharmaceutically acceptable carrier: excipients such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, kaolin, and talc; binders such as gum arabic powder, tragacanth powder, gelatin, and ethanol; and disintegrants such as laminarin and agar.

[0031] When forming the suppository form, at least one selected from the group consisting of polyethylene glycol, cocoa butter, higher alcohols, esters of higher alcohols, gelatin, and semi-synthetic glycerides can be used as a pharmaceutically acceptable carrier.

[0032] Capsules are prepared by mixing a compound represented by general formula (1) or a pharmaceutically acceptable salt thereof with one of the pharmaceutically acceptable carriers exemplified above, in accordance with conventional methods, and filling the mixture into rigid gelatin capsules, soft gelatin capsules, or the like.

[0033] When prepared as an injectable preparation such as a liquid, emulsion, or suspension, it is preferable that these preparations be sterilized and isotonic with blood. In preparing these forms, at least one diluent selected from the group consisting of, for example, water, ethanol, macrogol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, and polyoxyethylene sorbitan fatty acid esters can be used. In this case, a sufficient amount of sodium chloride, glucose, or glycerin to prepare an isotonic solution may be included in the pharmaceutical preparation. In addition, ordinary solubilizers, buffers, or analgesics may be added.

[0034] When preparing ointments in the form of pastes, creams, or gels, at least one diluent selected from the group consisting of, for example, white petrolatum, paraffin, glycerin, cellulose derivatives, polyethylene glycol, silicone, and bentonite can be used.

[0035] The pharmaceutical composition may contain, as necessary, colorants, preservatives, fragrances, flavorings, sweeteners, and other pharmaceuticals.

[0036] The pharmaceutical composition preferably contains a therapeutically effective amount of the compound represented by general formula (1) or a pharmaceutically acceptable salt thereof. The pharmaceutical composition may contain, for example, about 0.5 to 90% by weight, preferably about 1 to 85% by weight, of the compound represented by general formula (1) or a pharmaceutically acceptable salt thereof.

[0037] There are no particular restrictions on the method of administering pharmaceutical compositions, and it is determined according to the various formulation forms, the patient's age, sex, the severity of the disease, and other conditions. For example, tablets, pills, liquids, suspensions, emulsions, granules, and capsules are administered orally, injectables are administered intravenously, intramuscularly, intradermally, subcutaneously, or intraperitoneally, or alone or mixed with conventional infusion fluids such as glucose or amino acids, and suppositories are administered rectally.

[0038] The dosage of the pharmaceutical composition is appropriately selected depending on its usage, the patient's age, sex, other conditions, and the severity of the disease. For example, the amount of the compound represented by general formula (1) or a pharmaceutically acceptable salt thereof can be about 0.5 to 20 mg per kg of body weight per adult per day, preferably about 1 to 10 mg. The pharmaceutical composition can be administered once a day or in 2 to 4 divided doses. [Examples]

[0039] The present invention will be described in more detail below with reference to examples, but the present invention is not limited thereto.

[0040] [Formulation Example 1] Preparation of Tablets Tablets (10,000 tablets) containing 300 mg of compound X per tablet were prepared using the compound from Example 281 described in WO2017 / 110237 (2-[[4-(5-chloro-2-(6-fluoropyridine-3-yl)-1H-imidazole-4-yl)-3-methoxyphenoxy]methyl]-3-fluoro-5-(trifluoromethyl)pyridine) (hereinafter referred to as "Compound X") as the active ingredient, according to the following formulation. All ingredients used are products of the Japanese Pharmacopoeia. Compound X 3000g Lactose 335g Cornstarch 165g Carboxymethylcellulose calcium 125g Methylcellulose 60g Magnesium stearate 15g

[0041] According to the above formulation, compound X, lactose, corn starch, and carboxymethylcellulose calcium were thoroughly mixed, the mixture was granulated using an aqueous methylcellulose solution, passed through a 24-mesh sieve, mixed with magnesium stearate, and pressed into tablets to obtain the desired tablets.

[0042] [Formulation Example 2] Preparation of Capsules Using compound X as the active ingredient, 10,000 hard gelatin capsules containing 200 mg of compound X per capsule were prepared according to the following formulation. All ingredients used are Japanese Pharmacopoeia products. Compound X 2000g Crystalline cellulose 300g Cornstarch 170g Talc 20g Magnesium stearate 10g

[0043] Following the above formulation, each component was finely powdered and mixed to form a uniform mixture. This mixture was then filled into orally administered gelatin capsules of the desired dimensions to obtain the target capsule.

[0044] [Pharmacology Test 1] The compounds used were Compound X, the compound from Example 255 and the compound from Example 361 described in WO2017 / 110237 (hereinafter referred to as "Compound Y" and "Compound Z," respectively). As a comparative compound, 3-hydroxypyrazine-2-carboxamide, a compound related to favipiravir (marketed under the trade name Avigan) and reported to have antiviral activity [Transboundary Emerging Dis., 63, e205.(2016)], was used. The chemical structures of these compounds are shown in Figure 1.

[0045] MRC-5 cells (obtained from the JCRB Cell Bank) were used as host cells and cultured in a 96-well plate until a single-layer sheet formed. Next, the culture medium was removed, and 50 μL of a mixed suspension medium containing human coronavirus HCoV-229E solution (obtained from ATCC) and the test compound at a predetermined dose (medium: Dulbecco's modified Eagle agar) was added and allowed to stand at room temperature for 1 hour. Note: The virus concentration The ratio was set to 3.5 TCID50 / mL on a logarithmic scale. Subsequently, the medium was removed and washed with phosphate-buffered saline (calcium and magnesium-free). Then, a new medium (containing 10% FBS (fetal bovine serum)) with the same dose of the test compound was added, and the culture was incubated at 33°C in the presence of 5% carbon dioxide until the cytopathic effect appeared (3-5 days). After culturing, the medium was frozen and thawed three times, and RNA was extracted from the medium and quantified by reverse transcription and qPCR. The conditions are as shown in the table below.

[0046] [Table 1]

[0047] [Table 2]

[0048] [Table 3]

[0049] [Table 4]

[0050] The results shown in the table and Figure 2 below demonstrate that the compounds of the present invention, represented by compounds X to Z, exhibit significantly higher coronavirus infection-suppressing activity than the comparative compounds.

[0051] [Table 5]

[0052] [Pharmacology Test - 2] Compound X, as described above, was used as the test compound. As comparative compound 1, favipiravir, which is approved in Japan as an anti-influenza drug and has been shown to be effective against the novel coronavirus (SARS-CoV-2), was used. As comparative compound 2, chloroquine phosphate, which was granted temporary emergency use authorization by the U.S. Food and Drug Administration (FDA) for patients with COVID-19, was used.

[0053] The test was conducted in the same manner as in pharmacological test 1 described above, except that HCT-8 (ATCC CCL-244) was used as the host cell, OC43 (ATCC VR1588) was used as the human coronavirus, and the culture medium was not included with the test compound during the initial 1-hour standing period at room temperature, and fetal bovine serum was not included in the culture medium containing the test compound used later. The conditions for the reverse transcription reaction and qPCR are as shown in the table below.

[0054] [Table 6]

[0055] [Table 7]

[0056] [Table 8]

[0057] [Table 9]

[0058] The results shown in the table and Figure 3 below demonstrate that the compound of the present invention exhibits significantly higher coronavirus infection-suppressing activity than both of the control compounds.

[0059] [Table 10]

[0060] [Pharmacology Test - 3] Compound X, as described above, was used as the test compound. Vero E6 (ATCC CRL1586) was used as the host cell and cultured in a 96-well plate until it formed a monolayer sheet. Next, the medium was removed and 50 μL of a mixed suspension medium of SARS-CoV-2 (hCoV-19 / Germany / BY-ChVir-929 / 2020) and the test compound at a predetermined dose was added and allowed to stand at 37°C for 1 hour. The virus concentration was 150 PFU / well. Subsequently, the medium was removed and washed with PBS. Then, a new medium (mixed with the same dose of the test compound as before) was added and cultured overnight at 37°C. After culturing, the amount of virus in the culture supernatant was quantified by qPCR. As primers and probes, those specific to the SARS-CoV-2 N1 protein as defined by the Centers for Disease Control and Prevention (CDC) were used, and the conditions were also as defined by the CDC. The number of PCR cycles (Ct value) required for the signal intensity of the PCR product to reach a predetermined intensity (threshold) was determined.

[0061] The results shown in the table and Figure 4 below demonstrate that the compounds of the present invention, represented by compound X, also exhibit infection-suppressing effects against the novel coronavirus SARS-CoV-2.

[0062] [Table 11]

Claims

1. Cold medicines comprising a compound represented by the following general formula (1) or a pharmaceutically acceptable salt thereof: 【Chemistry 1】 (In the formula, R １ This is a 3-fluoro-5-(trifluoromethyl)pyridine-2-yl group, R ２ , R ５ and R ６ It is a hydrogen atom, R ３ These are C1-C6 alkoxy groups or halogen atoms. R ４ This is a 6-fluoropyridine-3-yl group, R ６ is substituted only at either the N at the 1-position or the N at the 3-position of the imidazole skeleton, and when the bond between the N at the 3-position and the C at the 2-position of the imidazole skeleton is a double bond, R ６ is substituted at the N at the 1-position, and when the bond between the N at the 3-position and the C at the 2-position is a single bond, R ６ is substituted at the N at the 3-position, R ７ It is a halogen atom. A is a C1-C6 alkylene group, If the bond between the nitrogen at position 3 and the carbon at position 2 of the imidazole skeleton is a double bond, then the bond between the carbon at position 2 and the nitrogen at position 1 is a single bond. Conversely, if the bond between the nitrogen at position 3 and the carbon at position 2 is a single bond, then the bond between the carbon at position 2 and the nitrogen at position 1 is a double bond.

2. The cold medicine according to claim 1, wherein A is a methylene group.

3. The cold agent according to claim 1 or 2, wherein the compound is any of the following: 2-[[4-(5-bromo-2-(6-fluoropyridine-3-yl)-1H-imidazole-4-yl)-3-methoxyphenoxy]methyl]-3-fluoro-5-(trifluoromethyl)pyridine 2-[[4-(5-chloro-2-(6-fluoropyridine-3-yl)-1H-imidazole-4-yl)-3-methoxyphenoxy]methyl]-3-fluoro-5-(trifluoromethyl)pyridine 2-[[3-chloro-4-(5-chloro-2-(6-fluoropyridine-3-yl)-1H-imidazole-4-yl)phenoxy]methyl]-3-fluoro-5-(trifluoromethyl)pyridine

4. Anticoronavirus agents comprising a compound represented by the following general formula (1) or a pharmaceutically acceptable salt thereof: 【Chemistry 2】 (In the formula, R １ This is a 3-fluoro-5-(trifluoromethyl)pyridine-2-yl group, R ２ , R ５ and R ６ It is a hydrogen atom, R ３ These are C1-C6 alkoxy groups or halogen atoms. R ４ This is a 6-fluoropyridine-3-yl group, R ６ In the case where the substitution occurs at only one of the nitrogen atoms at position 1 or position 3 of the imidazole skeleton, and the bond between the nitrogen atom at position 3 and the carbon atom at position 2 of the imidazole skeleton is a double bond, R ６ If the N at position 1 is substituted and the bond between the N at position 3 and the C at position 2 is a single bond, then R ６ It is replaced with N in the third position, R ７ It is a halogen atom. A is a C1-C6 alkylene group, If the bond between the nitrogen at position 3 and the carbon at position 2 of the imidazole skeleton is a double bond, then the bond between the carbon at position 2 and the nitrogen at position 1 is a single bond. Conversely, if the bond between the nitrogen at position 3 and the carbon at position 2 is a single bond, then the bond between the carbon at position 2 and the nitrogen at position 1 is a double bond.

5. The antiviral agent according to claim 4, wherein A is a methylene group.

6. The antiviral agent according to claim 4 or 5, wherein the compound is any of the following: 2-[[4-(5-bromo-2-(6-fluoropyridine-3-yl)-1H-imidazole-4-yl)-3-methoxyphenoxy]methyl]-3-fluoro-5-(trifluoromethyl)pyridine 2-[[4-(5-chloro-2-(6-fluoropyridine-3-yl)-1H-imidazole-4-yl)-3-methoxyphenoxy]methyl]-3-fluoro-5-(trifluoromethyl)pyridine 2-[[3-chloro-4-(5-chloro-2-(6-fluoropyridine-3-yl)-1H-imidazole-4-yl)phenoxy]methyl]-3-fluoro-5-(trifluoromethyl)pyridine

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