Cold remedies and antiviral agents

Abstract

The present invention provides a novel cold medicine or antiviral agent. The cold medicine comprises a compound represented by the general formula (1) or a pharmaceutically acceptable salt thereof.

Description

Technical Field

[0001] Disclosed are inventions related to cold medicines and antiviral agents. Background Art

[0002] Colds are known to include the common cold, which is generally called "cold", and influenza, which is sometimes accompanied by severe symptoms, such as severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS). The common cold is caused by infection caused by four types of coronaviruses, HCoV-229E, HCoV-OC43, HCoV-NL63, and HCoV-HKU1. SARS and MERS are also known to be caused by infection caused by coronaviruses called SARS-CoV and MERS-CoV, respectively. Infections caused by new types of viruses such as SARS and MERS sometimes cause a global pandemic, which has a great impact on humans. In particular, in early 2020, the infectious disease (COVID-19) caused by the so-called new coronavirus caused a global pandemic, and many deaths occurred, and it continues to cause great harm to humans. Whether it is an epidemic or a serious cold, the main prescriptions for its treatment are also symptom-suppressing drugs such as antipyretics and antitussives.

[0003] Prior art literature

[0004] Patent Literature

[0005] Patent Document 1: WO2017 / 110237 Summary of the invention

[0006] Problems to be solved by the invention

[0007] One of the issues is to provide new cold or antiviral agents.

[0008] Means for solving problems

[0009] In order to solve the above-mentioned problems, the inventors have conducted intensive studies and found that the compound disclosed in Patent Document 1 as a compound having LPL activating action has antiviral activity. Based on such findings and further studies, the invention represented by the following is provided.

[0010] Item 1

[0011] A cold medicine comprising a compound represented by the following general formula (1) or a pharmaceutically acceptable salt thereof:

[0012] [Chemical formula 1]

[0013]

[0014] (Where,

[0015] R 1 is a pyridyl group having two groups selected from the group consisting of a halogen atom and a halogenated C1-C6 alkyl group as substituents,

[0016] R 2 , R 5 and R 6 is a hydrogen atom,

[0017] R 3 is a C1-C6 alkoxy group or a halogen atom,

[0018] R 4 is a pyridyl group having a halogen atom as a substituent,

[0019] R 6 When only one of the N at position 1 and the N at position 3 of the imidazole skeleton is substituted and the bond between the N at position 3 and the C at position 2 of the imidazole skeleton is a double bond, R 6 When 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, R 6 Substitute the N at position 3,

[0020] R 7 is a halogen atom,

[0021] A is a C1-C6 alkylene group,

[0022] When the bond between N at position 3 and C at position 2 of the imidazole skeleton is a double bond, the bond between C at position 2 and N at position 1 is a single bond; when the bond between N at position 3 and C at position 2 is a single bond, the bond between C at position 2 and N at position 1 is a double bond).

[0023] Item 2

[0024] The cold medicine according to item 1, wherein R 4 It is 6-halopyridin-3-yl.

[0025] Item 3

[0026] The cold medicine according to item 1 or 2, wherein R 1 It is a pyridin-2-yl group having a halogenated C1-C6 alkyl group at the 3-position and a halogen atom at the 5-position.

[0027] Item 4

[0028] The cold medicine according to any one of Items 1 to 3, wherein A is a methylene group.

[0029] Item 5

[0030] The cold medicine according to any one of items 1 to 4, wherein R 1 is 3-fluoro-5-(trifluoromethyl)pyridin-2-yl, R4 It is 6-fluoropyridin-3-yl.

[0031] Item 6

[0032] The cold medicine according to any one of Items 1 to 5, wherein the compound is any one of the following.

[0033] ·2-[[4-(5-bromo-2-(6-fluoropyridin-3-yl)-1H-imidazol-4-yl)-3-methoxyphenoxy]methyl]-3-fluoro-5-(trifluoromethyl)pyridine

[0034] ·2-[[4-(5-chloro-2-(6-fluoropyridin-3-yl)-1H-imidazol-4-yl)-3-methoxyphenoxy]methyl]-3-fluoro-5-(trifluoromethyl)pyridine

[0035] ·2-[[3-Chloro-4-(5-chloro-2-(6-fluoropyridin-3-yl)-1H-imidazol-4-yl)phenoxy]methyl]-3-fluoro-5-(trifluoromethyl)pyridine

[0036] Item 7

[0037] An antiviral agent comprising a compound represented by the following general formula (1) or a pharmaceutically acceptable salt thereof:

[0038] [Chemical formula 2]

[0039]

[0040] (Where,

[0041] R 1 is a pyridyl group having two groups selected from the group consisting of a halogen atom and a halogenated C1-C6 alkyl group as substituents,

[0042] R 2 , R 5 and R 6 is a hydrogen atom,

[0043] R 3 is a C1-C6 alkoxy group or a halogen atom,

[0044] R 4 is a pyridyl group having a halogen atom as a substituent,

[0045] R 6 When only one of the N at position 1 and the N at position 3 of the imidazole skeleton is substituted and the bond between the N at position 3 and the C at position 2 of the imidazole skeleton is a double bond, R 6 When 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, R 6 Substitute the N at position 3,

[0046] R 7 is a halogen atom,

[0047] A is a C1-C6 alkylene group,

[0048] When the bond between N at position 3 and C at position 2 of the imidazole skeleton is a double bond, the bond between C at position 2 and N at position 1 is a single bond; when the bond between N at position 3 and C at position 2 is a single bond, the bond between C at position 2 and N at position 1 is a double bond).

[0049] Item 8

[0050] The antiviral agent according to item 7, wherein R 4 It is 6-halopyridin-3-yl.

[0051] Item 9

[0052] The antiviral agent according to item 7 or 8, wherein R 1 It is a pyridin-2-yl group having a halogenated C1-C6 alkyl group at the 3-position and a halogen atom at the 5-position.

[0053] Item 10

[0054] The antiviral agent according to any one of items 7 to 9, wherein A is a methylene group.

[0055] Item 11

[0056] The antiviral agent according to any one of items 7 to 10, wherein R 1 is 3-fluoro-5-(trifluoromethyl)pyridin-2-yl, R 4 It is 6-fluoropyridin-3-yl.

[0057] Item 12

[0058] The antiviral agent according to any one of items 7 to 11, wherein the compound is any one of the following.

[0059] ·2-[[4-(5-bromo-2-(6-fluoropyridin-3-yl)-1H-imidazol-4-yl)-3-methoxyphenoxy]methyl]-3-fluoro-5-(trifluoromethyl)pyridine

[0060] ·2-[[4-(5-chloro-2-(6-fluoropyridin-3-yl)-1H-imidazol-4-yl)-3-methoxyphenoxy]methyl]-3-fluoro-5-(trifluoromethyl)pyridine

[0061] ·2-[[3-Chloro-4-(5-chloro-2-(6-fluoropyridin-3-yl)-1H-imidazol-4-yl)phenoxy]methyl]-3-fluoro-5-(trifluoromethyl)pyridine

[0062] Item 13

[0063] The antiviral agent according to items 7 to 12, wherein the virus is a coronavirus.

[0064] Item A1

[0065] A method for treating colds, comprising administering a compound represented by the following general formula (1) or a pharmaceutically acceptable salt thereof to a patient in need thereof:

[0066] [Chemical formula 3]

[0067]

[0068] (Where,

[0069] R 1 is a pyridyl group having two groups selected from the group consisting of a halogen atom and a halogenated C1-C6 alkyl group as substituents,

[0070] R 2 , R 5 and R 6 is a hydrogen atom,

[0071] R 3 is a C1-C6 alkoxy group or a halogen atom,

[0072] R 4 is a pyridyl group having a halogen atom as a substituent,

[0073] R 6 When only one of the N at position 1 and the N at position 3 of the imidazole skeleton is substituted and the bond between the N at position 3 and the C at position 2 of the imidazole skeleton is a double bond, R 6 When 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, R 6 Substitute the N at position 3,

[0074] R 7 is a halogen atom,

[0075] A is a C1-C6 alkylene group,

[0076] When the bond between N at position 3 and C at position 2 of the imidazole skeleton is a double bond, the bond between C at position 2 and N at position 1 is a single bond; when the bond between N at position 3 and C at position 2 is a single bond, the bond between C at position 2 and N at position 1 is a double bond).

[0077] Item A2

[0078] A method as described in item A1, wherein R 4 It is 6-halopyridin-3-yl.

[0079] Item A3

[0080] A method as described in item A1 or A2, wherein R 1 It is a pyridin-2-yl group having a halogenated C1-C6 alkyl group at the 3-position and a halogen atom at the 5-position.

[0081] Item A4

[0082] The method according to any one of Items A1 to A3, wherein A is a methylene group.

[0083] Item A5

[0084] A method as described in any one of items A1 to A4, wherein R 1 is 3-fluoro-5-(trifluoromethyl)pyridin-2-yl, R 4 It is 6-fluoropyridin-3-yl.

[0085] Item A6

[0086] The method according to any one of Items A1 to A5, wherein the compound is any one of the following.

[0087] ·2-[[4-(5-bromo-2-(6-fluoropyridin-3-yl)-1H-imidazol-4-yl)-3-methoxyphenoxy]methyl]-3-fluoro-5-(trifluoromethyl)pyridine

[0088] ·2-[[4-(5-chloro-2-(6-fluoropyridin-3-yl)-1H-imidazol-4-yl)-3-methoxyphenoxy]methyl]-3-fluoro-5-(trifluoromethyl)pyridine

[0089] ·2-[[3-Chloro-4-(5-chloro-2-(6-fluoropyridin-3-yl)-1H-imidazol-4-yl)phenoxy]methyl]-3-fluoro-5-(trifluoromethyl)pyridine

[0090] Item A7

[0091] A method for treating an infectious disease caused by a virus, comprising administering a compound represented by the following general formula (1) or a pharmaceutically acceptable salt thereof to a patient in need thereof:

[0092] [Chemical formula 4]

[0093]

[0094] (Where,

[0095] R 1 is a pyridyl group having two groups selected from the group consisting of a halogen atom and a halogenated C1-C6 alkyl group as substituents,

[0096] R 2 , R 5 and R 6 is a hydrogen atom,

[0097] R 3 is a C1-C6 alkoxy group or a halogen atom,

[0098] R 4 is a pyridyl group having a halogen atom as a substituent,

[0099] R 6 When only one of the N at position 1 and the N at position 3 of the imidazole skeleton is substituted and the bond between the N at position 3 and the C at position 2 of the imidazole skeleton is a double bond, R 6 When 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, R 6 Substitute the N at position 3,

[0100] R 7 is a halogen atom,

[0101] A is a C1-C6 alkylene group,

[0102] When the bond between N at position 3 and C at position 2 of the imidazole skeleton is a double bond, the bond between C at position 2 and N at position 1 is a single bond; when the bond between N at position 3 and C at position 2 is a single bond, the bond between C at position 2 and N at position 1 is a double bond).

[0103] Item A8

[0104] A method as described in item A7, wherein R 4 It is 6-halopyridin-3-yl.

[0105] Item A9

[0106] A method as described in item A7 or A8, wherein R 1 It is a pyridin-2-yl group having a halogenated C1-C6 alkyl group at the 3-position and a halogen atom at the 5-position.

[0107] Item A10

[0108] The method according to any one of Items A7 to A9, wherein A is a methylene group.

[0109] Item A11

[0110] A method as described in any one of items A7 to A10, wherein R 1 is 3-fluoro-5-(trifluoromethyl)pyridin-2-yl, R 4 It is 6-fluoropyridin-3-yl.

[0111] Item A12

[0112] The method according to any one of Items A7 to A11, wherein the compound is any one of the following.

[0113] ·2-[[4-(5-bromo-2-(6-fluoropyridin-3-yl)-1H-imidazol-4-yl)-3-methoxyphenoxy]methyl]-3-fluoro-5-(trifluoromethyl)pyridine

[0114] ·2-[[4-(5-chloro-2-(6-fluoropyridin-3-yl)-1H-imidazol-4-yl)-3-methoxyphenoxy]methyl]-3-fluoro-5-(trifluoromethyl)pyridine

[0115] ·2-[[3-Chloro-4-(5-chloro-2-(6-fluoropyridin-3-yl)-1H-imidazol-4-yl)phenoxy]methyl]-3-fluoro-5-(trifluoromethyl)pyridine

[0116] Item A13

[0117] A method as described in items A7 to A12, wherein the virus is a coronavirus.

[0118] Item B1

[0119] Use of the compound represented by the following general formula (1) or a pharmaceutically acceptable salt thereof for preparing a cold medicine:

[0120] [Chemical formula 5]

[0121]

[0122] (Where,

[0123] R 1 is a pyridyl group having two groups selected from the group consisting of a halogen atom and a halogenated C1-C6 alkyl group as substituents,

[0124] R 2 , R 5 and R 6 is a hydrogen atom,

[0125] R 3 is a C1-C6 alkoxy group or a halogen atom,

[0126] R 4 is a pyridyl group having a halogen atom as a substituent,

[0127] R 6 When only one of the N at position 1 and the N at position 3 of the imidazole skeleton is substituted and the bond between the N at position 3 and the C at position 2 of the imidazole skeleton is a double bond, R 6 When 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, R 6 Substitute the N at position 3,

[0128] R 7 is a halogen atom,

[0129] A is a C1-C6 alkylene group,

[0130] When the bond between N at position 3 and C at position 2 of the imidazole skeleton is a double bond, the bond between C at position 2 and N at position 1 is a single bond; when the bond between N at position 3 and C at position 2 is a single bond, the bond between C at position 2 and N at position 1 is a double bond).

[0131] Item B2

[0132] The use as described in item B1, wherein R 4 It is 6-halopyridin-3-yl.

[0133] Item B3

[0134] The use as described in item B1 or B2, wherein R 1 It is a pyridin-2-yl group having a halogenated C1-C6 alkyl group at the 3-position and a halogen atom at the 5-position.

[0135] Item B4

[0136] The use according to any one of items B1 to B3, wherein A is a methylene group.

[0137] Item B5

[0138] The use as described in any one of items B1 to B4, wherein R 1 is 3-fluoro-5-(trifluoromethyl)pyridin-2-yl, R 4 It is 6-fluoropyridin-3-yl.

[0139] Item B6

[0140] The use according to any one of Items B1 to B5, wherein the compound is any one of the following.

[0141] ·2-[[4-(5-bromo-2-(6-fluoropyridin-3-yl)-1H-imidazol-4-yl)-3-methoxyphenoxy]methyl]-3-fluoro-5-(trifluoromethyl)pyridine

[0142] ·2-[[4-(5-chloro-2-(6-fluoropyridin-3-yl)-1H-imidazol-4-yl)-3-methoxyphenoxy]methyl]-3-fluoro-5-(trifluoromethyl)pyridine

[0143] ·2-[[3-Chloro-4-(5-chloro-2-(6-fluoropyridin-3-yl)-1H-imidazol-4-yl)phenoxy]methyl]-3-fluoro-5-(trifluoromethyl)pyridine

[0144] Item B7

[0145] Use of the compound represented by the following general formula (1) or a pharmaceutically acceptable salt thereof for preparing an antiviral agent:

[0146] [Chemical formula 6]

[0147]

[0148] (Where,

[0149] R 1 is a pyridyl group having two groups selected from the group consisting of a halogen atom and a halogenated C1-C6 alkyl group as substituents,

[0150] R 2 , R 5 and R 6 is a hydrogen atom,

[0151] R 3 is a C1-C6 alkoxy group or a halogen atom,

[0152] R 4 is a pyridyl group having a halogen atom as a substituent,

[0153] R 6 When only one of the N at position 1 and the N at position 3 of the imidazole skeleton is substituted and the bond between the N at position 3 and the C at position 2 of the imidazole skeleton is a double bond, R 6 When 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, R 6 Substitute the N at position 3,

[0154] R 7 is a halogen atom,

[0155] A is a C1-C6 alkylene group,

[0156] When the bond between N at position 3 and C at position 2 of the imidazole skeleton is a double bond, the bond between C at position 2 and N at position 1 is a single bond; when the bond between N at position 3 and C at position 2 is a single bond, the bond between C at position 2 and N at position 1 is a double bond).

[0157] Item B8

[0158] The use as described in item B7, wherein R 4 It is 6-halopyridin-3-yl.

[0159] Item B9

[0160] The use as described in item B7 or B8, wherein R 1 It is a pyridin-2-yl group having a halogenated C1-C6 alkyl group at the 3-position and a halogen atom at the 5-position.

[0161] Item B10

[0162] The use as described in any one of Items B7 to B9, wherein A is a methylene group.

[0163] Item B11

[0164] The use as described in any one of items B7 to B10, wherein R 1 is 3-fluoro-5-(trifluoromethyl)pyridin-2-yl, R 4 It is 6-fluoropyridin-3-yl.

[0165] Item B12

[0166] The use according to any one of Items B7 to B11, wherein the compound is any one of the following.

[0167] ·2-[[4-(5-bromo-2-(6-fluoropyridin-3-yl)-1H-imidazol-4-yl)-3-methoxyphenoxy]methyl]-3-fluoro-5-(trifluoromethyl)pyridine

[0168] ·2-[[4-(5-chloro-2-(6-fluoropyridin-3-yl)-1H-imidazol-4-yl)-3-methoxyphenoxy]methyl]-3-fluoro-5-(trifluoromethyl)pyridine

[0169] ·2-[[3-Chloro-4-(5-chloro-2-(6-fluoropyridin-3-yl)-1H-imidazol-4-yl)phenoxy]methyl]-3-fluoro-5-(trifluoromethyl)pyridine

[0170] Item B13

[0171] The use as described in items B7 to B12, wherein the virus is a coronavirus.

[0172] Effects of the Invention

[0173] Provides a new and effective means for treating colds. BRIEF DESCRIPTION OF THE DRAWINGS

[0174] [ Figure 1 ] shows the structures of the compounds used in the pharmacological tests of the examples.

[0175] [ Figure 2 ] shows the results of pharmacological test 1 of the example.

[0176] [ Figure 3 ] shows the results of pharmacological test 2 of the example.

[0177] [ Figure 4 ] shows the results of pharmacological test 3 of the example. DETAILED DESCRIPTION

[0178] 1. Compounds of formula (1)

[0179] The halogen atom includes, for example, fluorine, chlorine, bromine and iodine.

[0180] The C1-C6 alkyl group includes, for example, a linear or branched alkyl group 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.

[0181] The C1-C6 alkoxy group includes linear or branched alkoxy groups having 1 to 6 carbon atoms, such as methoxy, ethoxy, n-propoxy, n-butoxy, n-pentyloxy, n-hexyloxy, 1-methylethoxy, tert-butoxy, and 2-methylbutoxy.

[0182] The C1-C6 alkylene group includes, for example, a linear or branched alkylene group having 1 to 6 carbon atoms, such as methylene, ethylene, ethylidene, trimethylene, tetramethylene, pentamethylene, and hexamethylene.

[0183] Halogenated C1-C6 alkyl groups include, for example, halogenated alkyl groups having a halogen atom selected from the group consisting of fluorine, chlorine, bromine and iodine atoms as a substituent, and the alkyl portion is a linear or branched alkyl group having 1 to 6 carbon atoms. Preferred halogenated C1-C6 alkyl groups are perhalogenated alkyl groups, 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.

[0184] Examples of the “pyridyl group having two groups selected from the group consisting of a halogen atom and a halogenated C1-C6 alkyl group as substituents” include 3,4-di(trifluoromethyl)-2-pyridyl, 3,5-di(trifluoromethyl)-2-pyridyl, 3,6-di(trifluoromethyl)-2-pyridyl, 2,4-di(trifluoromethyl)-3-pyridyl, 2,5-di(trifluoromethyl)-3-pyridyl, 2,6-di(trifluoromethyl)- 3-pyridyl, 2,3-bis(trifluoromethyl)-3-pyridyl, 3,5-bis(pentafluoroethyl)-2-pyridyl, 3,5-bis(heptafluoropropyl)-2-pyridyl, 3,5-bis(nonafluorobutyl)-2-pyridyl, 3,5-bis(undecafluoropentyl)-2-pyridyl, 3,5-bis(tridecafluorohexyl)-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- 3-fluoro-5-trifluoromethyl-2-pyridyl, 3-fluoro-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-undecfluoropentyl-2-pyridyl, 3-fluoro-5-tridecafluorohexyl-2-pyridyl, etc. As described above, the two groups selected from the group consisting of halogen atoms and halogenated C1~C6 alkyl groups may be the same or different.

[0185] In one embodiment, the preferred “pyridyl group having two groups selected from the group consisting of a halogen atom and a halogenated C1-C6 alkyl group as substituents” is a “pyridin-2-yl group having a halogenated C1-C6 alkyl group at the 3-position and a halogen atom at the 5-position”, for example, preferably 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, 3-fluoro-5-tridecafluorohexyl-2-pyridyl, and the like, and more preferably 3-fluoro-5-trifluoromethyl-2-pyridyl.

[0186] As the "pyridyl group having a halogen atom as a substituent", for example, 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, 6-iodo-3-pyridyl, etc. can be mentioned. Among them, 6-halogenopyridin-3-yl such as 6-fluoro-3-pyridyl, 6-chloro-3-pyridyl, 6-bromo-3-pyridyl, 6-iodo-3-pyridyl is preferred, and 6-fluoro-3-pyridyl is more preferred.

[0187] In one embodiment, as shown in the following (1-1), the bond between the 3-position N and the 2-position C of the imidazole skeleton of the general formula (1) is a double bond, and the bond between the 2-position C and the 1-position N is a single bond. In another embodiment, as shown in the following (1-2), the bond between the 3-position N and the 2-position C of the imidazole skeleton of the general formula (1) is a single bond, and the bond between the 2-position C and the 1-position N is a double bond.

[0188] [Chemical formula 7]

[0189]

[0190] Preferred specific examples of the compound represented by the general formula (1) include the following compounds.

[0191] ·2-[[4-(5-bromo-2-(6-fluoropyridin-3-yl)-1H-imidazol-4-yl)-3-methoxyphenoxy]methyl]-3-fluoro-5-(trifluoromethyl)pyridine

[0192] ·2-[[4-(5-chloro-2-(6-fluoropyridin-3-yl)-1H-imidazol-4-yl)-3-methoxyphenoxy]methyl]-3-fluoro-5-(trifluoromethyl)pyridine

[0193] ·2-[[3-Chloro-4-(5-chloro-2-(6-fluoropyridin-3-yl)-1H-imidazol-4-yl)phenoxy]methyl]-3-fluoro-5-(trifluoromethyl)pyridine

[0194] The compound represented by the general formula (1) may also be a pharmaceutically acceptable salt thereof. The 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 may be prepared according to conventional methods.

[0195] The compound represented by the general formula (1) may have an optical isomer having a carbon atom as a chiral center. The compound represented by the general formula (1) includes all racemates as a mixture of such optical isomers and optically active substances as individual optical isomers. Optical isomers can be separated by various known resolution methods.

[0196] 2. Manufacturing method

[0197] The compound represented by the general formula (1) can be produced according to the production method described in Patent Document 1.

[0198] 3. Preparation and administration method

[0199] The compound represented by the general formula (1) or a pharmaceutically acceptable salt thereof has excellent infection inhibition and proliferation inhibition effects on viruses. Therefore, the compound represented by the general formula (1) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the same can be used as a cold remedy, an antiviral agent, a viral infection inhibitor, or a preventive or therapeutic agent for viral infections.

[0200] The types of viruses and viral infections are not particularly limited. Examples of viral infections include digestive tract infectious viral infections (e.g., enterovirus, cytomegalovirus), respiratory tract infectious viral infections (e.g., infections caused by respiratory tract infectious viruses such as influenza virus, rhinovirus, coronavirus, parainfluenza virus, RS virus, adenovirus, reovirus, etc.), herpes zoster caused by herpes virus, diarrhea caused by rotavirus, viral hepatitis, AIDS, etc. In one embodiment, the virus is preferably a coronavirus (including SARS-CoV-2).

[0201] Provided is a pharmaceutical composition comprising a compound shown in the general formula (1) or a pharmaceutically acceptable salt thereof. The pharmaceutical composition can be in the form of a general pharmaceutical preparation. The pharmaceutical composition can also contain any pharmaceutically acceptable carrier acceptable in pharmacy in addition to the compound shown in the general formula (1) or a pharmaceutically acceptable salt thereof. As a pharmaceutically acceptable carrier, examples include fillers, extenders, binders, humectants, disintegrants, surfactants, lubricants, diluents, etc. They can be appropriately selected according to the unit administration form of the resulting pharmaceutical composition.

[0202] As the unit administration form of the above-mentioned pharmaceutical preparation, it can be selected from various forms according to the therapeutic purpose. Representative dosage forms include tablets, pills, powders, liquid preparations, suspensions, emulsions, granules, capsules, suppositories, injections (liquid preparations, suspensions, etc.), inhalants and ointments.

[0203] When formed into a tablet form, as the above-mentioned pharmaceutically acceptable carrier, for example, excipients selected from lactose, white sugar, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid and potassium phosphate; binders such as water, ethanol, propanol, monosyrup, glucose solution, starch solution, gelatin solution, carboxymethyl cellulose, hydroxypropyl cellulose, methyl cellulose and polyvinyl pyrrolidone; sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, dry starch, seaweed, etc. can be used. Disintegrants such as sodium alginate, agar powder, kelp polysaccharide powder, sodium bicarbonate and calcium carbonate; surfactants such as polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate and stearic acid monoglyceride; disintegration inhibitors such as white sugar, stearin, cocoa butter and hydrogenated oil; absorption promoters such as quaternary ammonium base and sodium lauryl sulfate; humectants such as glycerol and starch; adsorbents such as starch, lactose, kaolin, bentonite and colloidal silicic acid; lubricants such as purified talc, stearate, boric acid powder and polyethylene glycol, etc. At least one of the group. In addition, the tablet can be made into a tablet with a common coating material applied as needed, such as a sugar-coated tablet, a gelatin-coated tablet, an enteric-coated tablet, a film-coated tablet, or a double-layer tablet or a multi-layer tablet.

[0204] When formed into the form of pills, as a pharmaceutically acceptable carrier, at least one selected from the group consisting of, for example, 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; disintegrants such as kelp polysaccharide and agar, etc. can be used.

[0205] When the suppository is formed, at least one selected from the group consisting of polyethylene glycol, cocoa butter, higher alcohols and esters of higher alcohols, gelatin, and semi-synthetic glycerides can be used as a pharmaceutically acceptable carrier.

[0206] The compound represented by the general formula (1) or a pharmaceutically acceptable salt thereof can be mixed with various pharmaceutically acceptable carriers exemplified above according to conventional methods, and filled into hard gelatin capsules or soft gelatin capsules to prepare capsules.

[0207] In the case of preparation in the form of injections such as liquid preparations, emulsions or suspensions, they are preferably sterilized and isotonic with blood. When these forms are made, as diluent, at least one of the group consisting of, for example, water, ethanol, polyethylene glycol (macrogol), propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol and polyoxyethylene sorbitan fatty acid esters can be used. In this case, the pharmaceutical preparation can contain salt, glucose or glycerol in an amount sufficient to prepare isotonic solution. In addition, common cosolvents, buffers or analgesics etc. can also be added.

[0208] When the ointment is prepared in the form of a paste, cream or gel, at least one selected from the group consisting of white vaseline, paraffin, glycerin, cellulose derivatives, polyethylene glycol, silicone and bentonite can be used as a diluent.

[0209] The pharmaceutical composition may contain colorants, preservatives, fragrances, flavoring agents, sweeteners, and other drugs as necessary.

[0210] The pharmaceutical composition preferably contains the compound represented by general formula (1) or a pharmaceutically acceptable salt thereof in a therapeutically effective amount. For example, the pharmaceutical composition may contain 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.

[0211] The administration method of the pharmaceutical composition is not particularly limited and can be determined according to various preparation forms, the patient's age, sex, degree of disease, other conditions, etc. For example, tablets, pills, liquid preparations, suspensions, emulsions, granules and capsules can be administered orally, injections can be administered intravenously alone or mixed with glucose, amino acids and other common rehydration fluids, or administered intramuscularly, intradermally, subcutaneously or intraperitoneally, and suppositories can be administered rectally.

[0212] The dosage of the pharmaceutical composition can be appropriately selected according to its usage, the patient's age, sex, other conditions, the degree of the disease, etc. For example, the amount of the compound represented by the general formula (1) or a pharmaceutically acceptable salt thereof can be set to about 0.5 to 20 mg per kg body weight per adult per day, preferably about 1 to 10 mg. The pharmaceutical composition can be administered once a day, or divided into 2 to 4 doses.

[0213] Example

[0214] Hereinafter, the present invention will be described in more detail using examples, but the present invention is not limited thereto.

[0215] [Preparation Example 1] Preparation of Tablets

[0216] The compound of Example 281 described in WO2017 / 110237 (2-[[4-(5-chloro-2-(6-fluoropyridin-3-yl)-1H-imidazole-4-yl)-3-methoxyphenoxy]methyl]-3-fluoro-5-(trifluoromethyl)pyridine) (hereinafter referred to as "Compound X") was used as an active ingredient, and tablets (10,000 tablets) containing 300 mg of the compound per tablet were prepared according to the following formula. All the ingredients used were Japanese Pharmacopoeia products.

[0217]

[0218] According to the above formulation, compound X, lactose, corn starch and carboxymethylcellulose calcium were fully mixed, the mixture was granulated with a methylcellulose aqueous solution, passed through a 24-mesh sieve, mixed with magnesium stearate, and pressed into tablets to obtain the target tablets.

[0219] [Preparation Example 2] Preparation of capsules

[0220] Using compound X as an active ingredient, hard gelatin capsules (10,000 capsules) containing 200 mg of compound X per capsule were prepared according to the following formulation. All the ingredients used were Japanese Pharmacopoeia products.

[0221]

[0222] According to the above formulation, each component is finely powdered, mixed to form a uniform mixture, and then filled into a gelatin capsule for oral administration having a desired size to obtain the target capsule.

[0223] [Pharmacological test 1]

[0224] As test compounds, compound X, the compound of Example 255 described in WO2017 / 110237, and the compound of Example 361 (hereinafter referred to as "compound Y" and "compound Z", respectively) were used. As comparative compounds, 3-hydroxypyrazine-2-carboxamide, a similar compound of favipiravir (marketed as the trade name Avigan) for which antiviral activity has been reported [Transboundary Emerging Dis., 63, e205. (2016)], was used. Their chemical structures are shown in Figure 1 .

[0225] As a host cell, MRC-5 (distributed by JCRB Cell Bank) was used and cultured in a 96-well plate until it became a monolayer sheet. Next, the culture medium was removed, and 50 μL of a mixed suspension medium (culture medium: Dulbecco's modified Eagle medium) containing a human coronavirus HCoV-229E solution (distributed by ATCC) and a predetermined amount of the test compound was added, and allowed to stand at room temperature for 1 hour. It should be noted that the concentration of the virus was made to be 3.5 TCID50 / mL in logarithmic terms. Next, the culture medium was removed and washed with phosphate buffered saline (calcium and magnesium-free). Then, a new culture medium (containing 10% FBS (fetal bovine serum)) mixed with the same amount of the test compound as before was added, and cultured at 33°C in the presence of 5% carbon dioxide until a cytopathic effect appeared. After culture (3 to 5 days), freeze-thaw was repeated 3 times, RNA was extracted from the culture medium, and quantified by reverse transcription reaction and qPCR. The conditions are shown in the table below.

[0226] [Table 1]

[0227] Reverse transcription reaction conditions

[0228] step Reaction temperature (℃) Time (minutes) 1 25 10 2 37 1 20 3 85 5 4 4 ∞

[0229] [Table 2]

[0230] Primers and probes

[0231]

[0232] [Table 3]

[0233] qPCR reaction mixture

[0234] Reagents Final concentration Volume / tube Forward Primer 400nM 0.8μL Reverse primer 400nM 0.8μL Probe 300nM 0.6μL qPCR Master Mix 10μL Nuclease-free water 2.8μL Reverse transcription reaction solution 5μL total 20μL

[0235] [Table 4]

[0236] qPCR reaction conditions

[0237]

[0238] According to the following table and Figure 2 The results shown show that the compounds of the present invention represented by Compounds X to Z show particularly high coronavirus infection inhibitory effects compared to the comparative compounds.

[0239] [Table 5]

[0240]

[0241] In the table, “1.E+08” means 1×10 to the power of 8.

[0242] [Pharmacological Test-2]

[0243] As the test compound, the aforementioned compound X was used. As the comparative control compound 1, favipiravir was used, which is approved as an anti-influenza drug in Japan, suggesting that it is also effective against the new coronavirus (SARS-CoV-2). As the comparative control compound 2, chloroquine phosphate was used, which has been temporarily granted emergency use authorization for patients with new coronavirus infection by the U.S. Food and Drug Administration (FDA).

[0244] The test was performed in the same manner as in the above-mentioned pharmacological test 1 except that HCT-8 (ATCC CCL-244) was used as a host cell, OC43 (ATCC VR1588) was used as a human coronavirus, and the test compound was not contained in the medium at the initial 1 hour of standing at room temperature, and fetal bovine serum was not contained in the medium containing the test compound used thereafter. The conditions for the reverse transcription reaction and qPCR are shown in the following table.

[0245] [Table 6]

[0246] Reverse transcription reaction conditions

[0247] step Reaction temperature (℃) Time (minutes) 1 25 10 2 37 120 3 85 5 4 4 ∞

[0248] [Table 7]

[0249] Primers and probes

[0250]

[0251] [Table 8]

[0252] qPCR reaction mixture

[0253] Reagents Final concentration Volume / tube Forward primer 400nM 0.8μL Reverse primer 400nM 0.8μL Probe 300nM 0.6μL qPCR Master Mix 10μL Nuclease-free water 2.8μL Reverse transcription reaction solution 5μL total 20μL

[0254] [Table 9]

[0255] aPCR reaction conditions

[0256]

[0257] According to the following table and Figure 3 The results shown indicate that the compound of the present invention exhibits a particularly high inhibitory effect on coronavirus infection compared to the two comparative control compounds.

[0258] [Table 10]

[0259]

[0260] In the table, "1.E+08" means 1×10 raised to the eighth power. The same applies to other descriptions.

[0261] [Pharmacological test-3]

[0262] As a test compound, the aforementioned compound X was used. As a host cell, Vero E6 (ATCCCRL1586) was used and cultured in a 96-well plate until it became a monolayer sheet. Next, the culture medium was removed, and 50 μL of a mixed suspension medium of SARS-CoV-2 (hCoV-19 / Germany / BY-ChVir-929 / 2020) and a predetermined amount of the test compound was added, and allowed to stand at 37°C for 1 hour. The concentration of the virus was 150 PFU / well. Next, the culture medium was removed and washed with PBS. Then, a new culture medium mixed with the same amount of the test compound as before was added) and cultured at 37°C overnight. After culture, the amount of virus in the culture supernatant was quantified by qPCR. As primers and probes, primers and probes specific to the new coronavirus N1 protein specified by the Centers for Disease Control and Prevention (CDC) of the United States were used, and the conditions were also in accordance with the conditions specified by the CDC. The number of PCR cycles (Ct value) until the signal intensity of the PCR product reached the specified intensity (threshold) was determined.

[0263] According to the following table and Figure 4 The results shown indicate that the compounds of the present invention, represented by compound X, also exhibit an infection inhibitory effect on the new coronavirus SARS-CoV-2.

[0264] [Table 11]

[0265]

Claims

1. Use of a compound represented by the following general formula (1) or a pharmaceutically acceptable salt thereof for the manufacture of an anti-coronavirus agent: [Chemical formula 2] In formula (1), R 1 is 3-fluoro-5-(trifluoromethyl)pyridin-2-yl, R 2 , R 5 and R 6 is a hydrogen atom, R 3 is a C1-C6 alkoxy group or a halogen atom, R 4 is 6-fluoropyridin-3-yl, R 6 When only one of the N at position 1 and the N at position 3 of the imidazole skeleton is substituted and the bond between the N at position 3 and the C at position 2 of the imidazole skeleton is a double bond, R 6 When 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, R 6 Substitute the N at position 3, R 7 is a halogen atom, A is a methylene group, When the bond between N at position 3 and C at position 2 of the imidazole skeleton is a double bond, the bond between C at position 2 and N at position 1 is a single bond. When the bond between N at position 3 and C at position 2 is a single bond, the bond between C at position 2 and N at position 1 is a double bond.

2. The use according to claim 1, wherein The compound is any one of the following: 2-[[4-(5-bromo-2-(6-fluoropyridin-3-yl)-1H-imidazol-4-yl)-3-methoxyphenoxy]methyl]-3-fluoro-5-(trifluoromethyl)pyridine, 2-[[4-(5-chloro-2-(6-fluoropyridin-3-yl)-1H-imidazol-4-yl)-3-methoxyphenoxy]methyl]-3-fluoro-5-(trifluoromethyl)pyridine, · 2-[[3-Chloro-4-(5-chloro-2-(6-fluoropyridin-3-yl)-1H-imidazol-4-yl)phenoxy]methyl]-3-fluoro-5-(trifluoromethyl)pyridine.

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