Antifungal agent for human use

Abstract

Provided is a novel human antifungal agent, and a compound represented by formula (I) or (II) or a salt thereof is used as a human antifungal agent.

Description

Technical Field

[0001] This patent application claims priority based on Japanese Patent Application No. 2020-097174 filed on June 3, 2020, and the entire disclosure of the above prior patent application is incorporated herein by reference as part of this specification. Background Art

[0002] Malassezia spp. are basidiomycetous yeasts that inhabit the skin of humans and animals. Since they proliferate using lipids as a nutrient source, they colonize many parts of sebum and cause skin diseases such as pityriasis versicolor, seborrheic dermatitis, folliculitis, atopic dermatitis, or psoriasis vulgaris.

[0003] Examples of existing therapeutic agents for skin diseases originating from Malassezia spp. include selenium disulfide, 2-mercaptopyridine-N-oxide zinc, piroctone olamine, imidazole compounds such as miconazole nitrate or ketoconazole, and triazole compounds such as itraconazole or fluconazole.

[0004] Generally, skin resident bacteria have so-called barrier effects such as the effect of preventing scalp odor associated with the growth of miscellaneous bacteria on the skin and the effect of maintaining a weakly acidic state by moderately decomposing sebum. However, existing therapeutic agents not only kill pathogenic bacteria but also kill skin resident bacteria, so there is a concern about disrupting the skin's barrier effect. In addition, selenium disulfide has been reported to have side effects such as oral toxicity, hair loss, rash, debilitation, fatigue, and hair discoloration, and 2-mercaptopyridine-N-oxide zinc has been reported to have concerns about sulfur odor and environmental hormones. In addition, although imidazole compounds such as miconazole nitrate and triazole compounds such as itraconazole have the effect of inhibiting lipid synthesis in fungi, due to their property of expressing antibacterial activity by inhibiting the biosynthesis of the cell membrane of bacteria, it takes time to express sufficient effects and long-term administration is required. It is known that if the same drug is continuously administered for a long time, the risk of generating drug-resistant bacteria will increase significantly.

[0005] As described above, since lipid synthesis inhibitors do not rapidly express antibacterial activity even when the drug is administered, they are not suitable for administration methods that require rapid expression of antibacterial activity, such as preventing or treating skin diseases using medicated shampoos. Therefore, there is a need to develop compounds with higher safety, a different mechanism of action from existing therapeutic agents, and that rapidly exhibit antibacterial activity.

[0006] For example, Non-Patent Document 1 describes that the mechanism of action of cyazofamid, a cyanoimidazole compound, is respiratory inhibition.

[0007] It is described in Patent Document 1 that imidazole compounds containing cyazofamid are useful as pest control agents, and it is described in Patent Document 2 that a control agent containing an imidazole compound containing cyazofamid as an active ingredient is useful against animal diseases caused by parasites, such as parasites like coccidia. However, there is no report on the antibacterial activity of imidazole compounds against dermatophytes related to human diseases, such as Malassezia furfur, Candida spp., Malassezia spp., Trichophyton spp., Microsporum spp., Arthroderma spp., Aspergillus spp., and Cryptococcus spp.

[0008] Prior art documents

[0009] Patent Document 1: Japanese Patent Laid-Open No. 1-131163

[0010] Patent Document 2: International Publication Gazette WO 01 / 14341

[0011] Non-Patent Document 1: Pesticide Biochemistry and Physiology, 2001, vol. 71: 107-115 Summary of the invention

[0012] The inventors of the present application have found that the cyanoimidazole compounds represented by the following formula (I) or (II) (hereinafter, also referred to as the compounds of the present disclosure) can be used as novel human antifungal agents effective against dermatophytes related to human diseases.

[0013] Therefore, the present disclosure provides a novel human antifungal agent.

[0014] That is, the present disclosure provides a human antifungal agent containing a compound represented by formula (I) or (II) or a salt thereof.

[0015] [Chemical formula 1]

[0016]

[0017] [In the formula,

[0018] R 1 and R 2 are each independently

[0019] a hydrogen atom,

[0020] a halogen atom,

[0021] a hydroxyl group,

[0022] a nitro group,

[0023] a cyano group,

[0024] a thiocyanate group,

[0025] Trimethylsilyl,

[0026] Optionally substituted alkyl,

[0027] Optionally substituted alkenyl,

[0028] Optionally substituted alkynyl,

[0029] Optionally substituted alkoxy,

[0030] Optionally substituted alkenyloxy,

[0031] Optionally substituted alkynyloxy,

[0032] Optionally substituted aryl,

[0033] Optionally substituted aryloxy,

[0034] Optionally substituted 5- to 6-membered aromatic heterocyclic group,

[0035] -SO m R 3

[0036] (R 3 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted 5- to 6-membered aromatic heterocyclic group or -NR 4 R 5 group (R 4 and R 5 are optionally substituted alkyl), m is an integer from 0 to 2), or

[0037] a group represented by the following formula:

[0038] [Chemical formula 2]

[0039]

[0040] (wherein,

[0041] W 1 is an oxygen atom or a sulfur atom,

[0042] W 2 is an oxygen atom, a sulfur atom or -NH-,

[0043] n is an integer from 0 to 1,

[0044] R 6 is optionally substituted alkyl or optionally substituted aryl);

[0045] X is a hydrogen atom, a hydroxyl group or -OY;

[0046] Y is of the formula:

[0047] [Chemical formula 3]

[0048]

[0049] (wherein,

[0050] R 7 is a substitutable alkyl group,

[0051] a substitutable alkoxy group,

[0052] a substitutable alkenyl group,

[0053] a substitutable alkenyloxy group,

[0054] a substitutable aryl group,

[0055] a substitutable aryloxy group,

[0056] a substitutable 5- to 6-membered aromatic heterocyclic group,

[0057] -NR 8 R 9 group (R 8 and R 9 each independently represent a hydrogen atom, a substitutable alkyl group or a substitutable alkenyl group, or together with the adjacent nitrogen atom form a 5- to 7-membered saturated heterocycle, provided that R 8 and R 9 are not simultaneously hydrogen atoms) or

[0058] -CR 10 R 11 R 12 group (R 10 , R 11 and R 12 each independently represent a substitutable alkyl group, a substitutable alkenyl group or a substitutable aryl group)).]

[0059] According to the present disclosure, a novel human antifungal agent can be provided using the compound represented by formula (I) or (II) or a salt thereof. The compound represented by formula (I) or (II) or a salt thereof can be advantageously used for rapidly exerting excellent antibacterial activity against fungi associated with human diseases. Detailed Embodiments

[0060] In this specification, "halogen" means fluorine, chlorine, bromine, iodine, preferably fluorine, chlorine, bromine.

[0061] In addition, in this specification, unless otherwise defined, terms such as "alkyl", "alkenyl", or "alkynyl" as a group or part of a group respectively refer to an alkyl, alkenyl, or alkynyl group that is linear, branched, cyclic, or a combination thereof. In addition, for example, in the case of "alkyl having 1 to 6 carbon atoms" as a group or part of a group, "1 to 6 carbon atoms" means that the alkyl group has 1 to 6 carbon atoms.

[0062] In addition, in this specification, "alkyl may be substituted" means that one or more hydrogen atoms on the alkyl group may be substituted by one or more substituents (which may be the same or different). It is obvious to those skilled in the art that the maximum number of substituents is determined depending on the number of hydrogen atoms on the alkyl group that can be substituted. The same applies to functional groups other than alkyl groups.

[0063] When the alkyl group represented by R 1 ~R 12 is linear or branched, the number of carbon atoms of the linear or branched alkyl group is preferably 1 to 12, more preferably 1 to 6, and still more preferably 1 to 3. Examples of the linear or branched alkyl group include, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, heptyl, octyl, nonyl, or decyl, etc., preferably methyl, ethyl, n-propyl, or isopropyl, and more preferably methyl or ethyl.

[0064] When the alkyl group represented by R 1 ~R 12 is cyclic, the number of carbon atoms of the cyclic alkyl group (cycloalkyl) is preferably 3 to 7, and more preferably 3 to 6. Examples of the cycloalkyl group include, for example, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, etc.

[0065] The alkyl group may also be substituted. Examples of the substituent include a halogen atom; an alkoxy group that may be substituted by a halogen atom; an alkylthio group that may be substituted by a halogen atom; a phenyl group that may be substituted by a halogen atom; a phenyl group substituted by an alkyl group that may be substituted by a halogen atom; a hydroxyl group; and so on. When the alkyl group is cyclic (cycloalkyl), in addition to the above, an alkyl group that may be substituted by a halogen atom may also be cited as a substituent. The number of these substituents is preferably 0 to 5, and more preferably 1 or 2.

[0066] In R 1 、R 2 and R 7When the alkoxy group represented is linear or branched, the number of carbon atoms in the alkoxy group is preferably from 1 to 12, more preferably from 1 to 6, and still more preferably from 1 to 3. Examples of the linear or branched alkoxy group include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, tert-butoxy, n-pentyloxy, n-hexyloxy, heptyloxy, octyloxy, nonyloxy or decyloxy, etc., preferably methoxy, ethoxy, n-propoxy or isopropoxy, and more preferably methoxy or ethoxy.

[0067] In the case where R 1 , R 2 and R 7 represent a cyclic alkoxy group, the number of carbon atoms in the cyclic alkoxy group (cycloalkoxy group) is preferably from 3 to 7, more preferably from 3 to 6. Examples of the cycloalkoxy group include cyclopropoxy, cyclobutoxy, cyclopentyloxy or cyclohexyloxy, etc.

[0068] The above alkoxy group may also be substituted. Examples of the substituent include a halogen atom; an alkoxy group that may be substituted by a halogen atom; an alkylthio group that may be substituted by a halogen atom; a phenyl group that may be substituted by a halogen atom; a phenyl group substituted by an alkyl group that may be substituted by a halogen atom; a hydroxyl group; and so on. In the case where the alkoxy group is cyclic (cycloalkoxy group), in addition to the above, an alkyl group that may be substituted by a halogen atom may also be cited as a substituent. The number of these substituents is preferably from 0 to 5, and more preferably 1 or 2.

[0069] In the case where R 1 , R 2 , R 3 , R 7 , R 10 , R 11 and R 12 represent a linear or branched alkenyl group, the number of carbon atoms in the linear or branched alkenyl group is preferably from 2 to 12, more preferably from 2 to 6, and still more preferably from 2 to 4. Examples of the linear or branched alkenyl group include allyl or geranyl, etc.

[0070] In the case where R 1 , R 2 , R 3 , R 7 , R 10 , R 11 and R 12 represent a cyclic alkenyl group, the number of carbon atoms in the cyclic alkenyl group (cycloalkenyl group) is preferably from 5 to 8, more preferably from 5 to 6. Examples of the cycloalkenyl group include cyclopentenyl, cyclohexenyl or cyclooctenyl, etc.

[0071] The above-mentioned alkenyl group may also be substituted. Examples of the substituent include a halogen atom; an alkoxy group which may be substituted by a halogen atom; an alkylthio group which may be substituted by a halogen atom; a phenyl group which may be substituted by a halogen atom; a phenyl group substituted by an alkyl group which may be substituted by a halogen atom; a hydroxyl group; and the like. When the alkenyl group is cyclic (cycloalkenyl), examples of the substituent include, in addition to the above, an alkyl group which may be substituted by a halogen atom. The number of these substituents is preferably 0 to 5, more preferably 1 or 2.

[0072] When the alkenyloxy group represented by R 1 , R 2 and R 7 is linear or branched, the number of carbon atoms of the linear or branched alkenyloxy group is preferably 2 to 12, more preferably 2 to 6, and still more preferably 2 to 4. Examples of the linear or branched alkenyloxy group include 2-propenyloxy and the like.

[0073] When the alkenyloxy group represented by R 1 , R 2 and R 7 is cyclic, the number of carbon atoms of the cyclic alkenyloxy group (cycloalkenyloxy) is preferably 5 to 8, more preferably 5 to 6. Examples of the cycloalkenyloxy group include cyclopentyloxy, cyclohexyloxy, cyclooctenyloxy and the like.

[0074] The above-mentioned alkenyloxy group may also be substituted. Examples of the substituent include a halogen atom; an alkoxy group which may be substituted by a halogen atom; an alkylthio group which may be substituted by a halogen atom; a phenyl group which may be substituted by a halogen atom; a phenyl group substituted by an alkyl group which may be substituted by a halogen atom; a hydroxyl group; and the like. When the alkenyloxy group is cyclic (cycloalkenyloxy), examples of the substituent include, in addition to the above, an alkyl group which may be substituted by a halogen atom. The number of these substituents is preferably 0 to 5, more preferably 1 or 2. The number of these substituents is preferably 0 to 5, more preferably 1 or 2.

[0075] When the alkynyl group represented by R 1 , R 2 and R 3 is linear or branched, the number of carbon atoms of the linear or branched alkynyl group is preferably 2 to 12, more preferably 2 to 6, and still more preferably 2 to 4. Examples of the linear or branched alkynyl group include 2-propynyl and the like.

[0076] When the alkynyl group represented by R 1 , R 2 and R 3 is cyclic, the number of carbon atoms of the cyclic alkynyl group (cycloalkynyl) is preferably 6 to 10. Examples of the cycloalkynyl group include cyclooctynyl and the like.

[0077] The above-mentioned alkynyl group can also be substituted. Examples of the substituent include a halogen atom; an alkoxy group that can be substituted by a halogen atom; an alkylthio group that can be substituted by a halogen atom; a phenyl group that can be substituted by a halogen atom; a phenyl group substituted by an alkyl group that can be substituted by a halogen atom; a hydroxyl group; and the like. When the alkynyl group is cyclic (cycloalkynyl), in addition to the above, an alkyl group that can be substituted by a halogen atom can also be cited as a substituent. The number of these substituents is preferably 0 to 5, more preferably 1 or 2.

[0078] When the alkynyloxy group represented by R 1 and R 2 is linear or branched, the number of carbon atoms of the linear or branched alkynyloxy group is preferably 2 to 12, more preferably 2 to 6, and further preferably 2 to 4. Examples of the linear or branched alkynyloxy group include 2-propynyloxy and the like.

[0079] When the alkynyloxy group represented by R 1 and R 2 is cyclic, the number of carbon atoms of the cyclic alkynyloxy group (cycloalkynyloxy) is preferably 6 to 10. Examples of the cycloalkynyloxy group include cyclooctynyloxy and the like.

[0080] The above-mentioned alkynyloxy group can also be substituted. Examples of the substituent include a halogen atom; an alkoxy group that can be substituted by a halogen atom; an alkylthio group that can be substituted by a halogen atom; a phenyl group that can be substituted by a halogen atom; a phenyl group substituted by an alkyl group that can be substituted by a halogen atom; a hydroxyl group; and the like. When the alkynyloxy group is cyclic (cycloalkynyloxy), in addition to the above, an alkyl group that can be substituted by a halogen atom can also be cited as a substituent. The number of these substituents is preferably 0 to 5, more preferably 1 or 2.

[0081] R 1 、R 2 、R 3 、R 6 、R 7 、R 10 、R 11 and R 12 The number of carbon atoms of the aryl group represented is preferably 6 to 14, more preferably 6 to 10. Examples of the aryl group include a phenyl group, a naphthyl group, etc., and a phenyl group is preferred.

[0082] R 1 、R 2 、R 3 、R 6 、R 7 、R 10 、R 11 and R 12The number of carbon atoms in the aryl moiety of the aryloxy group represented is preferably from 6 to 14, more preferably from 6 to 10. As the aryloxy group, phenoxy group, naphthyloxy group, etc. can be mentioned, and a phenoxy group is preferred.

[0083] The above-mentioned aryl group or aryloxy group may also be substituted. As the substituent, a halogen atom; an alkyl group which may be substituted by a halogen atom; an alkoxy group which may be substituted by a halogen atom; an alkylthio group which may be substituted by a halogen atom; a phenyl group which may be substituted by a halogen atom; a phenyl group substituted by an alkyl group which may be substituted by a halogen atom; a hydroxyl group; etc. can be mentioned. The number of these substituents is preferably from 0 to 5, more preferably 1 or 2.

[0084] R 1 、R 2 、R 3 and R 7 The 5- to 6-membered aromatic heterocyclic group represented is preferably an aromatic heterocycle having one or more identical or different heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. The number of heteroatoms in the above-mentioned 5- to 6-membered aromatic heterocyclic group is preferably from 1 to 4, more preferably from 1 to 3, and further preferably 1 or 2. As the above-mentioned 5- to 6-membered aromatic heterocyclic group, for example, a thiophenyl group, a furyl group, a thiazolyl group or a pyridyl group, etc. can be mentioned.

[0085] The above-mentioned 5- to 6-membered aromatic heterocyclic group may also be substituted, and a halogen atom, a nitro group, a cyano group, an alkyl group which may be substituted by a halogen atom, an alkoxyalkyl group, an alkoxy group which may be substituted by a halogen atom, a methylenedioxy group which may be substituted by a halogen atom, -NR 13 R 14 group (R 13 and R 14 are a hydrogen atom, an alkyl group which may be substituted by a halogen atom or an alkanoyl group), -SOpR 15 group (R 15 is an alkyl group which may be substituted by a halogen atom, and p is an integer from 0 to 2), etc. can be mentioned. The number of these substituents is preferably from 0 to 5, more preferably 1 or 2. It should be noted that the alkyl moiety contained in R 13 to R 15 may also be the same as the alkyl moiety in the above-mentioned R 1 to R 12 .

[0086] As the 5- to 7-membered saturated heterocycle formed by the R 8 and R 9 groups together with the adjacent nitrogen atom, a saturated heterocycle having one or more identical or different heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur is preferred. The number of heteroatoms in the above-mentioned 5- to 7-membered saturated heterocycle is preferably from 1 to 4, more preferably from 1 to 3, and further preferably 1 or 2. As the above-mentioned 5- to 7-membered saturated heterocycle, for example, a piperidyl group, a pyrrolidinyl group, a morpholinyl group or a thiomorpholinyl group, etc. can be mentioned.

[0087] According to a preferred embodiment of the present disclosure, R 1 and R 2 are each independently a hydrogen atom, a halogen atom, a hydroxyl group, a nitro group, a cyano group, a thiocyanate group, a trimethylsilyl group, a linear or branched alkyl group which may be substituted, a cycloalkyl group which may be substituted, a linear or branched alkenyl group which may be substituted, a cycloalkenyl group which may be substituted, a linear or branched alkynyl group which may be substituted, a linear or branched alkoxy group which may be substituted, a phenoxy group which may be substituted, a phenyl group which may be substituted, a naphthyl group which may be substituted, a 5- to 6-membered aromatic heterocyclic group which may be substituted, -SO m R 3 (R 3 is a linear or branched alkyl group which may be substituted, a cycloalkyl group which may be substituted, a linear or branched alkenyl group which may be substituted, a cycloalkenyl group which may be substituted, a linear or branched alkynyl group which may be substituted, an aryl group which may be substituted, a pyridyl group which may be substituted, -NR 4 R 5 group (R 4 and R 5 are linear or branched alkyl groups), m is an integer from 0 to 2), or a group of the following formula:

[0088] [Chemical formula 4]

[0089]

[0090] (W 1 is an oxygen atom or a sulfur atom, W 2 is an oxygen atom, a sulfur atom or -NH-, n is an integer from 0 to 1, R 6 is a linear or branched alkyl group which may be substituted, or a phenyl group which may be substituted).

[0091] In addition, according to another preferred embodiment of the present disclosure, R 1 and R 2 are each independently a hydrogen atom, a halogen atom, a nitro group, a cyano group,

[0092] an alkyl group which may be substituted by a halogen atom,

[0093] an alkyl group which is substituted by an alkoxy group which may be substituted by a halogen atom,

[0094] an alkyl group which is substituted by a phenyl group,

[0095] an alkyl group which is substituted by a phenyl group which is substituted by an alkyl group, a halogen atom or a hydroxyl group,

[0096] an alkenyl group which may be substituted by a halogen atom,

[0097] an alkoxy group which may be substituted by a halogen atom,

[0098] phenyl which may be substituted by a halogen atom,

[0099] phenyl substituted by an alkyl group which may be substituted by a halogen atom,

[0100] phenyl substituted by an alkoxy group which may be substituted by a halogen atom,

[0101] thienyl which may be substituted by a halogen atom,

[0102] pyridyl,

[0103] furyl,

[0104] -S(O) m R 3 group (R 3 is an alkyl group which may be substituted by a phenyl group, phenyl which may be substituted by a halogen atom, pyridyl substituted by an alkyl group which may be substituted by a halogen atom, alkenyl or -NR 4 R 5 group (R 4 and R 5 are alkyl groups), m is an integer from 0 to 2), or

[0105] -C(=O)-(NH) n R 6 (R 6 is an alkyl group which may be substituted by a halogen atom, or phenyl which may be substituted by a halogen atom, n is an integer from 0 to 1).

[0106] In addition, according to another preferred embodiment of the present disclosure, R 1 is an unsubstituted alkyl group, an alkyl group substituted by a halogen atom, an alkyl group substituted by a phenyl group which may be substituted by a halogen atom, an alkenyl group which may be substituted by a halogen atom, an alkylthio group, an unsubstituted phenyl group, a phenyl group substituted by a halogen atom, a phenyl group substituted by an alkyl group which may be substituted by a halogen atom, a phenyl group substituted by an alkoxy group which may be substituted by a halogen atom, R 2 is a halogen atom.

[0107] In addition, according to another preferred embodiment of the present disclosure, R 1 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl, 3-chloro-n-propyl, 4-chloro-n-butyl, allyl, ethylthio, phenyl, 2-chlorophenyl, 2-fluorophenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-chloro-4-methylphenyl, 3-chloro-4-methylphenyl, 4-chloro-3-methylphenyl, benzyl or 2-fluorobenzyl, R 2 is a chlorine atom or a bromine atom.

[0108] In addition, according to a more preferred embodiment of the present disclosure, R 1 and R 2Each independently is a hydrogen atom, a halogen atom, or a phenyl group which may be substituted.

[0109] Further, according to a more preferred embodiment of the present disclosure, R 1 and R 2 Each independently is a hydrogen atom or a halogen atom, or a phenyl group which may be substituted by at least one group selected from an alkyl group and a halogen atom.

[0110] Further, according to a more preferred embodiment of the present disclosure, R 1 and R 2 Each independently is a hydrogen atom or a halogen atom, or a phenyl group which may be substituted by at least one group selected from an alkyl group having 1 to 6 carbon atoms and a halogen atom.

[0111] Further, according to a further preferred embodiment of the present disclosure, R 1 and R 2 Are different groups from each other.

[0112] Further, according to a more preferred embodiment of the present disclosure, X is a hydrogen atom, a hydroxyl group, or -OY, preferably a hydrogen atom or a hydroxyl group, and more preferably a hydrogen atom.

[0113] According to a more preferred embodiment of the present disclosure, Y is a group represented by the following formula:

[0114] [Chemical formula 5]

[0115]

[0116] (In the formula, R 7 Is a linear or branched alkyl group which may be substituted, a cycloalkyl group which may be substituted, a phenyl group which may be substituted, a thiophene group which may be substituted, a furan group which may be substituted, or -NR 8 R 9 Group (R 8 And R 9 Each independently is a hydrogen atom, an alkyl group which may be substituted, or an alkenyl group which may be substituted, or together with the adjacent nitrogen atom forms a 5- to 7-membered saturated heterocycle, provided that R 8 And R 9 Are not simultaneously hydrogen atoms).

[0117] Further, according to another preferred embodiment of the present disclosure, R 7 Is a linear or branched alkyl group which may be substituted, a linear or branched alkoxy group which may be substituted, a cycloalkyl group which may be substituted, a phenyl group which may be substituted, a phenoxy group which may be substituted, -NR 8 R 9 Group (R 8 And R 9Each independently is a hydrogen atom, a substituted alkyl group, or a substituted alkenyl group, or together with the adjacent nitrogen atoms forms a 5- to 7-membered saturated heterocycle, excluding R 8 and R 9 being hydrogen atoms simultaneously), or -CR 10 R 11 R 12 group (R 10 , R 11 and R 12 each independently is a substituted alkyl group or a substituted phenyl group).

[0118] In addition, according to another preferred embodiment of the present disclosure, R 7 is a substituted alkyl group, a substituted phenyl group, a substituted alkoxy group, a substituted phenoxy group, or -CR 10 R 11 R 12 group (R 10 , R 11 and R 12 each independently is a substituted alkyl group or a substituted phenyl group).

[0119] In addition, according to a particularly preferred embodiment of the present disclosure, the compound represented by formula (I) or (II) is selected from:

[0120] 5-chloro-4-(4-methylphenyl)-1 H -imidazole-2-carbonitrile, 4-(4-methylphenyl)-1 H -imidazole-2-carbonitrile,

[0121] 5-chloro-4-(3-methylphenyl)-1 H -imidazole-2-carbonitrile, 5-chloro-4-(2-methylphenyl)-1 H -imidazole-2-carbonitrile, 5-chloro-4-(2-chloro-4-methylphenyl)-1 H -imidazole-2-carbonitrile,

[0122] 5-chloro-4-(3-chloro-4-methylphenyl)-1 H -imidazole-2-carbonitrile,

[0123] 5-chloro-4-(4-chloro-3-methylphenyl)-1 H -imidazole-2-carbonitrile,

[0124] 4-(2-chloro-4-methylphenyl)-1 H -imidazole-2-carbonitrile, 5-chloro-1-hydroxy-4-(4-methylphenyl)-imidazole-2-carbonitrile, and

[0125] 4-chloro-1-hydroxy-5-(4-methylphenyl)-imidazole-2-carbonitrile.

[0126] It should be noted that the compounds represented by formula (I) or (II) or their salts can be produced by the methods described in, for example, Japanese Patent Laid-Open No. 8-283243 and Japanese Patent Laid-Open No. 8-225539.

[0127] The compounds of the present disclosure can be used alone or in combination of two or more.

[0128] According to a preferred embodiment, the compounds of the present disclosure may also be in the form of salts. The above salts are preferably pharmaceutically or cosmetically acceptable salts. The above pharmaceutically or cosmetically acceptable salts are salts that can be used as pharmaceuticals. For the compounds represented by formula (I) or (II), in the case of having an acidic group or a basic group, it can be reacted with a base or an acid to form a basic salt or an acidic salt.

[0129] Examples of acidic salts include inorganic acid salts such as hydrochloride, hydrobromide, sulfate, nitrate, and phosphate; organic acid salts such as acetate, propionate, tartrate, fumarate, maleate, malate, citrate, methanesulfonate, benzenesulfonate, and p-toluenesulfonate. In addition, examples of basic salts include alkali metal salts such as sodium salt and potassium salt, and alkaline earth metal salts such as calcium salt and magnesium salt.

[0130] The compounds or their salts of the present disclosure may sometimes absorb moisture and adsorb water or become hydrates due to being placed in the atmosphere or recrystallized. The compounds or their salts of the present disclosure also include these various hydrates, solvates, and polymorphic compounds.

[0131] The compounds or their salts of the present disclosure can be directly used as pharmaceuticals, or other additional components such as the above carriers, active ingredients, pharmacological components, and cosmetic components can be combined as needed and formulated by conventional methods.

[0132] According to a preferred embodiment of the present disclosure, in the above preparations, the content of the compounds of the present disclosure is usually 0.00001 to 30% by mass, preferably 0.0001 to 10% by mass, and more preferably 0.001 to 0.05% by mass.

[0133] According to a preferred embodiment of the present disclosure, as the carrier for the above preparations, a pharmaceutically or cosmetically acceptable carrier is preferred, and examples thereof include excipients, film formers, binders, extenders, disintegrants, lubricants, diluents, osmotic pressure regulators, pH regulators, dispersants, emulsifiers, preservatives, stabilizers, antioxidants, colorants, ultraviolet absorbers, humectants, thickeners, activity enhancers, fragrances, flavoring agents, and odor correctors, etc., which are commonly used carriers.

[0134] In addition, as other additional components, for example, humectants, anti-inflammatory agents, bactericides, antibacterial agents, ultraviolet protectants, cell activators, beauty ingredients, etc. can also be used.

[0135] Preparations containing the compounds or salts thereof of the present disclosure can be provided in the form of pharmaceuticals, quasi-pharmaceuticals or cosmetics, but are preferably used as pharmaceuticals.

[0136] According to a preferred embodiment, as the form of the preparation containing the compounds or salts thereof of the present disclosure, it can be made into any form such as creams, lotions, washes, suspensions, gels, powders, masks, sheets, patches, sticks, cakes, etc., but is not particularly limited to these.

[0137] In addition, as more specific forms of the above preparations, from the viewpoint of the treatment of dermatitis and the like, external medications such as washes, shampoos, creams, lotions, ointments, patches, etc., and cleaning agents for the head or body such as shampoos, body washes, hair conditioners, hair masks, hair creams, nourishing liquids, hair lotions, and washes, creams, lotions for the head or body, etc. can be cited, but are not particularly limited to these.

[0138] The preparations of the present disclosure can be administered orally or parenterally. As dosage forms for oral administration, for example, solid administration forms such as tablets, coated tablets, granules, powders, capsules, and liquid administration forms such as elixirs, syrups, suspensions can be cited. As dosage forms for parenteral administration, injections, infusions, topical administration, external agents, transdermal, transmucosal, nasal, enteral, inhalation, suppositories, boluses, patches, etc. can be cited. The preferred form of this preparation is a topical skin agent.

[0139] The compounds or salts thereof of the present disclosure can immediately exhibit excellent antibacterial activity against fungi that cause human diseases. Therefore, according to one embodiment, the preparations of the present disclosure can be used to improve symptoms or diseases caused by fungi. Here, "improvement" includes not only the treatment of established conditions, but also the prevention of conditions that may be established in the future or the delay thereof. In addition, the improvement in the present disclosure preferably includes: improving the symptoms or conditions of skin diseases, preventing or delaying the deterioration of the symptoms or conditions of skin diseases, reversing, preventing or delaying the progression of the symptoms or conditions of skin diseases.

[0140] As the fungi in the present disclosure, Candida spp., Malassezia spp., Trichophyton spp., Microsporum spp., Arthroderma spp., Aspergillus spp. or Cryptococcus spp. are preferred, and Candida spp., Trichophyton spp., Microsporum spp., Arthroderma spp., Aspergillus spp. or Cryptococcus spp. are more preferred.

[0141] In the present disclosure, Candida refers to a fungus belonging to the family Saccharomycetaceae, and examples thereof include Candida albicans, Candida glabrata and the like.

[0142] In the present disclosure, Malassezia ( Malassezia ) refers to a fungus belonging to the family Malasseziaceae ( Malasseziaceae ), and examples thereof include Malassezia furfur , Malassezia pachydermatis , Malassezia globosa , Malassezia obtusa , Malassezia restricta , Malassezia sympodialis , Malassezia slooffiae , Malassezia dermatis , Malassezia yamatoensis , Malassezia japonica , Malassezia nana and the like.

[0143] In the present disclosure, Trichophyton ( Trichophyton ) is a fungus belonging to the family Arthrodermataceae, and examples thereof include Trichophyton rubrum, Trichophyton interdegitale and the like.

[0144] In the present disclosure, Microsporum ( Microsporum ) is a fungus belonging to the family Arthrodermataceae, and examples thereof include Microsporum canis and the like.

[0145] In the present disclosure, Arthroderma ( Arthroderma ) is a fungus belonging to the family Arthrodermataceae ( Arthrodermataceae ), and examples thereof include Arthroderma vanbreuseghemii and the like.

[0146] In the present disclosure, Aspergillus ( Aspergillus ) is a fungus belonging to the family Trichocomaceae, and examples thereof include Aspergillus fumigatus, Aspergillus niger and the like.

[0147] In the present disclosure, Cryptococcus ( Cryptococcus ) is a fungus belonging to the family Tremellaceae, and examples thereof include Cryptococcus neoformans and the like.

[0148] According to a preferred embodiment, the symptom or disease caused by a fungus is a skin disease. Examples of such skin diseases include, for example, pityriasis versicolor, psoriasis vulgaris, dermatophytosis, candidiasis, pityrosporum folliculitis, aspergillosis, cryptococcosis, atopic dermatitis, or otitis externa, etc. Among them, dermatophytosis, candidiasis, aspergillosis, or cryptococcosis, etc. can be preferably cited.

[0149] The subject to which the compound or its salt of the present disclosure is administered is preferably a human. The administration site of the compound or its salt of the present disclosure is not particularly limited and can be tissues, organs, cells such as the skin where the target fungus exists.

[0150] The compound or its salt of the present disclosure can inhibit the proliferation or sterilize fungi by administering an effective amount for producing antifungal activity to a subject in need thereof. Therefore, according to another aspect of the present disclosure, a method for inhibiting the proliferation or sterilizing fungi can be provided, which comprises administering an effective amount of the compound represented by formula (I) or (II) to a human subject in need thereof. According to another preferred embodiment, the above-mentioned fungus is Candida sp., Malassezia sp., Trichophyton sp., Microsporum sp., Arthroderma sp., Aspergillus sp., or Cryptococcus sp., more preferably Candida sp., Trichophyton sp., Microsporum sp., Arthroderma sp., Aspergillus sp., or Cryptococcus sp. In addition, according to another preferred embodiment of the present disclosure, a method for improving symptoms or diseases caused by fungi can be provided, which comprises administering an effective amount of the compound represented by formula (I) or (II) to a human subject in need thereof.

[0151] The method of the present disclosure is preferably a therapeutic method, but can also be a non-therapeutic method. Specifically, it can be for cosmetic purposes or for non-therapeutic purposes based on the purpose of promoting health. According to one aspect, according to a preferred embodiment of the present disclosure, the above method does not include medical acts, that is, acts of treating an individual through treatment.

[0152] The effective amount of the compound or its salt of the present disclosure varies depending on the animal species, sex, age, weight, condition, and other factors of the subject to be administered, and is an amount that makes the proliferation of the target fungus 50% or less, preferably 40% or less, more preferably 30% or less, further preferably 20% or less, and even more preferably 10% or less of the control.

[0153] The dosage, administration route, and administration interval of the compound of the present disclosure text in the above administration vary depending on the animal species, sex, age, weight, condition, and other factors of the administration subject, and thus cannot be generalized. For example, in the case of topical administration to the affected area of a human, for each adult with a body weight of 60 kg, the administration amount of the compound of the present disclosure text is usually 0.005 to 350 mg / day as the daily dosage, and the preferred dosage per week is 0.01 to 175 mg / week.

[0154] In addition, according to another aspect of the present disclosure, there is provided the use of the compound or its salt represented by formula (I) or (II) in the manufacture of a human antifungal agent. In addition, according to another preferred aspect of the present disclosure, there is provided the use of the compound or its salt represented by formula (I) or (II) in the manufacture of a preparation for improving symptoms or diseases caused by Malassezia spp. According to another preferred aspect, the above-mentioned fungi are Candida spp., Malassezia spp., Trichophyton spp., Microsporum spp., Arthroderma spp., Aspergillus spp., or Cryptococcus spp. In addition, according to another preferred aspect of the present disclosure, the above-mentioned symptoms or diseases are skin diseases. In addition, according to another preferred aspect of the present disclosure, the above-mentioned symptoms or diseases are pityriasis versicolor, psoriasis vulgaris, dermatophytosis, candidiasis, cutaneous malasseziasis, aspergillosis, cryptococcosis, atopic dermatitis, or otitis externa. In addition, according to another preferred aspect of the present disclosure, the above-mentioned antifungal agent is a pharmaceutical. In addition, according to another preferred aspect of the present disclosure, the above-mentioned use is a cosmetic or non-therapeutic use.

[0155] In addition, according to another aspect of the present disclosure, there is provided the compound or its salt represented by formula (I) or (II) for use as a human antifungal agent. In addition, according to another preferred aspect of the present disclosure, there is provided the compound or its salt represented by formula (I) or (II) for improving symptoms or diseases caused by Malassezia spp. According to another preferred aspect, the above-mentioned fungi are Candida spp., Malassezia spp., Trichophyton spp., Microsporum spp., Arthroderma spp., Aspergillus spp., or Cryptococcus spp. In addition, according to another preferred aspect of the present disclosure, the above-mentioned symptoms or diseases are skin diseases. In addition, according to another preferred aspect of the present disclosure, the above-mentioned symptoms or diseases are pityriasis versicolor, psoriasis vulgaris, dermatophytosis, candidiasis, cutaneous malasseziasis, aspergillosis, cryptococcosis, atopic dermatitis, or otitis externa. In addition, according to another preferred aspect of the present disclosure, the above-mentioned antifungal agent is a pharmaceutical.

[0156] In addition, according to one aspect of the present disclosure, the following solution can be provided.

[0157] [1] A human antifungal agent containing the compound or its salt represented by formula (I) or (II).

[0158] [Chemical Formula 6]

[0159]

[0160] [In the formula,

[0161] R 1 ~R 2 each independently represents

[0162] a hydrogen atom,

[0163] a halogen atom,

[0164] a hydroxyl group,

[0165] a nitro group,

[0166] a cyano group,

[0167] a thiocyanate group,

[0168] a trimethylsilyl group,

[0169] an optionally substituted alkyl group,

[0170] an optionally substituted alkenyl group,

[0171] an optionally substituted alkynyl group,

[0172] an optionally substituted alkoxy group,

[0173] an optionally substituted alkenyloxy group,

[0174] an optionally substituted alkynyloxy group,

[0175] an optionally substituted aryl group,

[0176] an optionally substituted aryloxy group,

[0177] an optionally substituted 5- to 6-membered aromatic heterocyclic group,

[0178] -SO m R 3

[0179] (In the formula, R 3 is an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted aryl group, an optionally substituted 5- to 6-membered aromatic heterocyclic group or -NR 4 R 5 group (in the formula, R 4 and R 5 are optionally substituted alkyl groups), m is an integer of 0 to 2), or

[0180] a group represented by the following formula:

[0181] [Chemical Formula 7]

[0182]

[0183] (wherein,

[0184] W 1 is an oxygen atom or a sulfur atom,

[0185] W 2 is an oxygen atom, a sulfur atom or -NH-,

[0186] n is an integer of 0 to 1,

[0187] R 6 is a substituted alkyl group or a substituted aryl group);

[0188] X is a hydrogen atom, a hydroxyl group or -OY;

[0189] Y is of the formula:

[0190] [Chemical formula 8]

[0191]

[0192] (wherein,

[0193] R 7 is a substituted alkyl group,

[0194] a substituted alkoxy group,

[0195] a substituted alkenyl group,

[0196] a substituted alkenyloxy group,

[0197] a substituted aryl group,

[0198] a substituted aryloxy group,

[0199] a substituted 5- to 6-membered aromatic heterocyclic group,

[0200] -NR 8 R 9 group (R 8 and R 9 are each independently a hydrogen atom, a substituted alkyl group or a substituted alkenyl group, or together with the adjacent nitrogen atom form a 5- to 7-membered saturated heterocycle, wherein, excluding the case where R 8 and R 9 are simultaneously hydrogen atoms) or

[0201] -CR 10 R 11 R 12 group (wherein, R 10 、R 11 and R 12Each independently is a substitutable alkyl group, a substitutable alkenyl group, or a substitutable aryl group)).]

[0202] [2] The antifungal agent according to [1], wherein R 1 and R 2 Each independently is a hydrogen atom, a halogen atom, or a substitutable phenyl group.

[0203] [3] The antifungal agent according to [1] or [2], wherein R 1 and R 2 Each independently is a hydrogen atom or a halogen atom, or a phenyl group substituted with at least one group selected from an alkyl group and a halogen atom.

[0204] [4] The antifungal agent according to any one of [1] to [3], wherein R 1 and R 2 Each independently is a hydrogen atom or a halogen atom, or a phenyl group substituted with at least one group selected from an alkyl group having 1 to 6 carbon atoms and a halogen atom.

[0205] [5] The antifungal agent according to any one of [1] to [4], wherein R 1 and R 2 Are different groups from each other.

[0206] [6] The antifungal agent according to any one of [1] to [5], wherein X is a hydrogen atom, a hydroxyl group, or -OY;

[0207] Y is a group represented by the following formula:

[0208] [Chemical formula 9]

[0209]

[0210] (In the formula, R 7 Is a substitutable alkyl group, a substitutable phenyl group, a substitutable alkoxy group, a substitutable phenoxy group, or -CR 10 R 11 R 12 Group (wherein R 10 , R 11 and R 12 Each independently is a substitutable alkyl group or a substitutable phenyl group).

[0211] [7] The antifungal agent according to any one of [1] to [6], wherein X is a hydrogen atom or a hydroxyl group.

[0212] [8] The antifungal agent according to any one of [1] to [7], wherein the compound represented by the above formula (I) or (II) is selected from:

[0213] 5-Chloro-4-(4-methylphenyl)-1 H -imidazole-2-carbonitrile,

[0214] 4-(4-methylphenyl)-1 H -imidazole-2-carbonitrile,

[0215] 5-Chloro-4-(3-methylphenyl)-1 H -imidazole-2-carbonitrile,

[0216] 5-Chloro-4-(2-methylphenyl)-1 H -imidazole-2-carbonitrile,

[0217] 5-Chloro-4-(2-chloro-4-methylphenyl)-1 H -imidazole-2-carbonitrile,

[0218] 5-Chloro-4-(3-chloro-4-methylphenyl)-1 H -imidazole-2-carbonitrile,

[0219] 5-Chloro-4-(4-chloro-3-methylphenyl)-1 H -imidazole-2-carbonitrile,

[0220] 4-(2-chloro-4-methylphenyl)-1 H -imidazole-2-carbonitrile,

[0221] 5-Chloro-1-hydroxy-4-(4-methylphenyl)-imidazole-2-carbonitrile, and

[0222] 4-Chloro-1-hydroxy-5-(4-methylphenyl)-imidazole-2-carbonitrile.

[0223] [9] The antifungal agent according to any one of [1] to [8], which is a pharmaceutical.

[0224]

[10] The antifungal agent according to any one of [1] to [9], wherein the fungus is at least one selected from the group consisting of Candida spp., Malassezia spp., Trichophyton spp., Microsporum spp., Arthroderma spp., Aspergillus spp., and Cryptococcus spp.

[0225]

[11] The antifungal agent according to any one of [1] to

[10] , wherein the fungus is at least one selected from the group consisting of Candida spp., Trichophyton spp., Microsporum spp., Arthroderma spp., Aspergillus spp., and Cryptococcus spp.

[0226]

[12] The antifungal agent according to any one of [1] to

[11] , which is used to improve symptoms or diseases caused by the above-mentioned fungus.

[0227]

[13] The antifungal agent according to

[12] , wherein the above-mentioned symptom or disease is a skin disease.

[0228]

[14] The antifungal agent according to

[12] or

[13] , wherein the above-mentioned symptom or disease is pityriasis versicolor, psoriasis vulgaris, dermatophytosis, candidiasis, pityriasis versicolor caused by Malassezia, aspergillosis, cryptococcosis, atopic dermatitis or otitis externa.

[0229]

[15] The antifungal agent according to any one of

[12] to

[14] , wherein the above-mentioned symptom or disease is pityriasis versicolor caused by Malassezia, dermatophytosis, candidiasis, aspergillosis or cryptococcosis.

[0230] Examples

[0231] Next, test examples related to the present disclosure are described, but they do not limit the present disclosure.

[0232] Production Example 1: 5-chloro-4-(4-methylphenyl)-1H-imidazole-2-carbonitrile (Compound No. 1)

[0233] 5-Chloro-4-(4-methylphenyl)-1H-imidazole-2-carbonitrile (Compound No. 1) (CAS No.: 120118-14-1) was produced according to the method described in Examples 1 to 5 of Japanese Patent Laid-Open No. 8-225539.

[0234] Production Example 2: 4-(4-methylphenyl)-1H-imidazole-2-carbonitrile (Compound No. 2)

[0235] Compound No. 2 (CAS No.: 120118-10-7) was produced in the same manner as described in Japanese Patent Laid-Open No. 8-225539, except that the raw material compound corresponding to the target compound was used.

[0236] MS: 184.2 [M+H] +

[0237] Production Example 3: 5-chloro-4-(3-methylphenyl)-1H-imidazole-2-carbonitrile (Compound No. 3)

[0238] Compound No. 3 (CAS No.: 120118-18-5) was produced in the same manner as described in Japanese Patent Laid-Open No. 8-225539, except that the raw material compound corresponding to the target compound was used.

[0239] MS: 218.2 [M+H] +

[0240] Production Example 4: 5-chloro-4-(2-methylphenyl)-1H-imidazole-2-carbonitrile (Compound No. 4)

[0241] Compound No. 4 was produced in the same manner as described in Japanese Patent Laid-Open No. 8-225539, except that the raw material compound corresponding to the target compound was used.

[0242] 1 1H-NMR (DMSO-d6): δ 7.45 - 7.31 (m, 4H), 3.45 - 3.28 (br, 1H), 2.23 (s, 3H)

[0243] MS: 218.1 [M+H] +

[0244] Production Example 5: 5-chloro-4-(2-chloro-4-methylphenyl)-1H-imidazole-2-carbonitrile (Compound No. 5)

[0245] Except for using the raw material compounds corresponding to the target compounds to be manufactured, Compound No. 5 (CAS No.: 2167064-69-7) was manufactured in the same manner as described in Japanese Patent Application Laid-Open No. 8-225539.

[0246] MS: 252.2 [M+H] +

[0247] Production Example 6: 5-chloro-4-(3-chloro-4-methylphenyl)-1H-imidazole-2-carbonitrile (Compound No. 6)

[0248] Except for using the raw material compounds corresponding to the target compounds to be manufactured, Compound No. 6 (CAS No.: 120118-82-3) was manufactured in the same manner as described in Japanese Patent Application Laid-Open No. 8-225539.

[0249] MS: 252.1 [M+H] +

[0250] Production Example 7: 5-chloro-4-(4-chloro-3-methylphenyl)-1H-imidazole-2-carbonitrile (Compound No. 7)

[0251] Except for using the raw material compounds corresponding to the target compounds to be manufactured, Compound No. 7 was manufactured in the same manner as described in Japanese Patent Application Laid-Open No. 8-225539.

[0252] 1 1H-NMR (DMSO-d6): δ 7.73 (s, 1H), 7.62 - 7.58 (m, 2H), 3.80 - 3.00 (br, 1H), 2.40 (s, 3H)

[0253] MS: 251.0 [M+H] +

[0254] Production Example 8: 4-(2-chloro-4-methylphenyl)-1H-imidazole-2-carbonitrile (Compound No. 8)

[0255] Except for using the raw material compounds corresponding to the target compounds to be manufactured, Compound No. 8 was manufactured in the same manner as described in Japanese Patent Application Laid-Open No. 8-225539.

[0256] 1H-NMR (DMSO-d6): δ 8.10 - 7.93 (br, 1H), 7.93 - 7.77 (br, 1H), 7.38 (s, 1H), 7.24 (d, 1H, J = 8.0 Hz), 3.32 (s, 1H), 2.34 (s, 3H)

[0257] MS: 218.1 [M+H] +

[0258] Production Example 9: 5-chloro-1-hydroxy-4-(4-methylphenyl)-imidazole-2-carbonitrile (Compound No. 9)

[0259] Except for using the raw material compounds corresponding to the target product to be manufactured, Compound No. 9 was manufactured according to the same method as described in Japanese Patent Laid-Open No. 8-225539.

[0260] 1 H-NMR (DMSO-d6): δ 7.72 (d, 2H, J = 8.0 Hz), 7.26 (d, 2H, J = 8.0 Hz), 3.45 - 3.15 (br, 1H), 2.31 (s, 3H)

[0261] MS: 234.1 [M+H] +

[0262] Production Example 10: 4-chloro-1-hydroxy-5-(4-methylphenyl)-imidazole-2-carbonitrile (Compound No. 10)

[0263] Except for using the raw material compounds corresponding to the target product to be manufactured, Compound No. 10 (CAS No.: 177762-70-8) was manufactured according to the same method as described in Japanese Patent Laid-Open No. 8-225539.

[0264] MS: 234.1 [M+H] +

[0265] Test Example 1-1: Antibacterial Activity Test

[0266] Test compound: Compound No. 1

[0267] Test strain: Candida albicans (TIMM1768 strain)

[0268] Test method: Candida obtained by culturing in YPD liquid medium at 37°C for 20 hours was recovered by centrifugation (3000 rpm, 5 minutes), washed twice with physiological saline, and then suspended in physiological saline to prepare a bacterial solution at a concentration of 2×10 3 cells / mL. 100 μL of the above bacterial solution was spread on Sabouraud medium containing the test compound dissolved in DMSO at a specified concentration. After culturing at 37°C for 48 hours, the presence or absence of colony formation was investigated.

[0269] As a result, Compound No.1 completely inhibited colony formation at 50 ppm.

[0270] Test Example 1-2: Antibacterial Activity Test

[0271] Test compound: Compound No.1

[0272] Test strain: Candida glabrata (TIMM6054 strain)

[0273] Test method: Candida obtained by culturing in YPD liquid medium at 37 °C for 20 hours was recovered by centrifugation (3000 rpm, 5 minutes), washed twice with physiological saline, and then suspended in physiological saline to prepare a bacterial solution at a concentration of 2×10 3 cells / mL. 100 μL of the above bacterial solution was spread on YPD medium containing the test compound dissolved in DMSO at a specified concentration. After culturing at 37 °C for 48 hours, the presence or absence of colony formation was investigated.

[0274] As a result, Compound No.1 completely inhibited colony formation at 200 ppm.

[0275] Test Example 1-3: Antibacterial Activity Test

[0276] Test compound: Compound No.1

[0277] Test strain: Cryptococcus neoformans (TIMM1316 strain) Test method: Cryptococcus obtained by culturing in YPD liquid medium at 37 °C for 20 hours was recovered by centrifugation (3000 rpm, 5 minutes), washed twice with physiological saline, and then suspended in physiological saline to prepare a bacterial solution at a concentration of 2×10 3 cells / mL. 100 μL of the above bacterial solution was spread on Sabouraud medium containing the test compound dissolved in DMSO at a specified concentration. After culturing at 37 °C for 48 hours, the presence or absence of colony formation was investigated.

[0278] As a result, Compound No.1 completely inhibited colony formation at 20 ppm.

[0279] Test Example 1-4: Antibacterial Activity Test

[0280] Test compound: Compound No.1

[0281] Test strain: Malassezia nana (CBS95574)

[0282] Malassezia obtained by culturing in Sabouraud's liquid medium containing Tween 80 (polyoxyethylene sorbitan monooleate: manufactured by Kanto Chemical Co., Inc.) (0.05% (v / v)) at 32°C for 20 hours was recovered by centrifugation (3000 rpm, 5 minutes). After washing twice with physiological saline, it was suspended in 10 mL of physiological saline. After standing for 15 minutes, the supernatant was recovered. The supernatant was prepared into a McFarland No. 0.5 bacterial solution with physiological saline, and compound No. 1 dissolved in DMSO was added in such a way as to be 100 ppm or 200 ppm and stirred. After standing at 30°C for 5 minutes, 100 μL of the bacterial solution was suspended in 10 mL of physiological saline, and Malassezia was recovered by centrifugation (3000 rpm, 5 minutes). After washing once with physiological saline, it was resuspended in 500 μL of physiological saline. 100 μL of the resuspended bacterial solution was spread on Sabouraud's medium containing Tween 80 (0.05% (v / v)) and cultured at 30°C for 5 days. Then, the number of colonies formed therein (colony formation number in the inventive area) and the number of colonies in the solvent without the test compound added (colony formation number in the non-drug treatment area) were counted, and the colony formation inhibition rate (%) was calculated according to the following formula.

[0283] Colony formation inhibition rate (%) = [(colony formation number in the non-drug treatment area - colony formation number in the inventive area) / colony formation number in the non-drug treatment area] × 100

[0284] As a result, the colony formation inhibition rate of compound No. 1 was 98.5% at 100 ppm and 99.9% at 200 ppm.

[0285] Test Example 1-5: Antibacterial Activity Test

[0286] Test compound: Compound No. 1

[0287] Test strain: Malassezia pachydermatis (TIMM10024)

[0288] The Malassezia obtained by culturing in Sabouraud liquid medium containing Tween 80 (polyoxyethylene sorbitan monooleate: manufactured by Kanto Chemical Co., Inc.) (0.05% (v / v)) at 32°C for 20 hours was recovered by centrifugation (3000 rpm, 5 minutes). After washing twice with physiological saline, it was suspended in 10 mL of physiological saline. After standing for 15 minutes, the supernatant was recovered. The supernatant was prepared into a McFarland No. 0.5 bacterial solution with physiological saline, and compound No. 1 dissolved in DMSO was added to make it 100 ppm or 200 ppm and stirred. After standing at 30°C for 5 minutes, 100 μL of the bacterial solution was suspended in 10 mL of physiological saline, and the Malassezia was recovered by centrifugation (3,000 rpm, 5 minutes). After washing once with physiological saline, it was resuspended in 500 μL of physiological saline. 100 μL of the resuspended bacterial solution was spread on Sabouraud medium containing Tween 80 (0.05% (v / v)), and after culturing at 30°C for 5 days, the number of colonies formed therein (colony formation number in the present invention area) and the number of colonies in the solvent without the test compound added (colony formation number in the non-drug treatment area) were counted, and the colony formation inhibition rate (%) was obtained by the same method as in Test Examples 1-4.

[0289] As a result, the colony formation inhibition rate of compound No. 1 was 98.1% at 100 ppm and 100% at 200 ppm.

[0290] Test Example 1-6: Antibacterial Activity Test

[0291] Test compound: Compound No. 1

[0292] Test strain: Aspergillusfumigatus (TIMM0063 strain), A.niger (TIMM4968 strain)

[0293] Test method: After culturing Aspergillus in PDA medium at 27°C for 3 days, the spores were collected in physiological saline containing Tween 80 (polyoxyethylene sorbitan monooleate: manufactured by Kanto Chemical Co., Inc.) (0.05% (v / v)) and filtered through a cell strainer (φ40 μm). The spores were recovered from the filtrate by centrifugation (3500 rpm, 5 minutes), washed twice with physiological saline, and a spore suspension (1×10 7 cells / mL) was prepared. 10 μL of the above spore suspension was inoculated into Sabouraud medium added with compound No. 1 dissolved in DMSO to a specified concentration. After culturing at 28°C for 48 hours, the presence or absence of bacterial growth was investigated, and the minimum inhibitory concentration was determined.

[0294] As a result, the minimum inhibitory concentration of Compound No.1 against the two strains was 100 ppm for both.

[0295] Test Example 1-7: Antibacterial Activity Test

[0296] Test compound: Compound No.1

[0297] Test strains: Trichophyton rubrum (CBS118892 strain), T. interdegitale (TIMM20065 strain), Microsporum canis (TIMM20080 strain), Arthroderma vanbreuseghemii (TIMM2789)

[0298] After culturing each strain in Sabouraud medium containing 500 μg / mL of cycloheximide and 50 μg / mL of chloramphenicol at 28 °C for 8 days, the spores were collected in physiological saline containing Tween 80 (polyoxyethylene sorbitan monooleate: Kanto Chemical Co., Inc.) (0.05% (v / v)) and filtered through a cell strainer (φ40 μm). The spores were recovered from the filtrate by centrifugation (3500 rpm, 5 minutes), washed twice with physiological saline, and a spore suspension (1×10 7 cells / mL) was prepared. 10 μL of the above spore suspension was inoculated into Sabouraud medium with Compound No.1 dissolved in DMSO added to reach a specified concentration. After culturing at 28 °C for 72 hours, the presence or absence of bacterial growth was investigated, and the minimum inhibitory concentration was determined.

[0299] As a result, the minimum inhibitory concentration of Compound No.1 against the four strains was 10 ppm for all.

[0300] Test Example 2

[0301] Test compound: Compound No.6

[0302] Test strains: Candida albicans (NBRC1594 strain), Candida glabrata (JCM3761 strain), Cryptococcus neoformans (JCM3685 strain), Aspergillus fumigatus (JCM10253), Aspergillus niger (ATCC6725), Trichophyton rubrum (ATCCMYA4607), Trichophyton interdegitale (ATCC9533), Microsporum canis (NBRC7863), Arthroderma vanbreuseghemii (JCM1891)

[0303] In Sabouraud's medium, Candida and Cryptococcus were cultured at 30 °C for 72 hours, and other bacteria were cultured at 25 °C for 120 hours. Then, they were suspended in 5 mL of PBS (containing 8 g of sodium chloride, 2.9 g of disodium hydrogen phosphate, 0.2 g of potassium chloride, and 0.2 g of potassium dihydrogen phosphate in 1000 mL) containing Tween 80 (polyoxyethylene sorbitan monooleate: Kanto Chemical Co., Inc.) (1% (V / V)) and filtered through a cell strainer (φ40 μm). The spores were recovered from the filtrate by centrifugation (3500 rpm, 5 minutes), washed twice with physiological saline, and a spore suspension (1×10 6 cells / mL) was prepared. 50 μL of the above spore suspension was inoculated into Sabouraud's medium containing the compound No. 6 dissolved in DMSO at a specified concentration. After culturing Candida and Cryptococcus at 30 °C for 72 hours and other bacteria at 25 °C for 120 hours, the presence or absence of colony growth was investigated, and the minimum inhibitory concentration was determined.

[0304] The results are shown in Table 1.

[0305] [Table 1]

[0306] Table 1

[0307] Strain Minimum Inhibitory Concentration <![CDATA Candida albicans > 250ppm <![CDATA Candida glabrata > 250ppm <![CDATA Cryptococcus neoformans > 31.3ppm <![CDATA Aspergillus fumigatus > 62.5ppm <![CDATA Aspergillus niger > 62.5ppm <![CDATA Trichophyton rubrum > 31.3ppm <![CDATA Trichophyton interdegitale > 62.5ppm <![CDATA Microsporum canis > 125ppm <![CDATA Arthroderma vanbreuseghemii > 7.8ppm

[0308] Test Example 3-1: Antifungal Activity Test

[0309] Test compound: Compound No. 6

[0310] Test strains: Malassezia furfur (IFM 55951), Malassezia sympodialis (IFM48588), Malassezia globosa (IFM 51946)

[0311] Malassezia ( Malassezia furfur, Malassezia sympodialis, Malassezia globosa) It was suspended in physiological saline and prepared such that the absorbance at 600 nm became 0.025. The test compound dissolved in DMSO was added thereto such that the final concentrations became 200, 100, 50, and 25 ppm. After 1 minute, 10 μL of the suspension and 10 mL of physiological saline were added to a syringe (Japanese: シリソジ), stirred, connected to a 37 mm mass monitor (manufactured by Pall Corporation), filtered, and washed twice with 10 mL of physiological saline. The membrane filter was removed from the mass monitor, placed on a Chromagar TM Malassezia / Candida growth medium, and cultured at 32 °C for 72 hours. The presence or absence of colony growth was investigated, and the minimum fungicidal concentration (MFC100) was determined. The results are shown in Table 2-1.

[0312] [Table 2-1]

[0313] Table 2-1

[0314] Strain Minimum Fungicidal Concentration (MFC100) <![CDATA Malassezia furfur > 50ppm <![CDATA Malassezia sympodialis > 50ppm <![CDATA Malassezia globosa > 50ppm

[0315] Test Example 3-2: Antifungal Activity Test

[0316] Test compound: Compound No. 6

[0317] Test strain: Malassezia restricta (IFM55992)

[0318] Malassezia obtained by culturing in a Chromagar TM Malassezia / Candida growth medium (peptone, special enzyme substrate mixture, chloramphenicol, olive oil, agar, manufactured by Kanto Chemical Co., Inc.) for 5 to 7 days Malassezia restricta ) was suspended in physiological saline and prepared such that the absorbance at 600 nm became 0.025. The test compound dissolved in DMSO was added thereto such that the final concentrations became 200, 100, 50, and 25 ppm. After 1 minute, 10 μL of the suspension and 10 mL of physiological saline were added to a syringe, stirred, connected to a 37 mm mass monitor (manufactured by Pall Corporation), filtered, and washed twice with 10 mL of physiological saline. The membrane filter was removed from the mass monitor, placed on a Leeming & Notman agar modified medium (MLNA medium) (peptone, glucose, yeast extract, dried ox bile, glycerol, glycerol monostearate, Tween 60, olive oil, agar), and cultured at 32 °C for 72 hours. The presence or absence of colony growth was investigated, and the minimum fungicidal concentration (MFC 100) was determined. The results are shown in Table 2-2.

[0319] [Table 2-2]

[0320] Table 2-2

[0321] Strain Minimum Fungicidal Concentration (MFC100) <![CDATA Malassezia restricta > 200ppm

[0322] Test Example 4: Antifungal Activity Test

[0323] Test compound: Compound No. 6

[0324] Test strains: Trichophyton rubrum (ATCC MYA4607), Microsporum canis (IFM63627)

[0325] The method of Test Example 2 was partially modified to study the antifungal activity. At 32 °C, using Sabouraud medium to culture Trichophyton rubrum , using 1 / 10 Sabouraud medium to culture Microsporum canis , and culturing for 168 hours to form spores. For Trichophyton rubrum , the mycelium was peeled off from the surface of the medium, collected into a tube, physiological saline (Otsuka Shosei Note: containing 9 g of sodium chloride in 1000 mL) was added, and the whole was mixed and dispersed using a disposable inoculation loop (Type 1 (1 μL)) to collect the spore suspension containing the mycelium. For Microsporum canis , 10 mL of physiological saline Direct was added to Culture medium , and the surface was wiped with a disposable inoculation loop to collect the spore suspension containing the mycelium. The spore suspension containing the mycelium of Trichophyton rubrum and Microsporum canis was filtered through a cell strainer (φ40 μm). The spores were recovered from the filtrate by centrifugation (3500 rpm, 5 minutes), washed twice with physiological saline, and then a spore suspension (1×10 7 cells / mL) was prepared. 10 μL of the above spore suspension was inoculated into Sabouraud medium with the test compound dissolved in DMSO added to a specified concentration. Trichophyton rubrum , Microsporum canis After culturing at 32 °C for 72 hours, the presence or absence of colony growth was investigated, and the minimum inhibitory concentration (MIC100) was determined.

[0326] The results are shown in Table 3.

[0327] [Table 3]

[0328] Table 3

[0329] Strain Minimum inhibitory concentration (MIC100) <![CDATA Trichophyton rubrum > 5ppm <![CDATA Microsporum canis > 5ppm

[0330] Test Example 5: Antifungal activity test

[0331] Test compound: Compound No. 6

[0332] Test strains: Trichophyton rubrum (ATCC MYA4607), Microsporum canis (IFM63627)

[0333] At 32°C, using Sabouraud medium to culture Trichophyton rubrum , using 1 / 10 Sabouraud medium to culture Microsporum canis , culture for 168 hours to form spores. For Trichophyton rubrum , peel the mycelium from the surface of the medium, recover it into a tube, add physiological saline (manufactured by Otsuka Pharmaceutical Co., Ltd.; containing 9 g of sodium chloride in 1000 mL), and use a disposable inoculation loop (type 1 (1 μL)) to mix and disperse the whole, and recover the spore suspension containing the mycelium. For Microsporum canis , add 10 mL of physiological saline Direct to Culture medium , wipe the surface with a disposable inoculation loop, and recover the spore suspension containing the mycelium. Filter the spore suspension containing the mycelium of Trichophyton rubrum and Microsporum canis through a cell strainer (φ40 μm). Recover the spores from the filtrate by centrifugation (3500 rpm, 5 minutes), wash twice with physiological saline, and prepare a spore suspension (1×10 7 cells / mL). In 90 μL of physiological saline containing the test compound dissolved in DMSO in such a way as to reach a specified concentration, inoculate 10 μL of the above spore suspension. Every time a specified time passes, collect 10 μL of the test solution containing the spores, recover the spores by centrifugation (3500 rpm, 5 minutes), wash twice with physiological saline, and prepare 10 μL of a spore suspension. Spot 10 μL of the spore suspension on Sabouraud medium, culture at 32°C for 72 hours, and then investigate the presence or absence of colony growth to determine the minimum fungicidal concentration (MFC100).

[0334] The results are shown in Table 4.

[0335] [Table 4]

[0336] Table 4

[0337]

Claims

Use of a compound represented by formula (I) or (II) or a salt thereof in the manufacture of an antifungal agent for human use, wherein the fungus is at least one selected from the group consisting of Candida spp., Malassezia spp., Trichophyton spp., Microsporum spp., Arthroderma spp., Aspergillus spp. and Cryptococcus spp. [Chemical formula 1] In formula (I) and (II), R 1 and R 2 each independently represents a hydrogen atom or a halogen atom, or a phenyl group which may be substituted by at least one group selected from alkyl groups having 1 to 6 carbon atoms and halogen atoms; X is a hydrogen atom or a hydroxyl group.

2. The application according to claim 1, wherein, R 1 and R 2 are different groups from each other.

3. The application according to claim 1 or 2, wherein The compound represented by formula (I) or (II) is selected from: 5-Chloro-4-(4-methylphenyl)-1 H -imidazole-2-carbonitrile, 4-(4-Methylphenyl)-1 H -imidazole-2-carbonitrile, 5-Chloro-4-(3-methylphenyl)-1 H -imidazole-2-carbonitrile, 5-chloro-4-(2-methylphenyl)-1 H -imidazole-2-carbonitrile, 5-Chloro-4-(2-chloro-4-methylphenyl)-1 H -imidazole-2-carbonitrile, 5-Chloro-4-(3-chloro-4-methylphenyl)-1 H -imidazole-2-carbonitrile, 5-Chloro-4-(4-chloro-3-methylphenyl)-1 H -imidazole-2-carbonitrile, 4-(2-chloro-4-methylphenyl)-1 H -imidazole-2-carbonitrile, 5-chloro-1-hydroxy-4-(4-methylphenyl)-imidazole-2-carbonitrile, and 4-chloro-1-hydroxy-5-(4-methylphenyl)-imidazole-2-carbonitrile.

4. The application according to claim 1 or 2, wherein, The antifungal agent for human use is a pharmaceutical.

5. The application according to claim 1 or 2, wherein The fungus is at least one selected from the group consisting of Candida spp., Trichophyton spp., Microsporum spp., Arthroderma spp., Aspergillus spp. and Cryptococcus spp.

6. The application according to claim 1 or 2, wherein The antifungal agent for human use is used to improve symptoms or diseases caused by the fungus, and the symptoms or diseases are skin diseases, and the skin diseases are dermatophytosis, candidiasis, cutaneous malasseziasis, aspergillosis, cryptococcosis or otomycosis.

7. The application according to claim 6, wherein, The skin disease is dermatophytosis or cutaneous malasseziasis.

8. The application according to claim 6, wherein, The skin disease is tinea versicolor.

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