Human antifungal agents

Abstract

Provided is a novel antifungal agent for use in humans. A compound represented by formula (I) or formula (II), or a salt thereof, is used as this antifungal agent for use in humans.

Description

REFERENCE TO RELATED APPLICATIONS

[0001] This patent application claims priority to Japanese Patent Application No. 2020-097174, filed on June 3, 2020, the entire disclosure of which is incorporated herein by reference. [Technical Field]

[0002] Malassezia is a basidiomycete yeast that is normally present on the skin of humans and animals. Because it grows using lipids as a nutrient source, it settles in areas with a high sebum content and is known to cause skin diseases such as tinea versicolor, seborrheic dermatitis, folliculitis, atopic dermatitis, and psoriasis vulgaris.

[0003] Conventional therapeutic agents for skin diseases caused by Malassezia fungi include selenium disulfide, 2-mercaptopyridine zinc N-oxide, piroctone olamine, imidazole compounds such as miconazole nitrate and ketoconazole, and triazole compounds such as itraconazole and fluconazole.

[0004] Resident skin bacteria typically have a barrier effect, preventing scalp odor associated with bacterial proliferation and maintaining a weakly acidic state through the moderate breakdown of sebum. However, conventional treatments sterilize not only pathogenic bacteria but also resident skin bacteria, raising concerns that this barrier effect may be disrupted. Furthermore, selenium disulfide has been noted to have side effects such as oral toxicity, hair loss, skin irritation, weakness, fatigue, and hair discoloration, while 2-mercaptopyridine N-zinc oxide has been noted to have a sulfurous odor and environmental hormone-releasing properties. Furthermore, imidazole compounds such as miconazole nitrate and triazole compounds such as itraconazole inhibit fungal lipid synthesis, but because their antibacterial activity manifests through inhibition of bacterial cell membrane biosynthesis, they require prolonged administration to achieve full efficacy. It is known that continuous administration of the same drug over a long period of time significantly increases the risk of developing resistant bacteria.

[0005] As described above, lipid synthesis inhibitors do not immediately exert antibacterial activity when administered, and therefore are not suitable for administration methods that require immediate antibacterial activity, such as the prevention or treatment of skin diseases using medical shampoos. Therefore, there has been a need for the development of compounds that are highly safe, have a mechanism of action different from that of conventional therapeutic agents, and exhibit immediate antibacterial activity.

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

[0007] Patent Document 1 describes that imidazole compounds including cyazofamid are useful as pest control agents, and Patent Document 2 describes that control agents containing imidazole compounds including cyazofamid as active ingredients are useful against animal diseases caused by parasites, such as coccidia. However, there has been no report on the antibacterial activity of imidazole compounds against skin fungi involved in human diseases, such as cutaneous Malassezia, Candida, Malassezia, Trichophyton, Microsporum, Arthroderma, Aspergillus, and Cryptococcus.

[0008] [Patent Document 1] Japanese Patent Application Publication No. 1-131163 [Patent Document 2] International Publication WO 01 / 14341

[0009] [Non-Patent Document 1] Pesticide Biochemistry and Physiology, 2001, vol.71:107-115 Summary of the Invention

[0010] The present inventors have discovered that cyanoimidazole compounds represented by formula (I) or (II) described below (hereinafter also referred to as the compounds of the present disclosure) can be used as novel antifungal agents for humans that are effective against dermatomycoses involved in human diseases.

[0011] Thus, the present disclosure provides novel antifungal agents for humans.

[0012] That is, the present disclosure provides an antifungal agent for humans containing a compound represented by formula (I) or (II) or a salt thereof. [ka] [In the formula, R 1 and R 2 are each independently hydrogen atoms, halogen atoms, hydroxyl groups, nitro group, cyano group, thiocyanate group, trimethylsilyl group, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group; an optionally substituted alkyloxy group, an optionally substituted alkenyloxy group; an optionally substituted alkynyloxy group; an optionally substituted aryl group; an optionally substituted aryloxy group; an optionally substituted 5- or 6-membered aromatic heterocyclic group, -SO m R 3 (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 (R 4 and R5 is an optionally substituted alkyl group, and m is an integer of 0 to 2, or [ka] (In the formula, 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 an optionally substituted alkyl group or an optionally substituted aryl group) and; X is a hydrogen atom, a hydroxyl group, or -OY; Y is a group having the formula: [ka] (In the formula, R 7 is an optionally substituted alkyl group, an optionally substituted alkyloxy group, an optionally substituted alkenyl group, an optionally substituted alkenyloxy group; an optionally substituted aryl group; an optionally substituted aryloxy group; an optionally substituted 5- or 6-membered aromatic heterocyclic group, -NR 8 R 9 Group (R 8 and R 9 are each independently a hydrogen atom, an optionally substituted alkyl group, or an optionally substituted alkenyl group, or form a 5- to 7-membered saturated heterocycle together with the nitrogen atom adjacent to each other, with the proviso that R 8 and R 9 and are simultaneously hydrogen atoms) or -CR 10 R 11 R 12 Group (R 10 , R 11 and R 12are each independently an optionally substituted alkyl group, an optionally substituted alkenyl group, or an optionally substituted aryl group.

[0013] According to the present disclosure, a novel antifungal agent for human use can be provided using a 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 to rapidly exert excellent antibacterial activity against fungi associated with human diseases. Specific Description of the Invention

[0014] In this specification, the term "halogen" means fluorine, chlorine, bromine, or iodine, and is preferably fluorine, chlorine, or bromine.

[0015] Furthermore, in this specification, the terms "alkyl," "alkenyl," and "alkynyl" as a group or part of a group respectively mean alkyl, alkenyl, or alkynyl groups that are linear, branched, cyclic, or a combination thereof, unless otherwise defined. For example, when referring to an "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.

[0016] In addition, in this specification, the term "optionally substituted" for an alkyl group means that one or more hydrogen atoms on the alkyl group may be substituted with one or more substituents (which may be the same or different). It will be clear to those skilled in the art that the maximum number of substituents can be determined depending on the number of hydrogen atoms that can be substituted on the alkyl group. This also applies to functional groups other than alkyl groups.

[0017] R 1 ~R 12When the alkyl group represented by is linear or branched, the number of carbon atoms in the linear or branched alkyl group is preferably 1 to 12, more preferably 1 to 6, and even more preferably 1 to 3. Examples of the linear or branched alkyl group include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, a sec-butyl group, an isobutyl group, a tert-butyl group, an n-pentyl group, an n-hexyl group, a heptyl group, an octyl group, a nonyl group, and a decyl group, and preferably a methyl group, an ethyl group, an n-propyl group, or an isopropyl group, and more preferably a methyl group or an ethyl group.

[0018] R 1 ~R 12 When the alkyl group represented by is cyclic, the number of carbon atoms in the cyclic alkyl group (cycloalkyl group) is preferably 3 to 7, more preferably 3 to 6. Examples of the cycloalkyl group include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group.

[0019] The alkyl group may be substituted, and examples of the substituent include a halogen atom, an alkyloxy group which may be substituted with a halogen atom, an alkylthio group which may be substituted with a halogen atom, a phenyl group which may be substituted with a halogen atom, a phenyl group substituted with an alkyl group which may be substituted with a halogen atom, and a hydroxyl group. When the alkyl group is cyclic (cycloalkyl group), examples of the substituent include an alkyl group which may be substituted with a halogen atom in addition to the above. The number of these substituents is preferably 0 to 5, more preferably 1 or 2.

[0020] R 1 , R 2 and R 7When the alkyloxy group represented by is linear or branched, the number of carbon atoms in the alkyloxy group is preferably 1 to 12, more preferably 1 to 6, and even more preferably 1 to 3. Examples of the linear or branched alkyloxy group include a methoxy group, an ethoxy group, an n-propyloxy group, an isopropyloxy group, an n-butyloxy group, a sec-butyloxy group, an isobutyloxy group, a tert-butyloxy group, an n-pentyloxy group, an n-hexyloxy group, a heptyloxy group, an octyloxy group, a nonyloxy group, and a decyloxy group, and preferably a methoxy group, an ethoxy group, an n-propyloxy group, or an isopropyloxy group, and more preferably a methoxy group or an ethoxy group.

[0021] R 1 , R 2 and R 7 When the alkyloxy group represented by is cyclic, the number of carbon atoms in the cyclic alkyloxy group (cycloalkyloxy group) is preferably 3 to 7, more preferably 3 to 6. Examples of the cycloalkyloxy group include a cyclopropyloxy group, a cyclobutyloxy group, a cyclopentyloxy group, and a cyclohexyloxy group.

[0022] The alkyloxy group may be substituted, and examples of the substituent include a halogen atom; an alkyloxy group which may be substituted with a halogen atom; an alkylthio group which may be substituted with a halogen atom; a phenyl group which may be substituted with a halogen atom; a phenyl group substituted with an alkyl group which may be substituted with a halogen atom; and a hydroxyl group. When the alkyloxy group is cyclic (a cycloalkyloxy group), examples of the substituent include an alkyl group which may be substituted with a halogen atom in addition to the above. The number of these substituents is preferably 0 to 5, more preferably 1 or 2.

[0023] R 1 , R 2 , R 3 , R 7 , R 10 , R 11 and R 12When the alkenyl group represented by is linear or branched, the number of carbon atoms in the linear or branched alkenyl group is preferably 2 to 12, more preferably 2 to 6, and even more preferably 2 to 4. Examples of the linear or branched alkenyl group include an allyl group and a geranyl group.

[0024] R 1 , R 2 , R 3 , R 7 , R 10 , R 11 and R 12 When the alkenyl group represented by is cyclic, the number of carbon atoms in the cyclic alkenyl group (cycloalkenyl group) is preferably 5 to 8, more preferably 5 to 6. Examples of the cycloalkenyl group include a cyclopentenyl group, a cyclohexenyl group, and a cyclooctenyl group.

[0025] The alkenyl group may be substituted, and examples of the substituent include a halogen atom, an alkyloxy group which may be substituted with a halogen atom, an alkylthio group which may be substituted with a halogen atom, a phenyl group which may be substituted with a halogen atom, a phenyl group substituted with an alkyl group which may be substituted with a halogen atom, and a hydroxyl group. When the alkenyl group is cyclic (a cycloalkenyl group), examples of the substituent include an alkyl group which may be substituted with a halogen atom in addition to the above. The number of these substituents is preferably 0 to 5, more preferably 1 or 2.

[0026] R 1 , R 2 and R 7 When the alkenyloxy group represented by is linear or branched, the number of carbon atoms in the linear or branched alkenyloxy group is preferably 2 to 12, more preferably 2 to 6, and even more preferably 2 to 4. Examples of linear or branched alkenyloxy groups include a 2-propenyloxy group.

[0027] R 1 , R 2 and R7 When the alkenyloxy group represented by the formula (I) is cyclic, the number of carbon atoms in the cyclic alkenyloxy group (cycloalkenyloxy group) is preferably 5 to 8, more preferably 5 to 6. Examples of the cycloalkenyloxy group include a cyclopentenyloxy group, a cyclohexenyloxy group, and a cyclooctenyloxy group.

[0028] The alkenyloxy group may be substituted, and examples of the substituent include a halogen atom; an alkyloxy group which may be substituted with a halogen atom; an alkylthio group which may be substituted with a halogen atom; a phenyl group which may be substituted with a halogen atom; a phenyl group substituted with an alkyl group which may be substituted with a halogen atom; and a hydroxyl group. When the alkenyloxy group is cyclic (a cycloalkenyloxy group), examples of the substituent include an alkyl group which may be substituted with a halogen atom in addition to the above. 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.

[0029] R 1 , R 2 and R 3 When the alkynyl group represented by is linear or branched, the number of carbon atoms in the linear or branched alkynyl group is preferably 2 to 12, more preferably 2 to 6, and even more preferably 2 to 4. Examples of linear or branched alkynyl groups include a 2-propynyl group.

[0030] R 1 , R 2 and R 3 When the alkynyl group represented by the formula (I) is cyclic, the number of carbon atoms in the cyclic alkynyl group (cycloalkynyl group) is preferably 6 to 10. Examples of the cycloalkynyl group include a cyclooctynyl group.

[0031] The alkynyl group may be substituted, and examples of the substituent include a halogen atom, an alkyloxy group which may be substituted with a halogen atom, an alkylthio group which may be substituted with a halogen atom, a phenyl group which may be substituted with a halogen atom, a phenyl group substituted with an alkyl group which may be substituted with a halogen atom, and a hydroxyl group. When the alkynyl group is cyclic (a cycloalkynyl group), examples of the substituent include an alkyl group which may be substituted with a halogen atom in addition to the above. The number of these substituents is preferably 0 to 5, more preferably 1 or 2.

[0032] R 1 and R 2 When the alkynyloxy group represented by is linear or branched, the number of carbon atoms in the linear or branched alkynyloxy group is preferably 2 to 12, more preferably 2 to 6, and even more preferably 2 to 4. Examples of linear or branched alkynyloxy groups include a 2-propynyloxy group.

[0033] R 1 and R 2 When the alkynyloxy group represented by the formula (I) is cyclic, the number of carbon atoms in the cyclic alkynyloxy group (cycloalkynyloxy group) is preferably 6 to 10. Examples of the cycloalkynyloxy group include a cyclooctynyloxy group.

[0034] The alkynyloxy group may be substituted, and examples of the substituent include a halogen atom, an alkyloxy group which may be substituted with a halogen atom, an alkylthio group which may be substituted with a halogen atom, a phenyl group which may be substituted with a halogen atom, a phenyl group substituted with an alkyl group which may be substituted with a halogen atom, and a hydroxyl group. When the alkynyloxy group is cyclic (a cycloalkynyloxy group), examples of the substituent include an alkyl group which may be substituted with a halogen atom in addition to the above. The number of these substituents is preferably 0 to 5, more preferably 1 or 2.

[0035] R 1 , R2 , R 3 , R 6 , R 7 , R 10 , R 11 and R 12 The number of carbon atoms in the aryl group represented by is preferably 6 to 14, more preferably 6 to 10. Examples of the aryl group include a phenyl group and a naphthyl group, with a phenyl group being preferred.

[0036] R 1 , R 2 , R 3 , R 6 , R 7 , R 10 , R 11 and R 12 The number of carbon atoms in the aryl moiety of the aryloxy group represented by the formula (I) is preferably 6 to 14, more preferably 6 to 10. Examples of the aryloxy group include a phenyloxy group and a naphthyloxy group, with a phenyloxy group being preferred.

[0037] The aryl group or aryloxy group may be substituted, and examples of the substituent include a halogen atom, an alkyl group which may be substituted with a halogen atom, an alkyloxy group which may be substituted with a halogen atom, an alkylthio group which may be substituted with a halogen atom, a phenyl group which may be substituted with a halogen atom, a phenyl group substituted with an alkyl group which may be substituted with a halogen atom, a hydroxyl group, etc. The number of these substituents is preferably 0 to 5, and more preferably 1 or 2.

[0038] R 1 , R 2 , R 3 and R 7The 5- or 6-membered aromatic heterocyclic group represented by the formula (I) is preferably an aromatic heterocycle having one or more heteroatoms, which may be the same or different, selected from the group consisting of nitrogen, oxygen, and sulfur. The number of heteroatoms in the 5- or 6-membered aromatic heterocyclic group is preferably 1 to 4, more preferably 1 to 3, and even more preferably 1 or 2. Examples of the 5- or 6-membered aromatic heterocyclic group include a thienyl group, a furyl group, a thiazolyl group, and a pyridyl group.

[0039] The above 5- to 6-membered aromatic heterocyclic group may be substituted, and may be substituted with a halogen atom, a nitro group, a cyano group, an alkyl group which may be substituted with a halogen atom, an alkyloxyalkyl group, an alkyloxy group which may be substituted with a halogen atom, a methylenedioxy group which may be substituted with a halogen atom, -NR 13 R 14 Group (R 13 and R 14 represents a hydrogen atom, an alkyl group which may be substituted with a halogen atom, or an alkanoyl group, -SOpR 15 Group (R 15 is an alkyl group which may be substituted with a halogen atom, and p is an integer of 0 to 2. The number of these substituents is preferably 0 to 5, and more preferably 1 or 2. 13 ~R 15 The alkyl moiety contained in the above R 1 ~R 12 It may be the same as the alkyl moiety in the above.

[0040] R 8 and R 9 The 5- to 7-membered saturated heterocyclic ring formed by the groups together with adjacent nitrogen atoms is preferably a saturated heterocyclic ring having one or more heteroatoms, which may be the same or different, selected from the group consisting of nitrogen, oxygen, and sulfur. The number of heteroatoms in the 5- to 7-membered saturated heterocyclic ring is preferably 1 to 4, more preferably 1 to 3, and even more preferably 1 or 2. Examples of the 5- to 7-membered saturated heterocyclic ring include a piperidine group, a pyrrolidine group, a morpholine group, and a thiomorpholine group.

[0041] 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 thiocyanato group, a trimethylsilyl group, an optionally substituted linear or branched alkyl group, an optionally substituted cycloalkyl group, an optionally substituted linear or branched alkenyl group, an optionally substituted cycloalkenyl group, an optionally substituted linear or branched alkynyl group, an optionally substituted linear or branched alkyloxy group, an optionally substituted phenyloxy group, an optionally substituted phenyl group, an optionally substituted naphthyl group, an optionally substituted 5- to 6-membered aromatic heterocyclic group, -SO m R 3 (R 3 represents an optionally substituted linear or branched alkyl group, an optionally substituted cycloalkyl group, an optionally substituted linear or branched alkenyl group, an optionally substituted cycloalkenyl group, an optionally substituted linear or branched alkynyl group, an optionally substituted aryl group, an optionally substituted pyridyl group, -NR 4 R 5 Group (R 4 and R 5 is a linear or branched alkyl group, and m is an integer of 0 to 2, or [ka] Base(W 1 is an oxygen atom or a sulfur atom, and W 2 is an oxygen atom, a sulfur atom, or -NH-, n is an integer of 0 to 1, and R 6 is an optionally substituted linear or branched alkyl group or an optionally substituted phenyl group).

[0042] 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, an alkyl group optionally substituted with a halogen atom; an alkyl group substituted with an alkyloxy group which may be substituted with a halogen atom; an alkyl group substituted with a phenyl group; an alkyl group substituted with an alkyl group, a phenyl group substituted with a halogen atom or a hydroxyl group; an alkenyl group optionally substituted with a halogen atom; an alkyloxy group optionally substituted with a halogen atom; a phenyl group optionally substituted with a halogen atom; a phenyl group substituted by an alkyl group which may be substituted by a halogen atom; a phenyl group substituted with an alkyloxy group which may be substituted with a halogen atom; a thienyl group optionally substituted with a halogen atom; pyridyl group, furyl group, -S(O) m R 3 Group (R 3 represents an alkyl group which may be substituted with a phenyl group, a phenyl group which may be substituted with a halogen atom, a pyridyl group which may be substituted with an alkyl group substituted with a halogen atom, an alkenyl group, or -NR 4 R 5 Group (R 4 and R 5 is an alkyl group, and m is an integer of 0 to 2, or -C(=O)-(NH) n R 6 (R 6 represents an alkyl group which may be substituted with a halogen atom, or a phenyl group which may be substituted with a halogen atom, and n is an integer of 0 to 1).

[0043] According to another preferred embodiment of the present disclosure, R 1represents an unsubstituted alkyl group, an alkyl group substituted with a halogen atom, an alkyl group substituted with a phenyl group which may be substituted with a halogen atom, an alkenyl group which may be substituted with a halogen atom, an alkylthio group, an unsubstituted phenyl group, a phenyl group substituted with a halogen atom, a phenyl group substituted with an alkyl group which may be substituted with a halogen atom, or a phenyl group substituted with an alkyloxy group which may be substituted with a halogen atom; R 2 is a halogen atom.

[0044] According to another preferred embodiment of the present disclosure, R 1 is a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, an n-pentyl group, a 3-chloro-n-propyl group, a 4-chloro-n-butyl group, an allyl group, an ethylthio group, a phenyl group, a 2-chlorophenyl group, a 2-fluorophenyl group, a 2-methylphenyl group, a 3-methylphenyl group, a 4-methylphenyl group, a 2-chloro-4-methylphenyl group, a 3-chloro-4-methylphenyl group, a 4-chloro-3-methylphenyl group, a benzyl group, or a 2-fluorobenzyl group; R 2 is a chlorine atom or a bromine atom.

[0045] According to a more preferred embodiment of the present disclosure, R 1 and R 2 are each independently a hydrogen atom, a halogen atom, or an optionally substituted phenyl group.

[0046] According to a more preferred embodiment of the present disclosure, R 1 and R 2 are each independently a hydrogen atom or a halogen atom, or a phenyl group which may be substituted with at least one group selected from the group consisting of an alkyl group and a halogen atom.

[0047] According to a more preferred embodiment of the present disclosure, R 1 and R 2are each independently a hydrogen atom or a halogen atom, or a phenyl group which may be substituted with at least one group selected from an alkyl group having 1 to 6 carbon atoms and a halogen atom.

[0048] According to a more preferred embodiment of the present disclosure, R 1 and R 2 are different groups.

[0049] Furthermore, 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.

[0050] According to a more preferred embodiment of the present disclosure, Y is of the formula: [ka] (In the formula, R 7 is an optionally substituted linear or branched alkyl group, an optionally substituted cycloalkyl group, an optionally substituted phenyl group, an optionally substituted thienyl group, an optionally substituted furyl group, or —NR 8 R 9 Group (R 8 and R 9 are each independently a hydrogen atom, an optionally substituted alkyl group, or an optionally substituted alkenyl group, or form a 5- to 7-membered saturated heterocycle together with the nitrogen atom adjacent to each other, with the proviso that R 8 and R 9 and are simultaneously hydrogen atoms).

[0051] According to another preferred embodiment of the present disclosure, R 7 represents an optionally substituted linear or branched alkyl group, an optionally substituted linear or branched alkyloxy group, an optionally substituted cycloalkyl group, an optionally substituted phenyl group, an optionally substituted phenyloxy group, -NR 8 R 9 Group (R 8 and R 9are each independently a hydrogen atom, an optionally substituted alkyl group, or an optionally substituted alkenyl group, or form a 5- to 7-membered saturated heterocycle together with the nitrogen atom adjacent to each other, with the proviso that R 8 and R 9 and -CR are hydrogen atoms), or 10 R 11 R 12 Group (R 10 , R 11 and R 12 are each independently an optionally substituted alkyl group or an optionally substituted phenyl group).

[0052] According to another preferred embodiment of the present disclosure, R 7 is an optionally substituted alkyl group, an optionally substituted phenyl group, an optionally substituted alkyloxy group, an optionally substituted phenyloxy group, or -CR 10 R 11 R 12 Group (R 10 , R 11 and R 12 are each independently an optionally substituted alkyl group or an optionally substituted phenyl group).

[0053] According to a particularly preferred embodiment of the present disclosure, the compound represented by formula (I) or (II) is 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)-1 H -imidazole-2-carbonitrile, and 4-chloro-1-hydroxy-5-(4-methylphenyl)-1 H -imidazole-2-carbonitrile It is selected from:

[0054] The compounds represented by formula (I) or (II) or salts thereof can be produced by the methods described in JP-A-8-283243 and JP-A-8-225539.

[0055] The compounds of the present disclosure may be used alone or in combination of two or more.

[0056] According to a preferred embodiment, the compound of the present disclosure may be in the form of a salt. The salt is preferably a pharmaceutically or cosmetically acceptable salt. The pharmaceutically or cosmetically acceptable salt refers to a salt that can be used as a medicine. When the compound represented by formula (I) or (II) has an acidic or basic group, it can be converted into a basic salt or an acid salt by reacting with a base or an acid.

[0057] Examples of acidic salts include inorganic acid salts such as hydrochloride, hydrobromide, sulfate, nitrate, phosphate, etc., and organic acid salts such as acetate, propionate, tartrate, fumarate, maleate, malate, citrate, methanesulfonate, benzenesulfonate, paratoluenesulfonate, etc. Examples of basic salts include alkali metal salts such as sodium salt, potassium salt, etc., and alkaline earth metal salts such as calcium salt, magnesium salt, etc.

[0058] The compound of the present disclosure or a salt thereof may absorb moisture when left in the air or when recrystallized, and may become adsorbed water or become a hydrate. The compound of the present disclosure or a salt thereof also encompasses such various hydrates, solvates, and crystalline polymorphic compounds.

[0059] The compound of the present disclosure or a salt thereof may be used as a drug as it is, but can also be formulated by a conventional method by combining it with other additional ingredients such as the above-mentioned carrier, active ingredient, pharmacological ingredient, cosmetic ingredient, etc., as needed.

[0060] According to a preferred embodiment of the present disclosure, the content of the compound of the present disclosure in the formulation is generally 0.00001 to 30% by mass, preferably 0.0001 to 10% by mass, and more preferably 0.001 to 0.05% by mass.

[0061] According to a preferred embodiment of the present disclosure, the carrier used in the above-mentioned formulation is preferably a pharmaceutically or cosmetically acceptable carrier, and examples thereof include commonly used carriers such as excipients, coating agents, binders, bulking agents, disintegrants, lubricants, diluents, osmotic pressure adjusters, pH adjusters, dispersants, emulsifiers, preservatives, stabilizers, antioxidants, colorants, UV absorbers, moisturizers, thickeners, activity enhancers, fragrances, flavorings, and odor enhancers.

[0062] Other additional ingredients may also be used, such as moisturizers, anti-inflammatory agents, germicides, antibacterial agents, UV protection agents, cell activators, and makeup ingredients.

[0063] A formulation containing the compound of the present disclosure or a salt thereof can be provided as a pharmaceutical product, a quasi-drug, or a cosmetic, but is preferably used as a pharmaceutical product.

[0064] According to a preferred embodiment, the formulation containing the compound of the present disclosure or a salt thereof may be in any form, such as, for example, a cream, emulsion, lotion, suspension, gel, powder, pack, sheet, patch, stick, cake, etc., but is not particularly limited to these.

[0065] Furthermore, from the viewpoint of treating dermatitis and the like, more specific forms of the above-mentioned preparations include topical medications such as lotions, shampoos, creams, emulsions, ointments, and patches, as well as cleansers for the head or body such as shampoos and body shampoos, rinses, conditioners, treatments, hair packs, hair tonics, hair creams, and lotions, creams, and emulsions for the head or body, but are not particularly limited to these.

[0066] The formulations of the present disclosure may be administered orally or parenterally. Examples of dosage forms for oral administration include solid dosage forms such as tablets, coated tablets, granules, powders, and capsules, as well as liquid dosage forms such as elixirs, syrups, and suspensions. Examples of dosage forms for parenteral administration include injections, infusions, topical, external, transdermal, transmucosal, nasal, rectal, inhalation, suppositories, boluses, and patches. A preferred form of the formulation is an external skin formulation.

[0067] The compounds or salts thereof disclosed herein can immediately exhibit excellent antibacterial activity against fungi that cause human diseases. Therefore, in one embodiment, the formulations disclosed herein are used to improve symptoms or diseases caused by fungi. Here, "improvement" includes not only the treatment of established pathologies, but also prevention, which prevents or delays pathologies that may be established in the future. Furthermore, improvement in the present disclosure preferably also includes improvement of the symptoms or condition of skin diseases, prevention or delay of worsening of the symptoms or condition of skin diseases, and reversal, prevention, or delay of the progression of the symptoms or condition of skin diseases.

[0068] The fungi in the present disclosure are preferably Candida, Malassezia, Trichophyton, Microsporum, Arthroderma, Aspergillus, or Cryptococcus, and more preferably Candida, Trichophyton, Microsporum, Arthroderma, Aspergillus, or Cryptococcus.

[0069] In the present disclosure, Candida refers to fungi belonging to the Saccharomycetaceae family, such as: Candida albicans , Candida glabrata etc.

[0070] In the present disclosure, Malassezia spp. Malassezia) Malassezia family ( Malasseziaceae ), such as Malassezia furfur , Malassezia pachydermatis , Malassezia globosa , Malassezia obtusa , Malassezia restricta , Malassezia sympodialis , Malassezia slooffiae , Malassezia dermatis , Malassezia yamatoensis , Malassezia japonica , Malassezia nana etc.

[0071] In the present disclosure, Trichophyton spp. Trichophyton) Examples of fungi include those belonging to the Arthrodermataceae family, such as: Trichophyton rubrum , Trichophyton interdigital etc.

[0072] In the present disclosure, Microsporum sp. Microsporum) Examples of fungi include those belonging to the Arthrodermataceae family, such as: Microsporum canis etc.

[0073] In the present disclosure, Arthroderma sp. Arthroderma) As for Arthrodermataceae ( Arthrodermataceae ), such as Arthroderma vanbreuseghemii etc.

[0074] In the present disclosure, Aspergillus spp. Aspergillus It is a fungus belonging to the Trichocomaceae family, for example, Aspergillus fumigatus , Aspergillus Niger etc.

[0075] In the present disclosure, Cryptococcus spp. Cryptococcus Examples of the fungi include those belonging to the Tremellaceae family, such as Cryptococcus neoformans etc.

[0076] In a preferred embodiment, the symptom or disease caused by a fungus is a skin disease, such as tinea versicolor, psoriasis vulgaris, dermatophytosis, candidiasis, cutaneous malasseziosis, aspergillosis, cryptococcosis, atopic dermatitis, or otitis externa, preferably dermatophytosis, candidiasis, aspergillosis, or cryptococcosis.

[0077] The subject to which the compound of the present disclosure or a salt thereof is administered is preferably a human. The site to which the compound of the present disclosure or a salt thereof is administered is not particularly limited, and may be a tissue such as skin, an organ, or a cell where the target fungus is present.

[0078] The compound or salt thereof of the present disclosure can inhibit or kill fungal growth by administering an effective amount for producing antifungal activity to a subject in need thereof. Therefore, according to another aspect of the present disclosure, there is provided a method for inhibiting or killing fungal growth, comprising administering an effective amount of a compound represented by formula (I) or (II) to a human subject in need thereof. According to another preferred aspect, the fungus is a Candida, Malassezia, Trichophyton, Microsporum, Arthroderma, Aspergillus, or Cryptococcus, more preferably a Candida, Trichophyton, Microsporum, Arthroderma, Aspergillus, or Cryptococcus. According to another preferred aspect of the present disclosure, there is provided a method for improving symptoms or diseases caused by fungi, comprising administering an effective amount of a compound represented by formula (I) or (II) to a human subject in need thereof.

[0079] The method of the present disclosure is preferably a therapeutic method, but may also be a non-therapeutic method. Specifically, it may be used for cosmetic purposes or for health promotion purposes. In one embodiment, according to a preferred embodiment of the present disclosure, the method does not include medical treatment, i.e., treatment of an individual by therapy.

[0080] The effective amount of the compound or salt thereof of the present disclosure varies depending on the species, sex, age, weight, condition and other factors of the animal to which it is administered, but is an amount that reduces the growth of the target bacteria to 50% or less, preferably 40% or less, more preferably 30% or less, even more preferably 20% or less, and even more preferably 10% or less of the control.

[0081] The dose, administration route, and administration interval of the compound of the present disclosure in the above-mentioned administration cannot be generally specified because they vary depending on the species, sex, age, body weight, condition, and other factors of the animal to be administered. For example, when administered locally to the affected area of ​​a human, the dose of the compound of the present disclosure is usually 0.005 to 350 mg / day as a daily dose for an adult weighing 60 kg, and preferably 0.01 to 175 mg / week as a weekly dose.

[0082] According to another aspect of the present disclosure, there is provided use of a compound represented by formula (I) or (II) or a salt thereof in the manufacture of an antifungal agent for human use. According to another preferred aspect of the present disclosure, there is provided use of a compound represented by formula (I) or (II) or a salt thereof in the manufacture of a formulation for ameliorating symptoms or diseases caused by Malassezia fungi. According to another preferred aspect, the fungus is a fungus of the genus Candida, Malassezia, Trichophyton, Microsporum, Arthroderma, Aspergillus, or Cryptococcus. According to another preferred aspect of the present disclosure, the symptom or disease is a skin disease. According to another preferred aspect of the present disclosure, the symptom or disease is tinea versicolor, psoriasis vulgaris, dermatophytosis, candidiasis, cutaneous Malassezia, aspergillosis, cryptococcosis, atopic dermatitis, or otitis externa. According to another preferred aspect of the present disclosure, the antifungal agent is a medicine. According to another preferred aspect of the present disclosure, the use is a cosmetic or non-therapeutic use.

[0083] According to another aspect of the present disclosure, there is provided a compound represented by formula (I) or (II) or a salt thereof for use as an antifungal agent for humans. According to another preferred aspect of the present disclosure, there is provided a compound represented by formula (I) or (II) or a salt thereof for ameliorating symptoms or diseases caused by Malassezia fungi. According to another preferred aspect, the fungi are Candida, Malassezia, Trichophyton, Microsporum, Arthroderma, Aspergillus, or Cryptococcus fungi. According to another preferred aspect of the present disclosure, the symptoms or diseases are skin diseases. According to another preferred aspect of the present disclosure, the symptoms or diseases are tinea versicolor, psoriasis vulgaris, dermatophytosis, candidiasis, cutaneous Malassezia, aspergillosis, cryptococcosis, atopic dermatitis, or otitis externa. According to another preferred aspect of the present disclosure, the antifungal agent is a medicine.

[0084] According to one aspect of the present disclosure, the following is provided: [1] An antifungal agent for human use, comprising a compound represented by formula (I) or (II) or a salt thereof. [ka] [In the formula, R 1 and R 2 are each independently hydrogen atoms, halogen atoms, hydroxyl groups, nitro group, cyano group, thiocyanate group, trimethylsilyl group, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group; an optionally substituted alkyloxy group, an optionally substituted alkenyloxy group; an optionally substituted alkynyloxy group; an optionally substituted aryl group; an optionally substituted aryloxy group; an optionally substituted 5- or 6-membered aromatic heterocyclic group, -SO m R 3 (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 is an optionally substituted alkyl group, and m is an integer of 0 to 2, or [ka] (In the formula, 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 an optionally substituted alkyl group or an optionally substituted aryl group) and; X is a hydrogen atom, a hydroxyl group, or -OY; Y is a group having the formula: [ka] (In the formula, R 7 is an optionally substituted alkyl group, an optionally substituted alkyloxy group, an optionally substituted alkenyl group, an optionally substituted alkenyloxy group; an optionally substituted aryl group; an optionally substituted aryloxy group; an optionally substituted 5- or 6-membered aromatic heterocyclic group, -NR 8 R 9 Group (R 8 and R 9 are each independently a hydrogen atom, an optionally substituted alkyl group, or an optionally substituted alkenyl group, or form a 5- to 7-membered saturated heterocycle together with the nitrogen atom adjacent to each other, with the proviso that R 8 and R 9 and are simultaneously hydrogen atoms) or -CR 10 R 11 R 12 group (in the formula, R 10 , R 11 and R 12 are each independently an optionally substituted alkyl group, an optionally substituted alkenyl group, or an optionally substituted aryl group. [2]R 1 and R 2 and each independently represent a hydrogen atom, a halogen atom, or an optionally substituted phenyl group. [3]R 1 and R 2are each independently a hydrogen atom or a halogen atom, or a phenyl group optionally substituted with at least one group selected from the group consisting of an alkyl group and a halogen atom. [4]R 1 and R 2 are each independently a hydrogen atom or a halogen atom, or a phenyl group which may be substituted with at least one group selected from an alkyl group having 1 to 6 carbon atoms and a halogen atom. The antifungal agent according to any one of [1] to [3]. [5]R 1 and R 2 and are different groups from each other. [6] X is a hydrogen atom, a hydroxyl group, or -OY; Y is a group having the formula: [ka] (In the formula, R 7 is an optionally substituted alkyl group, an optionally substituted phenyl group, an optionally substituted alkyloxy group, an optionally substituted phenyloxy group, or -CR 10 R 11 R 12 group (in the formula, R 10 , R 11 and R 12 and each independently represent an optionally substituted alkyl group or an optionally substituted phenyl group. [7] The antifungal agent according to any one of [1] to [6], wherein X is a hydrogen atom or a hydroxyl group. [8] The compound represented by formula (I) or (II) is 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)-1 H -imidazole-2-carbonitrile, and 4-chloro-1-hydroxy-5-(4-methylphenyl)-1 H -imidazole-2-carbonitrile The antifungal agent according to any one of [1] to [7], which is selected from the following: [9] The antifungal agent according to any one of [1] to [8], which is a medicine.

[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 fungi of the genus Candida, fungi of the genus Malassezia, fungi of the genus Trichophyton, fungi of the genus Microsporum, fungi of the genus Arthroderma, fungi of the genus Aspergillus, and fungi of the genus Cryptococcus.

[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 fungi of the genus Candida, Trichophyton, Microsporum, Arthroderma, Aspergillus, and Cryptococcus.

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

[11] for improving symptoms or diseases caused by the fungus.

[13] The antifungal agent according to

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

[14] The antifungal agent according to

[12] or

[13] , wherein the symptom or disease is tinea versicolor, psoriasis vulgaris, dermatophytosis, candidiasis, cutaneous malasseziosis, aspergillosis, cryptococcosis, atopic dermatitis, or otitis externa.

[15] The antifungal agent according to any one of

[12] to

[14] , wherein the symptom or disease is cutaneous malasseziasis, dermatophytosis, candidiasis, aspergillosis, or cryptococcosis. [Example]

[0085] Next, test examples relating to the present invention will be described, but these are not intended to limit the present invention.

[0086] Preparation Example 1: 5-chloro-4-(4-methylphenyl)-1H-imidazole-2-carbonitrile (Compound No. 1) 5-Chloro-4-(4-methylphenyl)-1H-imidazole-2-carbonitrile (Compound No. 1) was produced according to the method described in Examples 1 to 5 of JP-A-8-225539 (CAS No. 120118-14-1).

[0087] Preparation Example 2: 4-(4-methylphenyl)-1H-imidazole-2-carbonitrile (Compound No. 2) Compound No. 2 was produced in accordance with the same method as described in JP-A-8-225539, except that a raw material compound corresponding to the target compound was used (CAS No.: 120118-10-7). MS:184.2[M+H] +

[0088] Preparation Example 3: 5-chloro-4-(3-methylphenyl)-1H-imidazole-2-carbonitrile (Compound No. 3) Compound No. 3 was produced in accordance with the same method as described in JP-A-8-225539, except that a raw material compound corresponding to the target compound was used (CAS No.: 120118-18-5). MS:218.2[M+H] +

[0089] Preparation Example 4: 5-chloro-4-(2-methylphenyl)-1H-imidazole-2-carbonitrile (Compound No. 4) Compound No. 4 was produced in accordance with the same method as described in JP-A-8-225539, except that starting compounds corresponding to the target compound were used.

[0090] 1 H-NMR(DMSO-d6): δ7.45-7.31(m,4H),3.45-3.28(br,1H),2.23(s,3H) MS:218.1[M+H] +

[0091] Preparation Example 5: 5-chloro-4-(2-chloro-4-methylphenyl)-1H-imidazole-2-carbonitrile (Compound No. 5) Compound No. 5 (CAS No.: 2167064-69-7) was produced in accordance with the same method as described in JP-A-8-225539, except that a raw material compound corresponding to the target compound was used. MS:252.2[M+H] +

[0092] Preparation Example 6: 5-chloro-4-(3-chloro-4-methylphenyl)-1H-imidazole-2-carbonitrile (Compound No. 6) Compound No. 6 (CAS No.: 120118-82-3) was produced in accordance with the same method as described in JP-A-8-225539, except that a raw material compound corresponding to the target compound was used. MS:252.1[M+H] +

[0093] Preparation Example 7: 5-chloro-4-(4-chloro-3-methylphenyl)-1H-imidazole-2-carbonitrile (Compound No. 7) Compound No. 7 was produced in accordance with the same method as described in JP-A-8-225539, except that starting compounds corresponding to the target compound were used.

[0094] 1 H-NMR(DMSO-d6): δ7.73(s,1H),7.62-7.58(m,2H),3.80-3.00(br,1H),2.40(s,3H) MS:251.0[M+H] +

[0095] Preparation Example 8: 4-(2-chloro-4-methylphenyl)-1H-imidazole-2-carbonitrile (Compound No. 8) Compound No. 8 was produced in accordance with the same method as described in JP-A-8-225539, except that starting compounds corresponding to the target compound were used.

[0096] 1H-NMR (DMSO-d6): δ8.10-7.93(br,1H),7.93-7.77(br,1H),7.38(s,1H),7.24(d,1H,J=8.0Hz),3.32(s,1H),2.34(s,3H) MS:218.1[M+H] +

[0097] Preparation Example 9: 5-Chloro-1-hydroxy-4-(4-methylphenyl)-1H-imidazole-2-carbonitrile (Compound No. 9) Compound No. 9 was produced in accordance with the same method as described in JP-A-8-225539, except that starting compounds corresponding to the target compound were used.

[0098] 1 H-NMR (DMSO-d6): δ7.72(d,2H,J=8.0Hz),7.26(d,2H,J=8.0Hz),3.45-3.15(br,1H),2.31(s,3H) MS:234.1[M+H] +

[0099] Preparation Example 10: 4-Chloro-1-hydroxy-5-(4-methylphenyl)-1H-imidazole-2-carbonitrile (Compound No. 10) Compound No. 10 (CAS No.: 177762-70-8) was produced in accordance with the same method as described in JP-A-8-225539, except that a raw material compound corresponding to the target compound was used. MS:234.1[M+H] +

[0100] Test Example 1-1: Antibacterial activity test Test compound: Compound No.1 Test strains: Candida albicans (TIMM1768 strain) Test method: Candida bacteria were cultured in YPD liquid medium at 37°C for 20 hours and then collected by centrifugation (3000 rpm, 5 minutes). After washing twice with saline, they were suspended in saline and diluted to 2 x 10 3 A bacterial solution was prepared so that the concentration of cells / mL was 100 μL. A test compound dissolved in DMSO was added to a Sabouraud medium to a predetermined concentration, and 100 μL of the bacterial solution was applied to the medium. After culturing at 37°C for 48 hours, the presence or absence of colony formation was examined. As a result, Compound No. 1 completely inhibited colony formation at 50 ppm.

[0101] Test Example 1-2: Antibacterial activity test Test compound: Compound No.1 Test strains: Candida glabrata (TIMM6054 strain) Test method: Candida bacteria were cultured in YPD liquid medium at 37°C for 20 hours and then collected by centrifugation (3000 rpm, 5 minutes). After washing twice with saline, they were suspended in saline and diluted to 2 x 10 3 A bacterial solution was prepared so that the concentration of cells / mL was 100 μL of the bacterial solution was applied to a YPD medium to which a test compound dissolved in DMSO had been added to give a predetermined concentration. After culturing at 37°C for 48 hours, the presence or absence of colony formation was examined. As a result, Compound No. 1 completely inhibited colony formation at 200 ppm.

[0102] Test Example 1-3: Antibacterial activity test Test compound: Compound No.1 Test strains: Cryptococcus neoformans (TIMM1316 strain) Test method: Cryptococcus bacteria were cultured in YPD liquid medium at 37°C for 20 hours and then collected by centrifugation (3000 rpm, 5 minutes). After washing twice with saline, they were suspended in saline and diluted to 2 x 10 3 A bacterial solution was prepared so that the concentration of cells / mL was 100 μL. A test compound dissolved in DMSO was added to a Sabouraud medium to a predetermined concentration, and 100 μL of the bacterial solution was applied to the medium. After culturing at 37°C for 48 hours, the presence or absence of colony formation was examined. As a result, Compound No. 1 completely inhibited colony formation at 20 ppm.

[0103] Test Example 1-4: Antibacterial activity test Test compound: Compound No.1 Test strains: Malassezia nana (CBS95574)

[0104] Malassezia fungi were cultured in Sabouraud liquid medium containing 0.05% (v / v) Tween 80 (polyoxyethylene sorbitan monooleate, manufactured by Kanto Chemical Co., Inc.) at 32°C for 20 hours. The fungi were collected by centrifugation at 3,000 rpm for 5 minutes, washed twice with saline, suspended in 10 mL of saline, and allowed to stand for 15 minutes. The supernatant was then collected. A McFarland No. 0.5 bacterial suspension was prepared from the supernatant using saline. Compound No. 1 dissolved in DMSO was added to the suspension at 100 ppm or 200 ppm, and the mixture was stirred. After allowing to stand for 5 minutes at 30°C, 100 μL of the bacterial suspension was suspended in 10 mL of saline. Malassezia fungi were collected by centrifugation at 3,000 rpm for 5 minutes, washed once with saline, and resuspended in 500 μL of saline. 100 μL of the resuspended bacterial solution was applied to Sabouraud medium containing Tween 80 (0.05% (v / v)) and cultured at 30°C for 5 days. After that, the number of colonies formed there (number of colonies formed in the present invention group) and the number of colonies in the solvent without the addition of the test compound (number of colonies formed in the drug-untreated group) were counted, and the colony formation inhibition rate (%) was calculated according to the following formula. Colony formation inhibition rate (%) = [(number of colonies formed in the untreated group - number of colonies formed in the group according to the present invention) / number of colonies formed in the untreated group] x 100 As a result, the colony formation inhibition rate of Compound No. 1 was 98.5% at 100 ppm and 99.9% at 200 ppm.

[0105] Test Example 1-5: Antibacterial activity test Test compound: Compound No.1 Test strains: Malassezia pachydermatis (TIMM10024)

[0106] Malassezia fungi were cultured in Sabouraud liquid medium containing 0.05% (v / v) Tween 80 (polyoxyethylene sorbitan monooleate, manufactured by Kanto Chemical Co., Inc.) at 32°C for 20 hours. The fungi were collected by centrifugation at 3,000 rpm for 5 minutes, washed twice with saline, suspended in 10 mL of saline, and allowed to stand for 15 minutes. The supernatant was then collected. A McFarland No. 0.5 bacterial suspension was prepared from the supernatant using saline. Compound No. 1 dissolved in DMSO was added to the suspension at 100 ppm or 200 ppm, and the mixture was stirred. After allowing to stand for 5 minutes at 30°C, 100 μL of the bacterial suspension was suspended in 10 mL of saline. Malassezia fungi were collected by centrifugation at 3,000 rpm for 5 minutes, washed once with saline, and resuspended in 500 μL of saline. 100 μL of the resuspended bacterial solution was applied to Sabouraud medium containing Tween 80 (0.05% (v / v)) and cultured at 30°C for 5 days. After that, the number of colonies formed there (number of colonies formed in the present invention group) and the number of colonies in the solvent without the addition of the test compound (number of colonies formed in the drug-untreated group) were counted, and the colony formation inhibition rate (%) was calculated using the same method as in Test Example 1-4. As a result, the colony formation inhibition rate of Compound No. 1 was 98.1% at 100 ppm and 100% at 200 ppm.

[0107] Test Example 1-6: Antibacterial activity test Test compound: Compound No.1 Test strains: Aspergillus fumigatus (TIMM0063 strain), A. niger (TIMM4968 strain) Test method: After culturing Aspergillus fungi in PDA medium at 27°C for 3 days, spores were collected in saline containing Tween 80 (polyoxyethylene sorbitan monooleate, manufactured by Kanto Chemical Co., Ltd.) (0.05% (v / v)) and filtered through a cell strainer (φ40 μm). Spores were recovered from the filtrate by centrifugation (3500 rpm, 5 minutes), washed twice with saline, and a spore suspension (1 × 10 7 10 μL of the spore suspension was inoculated into Sabouraud medium to which Compound No. 1 dissolved in DMSO had been added to a predetermined concentration. After culturing at 28°C for 48 hours, the presence or absence of bacterial growth was examined, and the minimum inhibitory concentration was determined. As a result, the minimum inhibitory concentration of Compound No. 1 against both strains was 100 ppm.

[0108] Test Example 1-7: Antibacterial activity test Test compound: Compound No.1 Test strains: Trichophyton rubrum (CBS118892 strain), T. interdigital (TIMM20065 strain), Microsporum canis (TIMM20080 stock), Arthroderma vanbreuseghemii (TIMM2789)

[0109] Each strain was cultured at 28°C for 8 days in Sabouraud medium containing 500 μg / mL cycloheximide and 50 μg / mL chloramphenicol. Spores were then collected in saline containing Tween 80 (polyoxyethylene sorbitan monooleate, manufactured by Kanto Chemical Co., Ltd.) (0.05% (v / v)) and filtered through a cell strainer (φ40 μm). Spores were collected from the filtrate by centrifugation (3500 rpm, 5 minutes), washed twice with saline, and a spore suspension (1 × 10 7 10 μL of the spore suspension was inoculated into Sabouraud medium to which Compound No. 1 dissolved in DMSO had been added to a predetermined concentration. After culturing at 28°C for 72 hours, the presence or absence of bacterial growth was examined, and the minimum inhibitory concentration was determined. As a result, the minimum inhibitory concentration of Compound No. 1 against all four strains was 10 ppm.

[0110] Test Example 2 Test compound: Compound No.6 Test strains: Candida albicans (NBRC1594 strain), Candida glabrata (JCM3761 strain), Cryptococcus neoformans (JCM3685 strain), Aspergillus fumigatus (JCM10253), Aspergillus niger (ATCC6725), Trichophyton rubrum (ATCCMYA4607), Trichophyton interdigitale (ATCC9533), Microsporum canis (NBRC7863), Arthroderma vanbreuseghemii (JCM1891)

[0111] Candida and Cryptococcus were cultured in Sabouraud medium at 30°C for 72 hours, and other bacteria at 25°C for 120 hours. After that, 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 per 1000 mL) containing Tween 80 (polyoxyethylene sorbitan monooleate, Kanto Chemical Co., Ltd.) (1% (V / V)) and filtered through a cell strainer (φ40 μm). Spores were collected from the filtrate by centrifugation (3500 rpm, 5 minutes), washed twice with physiological saline, and a spore suspension (1 × 10 6 50 μL of the spore suspension was inoculated onto Sabouraud medium to which Compound No. 6 dissolved in DMSO had been added to a predetermined concentration. Candida and Cryptococcus were cultured at 30°C for 72 hours, and the other bacteria were cultured at 25°C for 120 hours. After incubation, the presence or absence of colony growth was examined and the minimum inhibitory concentration was determined. The results are shown in Table 1.

[0112] [Table 1]

[0113] Test Example 3-1: Antifungal activity test Test compound: Compound No.6 Test strains: Malassezia furfur (IFM 55951), Malassezia sympodialis (IFM 48588), Malassezia globosa (IFM 51946)

[0114] Chromagar™ Malassezia / Candida Culture Medium (peptone, special enzyme substrate mixture, chloramphenicol, olive oil, agar, manufactured by Kanto Chemical Co., Ltd.) for 5 to 7 days. Malassezia furfur , Malassezia sympodialis , Malassezia globosa) was suspended in saline to an absorbance of 0.025 at 600 nm. Test compounds dissolved in DMSO were added to the suspension to final concentrations of 200, 100, 50, and 25 ppm. After 1 minute, 10 μL of the suspension and 10 mL of saline were added to a syringe and stirred. The mixture was then connected to a 37 mm Quality Monitor (Pall), filtered, and washed twice with 10 mL of saline. The membrane filter was removed from the Quality Monitor and placed on Chromagar™ Malassezia / Candida live medium. The mixture was incubated at 32°C for 72 hours, and the presence or absence of colony growth was examined to determine the minimum fungicidal concentration (MFC100). The results are shown in Table 2-1.

[0115] [Table 2-1]

[0116] Test Example 3-2: Antifungal activity test Test compound: Compound No.6 Test strains: Malassezia restricta (IFM55992)

[0117] Chromagar™ Malassezia / Candida Culture Medium (peptone, special enzyme substrate mixture, chloramphenicol, olive oil, agar, manufactured by Kanto Chemical Co., Ltd.) for 5 to 7 days. Malassezia restricta) was suspended in saline and adjusted to an absorbance of 0.025 at 600 nm. Test compounds dissolved in DMSO were added to the suspension to final concentrations of 200, 100, 50, and 25 ppm. After 1 minute, 10 μL of the suspension and 10 mL of saline were added to a syringe and stirred. The mixture was then connected to a 37 mm quality monitor (Pall), filtered, and washed twice with 10 mL of saline. The membrane filter was removed from the quality monitor and placed on Leeming & Notman agar modified medium (MLNA medium) (peptone, glucose, yeast extract, dried ox bile, glycerol, glycerol stearate, Tween 60, olive oil, agar) and incubated at 32°C for 72 hours. Colony growth was monitored, and the minimum fungicidal concentration (MFC100) was determined. The results are shown in Table 2-2.

[0118] [Table 2-2]

[0119] Test Example 4: Antifungal activity test Test compound: Compound No.6 Test strains: Trichophyton rubrum (ATCCMYA4607), Microsporum canis (IFM63627)

[0120] The antifungal activity was examined using the method of Test Example 2 with some modifications. Trichophyton rubrum was grown on Sabouraud medium. , Microsporum canis The strain was cultured in 1 / 10 Sabouraud medium at 32°C for 168 hours to form spores. Trichophyton rubrum The mycelia were peeled off from the surface of the medium and collected in a tube. Physiological saline (Otsuka saline; containing the equivalent of 9 g of sodium chloride per 1000 mL) was added, and the whole was mixed and dispersed using a disposable loop (type 1 (1 μL)), and a spore suspension containing mycelia was collected. Microsporum canis 10 mL of saline Directly on medium In addition, the surface was scraped with a disposable loop to collect a spore suspension containing mycelia. Trichophyton rubrum and Microsporum canisThe spore suspension containing mycelia was filtered through a cell strainer (φ40 μm). Spores were collected from the filtrate by centrifugation (3500 rpm, 5 minutes), washed twice with physiological saline, and then a spore suspension (1 × 10 7 10 μL of the spore suspension was inoculated onto Sabouraud medium to which a test compound dissolved in DMSO had been added to a predetermined concentration. Trichophyton rubrum , Microsporum canis After culturing at 32°C for 72 hours, the presence or absence of colony growth was examined and the minimum inhibitory concentration (MIC100) was calculated. The results are shown in Table 3.

[0121] [Table 3]

[0122] Test Example 5: Antifungal activity test Test compound: Compound No.6 Test strains: Trichophyton rubrum (ATCCMYA4607), Microsporum canis (IFM63627)

[0123] Trichophyton rubrum was grown on Sabouraud medium. , Microsporum canis The strain was cultured in 1 / 10 Sabouraud medium at 32°C for 168 hours to form spores. Trichophyton rubrum The mycelia were peeled off from the surface of the medium and collected in a tube. Physiological saline (Otsuka saline; containing the equivalent of 9 g of sodium chloride per 1000 mL) was added, and the whole was mixed and dispersed using a disposable loop (type 1 (1 μL)), and a spore suspension containing mycelia was collected. Microsporum canis 10 mL of saline Directly on medium In addition, the surface was scraped with a disposable loop to collect a spore suspension containing mycelia. Trichophyton rubrum and Microsporum canis The spore suspension containing mycelia was filtered through a cell strainer (φ40 μm). Spores were collected from the filtrate by centrifugation (3500 rpm, 5 minutes), washed twice with physiological saline, and then a spore suspension (1 × 10 7(cells / mL). 10 μL of the spore suspension was inoculated into 90 μL of physiological saline solution to which a test compound dissolved in DMSO had been added to a predetermined concentration. At predetermined intervals, 10 μL of the test solution containing spores was sampled, centrifuged (3500 rpm, 5 minutes) to recover the spores, washed twice with physiological saline, and then 10 μL of the spore suspension was prepared. 10 μL of the spore suspension was spotted onto Sabouraud medium and cultured at 32°C for 72 hours. The presence or absence of colony growth was then examined, and the minimum fungicidal concentration (MFC100) was determined. The results are shown in Table 4.

[0124] [Table 4]

Claims

1. An antifungal agent for human use, comprising a compound represented by formula (I) or (II) or a salt thereof. 【Chemistry 1】 [In the formula, R １ and R ２ one of the groups is a halogen atom, and the other is a phenyl group which may be substituted with at least one group selected from an alkyl group having 1 to 6 carbon atoms and a halogen atom; X is a hydrogen atom.

2. R １ and R ２ The antifungal agent according to claim 1, wherein one of the groups is a chlorine atom, and the other is a phenyl group which may be substituted with at least one group selected from the group consisting of a methyl group and a chlorine atom.

3. The compound represented by formula (I) or (II) is 5-chloro-4-(4-methylphenyl)-1H-imidazole-2-carbonitrile, 5-chloro-4-(3-methylphenyl)-1H-imidazole-2-carbonitrile, 5-chloro-4-(2-methylphenyl)-1H-imidazole-2-carbonitrile, 5-chloro-4-(2-chloro-4-methylphenyl)-1H-imidazole-2-carbonitrile, 5-chloro-4-(3-chloro-4-methylphenyl)-1H-imidazole-2-carbonitrile, and 5-chloro-4-(4-chloro-3-methylphenyl)-1H-imidazole-2-carbonitrile The antifungal agent according to claim 1 or 2, which is selected from the group consisting of:

4. The antifungal agent according to any one of claims 1 to 3, which is a medicine.

5. The antifungal agent according to any one of claims 1 to 4, wherein the fungus is at least one selected from the group consisting of fungi of the genus Candida, fungi of the genus Malassezia, fungi of the genus Trichophyton, fungi of the genus Microsporum, fungi of the genus Arthroderma, fungi of the genus Aspergillus, and fungi of the genus Cryptococcus.

6. The antifungal agent according to any one of claims 1 to 5, wherein the fungus is at least one selected from the group consisting of Candida, Trichophyton, Microsporum, Arthroderma, Aspergillus, and Cryptococcus.

7. The antifungal agent according to any one of claims 1 to 6, for improving symptoms or diseases caused by said fungi.

8. The antifungal agent according to claim 7, wherein the symptom or disease is a skin disease.

9. The antifungal agent according to claim 7 or 8, wherein the symptom or disease is tinea versicolor, psoriasis vulgaris, dermatophytosis, candidiasis, cutaneous malasseziosis, aspergillosis, cryptococcosis, atopic dermatitis, or otitis externa.

10. The antifungal agent according to any one of claims 7 to 9, wherein the symptom or disease is cutaneous malasseziasis, dermatophytosis, candidiasis, aspergillosis, or cryptococcosis.

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