Antibacterial agents for non-human animals

Abstract

The present invention provides a novel antimicrobial agent, in which a compound represented by formula (I) or (II) or a salt thereof is used as an antimicrobial agent for a nonhuman animal.

Description

REFERENCE TO RELATED APPLICATIONS

[0001] This patent application claims priority to Japanese Patent Application No. 2020-097170, filed on June 3, 2020, the entire disclosure of which is incorporated herein by reference. [Technical Field]

[0002] The present disclosure relates to antimicrobial agents for non-human animals. [Background technology]

[0003] Malassezia is a basidiomycete yeast that is normally present on the skin of 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.

[0004] 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.

[0005] Resident skin flora typically possesses a barrier effect, preventing scalp odor associated with bacterial proliferation and maintaining a mildly acidic state through the moderate breakdown of sebum. However, conventional veterinary treatments sterilize not only pathogenic bacteria but also resident skin flora, 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. Continuous administration of the same drug over a long period of time significantly increases the risk of developing resistant bacteria.

[0006] As described above, lipid synthesis inhibitors do not immediately exert antibacterial activity upon administration, and therefore are not suitable for use in administration methods that require immediate antibacterial activity, such as the prevention or treatment of animal skin diseases using medical shampoos. Therefore, there has been a need for the development of a highly safe veterinary therapeutic agent that has a mechanism of action different from that of conventional therapeutic agents and exhibits immediate antibacterial activity.

[0007] For example, Non-Patent Document 1 describes that the mechanism of action of cyazofamid, a cyanoimidazole compound, is respiratory inhibition.

[0008] 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, these publications do not describe the antibacterial activity of the compounds or a method for suppressing animal skin diseases caused by Malassezia fungi.

[0009] [Patent Document 1] Japanese Patent Application Publication No. 1-131163 [Patent Document 2] International Publication WO 01 / 14341

[0010] [Non-Patent Document 1] Pesticide Biochemistry and Physiology, 2001, vol.71:107-115 Summary of the Invention

[0011] The present inventors have discovered that a cyanoimidazole compound represented by formula (I) or (II) described below (hereinafter also referred to as the compound of the present disclosure) can be used as a novel antibacterial agent for non-human animals.

[0012] Thus, the present disclosure provides novel antibacterial agents for non-human animals.

[0013] That is, the present disclosure provides an antibacterial agent for non-human animals, which contains 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 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 R9 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 12 are each independently an optionally substituted alkyl group, an optionally substituted alkenyl group, or an optionally substituted aryl group.

[0014] According to the present disclosure, a novel antibacterial agent for non-human animals 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 including Malassezia genus. Furthermore, the compound represented by formula (I) or (II) or a salt thereof can be advantageously used to rapidly exert excellent antibacterial activity against bacteria including Staphylococcus genus. Specific Description of the Invention

[0015] In this specification, the term "halogen" means fluorine, chlorine, bromine, or iodine, and is preferably fluorine, chlorine, or bromine.

[0016] 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.

[0017] 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.

[0018] R 1 ~R 12 When 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.

[0019] 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.

[0020] 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.

[0021] R 1 , R 2 and R 7 When 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.

[0022] 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.

[0023] 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.

[0024] R 1 , R2 , R 3 , R 7 , R 10 , R 11 and R 12 When 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.

[0025] 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.

[0026] 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.

[0027] R 1 , R 2 and R 7When 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.

[0028] R 1 , R 2 and R 7 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.

[0029] 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.

[0030] 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.

[0031] R 1 , R 2 and R3 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.

[0032] 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.

[0033] 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.

[0034] 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.

[0035] 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.

[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 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.

[0037] 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.

[0038] 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.

[0039] R 1 , R 2 , R 3 and R 7 The 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.

[0040] 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 12It may be the same as the alkyl moiety in the above.

[0041] 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.

[0042] 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).

[0043] 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 R6 (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).

[0044] According to another preferred embodiment of the present disclosure, R 1 represents 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.

[0045] 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.

[0046] 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.

[0047] 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.

[0048] 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 an alkyl group having 1 to 6 carbon atoms and a halogen atom.

[0049] According to a more preferred embodiment of the present disclosure, R 1 and R 2 are different groups.

[0050] 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.

[0051] 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).

[0052] According to another preferred embodiment of the present disclosure, R 7represents 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 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 -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).

[0053] 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).

[0054] 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) - имидазол -2-carbonitrile, and 4-chloro-1-hydroxy-5-(4-methylphenyl) - имидазол -2-carbonitrile It is selected from:

[0055] 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.

[0056] The compounds of the present disclosure may be used alone or in combination of two or more.

[0057] 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.

[0058] 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.

[0059] 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.

[0060] 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.

[0061] 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.

[0062] 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.

[0063] Other additional ingredients may also be used, such as moisturizers, anti-inflammatory agents, germicides, antibacterial agents, UV protection agents, cell activators, and makeup ingredients.

[0064] A formulation containing the compound of the present disclosure or a salt thereof can be provided as a pharmaceutical product, a quasi-drug, an animal drug, or a cosmetic.

[0065] According to a preferred embodiment, the form of a formulation containing the compound of the present disclosure or a salt thereof can be any form that can be used in cosmetics, such as, for example, a cream, emulsion, lotion, suspension, gel, powder, pack, sheet, patch, stick, cake, etc., but is not particularly limited to these.

[0066] Further, 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 cosmetics for the head or body such as lotions, creams, and emulsions for the head or body, but are not particularly limited to these.

[0067] 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. Preferred forms of the formulations are external skin preparations such as external powders, liniments, lotions, ointments, creams, gels, aerosol sprays, pump sprays, tapes, and poultices.

[0068] The compounds or salts thereof disclosed herein can immediately exhibit excellent antibacterial activity against fungi, including those of the genus Malassezia. Therefore, in one embodiment, the formulations disclosed herein are used to improve symptoms or diseases caused by Malassezia. 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.

[0069] In the present disclosure, Malassezia spp. Malassezia) Malassezia family ( Malassezia ), such as Malassezia bran , Malassezia pachyderm , Malassezia globular , Malassezia blunt , Malassezia restricted , Malassezia sympodial , Malassezia sloofahs , Malassezia skin , Malassezia from Yamato , Malassezia Japanese , Malassezia dwarf etc.

[0070] In the present disclosure, Microsporum sp. Microsporum) is a fungus belonging to the family Arthrodermataceae, for example, Microsporum dog etc.

[0071] In the present disclosure, Arthroderma sp. Arthroderma) As for Arthrodermataceae ( Arthrodermataceae ), such as Arthroderma vanbreuseghemii etc.

[0072] In a preferred embodiment, the symptom or disease caused by fungi of the genus Malassezia is a skin disease. Examples of skin diseases caused by fungi of the genus Malassezia include tinea versicolor, folliculitis, seborrheic dermatitis, psoriasis vulgaris, and allergic dermatitis, and preferably include tinea versicolor, folliculitis, seborrheic dermatitis, psoriasis vulgaris, allergic dermatitis, canine Malassezia dermatitis, atopic dermatitis, Malassezia otitis externa, feline Malassezia dermatitis, Malassezia otitis externa, and equine Malassezia dermatitis.

[0073] The compounds or salts thereof disclosed herein can immediately exhibit excellent antibacterial activity against bacteria, including Staphylococcus. Therefore, in one embodiment, the formulations disclosed herein are used to improve symptoms or diseases caused by Staphylococcus. Here, "improvement" includes not only the treatment of established pathologies, but also prevention, which prevents or delays the development of 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 the 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.

[0074] In the present disclosure, examples of bacteria include Staphylococcus, Streptococcus, Pasteurella, Escherichia, Pseudomonas, Proteus, and Klebsiella.

[0075] In the present disclosure, Staphylococcus spp. Staphylococcus ) is a member of the Staphylococcus family ( Staphylococcaceae ) bacteria, such as Staphylococcus pseudintermediaus , Staphylococcus intermedius , Staphylococcus schleiferi , Staphylococcus delphini , Staphylococcus epidermidis , Staphylococcus xylose , Staphylococcus aureus etc.

[0076] In the present disclosure, Streptococcus spp. Streptococcus ) is a member of the Streptococcus family ( Streptococci ) bacteria, such as Streptococcus canis , Streptococcus pyogenes , Streptococcus suis , Streptococcus dysgalactiae etc.

[0077] In the present disclosure, Pasteurella spp. Pasteurella ) is a member of the Pasteurellaceae family ( Pasteurellaceae ) bacteria, such as Pasteurella multocida etc.

[0078] In the present disclosure, Escherichia spp. Escherichia ) is a member of the Enterobacteraceae family ( Enterobacteriaceae ) bacteria, such as Escherichia coli etc.

[0079] In the present disclosure, Pseudomonas spp. Pseudomonas ) is a member of the Pseudomonadaceae family ( Pseudomonas ) bacteria, such as Pseudomonas aeruginosa etc.

[0080] In the present disclosure, Proteus sp. Proteus ) is a member of the Enterobacteraceae family ( Enterobacteriaceae ) bacteria, such as Miraculous Proteus etc.

[0081] In the present disclosure, Klebsiella spp. Klebsiella ) is a member of the Enterobacteraceae family ( Enterobacteriaceae ) bacteria, such as Klebsiella pneumoniae etc.

[0082] In a preferred embodiment, the symptom or disease caused by bacteria is a skin disease, such as pyoderma and otitis externa.

[0083] Taking into consideration the need for sterilization of fungi such as Malassezia and bacteria such as Staphylococcus, it is preferable that the subject to which the compound of the present disclosure or a salt thereof is administered is a non-human animal. More specific subjects to which the compound of the present disclosure or a salt thereof is administered include animals that require inhibition of the growth of fungi such as Malassezia and bacteria such as Staphylococcus, or that require improvement of skin diseases caused by fungi such as Malassezia and bacteria such as Staphylococcus. More specifically, it is preferable to administer the compound of the present disclosure or a salt thereof to non-human animals such as dogs, cats, and horses. The site to which the compound of the present disclosure or a salt thereof is administered is not particularly limited, and may be tissues such as skin, organs, or cells where the target fungus is present.

[0084] The compound or salt thereof of the present disclosure can inhibit the growth of or kill fungi by administering to a subject in need thereof an amount effective to produce antifungal activity. Therefore, according to another aspect of the present disclosure, there is provided a method for inhibiting the growth of or killing fungi in a subject in need thereof, comprising administering an effective amount of a compound represented by formula (I) or (II) to the subject in need thereof. In another preferred aspect, the fungus is a fungus of the genus Malassezia. In another preferred aspect, the fungus is Malassezia pachyderm According to another preferred embodiment of the present disclosure, there is provided a method for improving symptoms or diseases caused by fungi of the genus Malassezia, which comprises administering an effective amount of a compound represented by formula (I) or (II) to a subject in need thereof. According to another preferred embodiment of the present disclosure, there is provided a method for improving symptoms or diseases caused by fungi of the genus Malassezia, which comprises administering an effective amount of a compound represented by formula (I) or (II) to a non-human animal in need thereof, such as a dog, cat, or horse. Malassezia pachyderm The present invention provides a method for improving symptoms or diseases caused by the above.

[0085] The compound or salt thereof of the present disclosure can inhibit bacterial growth or kill bacteria by administering to a subject in need thereof an amount effective to produce antibacterial activity. Therefore, according to another aspect of the present disclosure, there is provided a method for inhibiting bacterial growth or killing bacteria in a subject in need thereof, comprising administering to a subject in need thereof an effective amount of a compound represented by formula (I) or (II). In another preferred aspect, the bacterium is a Staphylococcus bacterium. In another preferred aspect, the bacterium is Staphylococcus pseudintermediaus According to another preferred embodiment of the present disclosure, there is provided a method for improving symptoms or diseases caused by Staphylococcus bacteria, which comprises administering an effective amount of a compound represented by formula (I) or (II) to a subject in need thereof. According to another preferred embodiment of the present disclosure, there is provided a method for improving symptoms or diseases caused by Staphylococcus bacteria, which comprises administering an effective amount of a compound represented by formula (I) or (II) to a non-human animal in need thereof, such as a dog, cat, or horse. Staphylococcus pseudintermediaus The present invention provides a method for improving symptoms or diseases caused by the above.

[0086] The methods of the present disclosure may be therapeutic or non-therapeutic. Specifically, they may be used for cosmetic purposes or for non-therapeutic purposes to promote health. Thus, according to a preferred embodiment of the present disclosure, the methods do not involve medical procedures, i.e., the treatment of an individual with a therapy.

[0087] 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.

[0088] The dosage, administration route, and administration interval of the compound of the present disclosure in the above-mentioned administration cannot be generally defined, since they vary depending on the species, sex, age, weight, condition, and other factors of the animal to be administered. For example, when administered locally to the affected area of ​​a dog, the dosage of the compound of the present disclosure is typically 0.005 to 350 mg / day per adult dog weighing 10 kg, with a preferred weekly dose of 0.01 to 175 mg / week. When administered locally to the affected area of ​​a cat, the dosage of the compound of the present disclosure is typically 0.002 to 140 mg / day per adult cat weighing 4 kg, with a preferred weekly dose of 0.004 to 70 mg / week.

[0089] 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. 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 fungi of the genus Malassezia. 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, folliculitis, seborrheic dermatitis, psoriasis vulgaris, atopic dermatitis, or otitis externa. According to another preferred aspect of the present disclosure, the use is cosmetic or non-therapeutic.

[0090] 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 antibacterial agent. 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 Staphylococcus bacteria. 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 pyoderma or otitis externa. According to another preferred aspect of the present disclosure, the use is cosmetic or non-therapeutic.

[0091] 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. 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 fungi of the genus Malassezia. 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, folliculitis, seborrheic dermatitis, psoriasis vulgaris, atopic dermatitis, or otitis externa. According to another preferred aspect of the present disclosure, the antifungal agent is an animal drug.

[0092] 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 antibacterial agent. 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 Staphylococcus bacteria. 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 pyoderma or otitis externa. According to another preferred aspect of the present disclosure, the antibacterial agent is an animal drug.

[0093] According to one aspect of the present disclosure, the following is provided: [1] An antibacterial agent for non-human animals, 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 are each independently a hydrogen atom, a halogen atom, or an optionally substituted phenyl group. [3]R 1 and R 2 are 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 and each independently represent a hydrogen atom or a halogen atom, or a phenyl group optionally substituted with at least one group selected from an alkyl group having 1 to 6 carbon atoms and a halogen atom. [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 antibacterial 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) - имидазол -2-carbonitrile, and 4-chloro-1-hydroxy-5-(4-methylphenyl) ) - -2-carbonitrile The antibacterial agent according to any one of [1] to [7], which is selected from the following: [9] The antibacterial agent according to any one of [1] to [8], wherein the bacterium is a fungus.

[10] The antibacterial agent according to [9], wherein the fungus is at least one selected from the genus Malassezia, the genus Microsporum, and the genus Arthroderma.

[11] The antibacterial agent according to [9] or

[10] for improving symptoms or diseases caused by at least one selected from the genus Malassezia, the genus Microsporum, and the genus Arthroderma.

[12] The antibacterial agent according to

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

[13] The antibacterial agent according to

[11] or

[12] , wherein the symptom or disease is tinea versicolor, folliculitis, seborrheic dermatitis, psoriasis vulgaris, atopic dermatitis, dermatophytosis, or otitis externa.

[14] The antibacterial agent according to any one of [1] to [8], wherein the fungus is a bacterium.

[15] The antibacterial agent according to

[14] , wherein the bacterium is at least one selected from the group consisting of Staphylococcus, Streptococcus, Pasteurella, Escherichia, Pseudomonaceae, Proteus, and Klebsiella.

[16] The antibacterial agent according to

[14] or

[15] for improving symptoms or diseases caused by at least one selected from the genus Staphylococcus, the genus Streptococcus, the genus Pasteurella, the genus Escherichia, the genus Pseudomonas, the genus Proteus, and the genus Klebsiella.

[17] The antibacterial agent according to

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

[18] The antibacterial agent according to

[16] or

[17] , wherein the symptom or disease is pyoderma or otitis externa.

[19] The antibacterial agent according to any one of [1] to

[18] , wherein the non-human animal is a dog, a cat, or a horse. [Example]

[0094] Next, test examples related to the present disclosure will be described, but these are not intended to limit the present disclosure.

[0095] 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).

[0096] 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] +

[0097] 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] +

[0098] 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.

[0099] 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] +

[0100] 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] +

[0101] 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] +

[0102] 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.

[0103] 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] +

[0104] 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.

[0105] 1 H-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] +

[0106] Preparation Example 9: 5-Chloro-1-hydroxy-4-(4-methylphenyl)-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.

[0107] 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] +

[0108] Preparation Example 10: 4-Chloro-1-hydroxy-5-(4-methylphenyl)-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] +

[0109] Test Example 1 Antibacterial activity test Test strains: Malassezia pachydermatis (IFM56528 strain, distributed by Chiba University)

[0110] Malassezia fungi ( ) were cultured for 5 to 7 days in Sabouraud medium (peptone 1%, dextrin 4%, agar 1.5%) supplemented with 0.5% Tween 40 (polyoxyethylene sorbitan monopalmitate: Kanto Chemical Co., Ltd.). Malassezia pachydermatis) was suspended in physiological saline and adjusted to an absorbance of 0.25 at 550 nm. A test compound dissolved in DMSO was added to the mixture to a final concentration of 500 ppm. After 1 minute, 10 μL of the suspension and 10 mL of physiological saline were added to a syringe and stirred. The mixture was then connected to a 37 mm quality monitor (Pall Corporation), filtered, and washed. The membrane filter was then infiltrated with Sabouraud medium supplemented with 1% Tween 80 (polyoxyethylene sorbitan monooleate, Kanto Chemical Co., Inc.) and cultured at 32°C for 72 hours. The number of colonies formed therein (the number of colonies in the present invention group) and the number of colonies in the solvent without the test compound (the number of colonies 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 in the untreated group - number of colonies in the group treated with the present invention) / number of colonies in the untreated group] x 100

[0111] As a result, all of Compounds No. 1 to 10 inhibited colony formation by 100%, confirming that Compounds No. 1 to 10 exhibited rapid-acting antibacterial activity against Malassezia fungi.

[0112] Test Example 2 Antibacterial activity test against various Malassezia species Test compound: Compound No. 1 (final concentration 500ppm) Test strains: Malassezia pachydermatis (IFM56528 stock), M.furfur (IMF55951 shares), M. sympodialis (IMF48588 shares), M. globosa (IMF51946 stocks), M.restricta (IMF55992 shares)

[0113] The colony formation inhibition rate for the test strain was determined in the same manner as in Test Example 1. The test results are shown in Table 1.

[0114] [Table 1]

[0115] Test Example 3: Malassezia otitis externa efficacy test (dogs) Test breed: Beagle (19-20 months old) Test strains: Malassezia pachydermatis (ATCC14522 strain)

[0116] Malassezia colonies pre-cultured on Sabouraud agar medium (7 days, 30°C) were suspended in sterilized saline (bacterial concentration 1.0 × 10 6 0.1 mL of the test compound (cells / mL) was inoculated into both ears of the test animals. Seven days after inoculation, 5 mL of a drug solution (sterilized saline, with 5% DMSO added) containing the test compound at a concentration of 500 ppm was filled into both ears, and after one minute, the ears were thoroughly rinsed with sterile saline. Seven days after drug solution treatment, the condition of the ears of the test animals was observed for four items: redness, earwax, itching, and rash. Each symptom was scored as 1 if observed and 0 if not, and the symptom improvement rate was calculated. The results are shown in Table 2.

[0117] In addition, the number of Malassezia fungi present inside the ears of the specimens was investigated using the following method. The surface of the ear canal was scraped three times with a cotton swab to collect bacteria. The collected bacteria, along with the swab, were suspended in 1 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) supplemented with 1% v / v Tween 80 (polyoxyethylene sorbitan monooleate, manufactured by Kanto Chemical Co., Inc.). The suspension was serially diluted 10-fold with the same PBS, and 0.1 mL of each was applied to Chromoagar Malassezia / Candida medium (trade name: peptone, special enzyme substrate mixture, chloramphenicol, olive oil, agar) and cultured at 30°C for 4 days. Pink-to-purple colonies were then counted, and a bacterial count score was calculated to determine the improvement rate. The results are shown in Table 3.

[0118] [Table 2]

[0119] [Table 3]

[0120] Test Example 4: Antibacterial activity test Test compound: Compound No.1 Test strains: Microsporum canis (TIMM20080 stock)

[0121] The strain was cultured in Sabouraud medium containing 500 μg / mL of cycloheximide and 50 μg / mL of chloramphenicol at 28°C for 8 days, and then spores were collected in saline containing Tween 80 (0.05% (v / v)). The spores were filtered through a cell strainer (φ40 μm). The spores were recovered from the filtrate by centrifugation (3500 rpm, 5 minutes). After washing twice with saline, a spore suspension (1 × 10 7 10 μL of the spore suspension was inoculated onto Sabouraud medium containing various concentrations of Compound No. 1 dissolved in DMSO. After 72 hours of incubation at 28°C, the amount of bacterial growth was investigated and the minimum inhibitory concentration was calculated. As a result, the minimum inhibitory concentration of Compound No. 1 was 10 ppm.

[0122] Test Example 5: Antibacterial activity test Test compound: Compound No.6 Test strains: Microsporum canis (NBRC7863)

[0123] The strain was cultured in Sabouraud medium, suspended in PBS containing Tween 80 (1% (V / V)), filtered through a cell strainer (φ40 μm), and spores were collected from the filtrate by centrifugation (3500 rpm, 5 minutes). After washing twice with physiological saline, a spore suspension (1 × 10 6 50 μL of the spore suspension was inoculated onto Sabouraud medium containing various concentrations of Compound No. 6 dissolved in DMSO. After 120 hours of incubation at 25°C, the presence or absence of bacterial growth was examined and the minimum inhibitory concentration was calculated. As a result, the minimum inhibitory concentration of Compound No. 6 was 125 ppm.

[0124] Test Example 6: Antibacterial activity test Test compound: Compound No.6 Test strains: Staphylococcus pseudintermedius (JCM 17571)

[0125] Staphylococcus aureus ( Staphylococcus pseudintermedius ) 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 connected to a 37 mm quality monitor (Pall), filtered, and washed twice with 10 mL of saline. The membrane filter was then infiltrated with LB medium and cultured at 30°C for 72 hours. Colony growth was monitored, and the minimum bactericidal concentration (MBC100) was determined. The results are shown in Table 4.

[0126] [Table 4]

[0127] Test Example 7: Antifungal activity test Test compound: Compound No.6 Test strains: Microsporum canis (IFM63627)

[0128] The antifungal activity was examined by partially modifying the method of Test Example 5. Microsporum canis The strain was cultured at 32°C for 168 hours to form spores, and then 10 mL of physiological saline (Otsuka saline injection; 1000 mL contains 9 g of sodium chloride equivalent) was added. Directly on medium The surface was scraped with a disposable loop (type 1 (1 μL)) to recover a spore suspension containing mycelia. The spore suspension containing mycelia was filtered through a cell strainer (φ40 μm). Spores were recovered from the filtrate by centrifugation (3500 rpm, 5 minutes), washed twice with physiological saline, and a spore suspension (1 × 10 710 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. 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 5.

[0129] [Table 5]

[0130] Test Example 8: Antifungal activity test Test compound: Compound No.6 Test strains: Microsporum canis (IFM63627)

[0131] 1 / 10 Sabouraud medium Microsporum canis The strain was cultured at 32°C for 168 hours to form spores, and then 10 mL of physiological saline (Otsuka saline injection; 1000 mL contains 9 g of sodium chloride equivalent) was added. Directly on medium The surface was scraped with a disposable loop (type 1 (1 μL)) to recover a spore suspension containing mycelia. The spore suspension containing mycelia was filtered through a cell strainer (φ40 μm). Spores were recovered from the filtrate by centrifugation (3500 rpm, 5 minutes), washed twice with physiological saline, and a spore suspension (1 × 10 7 10 μL of the spore suspension was inoculated into 90 μL of physiological saline solution to which Compound No. 6 dissolved in DMSO had been added to a predetermined concentration. At predetermined intervals, 10 μL of the test solution containing spores was collected, centrifuged (3500 rpm, 5 minutes), and the spores were recovered. After washing twice with physiological saline, 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 examined, and the minimum fungicidal concentration (MFC100) was calculated. The results are shown in Table 6.

[0132] [Table 6]

[0133] Test Example 9: Antifungal activity test Test compound: Compound No.1 Test strains: Arthroderma vanbreuseghemii (TIMM2789)

[0134] The strain was cultured in Sabouraud medium containing 500 μg / mL of cycloheximide and 50 μg / mL of chloramphenicol at 28°C for 8 days, and then spores were collected in saline containing Tween 80 (0.05% (v / v)). The spores were filtered through a cell strainer (φ40 μm). The spores were recovered from the filtrate by centrifugation (3500 rpm, 5 minutes). After washing twice with saline, a spore suspension (1 × 10 7 10 μL of the spore suspension was inoculated onto Sabouraud medium to which Compound No. 1 dissolved in DMSO had been added at various concentrations. After 72 hours of incubation at 28°C, the amount of bacterial growth was investigated and the minimum inhibitory concentration (MIC100) was calculated. The results are shown in Table 7.

[0135] [Table 7]

[0136] Test Example 10-1: Antifungal activity test Test compound: Compound No.6 Test strains: Malassezia pachydermatis (IFM56528)

[0137] Malassezia fungi ( Malassezia pachydermatis) 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 70, 65, 64, 60, 55, 45, 40, 35, 32, 20, 18, and 8 ppm. After 1 minute, 10 μL of the suspension and 10 mL of saline were added to a syringe, stirred, connected to a 37 mm quality monitor (Pall), and filtered and washed. The membrane filter was then infiltrated with Sabouraud medium and incubated at 32°C for 72 hours. The presence or absence of colony growth was examined, and the concentration at which no colony growth occurred was determined as the minimum fungicidal concentration (MFC100). When colonies were found to have grown, the number of colonies formed there (the number of colonies in the present invention group) and the number of colonies in the solvent without the test compound (the number of colonies in the drug-untreated group) were counted, and the colony formation inhibition rate (%) was calculated according to the following formula. The concentration showing 90% colony formation inhibition rate was defined as the 90% fungicidal concentration (MFC90), and the concentration showing 50% colony formation inhibition rate was defined as the median fungicidal concentration (MFC50). The results are shown in Table 8. Colony formation inhibition rate (%) = [(number of colonies in the untreated group - number of colonies in the group treated with the present invention) / number of colonies in the untreated group] x 100

[0138] [Table 8]

[0139] Test Example 10-2 Antifungal Activity Test Test compound: Compound No.1 Test strains: Malassezia pachydermatis (IFM56528)

[0140] Malassezia fungi ( Malassezia pachydermatis) 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 500, 250, 200, 190, 180, 170, 160, 150, 140, 130, 125, 120, 110, 100, 90, 80, 70, and 64 ppm. After 1 minute, 10 μL of the suspension and 10 mL of saline were added to a syringe, stirred, connected to a 37 mm quality monitor (Pall), and filtered and washed. The membrane filter was then infiltrated with Sabouraud medium and incubated at 32°C for 72 hours. The presence or absence of colony growth was examined, and the concentration at which no colony growth occurred was determined as the minimum fungicidal concentration (MFC100). When colonies were found to have grown, the number of colonies formed there (the number of colonies in the present invention group) and the number of colonies in the solvent without the test compound (the number of colonies in the drug-untreated group) were counted, and the colony formation inhibition rate (%) was calculated according to the following formula. The concentration showing 90% colony formation inhibition rate was defined as the 90% fungicidal concentration (MFC90), and the concentration showing 50% colony formation inhibition rate was defined as the median fungicidal concentration (MFC50). The results are shown in Table 9. Colony formation inhibition rate (%) = [(number of colonies in the untreated group - number of colonies in the group treated with the present invention) / number of colonies in the untreated group] x 100

[0141] [Table 9]

[0142] Test Example 11: Antifungal activity test Test compounds: Compound No.1, Compound No.6 Test strains: Malassezia pachydermatis (IFM56528)

[0143] Malassezia fungi ( Malassezia pachydermatis) was suspended in physiological saline to prepare a Malassezia suspension with an absorbance of 0.0025 at 600 nm. 190 μL of the Malassezia suspension was placed in a 96-well plate, and 10 μL of the test compound dissolved in DMSO was added to final concentrations of 500, 250, 125, 62.5, 31.25, 16, 8, 4, 2, 1, or 0.5 ppm. The plate was then cultured at 32°C for 72 hours. After the culture, 20 μL of WST-8 (a viable cell counting reagent, manufactured by Nacalai Tesque) was added to each well, and the plate was incubated at 32°C for 5 hours to allow color development. The absorbance at 450 nm was measured using a microplate reader (SpectraMax M2, manufactured by Molecular Devices). The absorbance of the wells containing the test compound (absorbance of the present invention group) and the absorbance of the wells containing the solvent without the test compound (absorbance of the drug-untreated group) were measured, and the survival rate (%) of Malassezia fungi was calculated according to the following formula. The drug concentration at which the survival rate was 0% was defined as the minimum inhibitory concentration (MIC100). The drug concentration at which the survival rate was 50% was defined as the median inhibitory concentration (MIC50). The results are shown in Table 10. Survival rate of Malassezia fungi (%) = [(absorbance of untreated area - absorbance of the present invention area) / absorbance of untreated area] x 100

[0144] [Table 10]

Claims

1. An antibacterial agent for non-human animals, 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 hydrogen atom or 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 or a hydroxyl group.

2. R １ and R ２ The antibacterial agent according to claim 1 , wherein one of the groups is a hydrogen atom or 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, 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, 5-chloro-4-(4-chloro-3-methylphenyl)-1H-imidazole-2-carbonitrile, 4-(2-chloro-4-methylphenyl)-1H-imidazole-2-carbonitrile, 5-chloro-1-hydroxy-4-(4-methylphenyl)-imidazole-2-carbonitrile, and 4-chloro-1-hydroxy-5-(4-methylphenyl)-imidazole-2-carbonitrile The antibacterial agent according to claim 1 or 2, which is selected from the group consisting of:

4. The antibacterial agent according to any one of claims 1 to 3, wherein the bacteria is a fungus.

5. The antibacterial agent according to claim 4, wherein the fungus is at least one selected from the group consisting of fungi of the genus Malassezia, Microsporum, and Arthroderma.

6. The antibacterial agent according to claim 4 or 5, for improving symptoms or diseases caused by at least one selected from the group consisting of fungi of the genus Malassezia, fungi of the genus Microsporum, and fungi of the genus Arthroderma.

7. The antibacterial agent according to claim 6, wherein the symptom or disease is a skin disease.

8. The antibacterial agent according to claim 6 or 7, wherein the symptom or disease is tinea versicolor, folliculitis, seborrheic dermatitis, psoriasis vulgaris, atopic dermatitis, dermatophytosis, or otitis externa.

9. The antibacterial agent according to any one of claims 1 to 3, wherein the fungus is a bacterium.

10. 10. The antibacterial agent according to claim 9, wherein the bacterium is at least one selected from the group consisting of Staphylococcus, Streptococcus, Pasteurella, Escherichia, Pseudomonas, Proteus, and Klebsiella.

11. The antibacterial agent according to claim 9 or 10, for improving symptoms or diseases caused by at least one selected from the genus Staphylococcus, the genus Streptococcus, the genus Pasteurella, the genus Escherichia, the genus Pseudomonas, the genus Proteus, and the genus Klebsiella.

12. The antibacterial agent according to claim 11, wherein the condition or disease is a skin disease.

13. The antibacterial agent according to claim 11 or 12, wherein the symptom or disease is pyoderma or otitis externa.

14. The antibacterial agent according to any one of claims 1 to 13, wherein the non-human animal is a dog, a cat or a horse.

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