JP2012153606A - Anti-trichophyton agent composition - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an anti-Trichophyton agent composition developing effective antimicrobial action against Trichophyton, having high safety and widely applicable to various industrial products.SOLUTION: One or more substances selected from the group consisting of prochloraz, flusilazole and their salts are included in a carrier such as a solvent. Good antimicrobial activity against Trichophyton is attainable also in the case of using the substances in combination with one or more substances selected from the group consisting of isothiazoline compounds, benzisothiazoline compounds, benzimidazole compounds, haloacetylene compounds, tetrahydrothiophene dioxide compounds, quinolone compounds, their salts, tetracycline antibiotics, pyrithione and its metal salt.

Description

  The present invention relates to an anti- ringworm fungus agent composition containing one or more selected from the group consisting of prochloraz, flusilazole and salts thereof.

  Prochloraz (chemical name; N-propyl-N- [2- (2,4,6-trichlorophenoxy) ethyl] -1H-imidazole-1-carboxamide) is a compound represented by the following formula (1). Further, flusilazole (chemical name: methylbis (4-fluorophenyl) (1H-1,2,4-triazol-1-ylmethyl) silane) is a compound represented by the following formula (2). Both of these are known to be used as pesticides for grains such as rice, corn, and beans, fruits such as apples, peaches, grapes, and bananas, as well as plant pathogens such as sugar beet, rape, and sunflower (patents). Document 1, Non-Patent Document 1).

  In addition, the present inventors have found that the above compounds are useful as industrial antibacterial agents and have already disclosed them (Japanese Patent Application Nos. 2009-238744 and 2009-249449). However, the effectiveness against specific pathogens that infect humans such as ringworm is not known at all.

  Ringworm is a dermatophyte that causes ringworm. Ringworm fungus is known to be transmitted through various items such as towels, clothes, slippers, bath mats, etc., and floors, walls, tiles, etc. in contact with patients in homes, schools, workplaces, lodging / entertainment facilities, etc. ing. It is also known that the symptoms of ringworm are worsened by wearing shoes with poor ventilation for a long time. Treatment of ringworm depends on an antifungal agent, but keratinous and thickened keratinized forms and onychomycosis are intractable. Even for ringworms other than ringworm, it is necessary to patiently continue drug treatment for complete cure There is. Therefore, development of an anti- ringworm fungus agent composition that can prevent infection with ringworm is desired.

  Antifungal agents that exhibit specific antibacterial activity against ringworm are pharmaceuticals, and are difficult to use in anti-ringworm fungus compositions for preventing infection as described above, due to regulations in the Pharmaceutical Affairs Law and side effects. It is. In products currently being sold for ringworm, keratolytic agents such as wood vinegar and organic acids, and essential oils having antibacterial action such as tea tree oil are used. However, keratolytic agents are used for symptomatic treatments, and do not have an infection prevention effect against ringworm bacteria, and many have skin irritation properties. In addition, antibacterial substances such as essential oils cannot be said to exhibit sufficient antibacterial action against fungus ringworm.

JP-A-7-101183

The Pesticide Manual Twelfth Edition (British Crop Protection Council) pp.460-461, pp.759-760 (2000)

  Therefore, in the present invention, it exhibits an effective antibacterial action against ringworm fungus and is highly safe. Other than textile products such as socks, towels, mats, leather shoes products, paper products, plastic products, rubber products, etc. An object of the present invention is to obtain an anti- ringworm fungus composition that can be widely used in living environments such as floors, tiles, and building materials.

  As a result of intensive studies to solve the above problems, the present inventors have found that prochloraz, flusilazole, and salts thereof have a good antibacterial activity against ringworm bacteria, It has been found that when applied, it exhibits a good infection prevention effect. Furthermore, when a specific antibacterial compound is used in combination, it has been found that good anti-tinea activity is observed, and the present invention has been completed.

That is, the present invention relates to the following [1] to [14].
[1] An anti- ringworm fungus agent composition comprising one or more selected from the group consisting of prochloraz, flusilazole, and salts thereof.
[2] One or more selected from the group consisting of prochloraz, flusilazole, and salts thereof, an isothiazoline compound represented by formula (3), a benzoisothiazoline compound represented by formula (4), a formula (5) benzimidazole compound, haloacetylene compound represented by formula (6), tetrahydrothiophene dioxide compound represented by formula (7), quinolone compound represented by formula (8), and those An anti- ringworm fungus agent composition comprising one or more selected from the group consisting of: a salt of tetracycline, a tetracycline antibiotic, and pyrithione and a metal salt thereof.

[Wherein, R ₁ represents a hydrogen atom or an optionally substituted hydrocarbon group, and R ₂ and R ₃ are the same or different and each represents a hydrogen atom, a halogen atom or an optionally substituted hydrocarbon group. Show. ]

[Wherein, ring A ₁ represents an optionally substituted benzene ring, and Y represents a hydrogen atom or an optionally substituted hydrocarbon group. ]

[In the formula, A ₂ ring represents an optionally substituted benzene ring, and Z represents —NHCOOR ₄ (wherein R ₄ represents a hydrogen atom or an alkyl group) or a substituted group. A good 5- or 6-membered nitrogen-containing heterocyclic group is shown. ]

[Wherein, X represents a halogen atom, R ₅ and R ₆ are the same or different and each represents a hydrogen atom or an optionally substituted hydrocarbon group, and m represents an integer of 0 or 1. ]

[Wherein Y ₁ , Y ₂ , Y ₃ and Y ₄ are the same or different and each represents a hydrogen atom, a halogen atom or an optionally substituted hydrocarbon group. ]

[Wherein the A ₃ ring represents a 6-membered aromatic ring which may be substituted or a heterocyclic ring in which one or two carbon atoms are substituted with nitrogen atoms, and R ₇ and R ₈ are the same or different and each represents a hydrogen atom or an optionally substituted hydrocarbon group. R ₇ may form a ring together with a substituent of A ₃ ring. ]

[3] The isothiazoline-based compound is 2-methyl-4-isothiazolin-3-one, 2-n-octyl-4-isothiazolin-3-one, 4-chloro-2-n-octyl-4-isothiazoline-3- ON, 5-chloro-2-methyl-4-isothiazolin-3-one, 5-chloro-2-n-octyl-4-isothiazolin-3-one and 4,5-dichloro-2-n-octyl-4- The anti- ringworm fungus agent composition according to the above [2], which is one or more selected from the group consisting of isothiazoline-3-one.
[4] The isothiazoline-based compound is selected from 2-methyl-4-isothiazolin-3-one, 5-chloro-2-methyl-4-isothiazolin-3-one and 2-n-octyl-4-isothiazolin-3-one The anti- ringworm fungus agent composition according to the above [2], which is one or more selected.
[5] The above benzoisothiazoline compound is one or two selected from 1,2-benzisothiazolin-3-one and Nn-butyl-1,2-benzisothiazolin-3-one [2] The anti-tinea fungus agent composition according to [2].
[6] The above, wherein the benzimidazole compound is one or more selected from the group consisting of methyl 2-benzimidazole carbamate, ethyl 2-benzimidazole carbamate, and 2- (4-thiazolyl) benzimidazole. The anti- ringworm fungus agent composition according to [2].
[7] The anti- ringworm fungus agent composition described in [2] above, wherein the haloacetylene compound is 3-iodo-2-propynyl N-butylcarbamate.
[8] The anti- ringworm fungus agent composition according to [2] above, wherein the tetrahydrothiophene dioxide compound is 3,3,4,4-tetrachlorotetrahydrothiophene-1,1-dioxide.
[9] The quinolone compound is enoxacin, tosufloxacin, norfloxacin, sarafloxacin, difloxacin, fleroxacin, lomefloxacin, enrofloxacin, ciprofloxacin, gatifloxacin, sparfloxacin, danofloxacin, moxifloxacin, garenoxacin, Anti-tinea of the above-mentioned [2], which is one or more selected from the group consisting of sitafloxacin, orbifloxacin, oxolinic acid, nadifloxacin, ofloxacin, levofloxacin, pazufloxacin, and marbofloxacin Fungus composition.
[10] The anti-tinea fungus agent composition according to [2] above, wherein the tetracycline antibiotic is one or more selected from the group consisting of tetracycline, chlortetracycline, oxytetracycline and salts thereof.
[11] The anti-tinea fungus agent composition according to the above [2], wherein the metal salt of pyrithione is one or more selected from the group consisting of an alkali metal salt of pyrithione and a divalent metal salt of pyrithione. object.
[12] The anti- ringworm fungus agent composition according to the above [11], wherein the alkali metal salt of pyrithione is sodium pyrithione.
[13] The anti-tinea fungus agent composition described in [11] above, wherein the divalent metal salt of pyrithione is one or two selected from the group consisting of zinc pyrithione and copper pyrithione.
[14] An industrial product containing the anti- ringworm fungus composition according to any one of [1] to [13].

  ADVANTAGE OF THE INVENTION According to this invention, the anti- ringworm fungus agent composition which shows an effective antibacterial action with respect to a ringworm and has a favorable infection prevention effect is obtained. The anti- ringworm fungus composition of the present invention has an anti- ringworm fungus activity, solubility in various organic solvents, high stability and safety, etc., so that it can be used as an adhesive, deodorant, disinfectant, cleaning agent, fiber, etc. It can be widely added to industrial products such as products, leather shoes products, paper products, plastic products, rubber products and building materials.

  The anti-tinea agent composition of the present invention contains one or more selected from the group consisting of prochloraz, flusilazole, and salts thereof. Such salts include salts with inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid; formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid And salts with organic acids such as succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid. In the present invention, as prochloraz, flusilazole and salts thereof, commercially available products may be used, or those produced according to known techniques may be used, but it is convenient to use commercially available products.

  In addition to one or more selected from the group consisting of the above-mentioned prochloraz, flusilazole, and salts thereof, the anti-tinea fungus agent composition of the present invention is an isothiazoline compound, a benzoisothiazoline compound, a benzimidazole compound Compound, haloacetylene compound, tetrahydrothiophene dioxide compound, quinolone compound, and salts thereof, and one or more antibacterial compounds selected from the group consisting of pyrithione and metal salts thereof Also good. Even when the antibacterial compound is used in combination, good anti-tinea activity is observed.

  The isothiazoline-based compound is represented by the following formula (3).

[Wherein, R ₁ represents a hydrogen atom or an optionally substituted hydrocarbon group, and R ₂ and R ₃ are the same or different and each represents a hydrogen atom, a halogen atom or an optionally substituted hydrocarbon group. Show. ]

In the formula (3), the hydrocarbon group of the optionally substituted hydrocarbon group represented by R ₁ is preferably a hydrocarbon group having 1 to 20 carbon atoms, more preferably a hydrocarbon group having 1 to 14 carbon atoms. Preferable examples include alkyl group, alkenyl group, alkynyl group, cycloalkyl group, and aryl group.

  Examples of the alkyl group include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, 1-methylbutyl, 1-ethylpropyl, 1,1- Dimethylpropyl, 2,2-dimethylpropyl, n-hexyl, isohexyl, 2-ethylbutyl, n-heptyl, isoheptyl, n-octyl, isooctyl, 1-methylheptyl, 1-ethylhexyl, 1-propylpentyl, 1,1- Examples thereof include alkyl groups having 1 to 10 carbon atoms such as dimethylhexyl, 1-ethyl-1-methylpentyl, 1,1-diethylbutyl, 2-ethylhexyl, nonyl and decyl, and preferably alkyl groups having 1 to 8 carbon atoms. .

  Examples of the alkenyl group include ethenyl (vinyl), 1-propenyl, 2-propenyl (allyl), isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-1-propenyl, 1-pentenyl, Examples thereof include alkenyl groups having 2 to 6 carbon atoms such as 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, and 5-hexenyl.

  Examples of the alkynyl group include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, Examples thereof include alkynyl groups having 2 to 6 carbon atoms such as 2-hexynyl, 3-hexynyl, 4-hexynyl and 5-hexynyl.

  Examples of the cycloalkyl group include cycloalkyl groups having 3 to 8 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.

  Examples of the aryl group include aryl groups having 6 to 14 carbon atoms such as phenyl, naphthyl, anthracenyl, phenanthrenyl and the like.

Examples of the substituent of the optionally substituted hydrocarbon group represented by R ₁ include hydroxyl group; halogen atom of chlorine, fluorine, bromine and iodine; cyano group; amino group; carboxyl group; methoxy, ethoxy, propoxy, butoxy and the like An alkoxy group having 1 to 4 carbon atoms; an aryloxy group having 6 to 20 carbon atoms such as phenoxy, preferably 6 to 10 carbon atoms; an alkylthio group having 1 to 4 carbon atoms such as methylthio, ethylthio, propylthio, butylthio; C6-C20 arylthio groups, etc. are mentioned. The substituents may be the same or different, and 1 to 5, preferably 1 to 3 may be substituted.

As the optionally substituted hydrocarbon group represented by R ₁ , an unsubstituted hydrocarbon group is preferable, and among them, an alkyl group or a cycloalkyl group is preferable. As the alkyl group, an alkyl group having 1 to 8 carbon atoms is preferable, and an alkyl group having 1 to 4 carbon atoms such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl and the like, and n -8 carbon atoms such as octyl, isooctyl, 1-methylheptyl, 1-ethylhexyl, 1-propylpentyl, 1,1-dimethylhexyl, 1-ethyl-1-methylpentyl, 1,1-diethylbutyl, 2-ethylhexyl Are more preferable, and methyl, ethyl, n-butyl, and n-octyl are more preferable. As the cycloalkyl group, a cycloalkyl group having 3 to 8 carbon atoms is preferable, and cyclohexyl is more preferable.

R ₁ is preferably an alkyl group having 1 to 8 carbon atoms or a cycloalkyl group having 3 to 8 carbon atoms, more preferably an alkyl group having 1 to 8 carbon atoms, methyl, ethyl, propyl, isopropyl, n-butyl, C1-C4 alkyl groups such as isobutyl, sec-butyl, tert-butyl, and n-octyl, isooctyl, sec-octyl (1-methylheptyl, 1-ethylhexyl, 1-propylpentyl, etc.), tert-octyl More preferred are alkyl groups having 8 carbon atoms such as (1,1-dimethylhexyl, 1-ethyl-1-methylpentyl, 1,1-diethylbutyl, etc.), 2-ethylhexyl, and the like, methyl, ethyl, n-butyl, n -Octyl is particularly preferred.

In formula (3), examples of the halogen atom represented by R ₂ or R ₃ include fluorine, chlorine, bromine and iodine atoms, and among these, a chlorine atom is preferred.

Examples of the optionally substituted hydrocarbon group represented by R ₂ or R ₃ include the same as the optionally substituted hydrocarbon group represented by R ₁ described above. A hydrocarbon group is preferable, and an alkyl group having 1 to 4 carbon atoms such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl is particularly preferable.

R ₂ and R ₃ are the same or different and are each preferably a hydrogen atom or a halogen atom, more preferably a hydrogen atom or a chlorine atom.

  Specific examples of the isothiazoline-based compound include 2-methyl-4-isothiazolin-3-one, 2-ethyl-4-isothiazolin-3-one, 2-n-octyl-4-isothiazolin-3-one, and 5-chloro. 2-methyl-4-isothiazolin-3-one, 5-chloro-2-ethyl-4-isothiazolin-3-one, 5-chloro-2-n-octyl-4-isothiazolin-3-one, 4-chloro 2-n-octyl-4-isothiazolin-3-one, 4,5-dichloro-2-n-octyl-4-isothiazolin-3-one, 4,5-dichloro-2-cyclohexyl-4-isothiazoline-3 -ON etc. are mentioned. Of these, 2-methyl-4-isothiazolin-3-one, 2-n-octyl-4-isothiazolin-3-one, 4-chloro-2-n-octyl-4-isothiazolin-3-one, 5- Chloro-2-methyl-4-isothiazolin-3-one, 5-chloro-2-n-octyl-4-isothiazolin-3-one and 4,5-dichloro-2-n-octyl-4-isothiazoline-3- On is preferred, with 2-methyl-4-isothiazolin-3-one, 5-chloro-2-methyl-4-isothiazolin-3-one and 2-n-octyl-4-isothiazolin-3-one being particularly preferred. The above isothiazoline-based compounds may be used alone or in combination of two or more.

  The benzoisothiazoline compound is represented by the following formula (4).

[Wherein, ring A ₁ represents an optionally substituted benzene ring, and Y represents a hydrogen atom or an optionally substituted hydrocarbon group. ]

In formula (4), the substituent of the optionally substituted benzene ring represented by A ₁ ring is the same as the substituent of the optionally substituted hydrocarbon group represented by R ₁ described above. Among them, a halogen atom and an alkyl group having 1 to 4 carbon atoms such as methyl, ethyl, propyl, and butyl are preferable. These substituents may be the same or different, and 1 to 4, preferably 1 or 2 may be substituted on the benzene ring. As the benzene ring which may be substituted represented by A ₁ ring, unsubstituted benzene ring.

In the formula (4), examples of the optionally substituted hydrocarbon group represented by Y include the same as the optionally substituted hydrocarbon group represented by R ₁ described above. A hydrocarbon group is preferred, an alkyl group having 1 to 8 carbon atoms is more preferred, and an alkyl group having 1 to 4 carbon atoms (particularly n-butyl) is particularly preferred.

  Y is preferably a hydrogen atom or an alkyl group having 1 to 8 carbon atoms, particularly preferably a hydrogen atom or an alkyl group having 1 to 4 carbon atoms (particularly n-butyl).

  Preferable specific examples of the benzoisothiazoline compound include 1,2-benzisothiazoline-3-one, Nn-butyl-1,2-benzisothiazoline-3-one, and the like. The benzoisothiazoline compounds may be used alone or in combination of two or more.

  The benzimidazole compound is represented by the following formula (5).

[In the formula, A ₂ ring represents an optionally substituted benzene ring, and Z represents —NHCOOR ₄ (wherein R ₄ represents a hydrogen atom or an alkyl group) or a substituted group. A good 5- or 6-membered nitrogen-containing heterocyclic group is shown. ]

In the formula (5), the substituent of the optionally substituted benzene ring represented by the A ₂ ring is the same as the substituent of the hydrocarbon group optionally having the substituent represented by R ₁ described above. Among them, a halogen atom and an alkyl group having 1 to 4 carbon atoms such as methyl, ethyl, propyl, and butyl are preferable. These substituents may be the same or different, and 1 to 4, preferably 1 or 2, may be substituted on the benzene ring. As the benzene ring which may be substituted represented by A ₂ ring, a benzene ring is preferably unsubstituted.

In -NHCOOR ₄ represented by Z in the formula (5), the alkyl group represented by R ₄ includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n -C1-C8 alkyl groups, such as pentyl, n-hexyl, n-heptyl, and n-octyl, etc. are mentioned, Among these, C1-C3 alkyl groups, such as methyl, ethyl, and n-propyl Is particularly preferred.

  In the formula (5), the optionally substituted 5- or 6-membered nitrogen-containing heterocyclic group represented by Z contains 1 to 4 nitrogen atoms as ring constituent atoms, or 1 to 2 A 5- or 6-membered monocyclic heterocyclic group containing one nitrogen atom in addition to one oxygen atom or sulfur atom as a ring-constituting atom, or the 5- or 6-membered nitrogen-containing heterocyclic group Examples thereof include a condensed heterocyclic group in which a benzene ring or a 5-membered ring is condensed to the ring. Examples of the 5- or 6-membered nitrogen-containing monocyclic heterocyclic group include pyridyl groups such as 2-pyridyl, 3-pyridyl and 4-pyridyl; thiazolyl groups such as 2-thiazolyl, 4-thiazolyl and 5-thiazolyl; Isothiazolyl groups such as isothiazolyl, 4-isothiazolyl and 5-isothiazolyl; imidazolyl groups such as 1-imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl; pyrrolyl groups such as 1-pyrrolyl, 2-pyrrolyl and 3-pyrrolyl; Pyrrolinyl groups such as 2-pyrrolinyl and 3-pyrrolinyl; furazanyl groups; pyrrolidinyl groups such as 1-pyrrolidinyl, 2-pyrrolidinyl and 3-pyrrolidinyl; imidazolidinyl groups such as 2-imidazolidinyl, 4-imidazolidinyl and 5-imidazolidinyl; 1-pyrazolidinyl A pyrazolidinyl group such as 5-pyrazolyl An oxazolyl group such as 2-oxazolyl, 4-oxazolyl and 5-oxazolyl; an isoxazolyl group such as 3-isoxazolyl, 4-isoxazolyl and 5-isoxazolyl; a tetrazolyl group such as 1H-tetrazolyl and 2H-tetrazolyl; Pyrimidyl groups such as pyrimidyl, 4-pyrimidyl and 5-pyrimidyl; pyridazinyl groups such as 3-pyridazinyl and 4-pyridazinyl; pyrazinyl groups such as 2-pyrazinyl and 3-pyrazinyl; 1,2-thiazin-3-yl, 1, Thiazinyl such as 2-thiazin-4-yl, 1,3-thiazin-2-yl, 1,3-thiazin-4-yl, 1,4-thiazin-2-yl, 1,4-thiazin-3-yl Groups; piperazinyl groups such as 1-piperazinyl, 2-piperazinyl, 3-piperazinyl; -Thiadiazin-4-yl, 1,2,3-thiadiazin-5-yl, 1,2,3-thiadiazin-6-yl, 1,2,4-thiadiazin-3-yl, 1,3,4-thiadiazine Thiadiazinyl groups such as 2-yl; 1,3,4-oxadiazol-2-yl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl Oxadiazolyl groups such as 1,2,3-oxadiazol-4-yl, 1,2,3-oxadiazol-5-yl; 1,2,3-thiadiazol-4-yl, 1,2,3 A thiadiazolyl group such as thiadiazol-5-yl; a triazolyl group such as 1,2,3-triazol-4-yl, 1,2,4-triazol-3-yl; 2-thiomorpholinyl, 3-thiomorpholinyl, 4-thiomorpholinyl 5 Thiomorpholinyl groups such as thiomorpholinyl and 6-thiomorpholinyl; morpholinyl groups such as 2-morpholinyl, 3-morpholinyl, 4-morpholinyl, 5-morpholinyl and 6-morpholinyl; oxoimidazolinyl groups such as 2-oxoimidazolinyl 1,2,4-triazine-3,5-dione-1-yl, 1,2,4-triazine-3,5-dione-2-yl, 1,2,4-triazine-3,5-dione; And dioxotriazinyl groups such as -4-yl; piperidyl groups such as 1-piperidyl, 2-piperidyl, 3-piperidyl, 4-piperidyl and the like. Examples of the condensed heterocyclic group include quinolyl groups such as 2-quinolyl, 3-quinolyl and 4-quinolyl; isoquinolyl groups such as 3-isoquinolyl and 4-isoquinolyl; indolyl groups such as 2-indolyl and 3-indolyl; Isoindolyl groups such as isoindol-3-yl; quinolidinyl groups such as 8-quinolidinyl; purinyl groups such as 1H-purin-6-yl and 3H-purin-6-yl; cinnolinyl groups such as 3-cinnolinyl and 5-cinnolinyl An indazolyl group such as 3-indazolyl; a pteridinyl group such as 2-pteridinyl; a phthalazinyl group such as 4-phthalazinyl; a quinazolinyl group such as 2-quinazolinyl and 4-quinazolinyl; a quinoxalinyl group such as 2-quinoxalinyl and 3-quinoxalinyl; -An indolizinyl group such as indolizinyl; Benzooxazinyl groups such as zooxazin-2-yl; phenothiazinyl groups such as 2-phenothiazinyl and 3-phenothiazinyl; phenazinyl groups such as 2-phenazinyl and 3-phenazinyl; 2-phenoxazinyl, 3-phenoxazinyl, 4- Examples include phenoxazinyl groups such as phenoxazinyl. Of the above heterocyclic groups, a 5-membered nitrogen-containing heterocyclic group is preferable, and a thiazolyl group is particularly preferable.

  Examples of the substituent of the heterocyclic ring include alkyl groups having 1 to 4 carbon atoms such as methyl, ethyl, n-propyl, isopropyl, butyl, n-butyl, isobutyl, sec-butyl, tert-butyl; methoxy, ethoxy, n -C1-C4 alkoxy groups such as propoxy, isopropoxy, butoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy; halogen atoms such as fluorine, chlorine and bromine; hydroxyl groups; amino groups; nitro groups; A mercapto group etc. are mentioned.

  The optionally substituted 5- or 6-membered nitrogen-containing heterocyclic group represented by Z is preferably an unsubstituted 5- or 6-membered nitrogen-containing heterocyclic group, and an unsubstituted 5-membered nitrogen-containing heterocyclic group Are more preferable, and a thiazolyl group is particularly preferable.

Z is preferably a group represented by —NHCOOR ₄ (wherein R ₄ is an alkyl group having 1 to 8 carbon atoms) or an unsubstituted 5- or 6-membered nitrogen-containing heterocyclic group, and —NHCOOR ₄ (Wherein R ₄ is an alkyl group having 1 to 3 carbon atoms) or an unsubstituted 5-membered nitrogen-containing heterocyclic group is more preferred, and —NHCOOR ₄ (wherein R ₄ is carbon And a thiazolyl group is particularly preferable.

  Preferable specific examples of the benzimidazole compound include methyl 2-benzimidazole carbamate, ethyl 2-benzimidazole carbamate, 2- (4-thiazolyl) benzimidazole and the like. The said benzimidazole type compound may be used independently, or may use 2 or more types together.

  The haloacetylene compound is represented by the following formula (6).

[Wherein, X represents a halogen atom, R ₅ and R ₆ are the same or different and each represents a hydrogen atom or an optionally substituted hydrocarbon group, and m represents an integer of 0 or 1. ]

  In the formula (6), examples of the halogen atom represented by X include fluorine, chlorine, bromine and iodine, and iodine is particularly preferable.

In the formula (6), examples of the optionally substituted hydrocarbon group represented by R ₅ or R ₆ include the same as the optionally substituted hydrocarbon group represented by R ₁ described above. Among them, an unsubstituted hydrocarbon group is preferable, an alkyl group having 1 to 10 carbon atoms or a cycloalkyl group having 3 to 8 carbon atoms is more preferable, an alkyl group having 1 to 10 carbon atoms is further preferable, and an alkyl group having 1 to 4 carbon atoms is more preferable. Alkyl groups are even more preferred, and n-butyl is particularly preferred.
One of R ₅ and R _{6 is} a hydrocarbon group which may be substituted, the other is preferably a hydrogen atom, and one of R ₅ and R ₆ is an alkyl group having 1 to 10 carbon atoms. More preferably, the other is a hydrogen atom, one of R ₅ and R ₆ is an alkyl group having 1 to 4 carbon atoms (particularly n-butyl), and the other is particularly preferably a hydrogen atom.

  In Formula (6), m represents an integer of 0 or 1, and when m is 0, the haloacetylene compound is an acid amide derivative, and when m is 1, the haloacetylene compound is a carbamate derivative. Of these, carbamate derivatives of haloacetylene compounds in which m is 1 are preferred.

  Specific examples of the haloacetylene compound include 3-chloropropiolic acid amide, N-methyl-3-chloropropiolic acid amide, N-, as the haloacetylene-based compound (acid amide derivative) when m is 0. Ethyl-3-chloropropiolic acid amide, N-propyl-3-chloropropiolic acid amide, N-butyl-3-chloropropiolic acid amide, N-hexyl-3-chloropropiolic acid amide, N-octyl- (N-substituted-) 3-chloropropiolic acid amides such as 3-chloropropiolic acid amide, N-cyclohexyl-3-chloropropiolic acid amide; 3-bromopropiolic acid amide, N-methyl-3-bromo Propiolic acid amide, N-ethyl-3-bromopropiolic acid amide, N-propyl-3-bromopropiolic acid Amide, N-butyl-3-bromopropiolic amide, N-hexyl-3-bromopropiolic amide, N-octyl-3-bromopropiolic amide, N-cyclohexyl-3-bromopropiolic amide, etc. (N-substituted-) 3-bromopropiolic amides; 3-iodopropiolic amides, N-methyl-3-iodopropiolic amides, N-ethyl-3-iodopropiolic amides, N-propyl -3-iodopropiolic amide, N-butyl-3-iodopropiolic amide, N-hexyl-3-iodopropiolic amide, N-octyl-3-iodopropiolic amide, N-cyclohexyl-3 -(N-substituted-) 3-iodopropiolic amides such as iodopropiolic amide. Of these, (N-substituted-) 3-iodopropiolic acid amide is preferable, and N-butyl-3-iodopropiolic acid amide is more preferable.

Moreover, as a haloacetylene type compound (carbamate derivative) when m is 1, 3-iodo-2-propynyl N-methylcarbamate, 3-iodo-2-propynyl N-ethylcarbamate, 3-iodo-2-propynyl N-propyl carbamate, 3-iodo-2-propynyl N-butyl carbamate, 3-iodo-2-propynyl N-hexyl carbamate, 3-iodo-2-propynyl N-octyl carbamate, 3-iodo-2-propynyl N- Examples include 3-iodo-2-propynyl N-alkyl carbamate such as cyclohexyl carbamate, and among them, 3-iodo-2-propynyl N-butyl carbamate is preferable.
The said haloacetylene type compound may be used independently, or may use 2 or more types together.

  The tetrahydrothiophene dioxide compound is represented by the following formula (7).

[Wherein Y ₁ , Y ₂ , Y ₃ and Y ₄ are the same or different and each represents a hydrogen atom, a halogen atom or an optionally substituted hydrocarbon group. ]

In formula (7), examples of the halogen atom represented by Y ₁ , Y ₂ , Y ₃ or Y ₄ include fluorine, chlorine, bromine and iodine, with chlorine being particularly preferred. The optionally substituted hydrocarbon group represented by Y ₁ , Y ₂ , Y ₃ or Y ₄ is the same as the optionally substituted hydrocarbon group represented by R ₁ described above. Among them, an alkyl group having 1 to 4 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl is preferable.

As Y ₁ , Y ₂ , Y ₃ and Y ₄ , all of Y ₁ , Y ₂ , Y ₃ and Y ₄ are halogen atoms, or Y ₁ , Y ₂ and Y ₃ are halogen atoms and Y ₄ is It is preferably a hydrogen atom, or Y ₁ and Y ₄ are halogen atoms and Y ₂ and Y ₃ are preferably hydrogen atoms, and all of Y ₁ , Y ₂ , Y ₃ and Y ₄ are halogen atoms. More preferably, all of Y ₁ , Y ₂ , Y ₃ and Y ₄ are particularly preferably chlorine.

  Specific examples of the tetrahydrothiophene dioxide compound include 3,3,4,4-tetrachlorotetrahydrothiophene-1,1-dioxide, 3,3,4,4-tetrabromotetrahydrothiophene-1,1-dioxide, 3,4-dichlorotetrahydrothiophene-1,1-dioxide, 3,3,4-trichlorotetrahydrothiophene-1,1-dioxide, 3,3,4-tribromotetrahydrothiophene-1,1-dioxide Of these, 3,3,4,4-tetrachlorotetrahydrothiophene-1,1-dioxide is particularly preferred. The said tetrahydrothiophene dioxide type compound may be used independently, or may use 2 or more types together.

  The quinolone compound is represented by the following formula (8).

[Wherein the A ₃ ring represents a 6-membered aromatic ring which may be substituted or a heterocyclic ring in which one or two carbon atoms are substituted with nitrogen atoms, and R ₇ and R ₈ are the same or different and each represents a hydrogen atom or an optionally substituted hydrocarbon group. R ₇ may form a ring together with a substituent of A ₃ ring. ]

In the above formula (8), a 6-membered aromatic ring which may be substituted or a heterocycle in which one or two carbon atoms are substituted with a nitrogen atom, represented by A ₃ ring Among them, examples of the 6-membered aromatic ring that is the heterocyclic ring include pyridine, pyrimidine, pyridazine, and pyrazine, and examples of the 6-membered aromatic ring that is not the heterocyclic ring include benzene. Among these, benzene, pyridine and pyrimidine are preferable, and benzene or pyridine is particularly preferable.

A substituent of the “6-membered aromatic ring which may be substituted or may be a heterocyclic ring in which one or two carbon atoms are substituted with a nitrogen atom” represented by A ₃ ring is a hydroxyl group. A halogen atom, an optionally substituted alkoxy group, an optionally substituted hydrocarbon group, an optionally substituted amino group, an alkylenedioxy group, and the like.

  Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom, and a fluorine atom or a chlorine atom is preferable.

  Examples of the alkoxy group of the “optionally substituted alkoxy group” include an alkoxy group having 1 to 6 carbon atoms, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy and the like. An alkoxy group having 1 to 4 carbon atoms is preferred. Examples of the substituent of the “optionally substituted alkoxy group” include a halogen atom such as fluorine, chlorine and bromine; an alkoxy group having 1 to 4 carbon atoms; an aryl group having 1 to 14 carbon atoms such as phenyl and naphthyl; Can be mentioned.

Examples of the hydrocarbon group of the “optionally substituted hydrocarbon group” include the same hydrocarbon groups as those of the “optionally substituted hydrocarbon group” represented by R ₁ described above. Substituents of the “optionally substituted hydrocarbon group” include hydroxyl groups; halogen atoms of chlorine, fluorine, bromine and iodine; cyano groups; amino groups; carboxyl groups; carbon numbers such as acetyl, propanoyl, butanoyl and hexanoyl An acyl group having 1 to 6 carbon atoms; an alkoxy group having 1 to 4 carbon atoms such as methoxy, ethoxy, propoxy and butoxy; an aryloxy group having 6 to 20 carbon atoms such as phenoxy and naphthyloxy, preferably 6 to 10 carbon atoms; benzyl Aralkyloxy groups having 7 to 14 carbon atoms such as oxy and phenylethyloxy; alkylthio groups having 1 to 4 carbon atoms such as methylthio, ethylthio, propylthio and butylthio; arylthio groups having 6 to 20 carbon atoms such as phenylthio and the like. . The hydrocarbon group may have two or more of the substituents, and the substituents may be the same or different.

  The amino group of the “optionally substituted amino group” includes pyrrolidinyl, piperidyl, piperazinyl, azabicyclo [2.2.1] heptanyl, azabicyclo [2.2.2] octanyl, diazabicyclo [2.2.1]. Cyclic amino groups such as heptanyl, diazabicyclo [2.2.2] octanyl, octahydropyrrolopyridinyl, isoindolinyl, azaspiro [2.4] heptanyl are also included. Examples of the substituent of the “optionally substituted amino group” include a hydroxyl group, an alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, and an amino group.

  As said alkylene dioxy group, C1-C2 alkylene dioxy groups, such as methylene dioxy and ethylene dioxy, are mentioned as a preferable thing.

A ₃ ring is preferably substituted with 2-4 substituents. Examples of the substituent include a halogen atom; a cycloalkyl group having 3 to 6 carbon atoms substituted with an amino group; pyrrolidinyl, piperidyl, piperazinyl, diazabicyclo [2.2.1] heptanyl, octahydropyrrolopyridinyl, A cyclic amino group such as isoindolinyl, azaspiro [2.4] heptanyl; the cyclic amino group substituted by a hydroxyl group, an amino group or an alkyl group having 1 to 6 carbon atoms; an alkoxy group having 1 to 4 carbon atoms; substituted by a halogen atom The alkoxy group and methylenedioxy group are preferred.

In the formula (8), the “optionally substituted hydrocarbon group” represented by R ₇ or R ₈ is the same group as the “optionally substituted hydrocarbon group” of the A ₃ ring described above. Can be mentioned. In addition, the group represented by R ₇ may form a ring together with the substituent at the 8-position of the A ₃ ring. Examples of such rings include hydropyridine rings, hydrooxazine rings, hydrooxadiazine rings and the like.

  In the present invention, as the quinolone compound, compounds represented by formula (9) and formula (10) are preferably used.

[Wherein R ₇ and R ₈ are the same or different and each represents a hydrogen atom or an optionally substituted hydrocarbon group, R ₉ represents a hydrogen atom, a halogen atom or an amino group, and R ₁₀ represents a hydrogen atom or a halogen atom. , R ₁₁ represents an optionally substituted hydrocarbon group or an optionally substituted cyclic amino group. ]

[Wherein R ₇ and R ₈ are the same or different and each represents a hydrogen atom or an optionally substituted hydrocarbon group, R ₁₂ represents a hydrogen atom, a halogen atom or an amino group, and R ₁₃ represents a hydrogen atom or a halogen atom. , R ₁₄ represents an optionally substituted hydrocarbon group or an optionally substituted cyclic amino group. R ₁₃ may form an alkylenedioxy group having 1 to 2 carbon atoms together with R ₁₄ . R ₁₅ represents a hydrogen atom, a halogen atom, an optionally substituted alkoxy group or an optionally substituted hydrocarbon group. R ₇ may form a ring together with R ₁₅ . ]

  The compound represented by the above formula (9) is a compound having a naphthyridine skeleton, and the compound represented by the above formula (10) is a compound having a quinoline skeleton.

In the above formulas (9) and (10), the group represented by R ₇ or R ₈ has the same meaning as described above. Examples of the halogen atom represented by R ₉ or R ₁₀ or R ₁₂ or R ₁₃ include a fluorine atom, a chlorine atom, and a bromine atom. In addition, the “optionally substituted hydrocarbon group” and the “optionally substituted cyclic amino group” represented by R ₁₁ or R ₁₄ are the same as described above. In the above formulas (9) and (10), the group represented by R ₇ is an alkyl group having 1 to 4 carbon atoms such as ethyl; halogenated carbon atoms 1 to 4 such as 2-fluoroethyl. A cycloalkyl group having 3 to 6 carbon atoms such as cyclopropyl, cyclopentyl and cyclohexyl; a halogenated cycloalkyl group having 3 to 6 carbon atoms such as fluorocyclopropyl; halogenation such as fluorophenyl and difluorophenyl Preferred aryl groups. The group represented by R ₈ is preferably a hydrogen atom, the group represented by R ₉ or R ₁₂ is preferably a hydrogen atom, a fluorine atom or an amino group, and the group represented by R ₁₀ or R ₁₃ is a hydrogen atom. Or a fluorine atom is preferable. Examples of the group represented by R ₁₁ or R ₁₄ include an aminocyclopropyl group; a pyrrolidinyl group, a piperidyl group, a piperazinyl group, a diazabicyclo group that is substituted with a hydroxyl group, an amino group, or an alkyl group having 1 to 4 carbon atoms such as methyl or ethyl. .1] Heptyl, octahydropyrrolopyridinyl, isoindolinyl, azaspiro [2.4] heptanyl are preferred.

Further, in the above formula (10), the “optionally substituted alkoxy group” and the “optionally substituted hydrocarbon group” represented by R ₁₅ are the same as described above. In the above formula (10), the group represented by R ₁₅ includes a hydrogen atom; a halogen atom such as a fluorine atom or a chlorine atom; an alkyl group having 1 to 4 carbon atoms such as methyl; Alkoxy group: The alkoxy group substituted with a halogen atom such as difluoromethoxy is preferred. In the above formula (10), the group represented by R ₇ may form a ring together with the group represented by R ₁₅ , and examples of the ring include a hydropyridine ring, a hydrooxazine ring, and a hydrooxadiazine ring. Etc. Therefore, in the above formula (10), a benzoquinolidine skeleton, a pyridobenzoxazine skeleton or a pyridobenzooxadiazine skeleton in which a group represented by R ₇ and a group represented by R ₁₅ form a ring Those possessed are also exemplified as preferred compounds. The alkylenedioxy group formed by the group represented by R ₁₃ and the group represented by R ₁₄ is preferably a methylenedioxy group.

  In the present invention, as the quinolone compound, one or two or more types can be selected from the group consisting of the compounds represented by the above formulas (9) and (10).

As the quinolone compound which is more preferably used in the present invention, enoxacin having a naphthyridine skeleton (chemical name: 1,4-dihydro-1-ethyl-4-oxo-6-fluoro-7- (piperazin-1-yl)- 1,8-naphthyridine-3-carboxylic acid), tosufloxacin (chemical name; 1- (2,4-difluorophenyl) -6-fluoro-7- (3-amino-1-pyrrolidinyl) -1,4-dihydro- 4-oxo-1,8-naphthyridine-3-carboxylic acid), norfloxacin having a quinoline skeleton (chemical name; 1-ethyl-6-fluoro-7-piperazino-4-oxo-1,4-dihydroquinoline-3- Carboxylic acid), sarafloxacin (chemical formula; 1- (4-fluorophenyl) -4-oxo-6-fluoro-7-piperazino-1,4 Dihydroquinoline-3-carboxylic acid), difloxacin (chemical name; 1- (4-fluorophenyl) -4-oxo-6-fluoro-7- (4-methylpiperazino) -1,4-dihydroquinoline-3-carboxylic acid ), Fleroxacin (chemical name; 6,8-difluoro-1- (2-fluoroethyl) -1,4-dihydro-7- (4-methylpiperazino) -4-oxo-3-quinolinecarboxylic acid), lomefloxacin (chemical) 1-ethyl-6,8-difluoro-1,4-dihydro-4-oxo-7- (3-methyl-1-piperazinyl) quinoline-3-carboxylic acid), enrofloxacin (chemical name; 1 -Cyclopropyl-4-oxo-6-fluoro-7- (4-ethyl-1-piperazinyl) -1,4-dihydroquinoline-3-carboxylic acid), cyprof Xacin (chemical name; 1-cyclopropyl-4-oxo-6-fluoro-7- (1-piperazinyl) -1,4-dihydro-3-quinolinecarboxylic acid), gatifloxacin (chemical name; 1,4- Dihydro-1-cyclopropyl-4-oxo-6-fluoro-8-methoxy-7- (3-methylpiperazin-1-yl) quinoline-3-carboxylic acid), sparfloxacin (chemical name; 5-amino -1-cyclopropyl-6,8-difluoro-1,4-dihydro-7- (3α, 5α-dimethyl-1-piperazinyl) -4-oxoquinoline-3-carboxylic acid), danofloxacin (chemical name; 1- Cyclopropyl-6-fluoro-7-[(1α, 4α) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl] -4-oxo-1,4-dihydro Norin-3-carboxylic acid), moxifloxacin (chemical name; 1,4-dihydro-1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-7-[[(4aα, 7aα) -octahydro -1H-pyrrolo [3,4-b] pyridin] -6-yl] quinoline-3-carboxylic acid), galenoxacin (chemical name; 1-cyclopropyl-8- (difluoromethoxy) -7- (2,3- Dihydro-1β-methyl-1H-isoindol-5-yl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid), sitafloxacin (chemical name; 1,4-dihydro-1-[(1R, 2S) -2-Fluorocyclopropyl] -8-chloro-6-fluoro-7-[(4S) -4-aminospiro [pyrrolidin-3,1′-cyclopropane] -1-yl] -4-oxo Norin-3-carboxylic acid), orbifloxacin (chemical name: 1-cyclopropyl-7- (3α, 5α-dimethyl-1-piperazinyl) -5,6,8-trifluoro-1,4-dihydro- 4-oxo-3-quinolinecarboxylic acid), oxolinic acid (chemical name; 1-ethyl-6,7- (methylenedioxy) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid), benzoquino Nadifloxacin having a lysine skeleton (chemical name: 9-fluoro-6,7-dihydro-8- (4-hydroxypiperidino) -5α-methyl-1-oxo-1H, 5H-benzo [ij] quinolidine- 2-carboxylic acid and 9-fluoro-6,7-dihydro-8- (4-hydroxypiperidino) -5β-methyl-1-oxo-1H, 5H-benzo [ij] quinolizine-2- Carboxylic acid), ofloxacin having a pyridobenzoxazine skeleton (chemical name: rac-9-fluoro-2,3-dihydro-3α ^* -methyl-10- (4-methyl-1-piperazinyl) -7-oxo-7H -Pyrido [1,2,3-de] -1,4-benzoxazine-6-carboxylic acid), levofloxacin (chemical name; [3S, (−)]-9-fluoro-2,3-dihydro-3- Methyl-10- (4-methyl-1-piperazinyl) -7-oxo-7H-pyrido [1,2,3-de] [1,4] benzoxazine-6-carboxylic acid), pazufloxacin (chemical name; ( 3S) -10- (1-aminocyclopropyl) -9-fluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido [1,2,3-de] -1,4-benzoxazine -6 -Carboxylic acid), marvofloxacin having a pyridobenzooxadiazine skeleton (chemical name: 9-fluoro-2,3-dihydro-3-methyl-10- (4-methyl-1-piperazinyl) -7- Oxo-7H-pyrido [3,2,1-ij] [4,1,2] benzoxadiazine-6-carboxylic acid) and the like, and one or more selected from these may be used Can do.

  The above isothiazoline compounds, benzisothiazoline compounds, benzimidazole compounds, haloacetylene compounds, tetrahydrothiophene dioxide compounds and quinolone compounds may be used as salts with acids in the case of basic compounds. In the case of an acidic compound, it may be used as a salt with a base.

  Salts with acids include salts with inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid; formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, Examples include salts with organic acids such as citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid.

  As a salt with a base, a salt with an alkali metal such as sodium or potassium; a salt with an alkaline earth metal such as magnesium or calcium; an ammonium salt; a trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine or triethanolamine And salts with organic amines such as ethylenediamine, 1,6-hexamethylenediamine, tert-butylamine, cyclohexylamine, benzylamine, dicyclohexylamine, N, N-dibenzylethylenediamine, and the like.

  Isothiazoline compounds, benzisothiazoline compounds, benzimidazole compounds, haloacetylene compounds, tetrahydrothiophene dioxide compounds, quinolone compounds and salts thereof may be commercially available or manufactured according to known techniques However, it is convenient to use a commercially available product.

  The tetracycline antibiotic used in the present invention is a bacteriostatic antibiotic having a broad antibacterial spectrum. Various compounds are manufactured as tetracycline antibiotics, and examples include tetracycline, oxytetracycline, demethylchlorotetracycline, doxycycline, minocycline, chlortetracycline, and the like. Tetracycline antibiotics may be in the form of salts, such as salts with inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid; formic acid, acetic acid, trifluoroacetic acid, phthalic acid And salts with organic acids such as fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid. In the present invention, one or more of these are selected and used.

  Commercially available tetracycline antibiotics used in the present invention may be used, or those manufactured according to known techniques may be used, but it is convenient to use commercially available products.

  In the present invention, it is preferable to use one or more selected from the group consisting of tetracycline, chlorotetracycline, oxytetracycline, and salts thereof as the tetracycline antibiotic.

  Pyrithione (chemical name: 1-hydroxy-1,2-dihydropyridine-2-thione) that can be contained in the anti-tinea agent composition of the present invention is represented by the following formula (11).

  In the anti-tinea fungus agent composition of the present invention, one or more of pyrithione and a metal salt thereof can be selected and used, but a metal salt of pyrithione is preferably used from the viewpoint of excellent antibacterial activity. . As the metal salt of pyrithione, an alkali metal salt and a divalent metal salt are preferably used.

  The alkali metal salt of pyrithione is represented, for example, by the following formula (12).

[Wherein M ₁ represents an alkali metal. ]

Examples of the alkali metal salt of pyrithione include sodium pyrithione (M ₁ = Na in the above formula (12)).

  Moreover, the bivalent metal salt of pyrithione is represented by the following formula (13), for example.

[Wherein M ₂ represents a divalent metal. ]

The divalent metal represented by M ₂ in the formula (13) is preferably a Group 12 metal such as zinc capable of forming a complex with pyrithione or a transition metal. Preferable examples of the divalent metal salt of pyrithione include zinc pyrithione (M ₂ = Zn) and copper pyrithione (M ₂ = Cu).

  Commercially available products may be used as the pyrithione and the metal salts thereof, or those manufactured according to known techniques may be used, but it is convenient to use commercially available products.

  The content of prochloraz or a salt thereof in the anti-tinea fungus agent composition of the present invention is preferably 0.1% by weight to 100% by weight, and preferably 1% by weight to 100% by weight in order to obtain sufficient antibacterial activity against ringworm. % Is more preferable. In addition, the content of flusilazole or a salt thereof in the anti-tinea fungus composition of the present invention is preferably 0.1% by weight to 100% by weight, and more preferably 1% by weight to 100% by weight. When two or more kinds selected from the group consisting of prochloraz, flusilazole, and salts thereof are used in combination, the total amount thereof is preferably 0.1 wt% to 100 wt%, and preferably 1 wt% to 100 wt%. It is more preferable to set the weight%.

  One or more selected from the group consisting of prochloraz, flusilazole, and salts thereof, and the above-mentioned isothiazoline compounds, benzisothiazoline compounds, benzimidazole compounds, haloacetylene compounds, tetrahydrothiophene dioxide compounds In order to obtain good anti-tinea activity in combination with antibacterial compounds selected from the group consisting of quinolone compounds, salts thereof, tetracycline antibiotics, and pyrithione and metal salts thereof, prochloraz , Flusilazole, and one or more selected from the group consisting of salts thereof and the other antibacterial compound (the total amount of each compound when two or more are used) is 9 : 1 to 1: 9 (weight ratio), preferably 8: 2. 2: It is particularly preferred that the 8 (weight ratio). Further, although depending on the dosage form, application target, use environment, etc., the total content of one or more selected from the group consisting of prochloraz, flusilazole, and salts thereof is 0.01 wt% to 90% by weight is preferable, and 0.1% by weight to 90% by weight is more preferable. The content of antibacterial compounds other than the above (when two or more types are used, the total amount of each compound) is preferably 0.01% by weight to 90% by weight, more preferably 0.1% by weight to 90% by weight. .

  The anti-tinea fungus agent composition of the present invention comprises one or more selected from the group consisting of prochloraz, flusilazole and salts thereof, or an antibacterial compound other than the above, a liquid carrier, a solid carrier Various dosage forms can be obtained by dissolving, dispersing, adsorbing, etc. on various carriers such as. For example, it can be dissolved in a solvent, suspended or dispersed using a surfactant or a solubilizing agent, etc., and provided as a solution, suspension, or dispersant, or emulsified with a surfactant to provide an emulsion. it can. In addition, surfactants, gelling agents and solid carriers can be added to provide wettable powders, gels, flowables, powders, granules, tablets and the like. In addition, it can also be provided as an aerosol agent filled in a pressure-resistant can together with a jet gas such as liquefied petroleum gas.

  Examples of the solvent that can be used in the present invention include water; lower alcohols such as methanol, ethanol, n-propanol, isopropanol, and n-butanol; ethylene glycol, diethylene glycol, polyethylene glycol, propylene glycol, dipropylene glycol, polypropylene glycol, 1, 3-butanediol, 1,4-butanediol, 1,5-pentanediol, ethylene glycol monomethyl ether (methyl carbitol), ethylene glycol monoethyl ether (ethyl carbitol), ethylene glycol monobutyl ether (butyl carbitol), Polyhydric alcohols such as diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, triethylene glycol butyl ether; Ketones such as seton, methyl ethyl ketone, methyl isobutyl ketone and propylene carbonate; ethers such as dioxane, tetrahydrofuran and ethyl ether; ethyl acetate, butyl acetate, isobutyl acetate, 3-methyl-3-methoxybutyl acetate, γ-butyrolactone, adipine Esters such as dimethyl acid, dimethyl glutarate, dimethyl succinate; aromatic solvents such as benzene, toluene, xylene, methylnaphthalene, dimethylnaphthalene, isopropylnaphthalene, diisopropylnaphthalene, ethylbiphenyl, diethylbiphenyl, solvent naphtha; tetrachloride Halogenated hydrocarbon solvents such as carbon, chloroform, methylene chloride; dimethylformamide, dimethylacetamide, dimethylsulfoxide, acetonitrile, N -Polar organic solvents such as methylpyrrolidone. These solvents may be used alone or in combination of two or more. Of these solvents, water, lower alcohols and polyhydric alcohols are preferably used.

  Examples of the surfactant that can be used in the present invention include nonionic surfactants such as polyoxyethylene alkyl ether, polyoxyethylene sorbitan fatty acid ester, polyoxyethienonyl phenyl ether, polyoxyethylene polyoxypropylene glycol; Examples include anionic surfactants such as ester salts, alkyl (aryl) sulfonates, dialkyl sulfosuccinates, polyoxyethylene alkylaryl ether phosphate esters, lignin sulfonates, and naphthalene sulfonate formalin condensates. . These may be used alone or in combination of two or more.

  Examples of the dissolution aid that can be used in the present invention include carboxylic acids such as capric acid and adipic acid; esters such as diisopropyl adipate, diisopropyl sebacate, isopropyl myristate, and isopropyl palmitate; higher grades such as octyldodecanol and oleyl alcohol. Examples of alcohols include amines such as monoethanolamine and diethanolamine, and these may be used alone or in combination of two or more.

  Examples of solid carriers that can be used in the present invention include minerals such as kaolin clay, attapulgite clay, bentonite, montmorillonite, acid clay, pyrophyllite, talc, diatomaceous earth, calcite, and natural substances such as corn cob flour and walnut shell flour. Organic substances; synthetic organic substances such as urea; salts such as calcium carbonate and ammonium sulfate; fine powders or granules of synthetic inorganic substances such as synthetic hydrous silicon oxide.

  The preparation of the anti-tinea agent composition of the present invention is preferably carried out at 5 ° C to 40 ° C. Mixing with a solvent or the like is preferably performed by mixing and stirring for about 0.5 to 5 hours. When a surfactant, a dissolution aid or a solid carrier is used, the amount added to the total amount of these compositions is 0.1 wt% to 10 wt%, 0.1 wt% to 10 wt%, and 30 wt% to 30 wt%, respectively. About 95% by weight.

  In addition to other antibacterial and antifungal agents, excipients, binders, lubricants, and disintegrations are included in the anti-tinea fungus composition according to the present invention as long as the antibacterial activity and stability of the composition are not affected. Additives generally used in the formulation, such as an agent, a pH adjuster, an antioxidant, a light stabilizer, an antifoaming agent, a flavoring agent, and a coloring agent, can be added.

The anti- ringworm fungus agent composition of the present invention has good antibacterial activity against ringworm fungus. Trichophyton rubrum and Trichophyton mentagrophytes , which are the main causative bacteria such as ringworm of the body, tinea of the hips, tinea pedis (aquatic athlete's foot), nail tinea (aquatic athlete's foot), etc. ), Trichophyton verrucosum and Microsporum canis which are the main causative bacteria of Kellus acne, Trichophyton tonsurans which is a causative agent of ringworm which has been prevalent mainly in teenage judo and wrestling athletes in recent years. Examples include Microsporum gypseum , which has been found to be transmitted to children who prefer it, Trichophyton verrucosum, which has been reported to infect cattle and humans who are engaged in dairy farming, and fungi of the genus Trichophyton and Microsporum .

  In the anti- ringworm fungus agent composition of the present invention, when one or more selected from the group consisting of prochloraz, flusilazole, and salts thereof and an antibacterial compound other than the above are used in combination, antibacterial activity against ringworm Improvement is recognized.

The anti- ringworm fungus agent composition of the present invention is excellent in antibacterial activity against ringworm fungus, so that it comes into contact with ringworm bacteria present in the environment when it comes into contact with a ringworm infected person or adheres to clothing, furniture, dwellings, etc. In this case, infection with ringworm can be well prevented. Therefore, the anti-tinea fungus composition of the present invention includes towels, socks, tabi, underwear and other clothing, bedding such as futons and bed pads, shoes, boots, sandals, slippers, slippers, insole and other footwear, bath mats, It can be used for various industrial products such as carpet and other textile / leather products; building materials such as tiles, flooring materials and wall materials; and other paper products, plastic products and rubber products for household use. In addition, the anti-tinea fungus agent composition of the present invention can be added to the industrial product, or the industrial product can be processed with the anti-tinea agent composition of the present invention to impart antibacterial activity against trichomycosis. .
Furthermore, the anti- ringworm fungus composition of the present invention can be added to deodorants, disinfectants, cleaning agents, etc. of general formulations, and can be used for various adhesives, modifiers, coating agents, etc. It can also be added.

  The processing of the industrial product by the anti-tinea fungus agent composition of the present invention is a method of adding the anti-tinea fungus agent composition of the present invention to a raw material, mixing or kneading, and then preparing the product, the anti-tinea fungus agent composition of the present invention A method of processing, assembling, and the like of an industrial product by adding an adhesive to a modifier, and a method of coating an industrial product surface by adding the anti-tinea fungus composition of the present invention to a coating material or a coating agent And a method of dissolving or dispersing the anti-tinea fungus agent composition of the present invention in a solvent and immersing and impregnating product raw materials or industrial products. Moreover, it can also carry out by spraying or apply | coating the deodorizer, disinfectant | microbicide, washing | cleaning agent, etc. which added the anti-tinea agent composition of this invention.

  The anti-tinea fungus agent composition of the present invention may be appropriately selected depending on the dosage form, the type and material of the industrial product to be added or processed, the addition or processing method, etc. When added to the above, the total amount of prochloraz, flusilazole, and other antibacterial components per kg of the preparation is usually 5 mg to 50,000 mg, preferably 10 mg to 10,000 mg, and kneaded into the molded product. When used as a total amount of the antibacterial agent component per kg of the product, it is usually 5 mg to 100,000 mg, preferably 10 mg to 50,000 mg. The total amount of the antibacterial component per kg of the product is usually 5 mg to 50,000 mg, preferably 10 mg to 10,000 mg. There.

  Hereinafter, the present invention will be described in detail with reference to examples.

[Example 1]
Prochloraz standard product (N-propyl-N- [2- (2,4,6-trichlorophenoxy) ethyl] -1H-imidazole-1-carboxamide containing 98.0% by weight, manufactured by Wako Pure Chemical Industries, Ltd.) It added to methyl carbitol so that it might become 10 weight%, and it stirred and mixed at room temperature for 30 minutes, and obtained the anti- ringworm fungus agent composition which is a solution.

[Example 2]
Standard flusilazole (methylbis (4-fluorophenyl) (1H-1,2,4-triazol-1-ylmethyl) silane containing 98.0% by weight, manufactured by Wako Pure Chemical Industries, Ltd.) is 10% by weight. Was added to methyl carbitol and stirred and mixed at room temperature for 30 minutes to obtain an anti- ringworm fungus composition as a solution.

[Examples 3 and 4]
About each of said prochloraz and flusilazole, it was set as the powdery anti-tinea fungus agent composition as it was.

[Evaluation of anti-tinea activity]
Each anti- ringworm fungus composition of Examples 1 to 4 was sequentially diluted with sterilized purified water (10 times, 20 times, 40 times, 80 times, 160 times, 320 times, 640 times, 1,280 times, The plate medium was prepared by adding 1.0 mL of each diluted solution to glucose broth agar medium (pH 6.0) to 10.0 mL. On the plate medium, 1 platinum ear of Trichophyton mentagrophytes NBRC32409 was inoculated as a test bacterium and cultured at 28 ° C. for 3 days. As a control, were inoculated with glucose broth agar medium (pH 6.0) Trichophyton a plate medium prepared by 10.0mL (Trichophyton mentagrophytes NBRC32409), and cultured for 3 days at 28 ° C..

  After culturing, the state of growth of ringworms on each plate medium was observed, and the minimum inhibitory concentration (MIC) (ppm) was determined and shown in Table 1.

  In Table 1, it was found that prochloraz and flusilazole each exhibited antibacterial activity at low concentrations against ringworm.

[Examples 5-34]
Next, combined use of prochloraz or flusilazole with isothiazoline compounds, benzisothiazoline compounds, benzimidazole compounds, haloacetylene compounds, tetrahydrothiophene dioxide compounds, quinolone compounds, tetracycline antibiotics or metal salts of pyrithione The Example about is shown. As prochloraz or flusilazole, N-propyl-N- [2- (2,4,6-trichlorophenoxy) ethyl] -1H-imidazole-1-carboxamide or methylbis (4-fluorophenyl) ( 1H-1,2,4-triazol-1-ylmethyl) silane content 98% by weight was used as a standard product manufactured by Wako Pure Chemical Industries, Ltd. As the other antibacterial compounds, those shown in Table 2 were used. These Examples were prepared by dissolving or mixing each antibacterial compound in methyl carbitol according to the formulations shown in Tables 3 and 4. Examples of the combined use of prochloraz and flusilazole are also shown in Tables 3 and 4.

  About the anti- ringworm fungus agent composition of said Examples 5-34, MIC with respect to ringworm bacteria was calculated | required similarly to Examples 1-4. The MIC values for each composition are shown in Table 5 along with their dosage forms.

  As is clear from Table 5, even when prochloraz or flusilazole was used in combination with other antibacterial compounds, or when prochloraz and flusilazole were used in combination, good antibacterial activity was observed against ringworm.

  According to the present invention, it has excellent antibacterial activity against ringworm, and when it comes into contact with a person infected with ringworm, or when it comes into contact with clothes, furniture, a house, etc. It is possible to provide an anti- ringworm fungus agent composition that can satisfactorily prevent infection with bacteria. Therefore, the anti-tinea fungus composition of the present invention is suitable for various industrial products such as adhesives, deodorants, disinfectants, detergents, textiles / leather products, building materials, paper products, plastic products, rubber products, etc. These can be given good antibacterial activity against ringworm.

Claims (14)

  An anti-tinea fungus agent composition comprising one or more selected from the group consisting of prochloraz, flusilazole, and salts thereof. One or more selected from the group consisting of prochloraz, flusilazole, and salts thereof, an isothiazoline compound represented by formula (1), a benzoisothiazoline compound represented by formula (2), formula (3) A benzimidazole compound represented by the formula (4), a tetrahydrothiophene dioxide compound represented by the formula (5), a quinolone compound represented by the formula (6), and salts thereof: An anti- ringworm fungus composition comprising one or more selected from the group consisting of tetracycline antibiotics and pyrithione and metal salts thereof.

[Wherein, R ₁ represents a hydrogen atom or an optionally substituted hydrocarbon group, and R ₂ and R ₃ are the same or different and each represents a hydrogen atom, a halogen atom or an optionally substituted hydrocarbon group. Show. ]

[Wherein, ring A ₁ represents an optionally substituted benzene ring, and Y represents a hydrogen atom or an optionally substituted hydrocarbon group. ]

[In the formula, A ₂ ring represents an optionally substituted benzene ring, and Z represents —NHCOOR ₄ (wherein R ₄ represents a hydrogen atom or an alkyl group) or a substituted group. A good 5- or 6-membered nitrogen-containing heterocyclic group is shown. ]

[Wherein, X represents a halogen atom, R ₅ and R ₆ are the same or different and each represents a hydrogen atom or an optionally substituted hydrocarbon group, and m represents an integer of 0 or 1. ]

[Wherein Y ₁ , Y ₂ , Y ₃ and Y ₄ are the same or different and each represents a hydrogen atom, a halogen atom or an optionally substituted hydrocarbon group. ]

[Wherein the A ₃ ring represents a 6-membered aromatic ring which may be substituted or a heterocyclic ring in which one or two carbon atoms are substituted with nitrogen atoms, and R ₇ and R ₈ are the same or different and each represents a hydrogen atom or an optionally substituted hydrocarbon group. R ₇ may form a ring together with a substituent of A ₃ ring. ]   Isothiazoline-based compounds are 2-methyl-4-isothiazolin-3-one, 2-n-octyl-4-isothiazolin-3-one, 4-chloro-2-n-octyl-4-isothiazolin-3-one, 5 -Chloro-2-methyl-4-isothiazolin-3-one, 5-chloro-2-n-octyl-4-isothiazolin-3-one and 4,5-dichloro-2-n-octyl-4-isothiazoline-3 The anti- ringworm fungus agent composition according to claim 2, wherein the composition is one or more selected from the group consisting of -on.   The isothiazoline-based compound is selected from 2-methyl-4-isothiazolin-3-one, 5-chloro-2-methyl-4-isothiazolin-3-one and 2-n-octyl-4-isothiazolin-3-one The anti-tinea agent composition of Claim 2 which is 1 type (s) or 2 or more types.   The benzoisothiazoline-based compound is one or two selected from 1,2-benzisothiazolin-3-one and Nn-butyl-1,2-benzisothiazolin-3-one. Anti- ringworm fungus composition.   The benzimidazole compound is one or more selected from the group consisting of methyl 2-benzimidazole carbamate, ethyl 2-benzimidazole carbamate, and 2- (4-thiazolyl) benzimidazole. The anti-tinea agent composition of description.   The anti- ringworm fungus agent composition according to claim 2, wherein the haloacetylene compound is 3-iodo-2-propynyl N-butylcarbamate.   The anti- ringworm fungus agent composition according to claim 2, wherein the tetrahydrothiophene dioxide compound is 3,3,4,4-tetrachlorotetrahydrothiophene-1,1-dioxide.   The quinolone compounds are enoxacin, tosufloxacin, norfloxacin, sarafloxacin, difloxacin, fleroxacin, lomefloxacin, enrofloxacin, ciprofloxacin, gatifloxacin, sparfloxacin, danofloxacin, moxifloxacin, garenoxacin, sitafloxacin, orbi The anti-tinea fungus agent composition according to claim 2, wherein the composition is one or more selected from the group consisting of floxacin, oxolinic acid, nadifloxacin, ofloxacin, levofloxacin, pazufloxacin, and marvofloxacin. .   The anti-tinea fungus agent composition according to claim 2, wherein the tetracycline antibiotic is one or more selected from the group consisting of tetracycline, chlortetracycline, oxytetracycline, and salts thereof.   The anti-tinea fungus agent composition according to claim 2, wherein the metal salt of pyrithione is one or more selected from the group consisting of an alkali metal salt of pyrithione and a divalent metal salt of pyrithione.   The anti-tinea fungus agent composition according to claim 11, wherein the alkali metal salt of pyrithione is sodium pyrithione.   The anti- ringworm fungus agent composition according to claim 11, wherein the divalent metal salt of pyrithione is one or two selected from the group consisting of zinc pyrithione and copper pyrithione.   An industrial product containing the anti- ringworm fungus agent composition according to any one of claims 1 to 13.