JPH1121239A - Antimicrobial or microbicidal agent for human or animal consisting of naphtho(2,3-d)thiazol-4,9-dione derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject antimicrobial or microbicidal agent which has excellent antimicrobial and microbicidal activities and is effective for treatment for infectious disease of human and animal by formulating a naphtho[2,3- d]thiazol-4,9-dione derivative thereto. SOLUTION: The objective antimicrobial or micobicidal agent is obtained by formulating a compound (e.g. a compound of formula II) of formula I [R1 is H, an alkyl, a cycloalkyl, -N(R2 )R3 (R2 and R3 are each H, an alkyl, etc.), etc.; X is H, a halogen, nitro, amino and acetylamino; (n) is 1-4] thereto. As the dose of the antimicrobial or microbicidal agent in the usual case of oral administration to adults, the compound of formula I is preferably administrated once to several times a day at a dose of about 10-500 mg.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to an antibacterial agent or a bactericide, and more specifically, to naphtho [2,3].
-D] a human or animal antibacterial or fungicide comprising a thiazole-4,9-dione derivative. The bactericide according to the present invention includes a disinfectant / bactericide.

[0002]

2. Description of the Related Art Naphtho [2,3-d] thiazole-4,
For example, 9-dione is used as a wood preservative in Japanese Patent Application Laid-Open No. 56-110603, and is used for humans and animals that has antibacterial activity against mycoplasma, gram-negative bacteria and gram-positive bacteria in Japanese Patent Application Laid-Open No. 59-144718. As an antibacterial agent,
Further, JP-A-61-251675 discloses a bactericide,
Each is described as being used as a wood preservative or dye. On the other hand, derivatives of the above compounds are disclosed in
257903, JP-A-62-26278,
These are described in JP-A-62-185080, respectively. These include underwater antifouling agents against soil adhering to ship bottoms, fishing nets, etc., fungicides for agricultural and horticultural use against rice blast, apple spot leaf blight, etc. None of which relates to antibacterial or bactericidal agents for human or veterinary medicine.

[0003]

An antibacterial agent and a bactericide are:
Generally, there is a problem of resistant bacteria caused by using the same drug for a long period of time. Therefore, providing different kinds of antibacterial agents and bactericides having high antibacterial activity and bactericidal activity is significant for treatment of infectious diseases for humans or animals. That is, the object of the present invention is to provide a compound which is different from a compound used as an existing antibacterial or fungicide for humans or animals, and a compound which is extremely useful for the use as an active ingredient, Or to provide a disinfectant.

[0004]

Means for Solving the Problems The present inventors have intensively studied a new antibacterial or fungicide in order to solve the above-mentioned problems, and as a result, have found that naphtho [2,3-d] thiazole-4,9-dione derivatives Among them, a compound having excellent activity as an antibacterial or fungicide for humans or animals was found, and the present invention was completed.

That is, the present invention relates to a naphtho [2,3-d] thiazole having a novel structure not found in known human or veterinary drugs and having high antibacterial or bactericidal activity.
It is intended to provide an antibacterial or bactericide containing a 4,9-dione derivative as an active ingredient, and a preparation thereof.

More specifically, the present invention provides the following general formula (1)

Embedded image [Wherein, R ₁ represents —N (R ₂ ) R ₃ , —N (R ₃ ) COR ₄ ,
—S (O) mR ₅ , a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, a cycloalkyl group, an alkenyl group, a cycloalkenyl group, an alkynyl group, a phenyl group, a halogenoalkyl group,

[0007]

Embedded image (A is a halogen atom, an alkyl group, a nitro group, an acetyl group, an alkylamino group, an amino group, an acetylamino group,
And a group selected from the group consisting of an alkoxy group, an alkylthio group and a mercapto group. R ₂ , R ₃ and R _{4 each} represent a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, a cycloalkyl group, an alkenyl group, a cycloalkenyl group, an alkynyl group, a phenyl group, a halogenoalkyl group,

[0008]

Embedded image (A is a halogen atom, an alkyl group, a nitro group, an acetyl group, an alkylamino group, an amino group, an acetylamino group,
And a group selected from the group consisting of an alkoxy group, an alkylthio group and a mercapto group. R ₅ is an alkyl group, a cycloalkyl group, may be substituted with a halogen atom linear or branched alkyl group, an alkenyl group. X represents a group selected from the group consisting of a hydrogen atom, a halogen atom, a nitro group, an amino group, and an acetylamino group. n is 1 to
4, m represents an integer of 0 to 2. Where X and R ₁
However, those excluding hydrogen atoms are excluded. And a human or animal antibacterial or bactericide containing, as an active ingredient, a naphtho [2,3-d] thiazole-4,9-dione derivative represented by the formula:

The naphtho [2,3-d] thiazole-4,9-dione derivative according to the present invention has very excellent antibacterial and bactericidal activities and is useful for treating infectious diseases in humans and animals. For example, Candida, yeast-like fungi such as Cryptococcus, dermatophytes such as Trichophyton, and deep fungi caused by various fungi such as Aspergillus, deep dermatomycosis, superficial mycosis and the like. In addition to being useful for treatment, it is particularly effective against Gram-positive bacteria such as Staphylococcus aureus, and thus is useful for treating infectious diseases caused by MRSA (mesicillin-resistant Staphylococcus aureus), MRSE (mesicillin-resistant Staphylococcus epidermidis) and the like. In particular, the general formula (1)
Of which R ₁ is S (O) C ₂ H ₅ has excellent MI against Trichophyton
C (minimum inhibitory concentration) and has very good activity.

Furthermore, the present invention also relates to these naphtho [2,
3-d] an injection, an external preparation or an oral preparation having an antibacterial or bactericidal action containing a thiazole-4,9-dione derivative as an active ingredient.

[0011]

BEST MODE FOR CARRYING OUT THE INVENTION Preferred examples of the naphtho [2,3-d] thiazole-4,9-dione derivative of the general formula (1) in the present invention include fluorine, chlorine, Bromine or iodine is represented by alkyl, methyl, ethyl, n-propyl, iso.
-Propyl, n-butyl, iso-butyl, tert.
-An alkyl group having ₁ to ₈ carbon atoms such as butyl is a cycloalkyl group, a cycloalkyl group having ₃ to ₆ carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl is an allyl group as an alkenyl group; alkenyl group having a carbon number of C ₃ -C _6, such as a butenyl group, a cycloalkenyl group, the carbon number of C ₃ ~, such as cyclobutenyl
When the cycloalkenyl group at C ₆ is an alkoxy group, methoxy, ethoxy, n-butoxy, iso-butoxy,
tert. - alkoxy group with carbon number C ₁ -C ₆ butoxy, and the like respectively.

The derivative can be converted into a pharmaceutically acceptable salt form according to a conventional method. Examples of such a salt include inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid and phosphoric acid, and maleic acid and fumaric acid. , Oxalic acid, succinic acid, malonic acid,
Salts of organic acids such as lactic acid, citric acid, methanesulfonic acid, benzenesulfonic acid and acetic acid, or alkali metal salts such as lithium salt, sodium salt and potassium salt, alkaline earth metal salts such as calcium salt and magnesium salt, ammonium Examples thereof include inorganic salts such as salts and organic salts such as triethylamine salts, ethanolamine salts, triethanolamine salts, dicyclohexylamine salts, and the like, but are not limited thereto.

The dosage of the antibacterial or bactericide comprising the naphtho [2,3-d] thiazole-4,9-dione derivative of the present invention is appropriately determined according to the condition, age, sex, etc. of the administration subject. In general, when orally administered to an adult, the compound represented by the general formula (1) is administered in a single dose of 10 to 500 doses.
It is preferable to administer about 1 mg to about 1 to several times a day. Next, a method for producing the compound represented by the general formula (1) in the present invention is described by way of example in JP-A-61-257.
903, JP-A-62-26278 and JP-A-62-185080, or a method analogous thereto, but is not limited thereto.

When the compound represented by the general formula (1) is used as a medicine, it is used in the form of general pharmaceutical preparations such as injections, topical preparations and oral preparations. The preparation is prepared using a commonly used diluent or excipient such as a filler, a bulking agent, a binder, a humectant, a disintegrant, a surfactant and a lubricant. Representative examples include tablets, pills, suppositories, injections, pastes, ointments, creams, gels, gel creams, lotions, poultices, plasters, liniments, liquids, and aerosols. Preparations, powders, granules, capsules, syrups, oral preparations, eye drops, nasal drops, etc., as appropriate dosage forms, usually systemically or locally,
It can be stably administered orally or parenterally.

[0015] In the case of molding into tablets, a wide variety of carriers conventionally known in the art can be used, for example, lactose,
Excipients such as sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid, water, ethanol, propanol, simple syrup,
Glucose solution, starch solution, gelatin solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, polyvinylpyrrolidone and other binders, dried starch, sodium alginate, agar powder, laminaran powder, sodium hydrogen carbonate, calcium carbonate, polyoxyethylene sorbitan Disintegrators such as fatty acid esters, sodium lauryl sulfate, stearic acid monoglyceride, starch, lactose, disintegration inhibitors such as sucrose, stearin, cocoa butter, hydrogenated oils, etc., and absorption promoters such as quaternary ammonium bases and sodium lauryl sulfate And humectants such as glycerin and starch; adsorbents such as starch, lactose, kaolin, pentonite and colloidal silicic acid; and lubricants such as purified talc, stearates, boric acid powder, polyethylene glycol and the like. . Further, the tablet can be a tablet coated with a usual coating as required, for example, a sugar-coated tablet, a gelatin-encapsulated tablet, an enteric-coated tablet, a film-coated tablet or a double tablet or a multilayer tablet.

In the case of molding into a pill form, carriers conventionally known in this field can be widely used as a carrier, for example, excipients such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, kaolin, talc, and the like. Examples thereof include rubber powder, tragacanth powder, binders such as gelatin and ethanol, and disintegrants such as laminaran agar.

In forming a suppository, the suppository base is appropriately selected from conventionally known suppository bases, that is, lipophilic bases, water-soluble bases and emulsion bases. Is done. Suppository bases are selected, for example, from cocoa butter, hydrogenated peanut oil, synthetic oleaginous bases such as hydrogenated coconut oil, and water-soluble bases such as polyethylene glycols, monolen, turure, pluronic, and the like. A naphtho [2,3-d] thiazole-4,9-dione derivative, which is a medicinal ingredient, 0.01 to 10% by weight, an ultraviolet absorber 0.01 to 5% by weight, and if necessary, an antioxidant 0.01. By mixing up to 5% by weight, the suppository formulation containing the antibacterial agent or the fungicide of the present invention can be obtained. In addition, additives that can be added as necessary include local anesthetics, antihistamines, local astringents, sulfa drugs, antibiotics, wound treatments, surfactants, vitamins, crude drug extracts, bile acids, preservatives, preservatives, Excipients, absorption enhancers, amino acids and the like are used.

When prepared as an injection, a solution,
Emulsions and suspensions are preferably sterilized and isotonic with blood, and when formed into the form of solutions, emulsions and suspensions, any diluent known in the art can be widely used. For example, water, lactic acid aqueous solution, ethyl alcohol,
Examples include propylene glycol and polyoxyethylene sorbitan fatty acid esters. In this case, a sufficient amount of salt, glucose or glycerin to prepare an isotonic solution may be contained in the pharmaceutical preparation, and ordinary dissolution aids, buffers, soothing agents and the like may be added. May be. Further, a coloring agent, a preservative, a flavor, a flavoring agent, a sweetening agent, and the like and other pharmaceuticals may be contained in the pharmaceutical preparation as needed. Next, formulation examples of the present invention, such as ointments, gels, creams, lotions, pastes, etc., will be further described.

Ointment The ointment base is selected from known or commonly used ones. Examples thereof include higher fatty acids and esters thereof (eg, adipic acid, myristic acid, palmitic acid, stearic acid, oleic acid). , Adipates,
Myristate, palmitate, diethyl sebacate, hexyl laurate, cetyl isooctanoate, etc., waxes (eg, spermaceti, beeswax, ceresin, etc.), surfactants (eg, polyoxyethylene alkyl ether phosphate) ), Higher alcohols (eg, cetanol, stearyl alcohol, cetostearyl alcohol, etc.), silicone oils (eg, dimethylpolysiloxane,
Methylphenyl polysiloxane, glycol methyl polysiloxane, silicone glycol copolymer, etc.), hydrocarbons (eg, hydrophilic petrolatum, white petrolatum, purified lanolin, liquid paraffin, etc.), water, absorption promoters (eg, propylene carbonate, diisopropyl adipate, Crotamiton, azone, pyrothiodecane, etc.), humectants (eg, glycerin, propylene glycol, butylene glycol,
Sorbitol), rash preventives and other additives. The ointment of the present invention can be obtained by mixing a naphtho [2,3-d] thiazole-4,9-dione derivative as a medicinal ingredient with each of the above bases.

Preparation Example of Ointment 5 to 15% by weight of higher fatty acid ester, surfactant 1 to 1
0% by weight of naphtho [2,3-d] thiazole-4,9-
A dione derivative 0.01 to 10% by weight is mixed at room temperature or under heating, and waxes 4 to 10% by weight, hydrocarbons 50 to 90% are used.
The mixture is heated or melted by heating, and kept at 50 to 100 ° C. After all components become a transparent solution, they are mixed uniformly with a homomixer. Thereafter, the temperature is lowered to room temperature with stirring to obtain the ointment of the present invention. It is needless to say that the above-mentioned production example is merely an example, and that it can be produced by a known method or formulation similar thereto. In addition, the order of compounding each compound is not particularly limited. Hereinafter, this is common to the formulation examples and production examples of various preparations.

Gel The gel base is selected from various known or commonly used bases. Examples thereof include lower alcohols (eg, ethanol, isopropyl alcohol, etc.), water, and gelling agents (eg,
Carboxyvinyl polymer, hydroxyethylcellulose, hydroxypropylcellulose, methylcellulose, ethylcellulose, carboxymethylcellulose,
Propylene glycol alginate, etc.), neutralizing agents (eg, triethanolamine, diisopropanolamine, sodium hydroxide, etc.), surfactants (eg, sorbitan sesquioleate, sorbitan trioleate, sorbitan monooleate, monostearin) Sorbitan acid,
Sorbitan monolaurate, polyethylene glycol monostearate, polyoxyethylene nonylphenyl ether, polyoxyethylene cetyl ether, polyoxyethylene lauryl ether, etc., absorption promoters (eg: propylene carbonate, diethyl sebacate, diisopropyl adipate, crotamiton, aison) Propylene glycol, pyrothiodecane, etc.), rash preventives and other additives. The gel of the present invention can be obtained by adding a naphtho [2,3-d] thiazole-4,9-dione derivative as a medicinal ingredient to each of the above bases.

Preparation Example of Gel (A) 0.5 to 5% by weight of a gelling agent is added to 55% by weight or less of water to swell, while (B) naphtho [2,3-d] thiazole-4,9 Dissolving or suspending 0.01 to 10% by weight of a dione derivative in a dissolving agent, further dissolving it in a mixture of 40% by weight or less of glycols and 60% by weight or less of lower alcohol, and then (B) to (A) In addition to the above, a gel agent of the present invention can be obtained by adjusting the pH to 4 to 7 by adding a neutralizing agent.

Cream The cream base is selected from various known or commonly used bases. For example, higher fatty acid esters (eg, myristic ester, palmitic ester, diethyl sebacate, hexyl laurate, isooctanoic acid) Cetyl, etc.), lower alcohols (eg, ethanol, isopropanol, etc.), hydrocarbons (eg, liquid paraffin, squalane, etc.), polyhydric alcohols (eg, propylene glycol, 1,3-butylene glycol, etc.), higher alcohols (eg, : 2-hexyldecanol, cetanol, 2-octyldodecanol, etc.), emulsifier (eg, polyoxyethylene alkyl ethers, fatty acid esters, polyethylene glycol fatty acid ester, etc.), preservative (eg, paraoxybenzoate), absorption promotion Agents (eg: carbon dioxide Pyrene, diethyl sebacate, diisopropyl adipate, crotamiton, Azone, pirotiodecane, etc.), an irritation inhibitor, and other additives and the like. As described above, naphtho [2,3-d] thiazole-
The cream of the present invention can be obtained by adding and blending a 4,9-dione derivative.

Gel-like cream In order to obtain a gel-like cream having properties intermediate between creams and gels, a gelling agent (eg, carboxyvinyl polymer, hydroxyethylcellulose, hydroxypropylcellulose) is added to the above cream. , Ethylcellulose, carboxymethylcellulose, etc.) and a neutralizing agent (eg, diisopropanolamine, triethanolamine, sodium hydroxide, etc.) and adjust the pH to 4-8, preferably 5-6.5. The gel cream of the invention can be obtained.

Production Example of Gel Cream (A) 0.01 to 10% by weight of a naphtho [2,3-d] thiazole-4,9-dione derivative is added to higher fatty acid ester 2
Dissolve in a mixture of 5% by weight or less and a lower alcohol of 40% by weight or less, and further add a preservative of 0.5% by weight or less and an emulsifier of 5% by weight or less. On the other hand, (B) gelling agent 0.5 to water
5% by weight was added to swell, then (B) was added to (A) and homogenized uniformly with a homomixer. After emulsification, a neutralizing agent was added to adjust the pH value to 4 to 8. A creamy cream is obtained.

The poultice poultice base include a thickener (e.g. sodium polyacrylate,
Synthetic water-soluble polymers such as polyacrylic acid, poval, polyvinylpyrrolidone, polyethylene oxide and polyvinyl methacrylate, natural products such as gum arabic, starch and gelatin, methylcellulose, hydroxypropylcellulose, alginic acid, sodium alginate, ammonium alginate, carboxymethylcellulose Sodium), wetting agents (eg, urea, glycerin, propylene glycol, butylene glycol, sorbitol, etc.), fillers (eg, kaolin, zinc oxide, talc, titanium, benite, epoxy resins, organic acids (citric acid,
Tartaric acid, maleic acid, maleic anhydride, succinic acid, etc.),
Calcium, magnesium, aluminum, etc.), water, dissolution aids (eg, propylene carbonate, crotamiton, diisopropyl adipate, etc.), tackifiers (eg, rosin, ester gum, polybutene, polyacrylate, etc.), anti-rash agents ( Examples: diphenhydramine hydrochloride, chlorpheniramine maleate, glycyrrhizic acid, dexamethasone, betamethasone, fluocinolone acetonide, etc., and other additives (eg, salicylic acid, methyl salicylate, glycol salicylate, l-menthol, camphor, vanillyl amide nonylate) Thymol, capsicum extract, peppermint oil, azone, pyrothiodecane, etc.) and naphtho [2,3-
d] The poultice of the present invention can be obtained by adding and blending a thiazole-4,9-dione derivative.

Examples of the preparation of the poultice (A) 0.01 to 10% by weight of a naphtho [2,3-d] thiazole-4,9-dione derivative is added to 0.5 to 8 of a solubilizing agent.
% By weight and dissolved. Next, (B) 5 to 20% by weight, preferably 10 to 15% by weight of a thickener is mixed and dispersed and dissolved in 5 to 40% by weight of a wetting agent and 10 to 80% by weight of water, and 20% by weight or less of a filler is added. Make a uniform kneaded product.
Next, (A) is added to (B) and mixed to obtain a uniform kneaded product. The kneaded product of the present invention can be obtained by spreading and applying this kneaded product on a support by a usual method, and then applying a release coating thereon. The support is appropriately selected from stretchable or non-stretchable fabrics, nonwoven fabrics, nonwoven papers, etc., and the release coating is appropriately selected from polyethylene, polypropylene, polyvinyl chloride, polyester, polyvinylidene chloride, siliconized paper, etc. You.

Plasters Bases for plasters are known polymer bases (eg, acrylic compositions which are copolymers with vinyl monomers such as methacrylates, acrylonitrile, vinyl acetate, vinyl propionate, etc.) Silicone resin, polyisoprene rubber,
Polyisobutylene rubber, natural rubber, acrylic rubber, styrene-butadiene-styrene block copolymer, styrene-isoprene-styrene block copolymer, etc., fats and oils or higher fatty acids (eg, almond oil, olive oil, camellia oil, versic oil, Peanut oil, oleic oil, liquid paraffin, polybutene, etc.), tackifiers (eg, rosin, rosin modified maleic acid, hydrogenated rosin ester, etc.),
Selected from rash preventive agents, and other additives (eg, dl-camphor, 1-menthol, thymol, nonylate vanillylamide, pepper tincture, peppermint oil,
Crotamiton, peppermint oil, azone, pyrothiodecane, etc.) as necessary, and then a naphtho [2,3-d] thiazole-4,9-dione derivative, which is a medicinal ingredient, is blended and stretched or stretched. Support (eg, polypropylene, polyester, polyvinylidene chloride, polyacryl, polyurethane, rayon, cotton,
The spread is applied to an ethylene-vinyl acetate copolymer, a cloth, a nonwoven fabric, a nonwoven paper, etc.), and then a release coating is applied thereon to obtain the plaster of the present invention. In addition,
The production of plasters can be easily carried out according to a generally known method, and the compounding composition is a naphtho [2,3-d] thiazole-4, Plaster of the present invention by substituting 0.01 to 10% by weight of 9-dione derivative and further adding 0.01 to 5% by weight of ultraviolet absorber or 0.01 to 5% by weight of antioxidant as required. Can be obtained.

Liniment agent The liniment agent of the present invention may be any of alcohols (eg, monohydric alcohols such as ethanol, propanol and isopropanol, and polyhydric alcohols such as polyethylene glycol, propylene glycol and butylene glycol).
70% by weight, water 55% by weight or less, fatty acid ester (eg:
60% by weight or less of adipic acid, sebacic acid, myristic acid, etc.), 10% by weight or less of surfactant (eg, polyoxyethylene alkyl ether) and naphtho [2,3-d] thiazole-4 as a medicinal ingredient , 9-dione derivative in an amount of 0.01 to 10% by weight, an ultraviolet absorber in an amount of 0.01 to 5% by weight, and, if necessary, an antioxidant in an amount of 0.01 to 5%.
The liniment of the present invention can be obtained by blending the amount by weight.

It should be noted that the above formulation examples and production examples are merely examples, and the liniment of the present invention can be obtained by naturally known liniment production methods. Also, in the composition, the liniment of the present invention can be easily prepared by substituting the active ingredient of the known liniment with a naphtho [2,3-d] thiazole-4,9-dione derivative and blending it with an ultraviolet absorber. Agent can be obtained. further,
In the liniment of the present invention, if necessary, a neutralizing agent for adjusting pH or a viscosity-imparting agent such as methylcellulose, carboxyvinyl polymer, or hydroxypropylcellulose, an anti-rash agent, or other additives (eg, salicylic acid, methyl salicylate, Glycol salicylate, l
Menthol, camphor, peppermint oil, pepper extract, vanillyl amide nonylate, thymol, crotamiton, aison, propylene carbonate, diisopropyl adipate, pyrothiodecane, etc.).

[0031] The liquid solution is used as a disinfection and sterilization agent. The addition amount of the naphtho [2,3-d] thiazole-4,9-dione derivative to the solution is 0.01 to 10% by weight. As the lower monoalcohol to be blended in the liquid preparation of the present invention,
Primary, secondary and tertiary monoalcohols having 1 to 4 carbon atoms are preferred. For example, ethanol, ethanol for disinfection, anhydrous ethanol, isopropanol, propanol, butanol and the like can be mentioned. The blending amount of these lower monoalcohols is preferably from 60 to 90% by weight based on the whole liquid preparation. If the amount of the lower monoalcohol is less than 60% by weight, a sufficient antibacterial or bactericidal effect cannot be obtained. If the amount is more than 90% by weight, the retention time of the foam is short and may not be practical.

Examples of the nonionic surfactant incorporated in the liquid preparation of the present invention include polyoxyethylene sorbitan acyl ester polysorbate 80, polysorbate 60, polysorbate 20, and dimethylsiloxane methyl (PO) of silicone polyether copolymer.
E) siloxane copolymers and the like; polyoxyethylene acyl ester polyoxyl 40, polyoxyethylene lauryl ether and the like; polyoxyethylene alcohol ether lauromacrogam and the like; glyceryl monostearate glycerin monostearate and Decaglycerin monolaurate and the like; sorbitan fatty acid ester span60 monostearate and the like; sorbitan acyl ester sorbitan sesquioleate and the like; polyoxy hydrogenated castor oil HCO-60, HCO-
50 and the like; Pluronic F68 of polyoxyethylene propylene glycol monofatty acid ester and the like can be mentioned. These nonionic surfactants can be used alone or
Species or more may be used in combination at an appropriate ratio.

The HLB of these nonionic surfactants is 10
It is preferable that this is the case. If the HLB is less than 10, it may be difficult to obtain a desired foam having appropriate stability.
The content of the activator is preferably 0.5 to 3% by weight, more preferably 1 to 3% by weight, based on the whole liquid preparation. If the amount is less or more than this, it may be difficult to obtain a foam having appropriate stability as described above.

Next, as the water-soluble polymer compound, a natural or synthetic polymer compound is used. Examples of the natural high molecular compound include soluble polysaccharides such as acacia gum, xanthan gum, pectin, carrageenan, sodium alginate, etc., soluble polypeptides such as gelatin, chitins such as chitin and chitosan. Examples of the synthetic high-molecular compound include partially chemically processed natural high-molecular compounds, for example, sodium carboxymethylcellulose and hydroxypropylcellulose, which are soluble polysaccharides. Examples thereof include polyvinylpyrrolidone and its derivatives, and polyvinylpyrrolidone-based compounds. Among these, xanthan gum is preferred from the viewpoint of foam stability. The amount of these components is preferably 0.01 to 3% by weight based on the whole liquid preparation. If the amount is out of this range, it may be difficult to obtain a foam having appropriate stability as described above.

Examples of the humectant incorporated in the liquid preparation of the present invention include glycerin, propylene glycol, sorbitol, 1,3-butylene glycol, macrogol 4
And hyaluronic acid, and glycerin is particularly preferable in terms of foam stability, defoaming property, and moisture retention. One or more of these humectants may be blended in any ratio. Among them, from glycerin to macrogol 400, 1 to 10% by weight based on the whole liquid, and hyaluronic acid is used based on the whole liquid. It is preferable to add 0.01 to 1% by weight.

The liquid of the present invention may be mixed with water, in which case the amount is 3 to 35% by weight of the whole liquid. Water acts on a surfactant to improve foaming, and acts on a water-soluble polymer compound to stabilize foam. It has been conventionally known that when alcohols such as ethanol, which are useful as a liquid agent, are mixed with a foam at a high concentration, the foam becomes unstable and the foam disappears early. In the present invention, the retention time of foam can be appropriately adjusted by combining a high-concentration lower monoalcohol with a predetermined nonionic surfactant. Usually, when about 0.5 to 2 g of a foam liquid is taken on the palm and used by rubbing the hand, the range in which the user perceives that the liquid spreads sufficiently and the remaining foam is not too long is empirically determined. 5 to 30 seconds. Easy to handle,
To prepare an effective solution, it is necessary to keep the foam in this range while using a high concentration of alcohol. Further, the liquid preparation of the present invention can maintain the state of the foam clearly and stably by appropriately mixing the water-soluble polymer compound.

The solution of the present invention is usually made into an aerosol composition together with a propellant. As propellants, dimethyl ether, liquefied petroleum gas, nitrogen gas,
Examples thereof include nitrous oxide gas, carbon dioxide gas, and alternative chlorofluorocarbon gas. Compressed air can also be used without using a propellant. Moreover, you may use these mixtures. The mixing amount of the propellant is not particularly limited, but is preferably 0.1 to 80% by weight based on the total amount of the liquid agent of the present invention. In addition to the above, an appropriate amount of a perfume or a component usually blended in an external preparation, for example, l-menthol, tocopherol acetate, or a vegetable oil or an animal oil such as castor oil or squalene may be used in an appropriate amount.

[0038]

Examples of Compounds Some of the compounds represented by formula (1) are specifically shown in Table 1.

[Table 1] Table 1

Next, examples of pharmaceutical preparations prepared using the naphtho [2,3-d] thiazole-4,9-dione derivative having the antibacterial activity or the bactericidal activity of the present invention are shown. The compound represented by the general formula (1) can be administered as it is or together with a conventional pharmaceutical carrier. The dosage unit form is not particularly limited, and may be appropriately selected and used as needed. This formulation example is merely an example, and various formulations can be made according to a known method.

Formulation Example 1 A cream is prepared according to the following formulation. (Total amount 100 parts by weight) Compound represented by the general formula (1) 2 Diisopropyl adipate 5 Pyrothiodecane 3 Polyoxyethylene (23) sorbitan 5 Stearyl alcohol 5 Cetanol 5 Octyldodecanol 5 White petrolatum 10 Macrogol 400 10 Methyl paraben 0 ..2 Remaining purified water 100

Formulation Example 2 An ointment is prepared according to the following formulation. (Total amount: 100 parts by weight) Compound represented by general formula (1) 2 Diisopropyl adipate 5 Pyrothiodecane 3 Macrogol 400 10 Sorbitan monostearate 5 Octyldodecanol 20 Microcrystalline wax 10 White petrolatum Remaining amount 100

Formulation Example 3 A lotion is prepared according to the following formulation. (Total amount 100 parts by weight) Compound represented by the general formula (1) 2 Diisopropyl adipate 5 Macrogol 400 10 Oleyl alcohol 5 Ethanol 50 Purified water Remaining amount 100

Formulation Example 4 A gel is prepared according to the following formulation. (Total amount 100 parts by weight) Compound represented by general formula (1) 2 Diisopropyl adipate 5 Pyrothiodecane 3 Propylene glycol 10 Macrogol 400 10 Polyoxyethylene (60) hydrogenated castor oil 1 Ethanol 40 Carbopol 940 3 Hydroxypropyl cellulose 1 Diisopropanolamine 1.5 Purified water Remaining 100

Formulation Example 5 An injection (0.1%) is prepared according to the following formulation. Compound represented by general formula (1) 5 mg Tromethamine 30 mg Physiological saline 5 mL Aqueous injection pH 9.5

Formulation Example 6 An injection (0.1%) is prepared according to the following formulation. Compound represented by the general formula (1) 5 mg Tromethamine 20 mg α-cyclodextrin 50 mg Physiological saline 5 mL Aqueous injection pH 9.25

Formulation Example 7 An injection (0.1%) is prepared according to the following formulation. Compound represented by general formula (1) 5 mg Tromethamine 5 mg 2-hydroxypropyl-β-cyclodextrin 50 mg Physiological saline 5 mL Aqueous injection pH 8.5

Formulation Example 8 An injection (0.1%) is prepared according to the following formulation. Compound represented by general formula (1) 5 mg Tromethamine 5 mg Polyoxyethylene sorbitan monooleate 50 mg Physiological saline 5 mL Aqueous injection pH 8.6

Formulation Example 9 0.5 g of the compound represented by the general formula (1), ethanol 6
5 g, polyoxyethylene lauryl ether (HLB1
1.5) 1 g, glycerin 3 g, dimethylsiloxane
Methyl (POE) siloxane copolymer (HLB13.
0), 10 g of a 0.5% xanthan gum aqueous solution (0.05 g as xanthan gum) and 19.5% of water were prepared to prepare a liquid preparation according to a conventional method. This solution is used as a disinfectant / disinfectant. Next, the pharmacological action of the compound represented by the general formula (1) will be described. The antibacterial activity or the bactericidal activity of the compound represented by the general formula (1) was evaluated as shown in the following experimental examples.

EXPERIMENTAL EXAMPLE 1 The test strain was a standard strain obtained from Teikyo University Medical Mycology Research Center, and was a Candida albicans T.
IMM1768) Aspergillus
fumigatus TIMM1776) and Trichophyton ( Trichophyton ment)
agrophytes TIMM1189) and Gram-positive facultative anaerobic bacteria Staphylococcus aureus IFO13276
And Staphylococcus epiderumidis IF
O12993), a Gram-negative facultative anaerobic bacillus Escherichia coli ( Escher
ichia coli IFO3972). Two strains of Candida and Aspergillus used SAAMF medium, and two strains of Staphylococcus aureus and Escherichia coli used broth for susceptibility measurement, and prepared drug solutions prepared at 1 mg / ml and 10 mg / ml with dimethyl sulfoxide (DMSO), respectively. / 100 volumes to give 20 μg / ml and 200 μg / ml. Approximately 1 × 10 ⁴ cells / SAAMF broth or broth for sensitivity measurement was added to 100 μl of the drug-containing medium.
100 μl of the bacterial solution prepared in a 1 ml volume, and mixed at 37 ° C.
The cells were incubated in a microplate for hours.

The measurement of Trichophyton was carried out by the method of Fujita et al.
3, 199-206, 1992). That is, glucose peptone agar medium (Nissui lot No.180307 Nissui Pharmaceutical
0.5% agar lot No. APM7857 Wako) was sterilized in an autoclave and allowed to cool to about 60 ° C., and 1 ml was added to a multiplate to which 10 μl of each drug dilution had been added in advance to obtain a drug-containing medium. . Each drug is 1 in DMSO
It was prepared to be 00 μg / ml. DMSO
The final concentration was 1%. In the above medium, microconidia 1 ×
10 ⁴ were inoculated and cultured at 27 ° C. for 4 days. Judgment is made with the naked eye. If no growth of bacteria is recognized,
+, Those in which growth was partially suppressed were rated +, those in which growth was slightly suppressed were rated ±, and those in which no suppression was observed were rated-. Table 2 shows the results. 100 μg /
In fungi and Gram-positive bacteria at a concentration of less than ml, growth inhibition of the bacteria was observed. In some cases, such as Compound 9, a strong inhibition of the growth of the bacteria was observed even against Gram-negative bacteria. Thus, the derivative has an antibacterial or bactericidal action against fungi and Gram-positive and negative bacteria. In particular, a strong effect on Trichophyton has been observed.

[0051]

[Table 2] Table 2 (Ca; Candida albicans, Af; Aspergillus fumigatus, Sa; Staphylococcus aureus) (Ec; Escherichia coli, Tm; Trichophyton)

Experimental Example 2 The test strains were Gram-positive facultative anaerobic bacteria Staphylococcus aureus IFO13276 and Staphylococcus epiderumidis IFO12993, and Gram-negative facultative anaerobic bacterium Escherichia coli IFO39.
72), an obligate anaerobic actinomycete propionibacteria ( Propioniba
cterium acnes ATCC6919) used before 4 bacterial species Trypto soya broth (Nissui lot Nanba089302 Nissui Pharmaceutical Co.), overnight shaking culture at 37 ° C., variant GAM broth with regard P. acnes ( This was statically cultured for 3 days in Nissui lot No. 001306 (Nissui Pharmaceutical Co., Ltd.). The measurement of the antibacterial activity was performed by a modification of the serial dilution method for a trace liquid medium. That is, 2/100 volumes of a drug solution adjusted to 2 mg / ml were added to a sensitivity measurement broth (Nissui lot No. 018212 Nissui Pharmaceutical Co., Ltd.) and GAM broth to make 40 μg / ml. The above solution was used as a stock solution, and serially diluted to 0.31 μg / ml in the same medium according to a two-fold dilution technique. Further, 100 μl of a bacterial solution prepared to about 10 ⁵ cells / ml in sterile physiological saline was mixed with a serially diluted drug-containing medium, and the three bacterial species except P. acnes were placed in a microplate at 37 ° C. for 24 hours. , P.acnes in an anaerobic pot at 37 ° C,
The culture was allowed to stand for 3 days. Compounds were dissolved or uniformly suspended in DMSO. The final drug concentration at the start of culture is 0.16 ~
20 μg / ml. Judgment was made by setting the minimum concentration at which growth was not visible to the naked eye to the minimum inhibitory concentration MIC (Minimum Inhi
bitory Concentration)
mm or less, or when there is one colony). However, all the media were sterilized in an autoclave.

Table 3 shows an example of the result. A minimum growth inhibitory concentration MIC of 100 μg / ml or less was observed in most of the derivatives for which growth inhibition of bacteria was observed. In some cases, such as Compound 9, a strong inhibition of the growth of the bacteria was observed even against Gram-negative bacteria. As described above, the present derivative has an antibacterial or bactericidal action against Gram-positive and negative bacteria.

[0054]

[Table 3] Table 3 * Values in parentheses in the table indicate SUB-MIC.

EXPERIMENTAL EXAMPLE 3 The test strain was a standard strain obtained from Teikyo University Medical Mycology Research Center, and was a Candida albicans T.
IMM1768) Aspergillus
fumigatus TIMM1776) and Trichophyton ( Trichophyton ment)
agrophytes TIMM1189) was used to examine the antifungal activity of this compound. For the above Trichophyton, the preculture was performed on a K agar medium (0.2% Bacto peptone lot No. 756304).
Difco, 0.1% dextrose lot No. APR1541 Wako, 0.
1% KH ₂ PO ₄ lot No.AWP0059 Wako, 0.1% Mg
_{SO 4 · 7H 2 O lot No.PDP2120} Wako, 0.5% agar
lot No. APM7857Wako) was used. The measurement of the antifungal activity was carried out according to the method of Fujita et al. (Fungal Journal 33, 199-206, 1992). That is, Sabouraud dextrose soft agar medium (1%
Bacto peptone lot No.756304 Difco, 2% dextrose lo
t No.APR1541 Wako, 0.5% agar lot No.APM7857 Wa
After autoclaving, ko) was allowed to cool to about 60 ° C., and 1 ml each was added to a multiplate to which 10 μl of each drug diluent had been added in advance to obtain a drug-containing medium. 1 × 10 ⁴ conidia were inoculated into the above medium, cultured at 27 ° C. for 4 days, and MIC was determined from the growth of hypha. Each drug diluent was dissolved in DMSO, and the compound was prepared by a 2-fold dilution method using 100 μg / ml as a stock solution. The final concentration of DMSO was 1%. Judgment was made with the naked eye, and the concentration at which growth inhibition was clearly observed compared to the drug-free medium was determined.
C. In addition, those that have almost stopped growth are sub
-MIC.

Further, the above two strains of Candida and Aspergillus are YPG broth (0.5% yeast extrac.).
t, 1% Bacto pepton, 2% Glucose) at 37 ° C overnight with shaking. The measurement of the antifungal activity was carried out by a modification of the serial dilution method for a trace liquid medium. That is, 2/100 volume of a drug solution adjusted to 2 mg / ml was added to a sensitivity measurement broth (Nissui Pharmaceutical Co., Ltd.), and the solution was used as a stock solution according to a two-fold serial dilution technique. Further, 100 μl of a bacterial solution prepared to about 10 ⁵ cells / ml with sterile physiological saline was mixed with a serially diluted drug-containing medium, and cultured in a microplate at 37 ° C. for 24 hours. Compounds were dissolved or suspended in DMSO. Judgment was performed with the naked eye, and the concentration at which growth inhibition was clearly observed as compared with the drug-free medium was defined as MIC. In addition, those that almost inhibited growth were designated as sub-MICs.

Tables 4 and 5 show examples of the results. This derivative has a strong activity against fungi, especially Trichophyton.
As shown in Table 4, many MICs were 1 μg / ml or less, and excellent activity was found. Among them, compound 9 is 0.1%.
A very strong activity of 068 μg / ml was observed. From Table 5, it was also observed that the present derivative shows a strong activity in other fungi.

[0058]

[Table 4] Table 4

[0059]

[Table 5] Table 5 * Values in parentheses in the table indicate SUB-MIC.

[0060]

As described above, the naphtho [2,3-d] of the present invention
Drugs consisting of thiazole-4,9-dione derivatives are useful for fungal infections of humans and animals, such as dermatophytosis,
Versicolor wind, candidiasis, deep mycosis, superficial mycosis, etc.,
It is expected to be an effective antibacterial or bactericidal agent against bacterial and infectious diseases of humans and animals, such as pyoderma, eczema, acne, decubitus, erosion due to other diseases, skin ulcers and secondary infections. .

 ──────────────────────────────────────────────────続 き Continuing on the front page (72) Inventor Mitsuko Nakajima 408 Tashiro Daigakucho, Tosu City, Saga Prefecture Hisamitsu Pharmaceutical Co., Ltd.

Claims (8)

[Claims] [Claim 1] [Wherein R ₁ is —N (R ₂ ) R ₃ , —N (R ₃ ) CO
R ₄ , —S (O) mR ₅ , a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, a cycloalkyl group, an alkenyl group, a cycloalkenyl group, an alkynyl group, a phenyl group, a halogenoalkyl group, (A is a halogen atom, an alkyl group, a nitro group, an acetyl group, an alkylamino group, an amino group, an acetylamino group,
And a group selected from the group consisting of an alkoxy group, an alkylthio group and a mercapto group. R ₂ , R ₃ and R _{4 each} represent a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, a cycloalkyl group, an alkenyl group, a cycloalkenyl group, an alkynyl group, a phenyl group, a halogenoalkyl group, (A is a halogen atom, an alkyl group, a nitro group, an acetyl group, an alkylamino group, an amino group, an acetylamino group,
And a group selected from the group consisting of an alkoxy group, an alkylthio group and a mercapto group. R ₅ is an alkyl group, a cycloalkyl group, may be substituted with a halogen atom linear or branched alkyl group, an alkenyl group. X represents a group selected from the group consisting of a hydrogen atom, a halogen atom, a nitro group, an amino group, and an acetylamino group. n is 1 to
4, m represents an integer of 0 to 2. Where X and R ₁
However, those excluding hydrogen atoms are excluded. ] An antibacterial or bactericidal agent for humans or animals containing the naphtho [2,3-d] thiazole-4,9-dione derivative represented by the formula [1] as an active ingredient. 2. The naphtho [2,3- according to claim 1.
d] An antibacterial or bactericidal agent effective against infectious diseases caused by fungi comprising a thiazole-4,9-dione derivative. 3. The naphtho [2,3-
d] An antibacterial or bactericide comprising a thiazole-4,9-dione derivative effective against Trichophyton infection. 4. The naphtho [2,3-
d] An antibacterial or bactericidal agent effective against bacterial infections comprising a thiazole-4,9-dione derivative. 5. The naphtho [2,3-
d] An antibacterial or bactericidal agent effective against infectious diseases caused by Gram-positive bacteria comprising a thiazole-4,9-dione derivative. 6. The naphtho [2,3- according to claim 1.
d] An injection having an antibacterial or bactericidal action, comprising a thiazole-4,9-dione derivative as an active ingredient. 7. The naphtho [2,3- according to claim 1.
d] A topical external preparation having an antibacterial or bactericidal action, which comprises a thiazole-4,9-dione derivative as an active ingredient. 8. The naphtho [2,3-
d] An oral preparation having an antibacterial or bactericidal action, comprising a thiazole-4,9-dione derivative as an active ingredient.