JP2002114680A - Antifungal agent - Google Patents

Abstract

PROBLEM TO BE SOLVED: To enhance the action of a compound group of formula (I) by formulating the compound group with an antifungal agent or a germicide and to exhibit an excellent control effect on fungi of the genera Trichophyton and Candida. SOLUTION: This antifungal agent comprises a compound of formula (I) [R is H, phenyl or a phenyl substituted with a halogen, a lower alkyl, OH or a lower alkoxy; X is imidazolyl or 1,2,4-triazol-1-yl with the proviso that [4-(2-chlorophenyl)-1,3-dithiolan-2-ylidene]-1-imidazolylacetonitrile is excluded] and one or more compounds selected from a compound group having antifungal activities.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a composition for an antifungal agent. More specifically, the present invention relates to a therapeutic agent for athlete's foot and bugs, the efficacy of which is enhanced.

[0002]

2. Description of the Related Art The compound represented by the formula (I) is a known compound, and JP-A-60-218387 discloses that it is useful as an agricultural and horticultural fungicide.
JP-A-3227 and JP-A-11-199411 disclose that it is useful as an antifungal active agent.
JP-A-75877, JP-A-9-100797 and JP-A-11-199411 describe the optically active substance but do not mention the synergistic effect with other compounds.

[0003]

The treatment of athlete's foot, which is generally said to be difficult to cure, requires the application of a long-term drug, and the frequent occurrence of relapse has been a long-standing problem. For more fundamental treatment of athlete's foot, it is desired to develop a drug that not only suppresses the activity of bacteria but also has a high therapeutic effect. Furthermore, the distinction between athlete's foot symptoms and Trichophyton or Candida can be distinguished only by a specialist looking under a microscope or by culturing the fungus. is there.

[0004]

DISCLOSURE OF THE INVENTION The present inventors have developed a compound represented by the general formula (I), particularly (R)-(-)-(E)-, which is effective against both Trichophyton and Candida. [4-
(2,4-dichlorophenyl) -1,3-dithiolane-
As a result of examining various additives to further enhance the efficacy of 2-ylidene] -1-imidazolylacetonitrile (hereinafter, referred to as "compound A"), certain antifungal agents and fungicides significantly contain compound A. The inventors have found that the compound represented by the general formula (I) synergistically enhances the potency, and based on the finding, completed the present invention.

That is, the present invention relates to (A) a compound represented by the general formula (I):

Embedded image Wherein R is a hydrogen atom, a phenyl group or a halogen atom,
X represents a phenyl group substituted with a lower alkyl group, a hydroxy group or a lower alkoxy group, and X represents a 1-imidazolyl group or a 1,2,4-triazol-1-yl group. However, [4- (2-chlorophenyl) -1,3-dithiolan-2-ylidene] -1-imidazolylacetonitrile is excluded. A compound represented by the general formula (I ′);

Embedded image (Wherein, Y represents CH or N).
More specifically, (R)-(-)-(E)-[4- (2,
4-dichlorophenyl) -1,3-dithiolan-2-ylidene] -1-imidazolylacetonitrile (Compound A, development code NND-502) and

(B) Compounds having antifungal activity (compound (B) group), specifically, undecylenic acid, zinc undecylenate, phenol-11-iodo-
10-undecinoate, zinc diethyldithiocarbamate, ciclopirox olamine, pyrrolnitrin, thiantole, sulfur, 2,4,6-tribromophenylcaproic acid ester, phenol, trimethylcetyl ammonium pentachlorophenate, benzalkonium chloride, An antifungal agent comprising, as an active ingredient, one or more selected from the group consisting of compounds having antifungal activity such as benzethonium chloride, tolnaftate, tolcyclate, haloprosin, chlorhexidine hydrochloride and chlorhexidine glucuronate as an active ingredient. It is.

[0007]

BEST MODE FOR CARRYING OUT THE INVENTION In the present invention, "n-"
Represents normal, "t-" represents tertiary, "sec-" represents secondary, and the lower alkyl group is a linear or branched alkyl having 1 to 6 carbon atoms. A methyl group, an ethyl group, an isopropyl group, an n-butyl group, a sec-butyl group, a t-
A butyl group, an n-hexylbutyl group and the like. Further, the compound represented by the general formula (I) may be a hydrate thereof in some cases. The optically active substance may be a mixture containing any optically active substance in an arbitrary ratio. Further, the compound represented by the general formula (I) may be a salt of the compound in some cases. Salts are not particularly limited, but may be pharmacologically acceptable salts, for example, salts with organic acids such as oxalic acid, succinic acid, methanesulfonic acid, and metals such as copper and zinc. And salts with mineral acids such as hydrochloric acid and sulfuric acid. The compound represented by the general formula (I) is a known compound, and can be produced by a method described in the prior art. The effective compounding amount of the compound represented by the general formula (I) is not particularly limited.
The amount is, for example, 0.2 to 2 parts by weight, preferably 0.5 to 1 part by weight with respect to parts by weight. The amount of the active ingredient in the compound (B) group varies depending on the compound relative to 100 parts by weight of the preparation, and is not particularly limited. For example, the upper limit is about 30 parts by weight and the lower limit is about 0.025 parts. In terms of individual compounds, the effective compounding amount of undecylenic acid is, for example, 2 to 10 parts by weight, and preferably 5 to 10 parts by weight. The effective blending amount of zinc undecylenate is, for example, 4 to 20 parts by weight, and preferably 10 to 20 parts by weight. Phenol
The effective amount of 11-iodo-10-undecinoate is 0.1 to 0.5 part by weight, preferably 0.25 to 0.5 part by weight.
0.5 parts by weight. The effective amount of zinc diethyldithiocarbamate is, for example, 5 to 25 parts by weight, and preferably 12.5 to 25 parts by weight. The effective compounding amount of ciclopirox olamine is, for example, 0.2 to 1 part by weight, preferably 0.5 to 1 part by weight.

The effective amount of pyrrolenitrin is, for example, 0.1 to 1 part by weight, preferably 0.25 to 0.5 part by weight.
Parts by weight. The effective amount of Thiantol is, for example, 15
To 30 parts by weight, preferably 5 to 20 parts by weight. The effective amount of sulfur is, for example, 2 to 10 parts by weight, and preferably 5 to 10 parts by weight. 2,4,6-
The effective blending amount of tribromophenylcaproic acid ester is, for example, 0.4 to 2 parts by weight, preferably 1 to 2 parts by weight. The effective amount of benzalkonium chloride is, for example, 0.01 to 0.05 parts by weight, preferably 0.02 to 0.05 parts by weight.
5 to 0.05% by weight. The effective amount of benzethonium chloride is 0.1 to 0.5 parts by weight, preferably 0.1 to 0.5 parts by weight.
25 to 0.5% by weight. The effective compounding amount of tolnaftate is, for example, 0.4 to 2 parts by weight, preferably 1 to 2 parts by weight.
Parts by weight. The effective blending amount of the tolcyclate is, for example, 0.2 to 1 part by weight, and preferably 0.5 to 1 part by weight. The effective compounding amount of haloprosin is, for example, 0.2 to 1
Parts by weight, preferably 0.5 to 1 part by weight. The effective blending amount of chlorhexidine hydrochloride is, for example, 0.1 to 1 part by weight, and preferably 0.5 to 1 part by weight. The effective blending amount of the chlorhexidine glucuronate solution is, for example, 0.1.
It is 25 to 2.5 parts by weight, preferably 1 to 2.5 parts by weight.

The mixing ratio of undecylenic acid is, for example, 1 to 50 parts by weight, preferably 5 to 20 parts by weight, per 1 part by weight of the compound represented by the general formula (I). Zinc undecylenate is, for example, 2 to 100 parts by weight, preferably 10 to 40 parts by weight, per 1 part by weight of the compound represented by the general formula (I). Phenol
11-Iodo-10-undecinoate is used, for example, in an amount of 0.0 to 1 part by weight of the compound represented by the general formula (I).
It is 5 to 2.5 parts by weight, preferably 0.25 to 1 part by weight. Zinc diethyldithiocarbamate is used, for example, in an amount of 2.5 parts per part by weight of the compound represented by the general formula (I).
To 125 parts by weight, preferably 12.5 to 50 parts by weight. Ciclopirox olamine is, for example, 0.1 to 5 parts by weight, preferably 0.5 to 2 parts by weight, based on 1 part by weight of the compound represented by the general formula (I). Pyrrolenitrin is used in an amount of, for example, 0.025 to 5 parts by weight, preferably 0.25 to 1 part by weight, based on 1 part by weight of the compound represented by the general formula (I).

Thiantol is used in an amount of, for example, 2.5 to 150 parts by weight, preferably 15 to 60 parts by weight, based on 1 part by weight of the compound represented by the formula (I). Sulfur
The amount is, for example, 1 to 50 parts by weight, and preferably 5 to 20 parts by weight, per 1 part by weight of the compound represented by the general formula (I). 2,4,6-Tribromophenylcaproic acid ester is used in an amount of 1 part by weight of the compound represented by the general formula (I).
For example, it is 0.2 to 10 parts by weight, preferably 1 to 4 parts by weight. Benzalkonium chloride is used in an amount of, for example, 0.005 to 1 part by weight of the compound represented by the general formula (I).
0.25 parts by weight, preferably 0.025 to 0.1
Parts by weight. Benzethonium chloride is used, for example, in an amount of from 0.05 to 2.0 parts by weight based on 1 part by weight of the compound represented by the general formula (I).
5 parts by weight, preferably 0.25 to 1 part by weight. Tolnaftate is used in an amount of, for example, 0.2 to 10 parts by weight, preferably 1 to 4 parts by weight, based on 1 part by weight of the compound represented by the general formula (I). Tolucyclate is used in an amount of, for example, 0.1 part by weight based on 1 part by weight of the compound represented by the formula (I).
It is 1 to 5 parts by weight, preferably 0.5 to 2 parts by weight.

Haloprosin is used, for example, in an amount of 0.1 to 5 parts by weight, preferably 0.5 to 2 parts by weight, per part by weight of the compound represented by the formula (I). Chlorhexidine hydrochloride is, for example, 0.05 to 5 parts by weight, preferably 0.5 to 2 parts by weight, based on 1 part by weight of the compound represented by the general formula (I). The amount of the glucuronsanchlorhexidine solution is, for example, 0.125 to 12.5 parts by weight, preferably 1 to 5 parts by weight, based on 1 part by weight of the compound represented by the general formula (I).

The active ingredient of the present invention may be mixed with known additives and the like, if necessary, and creamed, liquid,
Lotions, emulsions, tinctures, ointments, aqueous gels,
External preparations such as oily gels, aerosols and powders can be prepared. Examples of water-soluble components include lower alcohols such as methanol, ethanol, propanol, and butyl alcohol; ethylene glycol, propylene glycol, dipropylene glycol, 1,3-butylene glycol, glycerin, macrogol (polyethylene glycol), and sorbitol. And lower ketones such as polyhydric alcohols and methyl ethyl ketone.

The oily components include limonene, 1-menthol, dl-menthol, terpenes such as peppermint oil, diisopropyl adipate, diethyl sebacate, isopropyl myristate, hexyl myristate, hexyl decyl myristate, isopropyl palmitate, Esters such as isostearyl palmitate, methyl salicylate, glycol salicylate and isopropyl linoleate; hydrocarbons such as petrolatum, microcrystalline wax and squalane; jojoba oil; esters such as liquid lanolin and gay wax; tallow and olive oil Examples include chain fatty acid triglycerides, higher alcohols such as stearyl alcohol, cetostearyl alcohol, cetanol and oleyl alcohol, and other crotamiton. Examples of the polymer include a carboxyvinyl polymer, methylcellulose, and ethylcellulose. pH
Examples of the preparation include citric acid, lactic acid, sodium hydroxide, urea, and organic amines such as diisopropanolamine. Examples of the antioxidant include dibutylhydroxytoluene (BHT), butylhydroxyanisole (BHA), α-tocopherol, erythorbic acid,
And sodium pyrosulfite.

As the surfactant, one or two or more selected from nonionic surfactants, anionic surfactants and amphoteric surfactants can be used.
For example, polyoxyethylene hydrogenated castor oil, sorbitan monostearate, sorbitan monopalmitate, glycerin monostearate, sorbitan monolaurate, polyoxyethylene polyoxypropylene block copolymer, polysorbates, sodium lauryl sulfate, sucrose fatty acid ester, lecithin And the like. Examples of the stabilizer include EDTA-2Na (ethylenediaminetetraacetic acid disodium salt). Preservatives include benzyl alcohol, parabens and the like. In addition, if necessary, an antihistamine (for example, diphenhydramine hydrochloride), an antipruritic (for example, crotamiton), and a local anesthetic (for example, dibucaine hydrochloride, lidocaine, lidocaine hydrochloride, etc.) can be blended. As all of these pharmaceutically acceptable additives, those generally used in pharmaceutical preparations can be used.

[0015]

The present invention will be described in more detail with reference to the following examples and test examples, but the present invention is not limited to these examples. Formulation Example 1 (Prescription example of cream) Compound represented by general formula (I) 100 g Tolnaphthalate 100 g Cetostearyl alcohol 1000 g Diethyl sebacate 600 g Medium-chain fatty acid triglyceride 800 g Polysorbate 60 400 g Sorbitan monostearate 200 g Methyl paraben 15 g Propyl paraben 5 g Benzyl alcohol 100 g Dibutyl Hydroxytoluene 2 g Purified water is added to add a total of 10,000 g (Production method) Oil phase component (compound represented by general formula (I), tolnaftate, cetostearyl alcohol, diethyl sebacate, medium-chain fatty acid triglyceride, polysorbate 60, sorbitan monostea Rate, propylparaben, benzyl alcohol, dibutylhydroxytoluene) after heating and mixing, and adding an aqueous phase component (methylparaben, purified water) with cooling and stirring to produce 10,000 g of a cream. .

Formulation Example 2 (Solution Formulation Example) Compound represented by general formula (I) 100 g Tolnaftate 100 g Macrogol 400 3,300 g Methyl ethyl ketone 1,000 mL Ethanol 4,500 mL Purified water Total 10,000 mL (Production method) Purified water was added to adjust the total volume to 10,000 ml to produce a liquid preparation.

Formulation Example 3 (Prescription example of cream) Compound represented by general formula (I) 100 g Pyrrolenitrin 50 g Cetostearyl alcohol 1000 g Diethyl sebacate 600 g Medium-chain fatty acid triglyceride 800 g Polysorbate 60 400 g Sorbitan monostearate 200 g Methyl paraben 15 g Propyl paraben 5g Benzyl alcohol 100g Dibutylhydroxytoluene 2g Purified water Total 10,000g (Production method) Formulation example 1. 10,000 cream according to
g was prepared.

Test Example 1 (Sample) Compound A was dissolved in dimethyl sulfoxide and pyrrolenitrin was dissolved in ethanol, and a two-fold dilution series was prepared with each solvent. A mixed solution of each compound was prepared, and at the time of antibacterial activity measurement, the drug and the medium were mixed at a ratio of 1:99. (Test method) Sabouraud agar medium (DIFCO) was used as a medium for measuring sensitivity. Candida inoculates the bacterial solution prepared at 105 spores / ml on Sabouraud agar medium containing the drug,
The cells were cultured at 35 ° C. for 2 days. Trichophyton was inoculated with a bacterial solution prepared at 10 6 conidia / ml and cultured at 27 ° C. for 7 days. The antibacterial activity is determined by the FIC index from the minimum drug concentration (MIC: minimum inhibitory concentration) at which no bacterial growth is observed at the end of culture.
(Fractional Inhibitory Concentration index) was calculated.

Formula: FIC index = a / a0 + b / b0, a: MIC of NND-502 when combined, a0: MIC of NND-502 alone, b: MIC of pyrrolnitrin when combined, b0: MIC of pyrrolnitrin alone

Criteria for judging presence or absence of combined effect FIC index ≧ 2: antagonistic effect, 2> FIC index ≧ 1: additive effect, FIC index <1: synergistic effect

Table 1. Antibacterial effect test on Trichophyton---------------------------------------------------------------------------------------------------------------- −−−−−−−−−−−−− mentagrophytes rubrum −−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−− −−−−−−−−−−−−−−−− MIC of Compound A 6.25 3.13 1.56 MIC of Pyrrolnitrin 2000> 2000 250 FIC index 0.187 <0.187 0.375 −−−−−−−−−−−−−−−− −−−−−−−−−−−−−−−−−− MIC of Zinc Undecylenate 12500 12500 − FIC index 0.750 0.749 − MIC of Ciclopirox Olamine 12500 12500 − FIC index 0.517 0.514 − MIC of Benzethonium chloride> 100 000> 100 000> 100 000 FIC index <0.312 <0.250 <0.258 MIC of Haloprogin − 3130 1560 FIC index − <0.561 <0.531 MIC of Tolnaphtate 98 49 49 FIC index 0.623 <0.652 <0.313 MIC of Chlorhexidine Hydrochloride 12500 25000 25000 FIC in dex 0.312 0.499 0.312 −−−−−−−−−−−−−−−−−−−−−−−−−−−−−−− Table 1. As shown in the figure, Compound A and pyrrolnitrin (Py
rrolnitrin), zinc undecylenat (Zinc Undecylenat)
e), Ciclopirox Olamin
e), Benzethonium chloride,
Haloprogin, Tolnaphtate (Tolnap)
htate) or Chlorhexidine H
The antifungal composition containing ydrochloride) has an FIC index of 1.0 or less against Trichophyton, and the composition containing the compound represented by the general formula (I) and pyrrolnitrin according to the present invention is effective against Trichophyton. Clearly, it has a synergistic effect.

Table 2. Antibacterial effect test against Candida albicans (C. albicans) C. albicans −−−−−−−−−−−−−−−−−−−−−−−−−−− −−−−−−−−−−−−−−−−−−− IFO1270 IFO0583 TIMM2640 TIMM3163 TIMM3166 −−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−− −−− MIC of compound A 12.5 12.5 12.5 50 12.5 MIC of Pyrrolnitrin 25 25 25 25 25 FIC index 0.0468 0.0624 0.0624 0.2502 0.1872 −−−−−−−−−−−−−−−−−−−−−−−− −−−−−−−− MIC of Zinc Undecylenate 12.5 12.5 12.5 − 12.5 FIC index 0.3124 <0.5004 <0.5624 − <0.6250 MIC of Ciclopirox Olamine 12.5 12.5 12.5 − 12.5 FIC index 0.2486 0.5008 0.3752 − 0.5624 MIC of Benzethonium choride 25 3.13 3.13 3.13 3.13 FIC index 0.1872 0.5639 0.4996 0.5639 0.5639 Haloprogin MIC 0.78 1.56 0.78 3.13 − FIC index 0.3188 0.3748 0.6248 0.5319 − Chlorhexidine Hydrocloride MIC 100 12.5 25 25 25 FIC index 0.0625 0.1560 0.0936 0.3124 0.3128 −−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−

Table 2. As shown in the above, the anti-fungal composition containing compound A and pyrrolnitrin, zinc undecylenate, cyclopyrosqualamine, benzethonium chloride, haloprosin or chlorhexidine hydrochloride has an FIC index for Candida of 1.0 or less, and the present invention It is clear that the composition of the invention has a synergistic effect on Candida. These compositions also show a synergistic effect against fluconazole resistant bacteria, TIMM3163 and TIMM3166.

[0024]

The drug of the present invention is a potent antifungal agent against Trichophyton and Candida, in which the action of NND-502 is synergistically enhanced by an antifungal agent or a bactericide.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) C07D 409/06 C07D 409/06 F-term (Reference) 4C063 AA01 BB03 CC97 DD25 DD41 EE01 4C069 AC06 BB08 BB44 4C086 AA01 AA02 BC05 BC38 BC60 GA04 GA07 MA01 MA04 NA05 ZB35

Claims (3)

[Claims] 1. A compound of the general formula (I): Wherein R is a hydrogen atom, a phenyl group or a halogen atom,
X represents a phenyl group substituted with a lower alkyl group, a hydroxy group or a lower alkoxy group, and X represents a 1-imidazolyl group or a 1,2,4-triazol-1-yl group. However, [4- (2-chlorophenyl) -1,3-dithiolan-2-ylidene] -1-imidazolylacetonitrile is excluded. An antifungal agent comprising, as an active ingredient, a compound represented by the formula: and one or more compounds selected from the group of compounds having antifungal activity. 2. A compound represented by the general formula (I) ′: (Wherein, Y represents CH or N) and 1 or 2 selected from the group consisting of compounds having antifungal activity
An antifungal agent comprising the above compound as an active ingredient. 3. The antifungal agent according to claim 1, wherein one or more compounds selected from the group of compounds having antifungal activity are pyrrolnitrin.