JPS635388B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to 1-[2-(2,6-dichlorophenylthio)-4-(4-chlorophenyl)-n-butyl]
The present invention relates to imidazole and its antimicrobial acid addition salts, compositions containing these compounds, and methods for producing the same. These compounds are useful as antifungal, antibacterial, and antiprotozoal agents. First-to-filed patent application filed on July 27, 1975
No. 89590 (JP 52-17472) discloses a substituted N-alkylimidazole compound represented by the following general formula and an antibacterial acid addition salt thereof. In the formula, R ¹ and R ² are each independently phenyl,
phenyl straight-chain lower alkyl or phenyl straight-chain lower alkenyl; or one of the above independently from the group consisting of lower alkyl, halo and trifluoromethyl having 1 to 4 carbon atoms in the phenyl ring; is substituted with one or more substituents selected from;
is oxygen or sulfur; n is an integer from 1 to 8 with the proviso that n is not 1 when R ¹ is phenyl or substituted phenyl. A series of compounds represented by the above formula and their salts are said to exhibit antifungal, antibacterial and antiprotozoal activities. It has now been found that one group of the above-mentioned compounds is particularly active. A group of highly active compounds different from the previously disclosed compounds of formula (A) above are those characterized by the following formula and their antibacterial acid addition salts. where X is chloro or fluoro, Y is bromo or chloro, respectively, at least one Y is in the 2'-position, and when Y is chloro, n
is 1 to 3, and when Y is other than chloro, n is 1 or 2. Among these, the preferred compound is 1-[2-(2,6-
dichlorophenylthio)-4-(4-chlorophenyl)-n-butyl]imidazole and its antimicrobial acid addition salt. These chemical structural features that give these compounds high activity are as follows: 1) The 1,4-butylene chain has an imidazole moiety and a P
- chloro or -fluorophenyl moiety, 2) halophenylthio moiety is 1,4-
C-2 counting from the imidazole part of the butylene chain
3) At least one halo must be attached to the carbon and, most notably, at least one halo at the 2'-position of the phenyl ring of the halophenylthio moiety. The combination of these features results in a class of different compounds with surprisingly high activity. In this specification, unless otherwise specified, the following terms are used with the following meanings. The term "halo" refers to bromo, chloro and fluoro. The "antimicrobial acid addition salt" of the base is one that retains the antimicrobial properties of the free base and is biologically and otherwise preferable, such as inorganic acids (e.g., hydrochloric acid, hydrogen bromide, acid, sulfuric acid, nitric acid or phosphoric acid),
or organic acids such as acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, oxalic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandaric acid, (methanesulfonic acid, ethanesulfonic acid, P-toluenesulfonic acid, salicylic acid, etc.). All compounds of formula () have at least one asymmetric center, namely a carbon atom to which S, H and two CH ₂ moieties are attached. Therefore, the compounds of the present invention can be produced as optically active forms or racemic mixtures. Unless otherwise specified, all compounds mentioned herein are in racemic form. However, the scope of the present invention is not limited to racemates, but also includes each optical isomer of the subject compound and various mixtures thereof. The racemic intermediate or final product prepared here may, if desired, be resolved into its optical antipodes by conventional resolution methods known per se [for example, a racemic compound of formula () and an optically active acid separation of diastereomeric salts resulting from the reaction (e.g. fractional crystallization) or separation of diastereomeric salts or esters resulting from the reaction of the racemic compound of formula () with an optically active acid). An example of such an optically active acid is camphor-
10-sulfonic acid, α-bromo-camphor-π-
Sulfonic acid, camphoric acid, methoxyacetic acid, tartaric acid, malic acid, diacetyltartaric acid, pyrrolidone-
Examples include optically active substances such as 5-carboxylic acid. The separated pure diastereomeric salts or esters are then cleaved by standard methods to give the optical isomers of compounds of formula () or (), respectively. The subject compound of formula () exhibits antifungal, antibacterial and antiprotozoal activities. For example, compounds of the invention exhibit antifungal activity against the following human and animal pathogens: The compounds of the invention also have antifungal activity against the following fungi of principal agricultural importance: Microsporum audouini, Microsporum gypseum, Microsporum gypseum-canis, Epidermophyton floccosum, Trichophyton mentagrophytes, Trichophyton rubrum, Trichophyton tonsurans, Candida albicans, and Cryptococcus neoformans. show. Aspergillus flavus, Aspergillus niger, Cladosporium herbarum, Penicillium
oxalicum, Fusarium graminearum, Penicillium
spinulosum, Penicillium notatum, and Pithomyces chartarum. In addition, the compounds of the present invention also exhibit antibacterial activity against the following human and mobile pathogens. Staphylococcus aureus, Streptococcus faecalis, Corynebacterium acnes, Erysipelothrix insidiosa, Escherichia coli, Proteus vulgaris, Salmonella choleraesuis, Pasteurella multocida, and Pseudomonas aeruginosa.
Trichomonas vaginalis and Trichomonas
Shows antiprotozoal activity against A. foetus). Compounds of interest of the present invention generally have low toxicity. Furthermore, this compound has good solubility in the stratum corneum. Since dermatophyte (i.e., parasitic fungal) infections usually occur in dead tissue of the stratum corneum, the solubility of antifungal agents in this tissue significantly enhances their effectiveness. In view of the above-mentioned activities, it can be seen that the target compound is a useful antibacterial agent that can be used not only in medicine but also in agriculture and industry. A further aspect of the invention therefore relates to pharmaceutical, agricultural and industrial compositions comprising a subject compound of formula () and a suitable carrier. A further aspect of the invention is to provide a host harboring or being attacked by fungi, bacteria or protozoa with an effective amount of a compound of the invention or a suitable composition comprising the same. , relating to methods of inhibiting the growth of bacteria and protozoa. When used pharmaceutically, the compositions may be in solid, semi-solid or liquid form (e.g. tablets, capsules, etc.).
powders, suppositories, solutions, suspensions, creams, lotions, ointments, etc.). Pharmaceutically acceptable non-toxic carriers or excipients commonly used for solid formulations include tricalcium phosphate, calcium carbonate, kaolin, bentonite, talc, gelatin, lactose, starch, etc., and for semisolid formulations. Examples include polyalkylene glycols, petrolatum and other cream bases; for liquid formulations, water, vegetable oils and low boiling solvents (e.g. isopropanol, hydrogenated naphthalene, etc.)
can be given. Pharmaceutical compositions containing compounds of the invention may be subjected to conventional pharmaceutical processes (e.g., sterilization) and may contain conventional pharmaceutical excipients (e.g., preservatives, stabilizers, emulsifiers, osmotic salts, and It can also contain a buffer solution. The composition may also contain other pharmaceutically active substances. In pharmaceutical use, the subject compounds and compositions are administered to humans and animals in a conventional manner (eg, topically, orally, parenterally, etc.). Parenteral administration includes intramuscular as well as subcutaneous and intravenous administration. Intravenous injections of antifungal agents of the imidazole type have been described as effective in the treatment of fungal diseases (e.g., Druge, Vol. 9, pp. 419-420, 1975) ,4-dichloro-β-(2′,4′-
dichlorobenzyloxy)phenethyl]-imidazole nitrate (Systemic
intravenous administration to patients with candidiasis). Local administration is preferred for pharmaceutical use. In such treatments, the compound or composition of interest is applied, for example, to areas where fungi, bacteria or protozoa are growing or to be protected from fungal, bacterial or protozoan attack.
spraying, cleaning, brushing, dipping, coating, coating,
Penetrate, etc. Topical pharmaceutical compositions containing compounds of the invention may be prepared over a wide range of concentrations (e.g., about
0.1 to 10.0% by weight) exhibits antifungal, antibacterial, and antiprotozoal activity. In any case, the composition administered will contain an amount of the subject compound effective to alleviate or prevent the particular condition being treated. The pharmaceutical composition typically comprises one or more subject compounds of formula () and a pharmaceutically acceptable non-toxic carrier, and is preferably formulated in a unit dose form suitable for administration. Amount is the amount of active ingredient administered at one time). For systemic administration (eg, oral or parenteral), the active ingredient is generally administered in an amount of between about 1 and 100 mg per kg of body weight per day, preferably between about 5 and 50 mg per kg of body weight per day. It is most effective when taken, preferably in several doses (eg, three doses of each dose). However, for topical administration, the amount of active ingredient required is relatively small. The precise prescription for pharmaceutical administration of the compounds and compositions disclosed herein will necessarily depend on the needs of each subject being treated, the type of treatment (e.g. prophylactic or curative), the type of organism involved and, of course, Based on the judgment of the examining doctor. For agricultural applications, the compounds of interest can be applied directly to plants (eg, seeds or leaves) or to the soil. For example, the compounds of the invention are applied to seeds alone or in a mixture with a powdered solid carrier.
Typical powder carriers are silicates of various minerals such as mica, talc, pyrophyllite and clay.
The subject compounds may also be applied to the seeds in a mixture with conventional surfactant wetting agents (with or without other solid carriers). Surface-active wetting agents that can be used are any conventional anionic, non-anionic or cationic ones. As a soil treatment agent for fungi, etc., the target compound is applied as a powder, which is a mixture with sand, soil, or a powdered solid carrier (for example, mineral silicate) (which may or may not contain a surfactant). Alternatively, the compound of interest can be applied as an aqueous spray containing an appropriate surfactant dispersant and a powdered solid carrier. As a foliar treatment, the compound of interest is applied to growing plants as an aqueous spray containing a surfactant dispersant (with or without a powdered solid carrier and a hydrocarbon solvent). In industrial applications, the compounds of interest can be used for the control of bacteria and fungi by contacting them with pathogens in any known manner. Contacting the target compound with substances that can infect bacteria or fungi,
Such materials can be protected by mixing or impregnating them. To increase this effect, the subject compounds may be used in conjunction with other pest control agents (eg, fungicides, bactericides, insecticides, acaricides, etc.). A particularly important industrial/agricultural use of the subject compounds of the present invention is as food preservatives against bacteria and fungi that cause food deterioration and spoilage. Compounds of formula () can be prepared from appropriate alcohols of formula () to form thioethers. In the formula, X is as defined above. Compounds of formula () can be prepared by various reaction sequences. For example, according to the reaction series A shown below, the formula ()
Compounds can be produced. In the formula, X shall be defined previously. In this reaction series, the terminal epoxide of formula () is opened with imidazole to form the imidazole alcohol of formula (). The reaction is generally carried out using at least 1 mole (preferably excess) of imidazole relative to the epoxide, optionally in the presence of a salt (preferably an alkali metal salt) of imidazole. The reaction may be carried out without a solvent or preferably in an inert organic solvent (eg dimethylformamide, hexamethylphosphoramide, acetonitrile, etc.). When such epoxides are cleaved, the temperature is usually from about -20 to about 100°C, and from about 20 to about 100°C.
60°C is most preferred. Epoxides of the formula (), insofar as they are not known, can be prepared by various well-known methods, such as by epoxidizing a terminal olefin (for example ()) with, for example, a peracid, or by
Reaction of a small aldehyde (for example ()) with trimethylsulfoxonium iodide or a ylide prepared from trimethylsulfonium iodide (for example, J. Am.
1965; Ibid., Vol. 87, p. 1353)]. Another reaction sequence for producing the compound of formula () is shown in B below. In the formula, X is as defined above, and Y' is chloro or bromo. In this reaction sequence, a hydroxy compound of formula () is prepared by reduction of the corresponding ketone, which is prepared by reaction of an α-haloketone () with imidazole. Alpha-haloketones can be readily prepared by methods generally known in the art, such as by reacting the acid chloride or bromide from the corresponding dihydrocinnamic acid with diazomethane and then treating the resulting diazoketone with HY'. Contacting this α-haloketone with imidazole in an inert solvent yields the ketoimidazole of formula (). The reaction is carried out using at least a 1 molar amount (preferably an excess amount) of imidazole relative to the haloketone. Although this reaction may be carried out without a solvent, it is preferably carried out in an inert solvent (eg dimethylformamide, hexamethylphosphoramide, acetonitrile, etc.). The suitable temperature for the reaction is initially between about -10 and 100°C;
Most preferably between about 25 and 80°C. In the next step, the ketoimidazole of formula () is
Reduction using a conventional metal hydride reducing agent (eg, sodium borohydride) provides the hydroxyimidazole of formula (). The reaction is preferably carried out in an alcoholic solvent (eg, methanol or ethanol) at reduced temperature (eg, between about -10 and +25°C, with about 0°C being most preferred). The compound of formula () can be produced from the compound of formula () through the following two-step series. The hydroxyl group is first converted to a suitable leaving group [e.g.

[Formula] (where Y and n are defined above) is reacted, preferably in the presence of a base (eg, calcium carbonate), or a metal salt thereof is used. Conversion of alcohols to halide or sulfonate esters is accomplished by methods well known in the art. For example, alcohol can be treated with a halogenating agent (e.g. thionyl chloride or thionyl bromide).
between about 0 and 80°C (preferably between about 20 and 80°C) neat or in an inert solvent (e.g. dichloromethane or chloroform)
Halogenates at a temperature of This halogenation reaction may be carried out in the presence of a molar equivalent of a base (eg pyridine), if desired. Other halogenation methods include, for example, the use of triphenylphosphine with carbon tetrachloride, carbon tetrabromide or N-chloro (or N-bromo)succinimide. If thionyl chloride or thionyl bromide is used and no base is added, the corresponding hydrochloride or hydrobromide salt of the halo compound is formed. This salt is either neutralized, for example with potassium carbonate, before use in the alkylation step, or the salt is used directly if excess thiophenol salt is used. Sulfonate esters can be prepared in standard manner by treating the alcohol with an excess of eg methanesulfonyl chloride or p-toluenesulfonyl chloride in the presence of a base (eg pyridine or triethylamine). The reaction is carried out at a temperature of about -20 to +50°C, preferably between about 0 and 20°C. The halide or sulfonate ester prepared above is then treated with thiophenol or a corresponding salt of thiophenol (preferably an alkali metal salt, such as a sodium or potassium salt) in an inert organic solvent (preferably in the presence of a base). (e.g. acetone, methanol, etc.) at temperatures between about 20 and about 80°C. If desired, metal salts of thiophenol may be prepared before addition of the halide. Compounds of formula () can also be used in the reaction sequence C shown below.
It can also be manufactured by and/or and/or In the formula, Y' is a leaving group, and X, Y and n are each defined above. In this series, the epoxide of the above formula () is cleaved with thiophenol or a metal salt thereof to form the compound (). The reaction is preferably carried out using an alkali metal salt of thiophenol (sodium salt being most preferred) in an inert organic solvent (e.g. tetrahydrofuran or acetone) at a temperature between about 0°C and 67°C, or Free thiophenol is catalyzed by an acid catalyst (e.g. perchloric acid)
used under similar conditions in the presence of In the next step, the hydroxyl group of the compound () is converted into a leaving group [e.g.
- toluenesulfonate or methanesulfonate)], e.g. with a halogenating agent (e.g. thionyl chloride, neat), preferably in an inert solvent (e.g. dichloromethane), or e.g.
Conversion is achieved by treatment with Pr toluenesulfonyl chloride in a solvent (eg pyridine). The products of formula () exist in both forms shown above and are interconvertible via episulfonium intermediates. In the final step, the compound of formula () is treated with imidazole to give the final product of formula (). This reaction is carried out in an inert organic solvent (e.g. acetonitrile,
about 0 to about 100 in dimethylformamide, etc.)
Carry out at a temperature of °C. Thiophenol reagents are prepared from the corresponding phenols by methods generally known in the art (e.g. MS).
Newman and HA Karnes, J.Org.Chem.
1973, Vol. 31, p. 3980). Compounds of interest of the present invention can be isolated as free bases. However, since some compounds are oily in their basic form, it is more convenient to isolate and identify the compounds as acid addition salts. Such salts are prepared in a conventional manner, ie by reacting a basic compound with a suitable inorganic or organic acid as mentioned above. Salts formed with dibasic acids (eg oxalic acid) contain one or two molecules of base per molecule of salt. All oxalates mentioned herein contain one molecule of oxalic acid per molecule of imidazole base. If desired,
Salts can be easily converted to the free base form by reaction with an alkali (eg potassium carbonate, sodium carbonate, sodium hydroxide or potassium hydroxide). The following specific manufacturing methods and examples are illustrative of the invention and are not intended to limit it in any way. Production method 1 3-(4-fluorophenyl)-1-propanol (34 g) in anhydrous methylene chloride (200 ml),
Add directly to a well-stirred suspension of pyridinium chlorochromate (71.5 g) in methylene chloride (400 ml). After 2 hours at room temperature, ether is added to precipitate the reagents, the reaction mixture is decanted and the residue is washed with ether. The combined organic extracts are passed through Florisil, evaporated and the product distilled under reduced pressure to give 3-(4-fluorophenyl)propionaldehyde as a colorless oil. Oil 3-(4-chlorophenyl)propionaldehyde is prepared in a similar manner. Production Method 2 This production method is an explanation of the reaction series A method. 3-(4-fluorophenyl)propionaldehyde (20.6 g) was dissolved under nitrogen from trimethylsulfonium iodide (31.8 g) and sodium hydride (55% dispersion in oil; 7.48 g) in dry dimethyl sulfoxide ( 100ml) Journal of
It is added to the ylide prepared by the method described in American Chemical Society, Vol. 87, p. 1353 (1965). After 1 hour at -10°C, the solution is brought to 0°C, poured into 500 ml of ice water, and the product is extracted with ether (3 x 300 ml). The extract was thoroughly washed with water, dried (MgSO ₄ ) and evaporated to give an oil, 1,2-epoxy-4-(4-fluorophenyl).
Butane is obtained, which is used directly in the next step. The oil obtained above in a few ml of tetrahydrofuran was added to a mixture prepared by reaction of imidazole (9.18 g) and sodium hydride (50% dispersion in mineral oil; 3.24 g) in 200 ml of tetrahydrofuran. Add until it no longer occurs. The mixture is heated under reflux overnight, evaporated to dryness and the residue is extracted with a little dichloromethane. This solution is filtered and chromatographed on silica gel (10
% methanol). Trituration with ethyl acetate/hexane gives colorless crystals of 1-[2-hydroxy-4-(4-fluorophenyl)-n-butyl]imidazole (interval point 120.5-122.5°C). In the same manner as above, instead of 3-(4-fluorophenyl)propionaldehyde, 3-
Using (4-chlorophenyl)propionaldehyde, 1-[2-hydroxy-4-(4-chlorophenyl)-n-butyl]imidazole (melting point 105
-109℃). Preparation 3 A solution of 6.0 g of 1-[2-hydroxy-4-(4-chlorophenyl)-n-butyl]imidazole in 30 ml of thionyl chloride is warmed to 65-70°C for 1 hour. When evaporated to dryness, 1-[2-
Chloro-4-(4-chlorophenyl)-n-butyl]imidazole hydrochloride is obtained. Similarly, 1-[2-chloro-4-(4-fluorophenyl)-n-butyl]-imidazole hydrochloride is produced. If the free base for the next alkylation step is desired, the hydrochloride is shaken in dichloromethane with an excess of aqueous potassium carbonate, the organic layer is washed with water, dried over magnesium sulfate and brought to dryness under reduced pressure. It is obtained by removing all traces of dichloromethane by evaporating it to . Example 1 A mixture of 6.46 g 1-[2-chloro-4-(4-chlorophenyl)-n-butyl]imidazole, 8.5 g 2,6-dichlorothiophenol and 6.4 g anhydrous potassium carbonate in 100 ml acetone. of
Stir and reflux for 18 hours. Remove the solvent under reduced pressure and add 100 ml of water. The mixture thus obtained
Extract with 300 ml of ether and dilute the ether extract with 2
After washing with water and drying (MgSO ₄ ), 1-[2-(2,
A solution containing 6-dichlorophenylthio)-4-(4-chlorophenyl)-n-butyl]imidazole is obtained. Nitrate precipitation is obtained by adding 70% nitric acid (d=1.42) dropwise to the ethereal solution until precipitation is complete. When the obtained salt is recrystallized from acetone-ethyl acetate, it becomes a colorless flake-like substance (melting point: 162-163°C; foaming). In a similar manner, 1-[2-(2,6-dichlorophenylthio)-4-(4-fluorophenyl)-n
-butyl]imidazole nitrate (melting point 131.5
-132.5℃). Example 2 1,2-epoxy-4- in acetone (60ml)
(4-chlorophenyl)butane (3.65g), 2,6
- A mixture of dichlorothiophenol (4.0 g) and anhydrous potassium carbonate (200 mg) is stirred at reflux under nitrogen for about 4 hours. After removing the solvent, ether (150 ml) was added and the extract was washed with water.
Dry (MgSO ₄ ) and evaporate. 6ml of the above substance in 100ml dichloromethane
of thionyl chloride, heated gently to reflux for 1 hour, evaporated the solution to dryness, and evacuated to remove traces of thionyl chloride. The residue is treated with 7 g of imidazole and 30 ml of acetonitrile and stirred at 55°C overnight and at 85°C for 1 day. After evaporating the solvent and adding 50 ml of water, the residue is extracted with ether. The ether extract was thoroughly washed with water and dried (MgSO ₄ ) to give 1-
[2-(2,6-dichlorophenylthio)-4-(4
-Chlorophenyl)-n-butyl]imidazole is obtained, which is used as its nitrate (melting point
162.5-164.5℃) and purify it. Similarly, 1-[2-(2,6-dichlorophenylthio)-4-(4-fluorophenyl)-n-butyl]
Imidazole nitrate (melting point 131.5-132.5℃)
Manufacture. Example 3 (Reference Example) Following Preparations 1, 2 and 3 and the method of Example 1 or 2 and using equivalent amounts of the appropriate starting materials, the following compounds are obtained. Where indicated, the compound is further confirmed by converting it into the indicated acid addition salt. 1-[2-(2,5-dichlorophenylthio)-
4-(4-chlorophenyl)-n-butyl]imidazole nitrate Melting point 155.5-157℃ 1-[2-(2,3-dichlorophenylthio)-
4-(4-chlorophenyl)-n-butyl]imidazole nitrate Melting point 136-139.5℃ 1-[2-(2-chlorophenylthio)-4-(4
-Chlorophenyl)-n-butyl]imidazole nitrate Melting point 136-136.5℃ 1-[2-(2-bromophenylthio)-4-(4
-Chlorophenyl)-n-butyl]imidazole nitrate Melting point 137-138℃ 1-[2-(2,6-dibromophenylthio)-
4-(4-chlorophenyl)-n-butyl]imidazole 1-[2-(2,4-dibromophenylthio)-
4-(4-chlorophenyl)-n-butyl]imidazole 1-[2-(2,4,6-trichlorophenylthio)-4-(4-chlorophenyl)-n-butyl]
Imidazole melting point 136-137℃, nitrate melting point 165-166℃ 1-[2-(2,5-dichlorophenylthio)-
4-(4-fluorophenyl)-n-butyl]-imidazole nitrate Melting point 128.5-131°C 1-[2-(2,3-dichlorophenylthio)-
4-(4-fluorophenyl)-n-butyl]-imidazole 1-[2-(2-chlorophenylthio)-4-(4
-fluorophenyl)-n-butyl]-imidazole nitrate Melting point 123-124°C 1-[2-(2-bromophenylthio)-4-(4
-fluorophenyl)butyl]imidazole 1-[2-(2,6-dibromophenylthio)-
4-(4-fluorophenyl)-n-butyl]imidazole 1-[2-(2,4-dibromophenylthio)-
4-(4-fluorophenyl)-n-butyl]imidazole 1-[2-(2,4,6-trichlorophenylthio)-4-(4-fluorophenyl)-n-butyl]
Imidazole nitrate melting point 163-164℃ 1-[2-(2,3,6-trichlorophenylthio)-4-(4-chlorophenyl)-n-butyl]
Imidazole nitrate melting point 138-142℃ (foaming) 1-[2-(2,3,4-trichlorophenylthio)-4-(4-chlorophenyl)-n-butyl]
Imidazole 1-[2-(2,3,5-trichlorophenylthio)-4-(4-chlorophenyl)-n-butyl]
Imidazole 1-[2-(2,3-dibromophenylthio)-
4-(4-chlorophenyl)-n-butyl]imidazole 1-[2-(2,5-dibromophenylthio)-
4-(4-chlorophenyl)-n-butyl]imidazole 1-[2-(2,6-difluorophenylthio)
-4-(4-chlorophenyl)-n-butyl]imidazole 1-[2-(2,5-difluorophenylthio)
-4-(4-chlorophenyl)-n-butyl]imidazole 1[2-(2,4-difluorophenylthio)-
4-(4-chlorophenyl)-n-butyl]imidazole 1-[2-(2-fluorophenylthio)-4-
(4-chlorophenyl)-n-butyl]imidazole 1-[2-(2,3-difluorophenylthio)
-4-(4-chlorophenyl)-n-butyl]imidazole 1-[2-(2,3,4-trichlorophenylthio)-4-(4-fluorophenyl)-n-butyl]
Imidazole 1-[2-(2,3,6-trichlorophenylthio)-4-(4-fluorophenyl)-n-butyl]
Imidazole 1-[2-(2,3,5-trichlorophenylthio)-4-(4-fluorophenyl)-n-butyl]
Imidazole 1-[2-(2,3-dibromophenylthio)-
4-(4-fluorophenyl)-n-butyl]imidazole 1-[2-(2,5-dibromophenylthio)-
4-(4-fluorophenyl)-n-butyl]imidazole 1-[2-(2-fluorophenylthio)-4-
(4-fluorophenyl)-n-butyl]imidazole 1-[2-(2,3-difluorophenylthio)
-4-(4-fluorophenyl)-n-butyl]imidazole 1-[2-(2,4-difluorophenylthio)
-4-(4-fluorophenyl)-n-butyl]imidazole 1-[2-(2,5-difluorophenylthio)
-4-(4-fluorophenyl)-n-butyl]imidazole and 1-[2-(2,6-difluorophenylthio)
-4-(4-fluorophenyl)-n-butyl]imidazole Example 4 (Reference example) 2.0 g of 1-[2-(2
To the stirred solution of -chlorophenylthio)-4-(4-chlorophenyl)-n-butyl]imidazole, nitric acid (70%; d=1.42) is added dropwise until precipitation is complete. The product was separated, washed with ether, air-dried, and recrystallized from ethyl acetate to give 1-[2
-(2-chlorophenylthio)-4-(4-chlorophenyl)-n-butyl]imidazole nitrate (melting point 136-136.5°C) is obtained. All compounds of formula () which take the base form in a similar manner can be prepared using suitable acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, propionic acid,
Glycolic acid, lactic acid, pyruvic acid, oxalic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, P- toluenesulfonic acid or salicylic acid)
It can be converted into an antibacterial acid addition salt by treatment with . Example 5 1-[2-(2,6-dichlorophenylthio)-4-(4-chlorophenyl) in 100 ml of ether
-n-butyl]imidazole nitrate is stirred with an excess of diluted potassium carbonate solution until the salt is completely dissolved. The organic layer was then separated, washed twice with water, dried over magnesium sulfate, and evaporated to form 1-[2-(2,6-dichlorophenylthio)-4-(4-chlorophenyl) after crystallization from cyclohexane.
-n-butyl]imidazole (melting point 68-70.5℃,
Foaming). All antimicrobial acid addition salts of compounds of formula () can be converted to the corresponding basic compounds in a similar manner. Example 6 The active compound can then be eg 1-[2-(2,
Using 6-dichlorophenylthio)-4-(4-chlorophenyl)-n-butyl]imidazole,
This book discusses formulation methods for typical drugs used to control fungi, bacteria, and protozoa. A. Topical preparation g Active compound 0.2-2 Span60 2 Tween60 2 Mineral oil 5 Petrolatum 10 Methylparaben 0.15 Propylparaben 0.05 BHA (butylated hydroxymanisole) 0.01 Water Amount to 100 Add all the above ingredients except water together. Heat to 60°C while stirring. Sufficient water at 60° C. is then added with vigorous stirring to give 100 g of cream, which is then cooled to room temperature. B. Intravenous (IV) formulation Active compound 0.5 g Propylene glycol 20 g Polyethylene glycol 400 20 g Tween 80 1 g 0.9 Saline Amount to make 100 ml The active compound is dissolved in propylene glycol, polyethylene glycol 400 and Tween 80.
Next, add a sufficient amount of 0.9% saline solution while stirring and
ml of IV solution, pass through a 0.2μ membrane, and package under aseptic conditions. C Oral preparation Parts by weight Active compound 200 Magnesium stearate 3 Starch 30 Lactose 116 PVP (polyvinylpyrrolidone) 3 The above ingredients are combined and granulated using methanol as a solvent. This preparation is then dried and processed into tablets (containing 200 mg of active compound) in a suitable tablet making machine.
Nasu. Example 7 The antibacterial activity of the compounds according to the invention is illustrated in the following test. A (Reference example) Trichophyton cultured for infection
Metagro-phytes are grown on agar slants of Sabouraud dextrose for 4 weeks at room temperature. Heat cornstarch in sterile distilled water to make a 2% solution. Approximately 7 ml of corn starch solution is added to each of the eight culture slants. Pipette the slant vigorously and swirl to form a microbial suspension. 10 guinea pigs (250-350g) (5 females)
The animals were divided into 10 experimental groups (5 males and 5 males). The day before challenge, all guinea pigs are clipped and shaved between the shoulder blades, taking care not to cause abrasions or lacerations. Apply a toothbrush dipped in the fungal suspension over a 1.5 cm x 1.5 cm area of the shaved area of each animal. Treatment with the test compound begins on the 3rd day after the attack and is continued once a day for 5 consecutive days.
Approximately 1 ml of the preparation is applied to the infected area using a tongue depressor for each treatment. Ten animals received no treatment;
Serve as untreated infected control. Remove hair from 10-20 infected areas of each guinea pig. The hairs are inoculated onto plates containing Mycosel agar. Each culture period for each animal (3 and 7 post-infection)
and 15 days).
Incubate the plate at room temperature (approximately 21℃) and inoculate it 7 days after inoculation.
Judgment will be made on the date.

[Table] ** Number of animals with positive culture results/Number of animals in group B 17-20g female Swiss/Webster
(Swiss/Webster) 0.25mg in 0.2ml volume for mouse
A suspension of β-estradiol is administered subcutaneously on days 1, 3, and 5 to induce estrus. Next 7
Give β-estradiol daily to maintain the oestrous period. Obtain clinical isolates from human sputum. The symptom for injection is Sabouraud dextrose agar (SDA)
Grow in a slant at 230℃ for 72 hours. On the day of challenge, add 2-3 ml of Sabouraud dextrose broth (SDB) to each slant of microorganisms.
Mix by pipetting to make a homogeneous suspension. The concentration of microorganisms for injection is approximately 10 ¹⁰ org/ml (2-3 ml of SDB is added to the microbial culture growing on the SDA slant). Seven days after the first estradiol injection, approximately 25 μl of the culture suspension is injected into the vagina of each mouse using a 20 gauge 2 mm round end feeding needle. Mice are treated with a cream or liquid formulation using a round-ended feeding needle, first 6 hours after challenge and then twice a day (6 hours apart). The fluid preparation is injected into the vagina until it overflows. Continue processing for 5 days. All animals are treated only once on day 5, allowing for incubation for the duration of the experiment (6 hours after treatment). Mice are cultured on day 4 post-challenge (6 hours post-treatment) and day 7 post-challenge (72 hours post-treatment). Culture is 18−20
Vaginal irrigation is obtained using approximately 0.1 ml of sterile distilled water using a 2 mm gauge round-ended feeding needle. cleaning solution
Contains 100μg/ml oxytetracycline
Inoculate into the SDB tube. This was heated to 48− at 30℃.
Incubate for 72 hours and then examine microscopically. Candida
albicans is confirmed by germ tube formation in sheep serum at 37°C.

[Table] Imidazole nitrate,
in cream

Claims (1)

[Claims] 1 1-[2-(2,6-dichlorophenylthio)
-4-(4-chlorophenyl)-n-butyl]imidazole and its antimicrobial acid addition salts. 2. The compound according to claim 1, wherein the antimicrobial acid addition salt is a nitrate. 3 1-[2-(2,6-dichlorophenylthio)
A composition for inhibiting the growth of fungi, bacteria, or protozoa, which contains -4-(4-chlorophenyl)-n-butyl]imidazole and its antimicrobial acid addition salt as an active ingredient. 4 1-[2-halo-4-(4-chlorophenyl)
-n-butyl]imidazole or its acid addition salt with 2,6-dichlorothiophenol or its salt and optionally converting the resulting compound into its acid addition salt; 1-[2-(2,6-dichlorophenylthio), characterized in that it is converted into the corresponding free compound.
-4-(4-chlorophenyl)-n-butyl]imidazole or an antimicrobial acid addition salt thereof. 5 1-Halo-2-(2,6-dichlorophenylthio)-4-(4-chlorophenyl)-n-butane and/or 1-(2,6-dichlorophenylthio)-2-halo- 4-(4-chlorophenyl)
1-[ 2-(2,
A method for producing 6-dichlorophenylthio)-4-(4-chlorophenyl)-n-butyl]imidazole or an antimicrobial acid addition salt thereof.