JPS6254768B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to compositions useful for inhibiting fungal or bacterial growth in humans and animals. More specifically, as the active compound the formula [In the formula, R is alkyl, phenyl or phenyl-
represents _C1 - _C4 alkyl, these phenyl groups may be substituted by halo, lower alkyl, lower alkoxy or trifluoromethyl; ^R1 is halo, lower alkyl, lower alkoxy,
1-[β-(R-thio)phenethyl]imidazole representing lower alkylthio or trifluoromethyl, and p is 1 or 2] or an acid addition salt thereof. Compositions useful for. As used herein and in the claims, the term "alkyl" means a saturated unbranched or branched acyclic hydrocarbon group containing 1 to 20 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl,
Refers to n-butyl, i-butyl, t-butyl, n-pentyl, n-heptyl, n-octyl, n-nonyl, n-dodecyl, n-octadecyl, etc. The term "lower alkyl" refers to an alkyl group as defined above containing 1 to 6 carbon atoms. The term "lower alkoxy" refers to a group having the formula lower alkyl-O-, where the lower alkyl substituents are as defined above. The term “phenyl”
" _C1 - _C4 alkyl" means that the alkyl moiety contains 1 to 4 carbon atoms, and representative examples thereof include benzyl, 3-phenylpropyl, and the like. The term "halo" as used herein refers to chloro, fluoro and brome. The term "acid addition salt" refers to inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid, or organic acids such as acetic acid,
Propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p - Refers to salts of the subject compound made with toluenesulfonic acid, salicylic acid, etc. All compounds of formula () have at least one asymmetric center, i.e.

[Formula] RS, H and

[Formula] has a carbon atom to which the moiety is attached. Accordingly, the compounds for use in the present invention may be prepared either in optically active form or in the form of a racemic mixture. Unless otherwise specified, all compounds described herein are in racemic form. However, the scope of the invention should not be viewed as limited to racemic forms, but is also intended to encompass the individual optical isomers of the compounds of formula. If necessary, the racemic intermediates or final products made herein are described, for example, in U.S. Pat.
3717655 and 3839574, or of diastereomeric salts of the formula The diastereomeric ester produced by the reaction of the racemic alcohol precursor of the compound () with an optically active acid can be separated into its optical antipodes by, for example, fractional crystallization. Good examples of such optically active acids are 10-sulfonic acid, α-bromo-π-sulfonic acid, 10-sulfonic acid, menthoxyacetic acid, tartaric acid, malic acid, diacetylacetic acid, and pyrrolidone-5-carboxylic acid. It is in active form. The resolved pure diastereomeric salts or esters can then be cleaved by standard means to yield the respective optical isomers of the compound of formula ( ) or precursor alcohol. A particularly suitable subgroup of compounds in the group defined by formula () is in which R ¹ is halo;
R is alkyl, phenyl, substituted phenyl, phenyl- _C1 - _C4 alkyl or halo-substituted phenyl-
It is _C1 - _C4 alkyl. Particularly suitable compounds in the above group are those in which [R ¹ ] _p is monohalo or dihalo, R is alkyl containing 1 to 12 carbon atoms, benzyl, chloro or fluoro-substituted benzyl, phenyl and chloro-substituted phenyl. Particularly most preferred compounds are those in which [R ¹ ] _p represents 2,4-dichloro, 2,4-dibrome or 2,4-difluoro. Compounds of formula () exhibit antifungal and antibacterial activity. For example, these compounds are effective against human and animal pathogens such as Microsporum audouini, Microsporum gypseum, Microsporum gypseum canis, Epidermophyton floccosum, Trichophyton menta Trichophyton mentagrophytes, Trichophyton rubrum, Trichophyton tonsurans, Candida albicans
It exhibits antifungal activity against Cryptococcus albicans) and Cryptococcus neoformans. Compounds of the formula are also used primarily in fungi of agricultural importance, such as Aspergillus flavus.
flavus), Cladosporium herbarum, Fusarium graminearum
graminearum), Penicillium notatum (Penicillium
notatum), Aspergillus niger, Penicillium oxalicum, Penicillium spinulosum, and Pithomyces
It exhibits antifungal activity against P. chartarum). Moreover, the compounds of the formula are compatible with human and animal pathogens, such as Staphylococcus aureus, Streptococcus faecalis, Corynebacterium acnes, Eyrysipelothrix insidiosa, Escherichia coli (Escherichia coli), Proteus vulgaris (Proteus vulgaris)
vulgaris), Salmonella cholerasuis, Pasteurella multocida
It exhibits antibacterial activity against Pseudomonas aeruginosa and Pseudomonas aeruginosa. Because of the aforementioned activities, the compounds of the formula prove to be useful antimicrobial agents having not only pharmaceutical applications but also agricultural and industrial applications. Accordingly, the present invention provides pharmaceutical, agricultural, and industrial compositions comprising a compound of formula () in combination with a suitable carrier. In pharmaceutical applications, the compositions may be tablets, capsules, powders, suppositories, solutions, suspensions, creams,
It may be solid, semi-solid, or liquid in the form of lotions, ointments, etc. Pharmaceutically acceptable non-toxic carriers or excipients commonly used in solid formulations include tricalcium phosphate, calcium carbonate, kaolin, bentonite, talc, gelatin, lactose, starch, etc.; Examples include polyalkylene glycols, petrolatum and other cream bases; for liquid formulations, examples include water, oils of vegetable origin, and low boiling solvents such as isopropanol, hydrogenated naphthalenes, etc. It will be done. Pharmaceutical compositions containing a compound of formula may be subjected to conventional pharmaceutical expedients such as sterilization and may be treated with conventional pharmaceutical auxiliaries such as preservatives, stabilizers, emulsifiers, and for regulating osmotic pressure. Salts and buffers may be included. The composition may also include other therapeutically active substances. In pharmaceutical applications, the compositions of the present invention are administered to humans and animals in a conventional manner.
For example, it can be administered topically, orally, parenterally, etc. For oral administration, a compound of formula
In dosages from about 12.5 mg to about 1000 mg per serving, alone or in admixture with a suitable carrier (70
(assuming a host subject of Kg), can be administered once or more daily over a period of several days to many weeks. Suppositories can contain from about 1 mg to 500 mg of active compound. Particularly good for topical application. For such treatments, the area containing any fungal or bacterial growth present;
Alternatively, the area to be protected against fungal or bacterial attack can be treated with the compositions of the invention, for example by dusting, liquid dusting, spraying, washing, brushing, dipping, smearing, coating, impregnating and the like. Compositions containing compounds of formula exhibit antifungal and antibacterial activity over a wide range of concentrations, eg, from about 0.1 to 10.0% by weight of the composition. in any case,
The composition to be administered will contain a certain amount of a compound of formula in an amount effective for alleviating or preventing the particular condition being treated. The precise control over the drug administration of the compositions described herein necessarily depends on the individual subject being treated, the type of treatment, e.g. prophylactic or therapeutic, the type of organism involved, and, of course, the attending physician. will depend on the judgment of In agricultural applications, compounds of the formula can be applied directly to plants (eg, seeds, leaves) or to the soil. For example, a compound of the formula can be applied alone or in a mixture with a powdered solid carrier. Typical powder carriers are various mineral silicates, such as mica,
These are talc, pyrophyllite, and clay. The compounds of the formula can also be applied to seeds in a mixture with conventional surface-active wetting agents, with or without additional solid carriers. Surface-active wetting agents that can be used are either conventionally anionic, non-anionic, or cationic. For soil treatment against fungi, etc., the compound of the formula may be mixed with sand, earth or a powdered solid carrier, such as mineral silicates, and applied as a dust with or without additional surfactants. Alternatively, the compounds of the formula can be applied as an aqueous spray, optionally containing a surface-active dispersant and a powdered solid carrier. As a foliar treatment, the compounds of the formula can be applied to growing plants as an aqueous spray containing a surface-active dispersant, with or without a powdered solid carrier and a hydrocarbon solvent. In industrial applications, compounds of the formula can be used to control bacteria and fungi by contacting the compounds with pathogens in a known manner. Materials capable of supporting bacteria and fungi can be protected by contacting, mixing or impregnating these materials with compounds of the formula. To enhance their effectiveness, the compounds of the formula can be combined with other pest control agents such as fungicides, fungicides, insecticides, acaricides and the like. A particularly important industrial/agricultural use of the compositions of the invention is as a food preservative against bacteria and fungi that cause food deterioration and spoilage. Compounds of formula can be prepared by the following reaction sequence: where R, R ¹ and p are as defined above and X is a conventional leaving group, e.g. chloro, bromo or a reactive ester group, e.g. CH ₃ -S(O) ₂
-O or p -CH ₃ -C ₆ H ₄ -S(O) ₂ -O-
represents. 1-[β-(R-thio)phenethyl]imidazoles of the formula are made by condensing compounds of the formula with the thiols listed in the table. In the condensation, the starting materials and reagents are brought into contact in any convenient manner and maintained at a temperature for a time sufficient to drive the reaction to completion.
Furthermore, the reaction products, as well as the reaction conditions themselves, can be evaluated using methods commonly used or known in the art for carrying out such or similar reactions. It can be isolated and collected from the reaction product.
There is no particular restriction on the type of leaving group (X), its selection being determined by the relative reaction rates known for this type of reaction. The chlor, bromo, and two ester groups mentioned above are given as typical examples only. Generally, the reaction of a compound of formula with a compound of formula (wherein R is alkyl or substituted or unsubstituted phenyl- _C1 - _C4 alkyl) is carried out in an inert organic solvent such as tetrahydrofuran, ether, menthanol, etc. In the presence of
It is then carried out in the presence of sodium hydride or other suitable base at a temperature of 20 to 66°C for 30 minutes to 24 hours. The reaction of a compound of formula with a compound of formula where R is phenyl or substituted phenyl is carried out in the presence of an inert organic solvent such as acetone, methanol, etc. and in the presence of potassium carbonate or other suitable base. in the presence of reflux for 30 minutes to 12 hours. Although a compound of formula can be isolated as the free base,
Since many of the basic forms of the compounds are oily or gummy, it is more convenient to isolate and identify the compounds as acid addition salts. These salts are prepared in conventional manner, ie by reaction of a basic compound with a suitable inorganic or organic acid. If desired, the salt can be readily converted to the basic form of the compound by treatment with an alkali such as potassium carbonate, sodium carbonate, or sodium or potassium hydroxide. Starting materials of the formula (wherein R ¹ is methyl, methoxy or halo) are described in US Pat. No. 3,679,697, along with their method of preparation. Compounds of formula (wherein R ¹ is a group other than that described in the above patent) can be prepared in a similar manner, i.e. by bromination of a suitable acetophenone, and reaction of the resulting 2-bromoacetophenone compound with imidazole. , reduction of the obtained 2-(1-imidazolyl)acetophenone compound with sodium tetrahydroborate, and finally reaction of the obtained 1-imidazole ethanol compound with thionyl halide to obtain a 1-(β-halofenethyl)imidazole compound of formula It can be manufactured by generating. The following Example A describes and illustrates the preparation of starting compounds of the formula, and Examples 1-11 the preparation of compounds of the formula. Example A 4-mercaptoacetophenone in 50 ml of acetone
A mixture of 1.52 g, 4-methoxybenzyl chloride, 1.72 g, and anhydrous potassium carbonate, 1.5 g, was stirred under nitrogen and brought to reflux. After 4 hours, the solvent and excess 4-methoxybenzyl chloride are evaporated under vacuum and water is added to the residue. The aqueous mixture obtained is extracted with ether, the ether extract is washed with water, dried over magnesium sulphate and evaporated to dryness. The resulting residue is recrystallized from cyclohexane to obtain 4-(4'-methoxybenzylthio)-acetophenone. Similarly, 4-methoxybenzyl chloride can be combined with other aralkyl halides or with at least one substituent selected from the group consisting of halo, lower alkyl, lower alkoxy, trifluoromethyl, nitro and cyano on the aryl moiety. When substituted with a substituted aralkyl halide, the corresponding substituted aralkylthioacetophenone can be made. The starting compounds of formula are prepared from the above-described substituted alkylthioacetophenones according to the method of US Pat. No. 3,679,697. Example 1 (A) A mixture of 1 g of 1-(2.4.β-trichlorophenethyl)imidazole, 1.8 g of 3.4-dichlorothiophenol and 1.5 g of potassium carbonate in 500 ml of acetone is stirred and refluxed for 4 hours. Evaporate the solvent in vacuo and add 20% water to the residue.
Add ml. The resulting aqueous mixture is extracted with ether and the ether extract is washed with 50 ml of saturated sodium chloride solution. The organic phase is dried over magnesium sulfate and evaporated to give 1-[2,4-dichloro-β-(3',4'-dichlorophenylthio)phenethyl]imidazole. The free base oxalate salt is prepared by adding ethereal oxalic acid dropwise to the free base in ether until precipitation ceases. The product was collected and recrystallized from a mixture of acetone and ethyl acetate to give 1-[2,4-dichloro-β-
(3′,4′-dichlorophenylthio)phenethyl]imidazole oxalate, melting point 161.5−
163.5℃ is obtained. (B) Similarly, instead of 1-(2.4.β-trichlorophenethyl)imidazole, other starting materials of the formula, such as 1-(β-chlorophenethyl)imidazole, 1-(β-chloro-4 -ethylphenethyl)
Imidazole, 1-(β-chloro-4-t-butylphenethyl)imidazole, 1-(β-chloro-4-ethoxyphenethyl)imidazole, 1-(β-chloro-4-n-butoxyphenethyl)imidazole , 1-(β-chloro-4-t-butoxyphenethyl)imidazole, 1-(4·β-dichlorophenethyl)imidazole, 1-(3·4·β-trichlorophenethyl)
Imidazole, 1-(4-bromo-β-chlorphenethyl)
Imidazole, 1-(2,4-dibromo-β-chlorophenethyl)imidazole, 1-(β-chloro-4-fluorophenethyl)imidazole, 1-(β-chloro-2,4-difluorophenethyl)imidazole , 1-(β-chloro-2-trifluoromethylphenethyl)imidazole, 1-(β-chloro-4-trifluoromethylphenethyl)imidazole, and, for example, the following 1-[β- (3′・
4'-Dichlorophenylthio)phenethyl]imidazoles can be prepared and the products are identified as acid addition salts by treatment with the appropriate acid in a conventional manner: 1-(4-tert-butyl-β -(3′,4′-dichlorophenylthio)phenethyl]imidazole,
Nitrate, decomposed at 142.5-146.5℃, 1-[3,4-dichloro-β-(3',4'-dichlorophenylthio)phenethyl]imidazole, nitrate, decomposed at 133-137℃, 1-[2. 4-Dibromo-β-(3',4'-dichlorophenylthio)phenethyl]imidazole, nitrate, decomposed at 132.5-134.5℃, 1-[2,4-dibromo-β-(3',4'-dichlorophenylthio)phenethyl] Rolfenylthio) phenethyl imidazole, oxalate salt, decomposes at 172.5-175°C. (c) Similarly, instead of 3,4-dichlorothiophenol, other starting materials of the formula, such as 4-
Using chlorothiophenol and 2,4-dichlorothiophenol and using the above starting compounds of formula, for example the following 1-[β-
(R-thio)phenethyl]imidazoles, which are identified as acid addition salts by treatment with the appropriate acid in a conventional manner: 1-[β-(4'-chlorophenylthio ) Phenethyl] imidazole, oxalate, 147.5−149
decomposed at 190-191°C, 1-[4-chloro-β-(4'-chlorophenylthio)phenethyl]imidazole, oxalate, decomposed at 190-191°C, 1-[2,4-dichloro-β-(4 '-Chlorphenylthio)phenethyl]imidazole, nitrate decomposed at 169.5-170℃, 1-[2,4-dichloro-β-(2',4'-dichlorophenylthio)phenethyl]imidazole, nitrate, melting point 150 -151℃, 1-[3,4-dichloro-β-(4'-chlorophenylthio)phenethyl]imidazole, nitrate decomposed at 123-125.5℃, 1-[3,4-dichloro-β-(2')・4'-Dichlorophenylthio)phenethyl]imidazole, oxalic acid decomposes at 169-171.5℃. Example 2 (A) 1-(2・4・β in 10ml of tetrahydrofuran
A solution of 1 g of -trichlorophenethyl)imidazole is added to a mixture of 1 g of 2,4-dichlorobenzylmercaptan and 220 mg of a 56% sodium hydride dispersion in 40 ml of tetrahydrofuran. After stirring for 12 hours at room temperature, the solvent is evaporated in vacuo and 10 ml of water are added to the residue. The resulting aqueous mixture is extracted with ether and the ether extract is washed with 50 ml of saturated sodium chloride solution. The organic phase was dried over magnesium sulfate and evaporated to give 1-[2,4-dichloro-β-(2'.
4'-Dichlorobenzylthio)phenethyl]imidazole is obtained. The nitrate salt of the free base is made by adding nitric acid dropwise to the free base in ether until precipitation is complete. The product was collected by filtration and recrystallized from ethyl acetate to yield 1-[2,4-dichloro-β-(2',4'-dichlorobenzylthio).
Phenethyl imidazole nitrate, decomposition point
133.5−134.5℃ is obtained. (B) Similarly, other starting materials of formula i.e. Example 1
For example, the following 1-[β-(2',4'-dichlorobenzylthio)phenethyl]imidazole can be prepared by substituting those listed in paragraph B of Upon treatment, it is identified as an acid addition salt: 1-[3,4-dichloro-β-(2',4'-dichlorobenzylthio)phenethyl]imidazole, nitrate decomposed at 107-110°C. (C) Similarly, instead of 2,4-dichlorobenzylmercaptan, other starting materials of the formula, such as 4-chlorobenzylmercaptan, 3,4-
Using dichlorobenzyl mercaptan or heptyl mercaptan and using starting materials of the formula listed in paragraph B of Example 1,
For example, the following 1-[β-(R-thio)phenethyl]imidazoles can be prepared and identified as acid addition salts by treatment with the appropriate acid in a conventional manner: 1-[4-t- Butyl-β-(4'-chlorobenzylthio)phenethyl]imidazole, oxalate decomposes at 156-158.5°C, 1-[4-n-butoxy-β-(4'-chlorobenzylthio)phenethyl]imidazole, nitrate Decomposed at 113-114°C, 1-[4-n-butoxy-β-(n-heptylthio)phenethyl]imidazole, oxuate
Decomposed at 124.5-130℃, 1-[4-chloro-β-(4'-chlorobenzylthio)phenethyl]imidazole, oxalate
Decomposes at 148-149.5℃, nitrate melting point 103.5-105.5
°C, 1-[2,4-dichloro-β-(4'-chlorobenzylthio)phenethyl]imidazole, nitrate, melting point 130.5-132 °C, acute oral toxicity (rat; mouse) (LD ₅₀ ) > 3200 mg/Kg, 1-[2,4-dichloro-β-(3',4'-dichlorobenzylthio)phenethyl]imidazole, nitrate decomposed at 95-96.5℃, 1-[2,4-dichloro-β-(n-heptylthio) ) Phenethyl] imidazole, oxalate, melting point 106-109°C, acute oral toxicity (rat;
Mouse) (LD ₅₀ )>3200mg/Kg, 1-[3,4-dichloro-β-(4'-chlorobenzylthio)phenethyl]imidazole, oxalate, decomposed at 174-175℃, 1-[3.4 -Dichloro-β-(3'-4'-dichlorobenzylthio)phenethyl]imidazole, oxalate, decomposed at 176-177.5℃, 1-[2,4-dibrome-β-(4'-chlorobenzylthio) ) Phenethyl]imidazole, nitrate decomposed at 126.5-128℃, 1-[2,4-difluoro-β-(3',4'-dichlorobenzylthio)phenethyl]imidazole, oxalate decomposed at 89.5-93.5℃, 1- [2-trifluoromethyl-β-(3′・
4'-Dichlorobenzylthio)phenethyl]imidazole, nitrate decomposed at 134.5-137℃. Example 3 1-(2.4.β-trichlorophenethyl)imidazole and 1-
(3.4.β-trichlorophenethyl)imidazole and 4-trifluoromethylthiophenol, 4-chloro-
3-trifluoromethylthiophenol, 3.
Repeating the process described in paragraph A of Example 1 using 4,5-trichlorothiophenol and pentachlorothiophenol yields e.g.
-[β-(R-thio)phenethyl]imidazoles can be prepared and these are identified as acid addition salts by treatment with the appropriate acid in a conventional manner: 1-[2,4-dichloro-β- (4'-trifluoromethylphenylthio)phenethyl]imidazole, oxalate decomposed at 178-178.5℃, 1-[2,4-dichloro-β-(4'-chloro-
3'-Trifluoromethylphenylthio)phenethyl]imidazole, oxalate decomposed at 186-187.5℃, 1-[2,4-dichloro-β-(3',4',5'-trichlorophenylthio)phenethyl [Imidazole, nitrate decomposed at 178-185.5℃, 1-[2,4-dichloro-β-(pentachlorphenylthio)phenethyl]imidazole, nitrate
201-202.5℃ decomposition, 1-[3,4-dichloro-β-(4'-trifluoromethylphenylthio)phenethyl]imidazole, oxalate 170-171℃ decomposition, 1-[3,4-dichloro- β-(4′-chlor-
3′-Trifluoromethylphenylthio)phenethyl]imidazole, oxalate decomposed at 165-166℃. Example 4 The procedure described in paragraph A of Example 2 is repeated, but instead of 2,4-dichlorobenzylmercaptan other starting materials of the formula are used, such as ethylmercaptan, pentylmercaptan, octylmercaptan, nonylmercaptan, dodecylmercaptan, ocdadecyl mercaptan, 3-phenylpropyl mercaptan, 3-hexyl mercaptan, benzyl mercaptan, 4-methylbenzyl mercaptan, 4-t-butylbenzyl mercaptan, 4-trifluoromethylbenzyl mercaptan, 4-methoxybenzyl mercaptan, 3.4 -5-trimethoxybenzyl mercaptan, 4-n-butoxybenzyl mercaptan, 2,4,5-trichlorobenzyl mercaptan, 4-bromobenzyl mercaptan, and 4-fluorobenzyl mercaptan, For example, the following 1-[ 2,4-Dichloro-β-(R-thio)phenethyl]imidazoles can be prepared and are identified as acid addition salts by treatment with the appropriate acid in a conventional manner. : 1-[2,4-dichloro-β-(n-pentylthio)phenethyl]imidazole, oxalate, 99
Aggregated at °C, 1-[2,4-dichloro-β-(n-octylthio)phenethyl]imidazole, oxalate melting point
101.5-103.5℃, 1-[2,4-dichloro-β-(n-nonylthio)phenethyl]imidazole, oxalate,
Gelled at 82.5°C, 1-[2,4-dichloro-β-(n-dodecylthio)phenethyl]imidazole, oxalate melting point
124.5℃, 1-[2,4-dichloro-β-(octadecylthio)phenethyl]imidazole, oxalate,
Gelled at 91.5-150°C, 1-[2,4-dichloro-β-(3-phenylpropylthio)phenethyl]imidazole, oxalate, mp 87.5-90°C, 1-[2,4-dichlor -β-(cyclohexylthio)phenethyl]imidazole, nitrate, melting point
114.5-117.5℃, 1-[2,4-dichloro-β-(cyclohexylmethylthio)phenethyl]imidazole, oxalate decomposed at 122.5-140℃, 1-[2,4-dichloro-β-(cyclohexylethylthio) Phenethyl]imidazole, oxalate Decomposes at 104-108.5℃, 1-[2,4-dichloro-β-(allylthio)phenethyl]imidazole, oxalate, melting point 84.5
-123℃, 1-[2,4-dichloro-β-(2-octenylthio)phenethyl]imidazole, oxalate,
Melting point 112.5-116.5℃, 1-[2,4-dichloro-β-(3-phenyl-
2-propenylthio)phenethyl]imidazole, oxalate, decomposed at 151-160.5°C, 1-[2,4-dichloro-β-(4'-chlorophenyl)-2-propenylthio)-phenethyl]imidazole, nitrate, Decomposed at 123-126℃, 1-[2,4-dichloro-β-(3-hexynylthio)phenethyl]imidazole, oxalate,
Melting point 90.5-95℃, 1-[2,4-dichloro-β-(2-octynylthio)phenethyl]imidazole, oxalate
Decomposed at 118-119.5℃, 1-[2,4-dichloro-β-(benzylthio)
Phenethyl imidazole, nitrate, melting point 110−
112℃, 1-[2,4-dichloro-β-(4'-methylbenzylthio)phenethyl]imidazole, nitrate,
Melting point 110.5-112℃, 1-[2,4-dichloro-β-(4'-t-butylbenzylthio)phenethyl]imidazole, nitrate 162.5-163℃ decomposition, 1-[2,4-dichloro-β-( 4'-Trifluoromethylbenzylthio)phenethyl]imidazole, nitrate decomposed at 112-114℃, 1-[2,4-dichloro-β-(4'-methoxybenzylthio)phenethyl]imidazole, nitrate
Decomposition at 118-119.5℃, 1-[2,4-dichloro-β-(3',4',5'-trimethoxybenzylthio)phenethyl]imidazole, oxalate gelation at 147℃, 1-[2,4 -dichloro-β-(4'-n-butoxybenzylthio)phenethyl]imidazole,
Decomposed at 106.5-108.5℃, 1-[2,4-dichloro-β-(2',4',5'-trichlorobenzylthio)phenethyl]imidazole, nitrate decomposed at 172.5-173.5℃, 1-[2,4- Dichloro-β-(4'-brombenzylthio)phenethyl]imidazole, nitrate
137-138℃ decomposition, and 1-[2,4-dichloro-β-(4'-fluorobenzylthio)phenethyl]imidazole, nitrate
104.5-107.5℃ decomposition, 1-[2,4-dichloro-β-(4'-nitrobenzylthio)phenethyl]imidazole, nitrate
129.5-132℃ decomposition, 1-[2,4-dichloro-β-(4'-cyanobenzylthio)phenethyl]imidazole, nitrate
Decomposed at 119.5−123℃. Example 5 1-(4·β-dichlorophenylethyl)imidazole and 1-(2·
4-β-trichlorophenethyl)imidazole and instead of 3,4-dichlorothiophenol other starting materials of the formula, such as thiophenol, 4-methylthiophenol, 4-methoxythiophenol, 3-methoxy Repeating the method described in paragraph A of Example 1 using thiophenol 2-chlorothiophenol, 3-chlorothiophenol 2,5-dichlorothiophenol 4-bromothiophenol, and 4-fluorothiophenol. , for example, the following 1-[4-chlor-
β-(R-thio)phenethyl]imidazole and 1-[2,4-dichloro-β-(R-thio)phenethyl]imidazole can be produced,
These are then identified as acid addition salts by treatment with the appropriate acid in a conventional manner: 1-[4-chloro-β-(phenylthio)phenethyl]imidazole, oxalate, decomposed at 166-167°C, 1 -[4-Chlor-β-(2-naphthylthio)phenethyl]imidazole, oxalate Melting point
193.5-194℃, 1-[4-chloro-β-(4'-methylphenylthio)phenethyl]imidazole, oxalate
199.5-200℃ decomposition, 1-[4-chloro-β-(4'-methoxyphenylthio)phenethyl]imidazole, oxalate
177-178℃ decomposition, 1-[4-chloro-β-(3'-methoxyphenylthio)phenethyl]imidazole, oxalate melting point 164.5-165.5℃, 1-[4-chloro-β-(2'- Chlorphenylthio)phenethyl]imidazole, oxalate melting point
177-178℃, 1-[4-chloro-β-(3'-chlorophenylthio)phenethyl]imidazole, oxalate melting point
169.5-171.5°C, 1-[4-chloro-β-(2',5'-dichlorophenylthio)phenethyl]imidazole, oxalate Melting point 181.5-183.5°C, 1-[4-chloro-β-(4 ′-bromphenylthio)phenethyl]imidazole, oxalate 185
-186.5°C decomposition, 1-[4-chloro-β-(4'-fluorophenylthio)phenethyl]imidazole, oxalate melting point 182.5-183°C, 1-[4-chloro-β-(4'-nitro Phenylthio)phenethyl]imidazole, oxalate melting point
203-204.5°C, 1-[4-chloro-β-(4'-acetamidophenylthio)phenethyl]imidazole, oxalate melting point 149.5-152°C. Example 6 1-[4-chloro-β-(4'-aminophenylthio)phenethyl]imidazole oxalate in 20 ml of tetrahydrofuran containing 1 ml of triethylamine.
Add 0.5 ml of hexanoyl chloride to the 400 mg solution.
After stirring for 30 minutes at room temperature, the solvent is evaporated under vacuum and aqueous potassium carbonate solution is added to the residue. The resulting aqueous mixture is extracted with dichloromethane and the organic phase is acidified with oxalic acid. The precipitated product was separated and recrystallized from a mixture of acetone and ethyl acetate to give 1-[4-chloro-β-(4'-hexanoylaminophenylthio)phenethyl]imidazole oxalate, mp 98.5-102. Get ℃. Similarly, if other acid chlorides such as propionyl chloride, n-valeryl chloride, decanoyl chloride, etc. are used in place of hexanoyl chloride, the corresponding 1-[4-chloro-β-(4'-propionylaminophene phenethyl]imidazole oxalate, 1-[4-chloro-β-(4'-valeroylaminophenylthio)phenethyl]imidazole oxalate, 1-[4-chloro-β-(4'-deca Noylaminophenylthio)phenethyl imidazole oxalate, etc. can be made. Example 7 1-[4-chloro-β-(4'-chlorophenylthio)phenethyl]imidazole nitrate (1 g)
is treated with aqueous potassium carbonate until a pH of about 11 is obtained, yielding the free base, 1-[4-chloro-β-(4'-chlorophenylthio)phenethyl].
The imidazole separates and is extracted with dichloromethane. The extract is dried over magnesium sulphate and evaporated. To the resulting residue, reduce it to 0
Dissolve in 50 ml of chloroform at ℃, and slowly add a solution of 700 mg of 85% m-chloroperbenzoic acid in 50 ml of chloroform while stirring. Once the addition is complete, continue stirring at 0°C for approximately 3 hours. The reaction mixture is then washed with aqueous potassium carbonate and sodium chloride solutions, dried over magnesium sulphate and evaporated. Crystallization of the residue from benzene yields 1-[4-chloro-β-
(4'-Chlorphenylsulfinyl)phenethyl]imidazole, melting point 139-140°C, is produced, which is further characterized as the oxalate salt, melting point 167-167.5°C. Similarly, 1-[β-(R
-thio)phenethyl]imidazole salt, the corresponding 1-[β-(R-
Sulfinyl)phenethyl]imidazoles are prepared and can be further characterized by conversion into the indicated acid addition salts by conventional methods. For example, 1-[2,4-dichloro-β-(n-dodecylsulfinyl)phenethyl]imidazole, oxalate decomposed at 134-138°C, 1-[4-chloro-β-(4'-chlorobenzylsulfinyl)] phenyl) phenethyl] imidazole, nitrate
161.5−162℃ decomposition, etc. Example 8 1-[4-(Chlor-β-(4'-chlorophenylthio)phenethyl]imidazole nitrate (1 g)
is treated with aqueous potassium carbonate until a pH of about 11 is obtained, resulting in the free base, i.e. 1-[4-chloro-
β-(4'-Chlorphenylthio)phenethyl]imidazole is separated and extracted with dichloromethane. The extract is dried over magnesium sulphate and evaporated. The resulting residue was dissolved in 50 ml of chloroform at room temperature, and 1.7 g of 85% m-chloroperbenzoic acid was added in 50 ml of chloroform while stirring.
Slowly add the solution. Once the addition is complete, continue stirring at room temperature for about 24 hours. The reaction mixture is then washed with aqueous potassium carbonate and sodium chloride solutions, dried over magnesium sulphate and evaporated. Crystallization of the residue from benzene gives 1-[4-chloro-β-(4'-chlorophenylsulfonyl)phenethyl]imidazole, mp 176-178.5°C. Similarly, 1-[β-(R
-thio)phenethyl]imidazole or acid addition salt, the corresponding 1-
[β-(R-sulfonyl)phenethyl]imidazole can be prepared and these can be further characterized by conversion into the indicated acid addition salts by conventional methods, e.g. 1-[2.4 -dichloro-β-(dodecylsulfonyl)phenethyl]imidazole, oxalate
105.5-110℃ decomposition, 1-[4-chloro-β-(4'-chlorobenzylsulfonyl)phenethyl]imidazole, nitrate
181℃ decomposition, etc. Example 9 A chloroform solution of 85% m-chloroperbenzoic acid (2 g/100 ml) was added to 1-[β
-Chloro-4-methylthiophenethyl]imidazole is added dropwise over the course of 1 hour to a stirred solution of 2.53 g of imidazole at 0°C. After 6 hours, the resulting solution is washed with aqueous potassium carbonate solution and water. The organic phase is separated and dried over magnesium sulphate. Evaporation of the solvent yields 1-[β-chloro-4-methylsulfinylphenethyl]imidazole. Similarly, in place of 1-[β-chloro-4-methylthiophenethyl]imidazole, other 1-
[β-chloro-thiophenethyl]imidazole,
For example, 1-[β-chloro-4-t-butylthiophenethyl]imidazole, 1-[β-chloro-4-benzylthiophenethyl]imidazole, 1-[β-chloro-4-(4'- Chlorbenzylthio)phenethyl]imidazole, 1-[β-chloro-4-(4'-methoxybenzylthio)phenethyl]imidazole, 1-[β-chloro-4-phenylthiophenethyl]imidazole, and 1- [β-chloro-4-(4'-chlorophenylthio)phenethyl]imidazole can be used. Example 10 Using 3,4-dichlorothiophenol as the starting material of the formula and replacing 1-(2,4.β-trichlorophenethyl)imidazole with other starting materials of the formula, e.g. -Chlor-4-methylthiophenethyl)imidazole, 1-(β-chloro-4-t-butylthiophenethyl)imidazole, 1-(β-chloro-4-benzylthiophenethyl)imidazole, 1- [β-chloro-4-(4′-chlorobenzylthio)phenethyl]imidazole, 1-[β-chloro-4-(4′-methoxybenzylthio)phenethyl]imidazole, 1-(β-chloro-4-phenethyl) enylthiophenethyl)imidazole, 1-[β-chloro-4-(4′-chlorophenylthio)phenethyl]imidazole, 1-(β-chloro-4-methylsulfinylphenethyl)imidazole, 1 -(β-chloro-4-t-butylsulfinylphenethyl)imidazole, 1-(β-chloro-4-benzylsulfinylphenethyl)imidazole, 1-[β-chloro-4-(4 The procedure described in paragraph A of Example 1 is repeated using phenethyl]imidazole, '-chlorobenzylsulfinyl). Example 11 Using 4-chlorobenzyl mercaptan as the starting material of the formula and replacing 1-(2.4.β-trichlorophenethyl)imidazole with other starting materials of the formula, i.e. the formula listed in Example 10. The method described in paragraph A of Example 2 is repeated using starting material of . Example 12 The process described in Example 7 is repeated with the products obtained in Examples 10 and 11. (using appropriate amount of m-chloroperbenzoic acid). Example 13 The process described in Example 8 is repeated with the products obtained in Examples 10 and 11. Example 14 By repeating the procedure described in Example 1 using the desired specific 1-[β-(R-thio)phenethyl]imidazole reactant, one can make e.g. the following compounds, which are , is identified as an acid addition salt by treatment with the appropriate acid in a conventional manner: 1-[2,4-dichloro-β-(4'-nitro-
3′-Trifluoromethylphenylthio)phenethyl]imidazole, nitrate decomposed at 127.5-130.5℃, 1-[4-trifluoromethyl-β-(4′-tert
-Butylphenylthio)phenethyl]imidazole, oxalate melting point 161-162°C 1-[2,4-dimethyl-β-(3',4'-dichlorophenylthio)phenethyl]imidazole, nitrate 165.5-166°C Decomposition, 1-[4-methoxy-β-(3',4'-dichlorophenylthio)phenethyl]imidazole, oxalate melting point 145.5°C, 1-[4-methoxy-β-(4'-tert-butyl) Phenylthio)phenethyl]imidazole, oxalate Melting point 139.5-141.5℃ 1-[2,4-dimethoxy-β-(3',4'-dichlorophenylthio)phenethyl]imidazole,
Nitrate 155.5-158℃ decomposition, 1-[4-nitro-β-(pentachlorophenylthio)phenethyl]imidazole, nitrate 163.5
~165.5°C decomposition, 1-[2,4-dichloro-β-(n-butoxyphenylthio)phenethyl]imidazole, oxalate melting point 143-144°C, 1-[4-cyano-β-(pentachlorphene) nilthio)phenethyl]imidazole, nitrate, melting point
182.5-183.5°C (foaming), 1-[4-n-butylthio-β-(4'-chlorophenylthio)phenethyl]imidazole, oxalate, decomposed at 159-162°C, and 1-[4- Methylthio-β-(3′,4′-dichlorophenylthio)phenethyl]imidazole, oxalate, decomposes at 146-148.5°C. Example 15 Repeating the procedure described in Example 2 using the reactants specified by the desired specific 1-[β-(R-thio)phenethyl]imidazole, one can make e.g. is identified as an acid addition salt by treatment with the appropriate acid in a conventional manner: 1-[2,4-difluoro-β-(n-nonylthio)phenethyl]imidazole, oxalate melting point
79.5-84℃, 1-[2,4-dimethyl-β-(4'-chlorobenzylthio)phenethyl]imidazole, oxalate 80.5-83℃ decomposition, 1-[4-methoxy-β-(3-ph) enylpropylthio)phenethyl]imidazole, oxalate melting point 75-83°C, 1-[4-methoxy-β-(n-dodecylthio)
Phenethyl imidazole, oxalate melting point 90−
93℃, 1-[2,4-dichloro-β-(1'-naphthylmethylthio)phenethyl]imidazole, oxalate 86℃ melting point, 86-121.5℃ foaming, 1-[4-chloro-β-(ethylthio) Phenethyl]imidazole, oxalate, melting point 157-158°C, 1-[2,4-dichloro-β-(n-undece-
10-Nylthio)phenethyl]imidazole, oxalate melting point 82-107°C, 1-[2,4-dichloro-β-(3-(4'-methylphenyl)propen-2-ylthio)phenethyl]imidazole, nitrate melting point 133.5 -137℃, 1-[2,4-dichloro-β-(3-(4'-tert
-butylphenyl)prop-2-nylthio)phenethyl]imidazole, nitrate melting point 147-153.5
°C, 1-[2,4-dichloro-β-(3-(4'-chlorophenyl)propylthio)phenethyl]imidazole, oxalate melting point 111-113 °C, 1-[4-n-butylthio-β-(4 '-Chlorbenzylthio)phenethyl]imidazole nitrate,
Decomposed at 122-124℃. Example 16 1-[4-chloro-β- in 100 ml of dichloromethane
(4'-Chlorphenylthio)phenethyl]imidazole nitrate (1 g) is mixed with excess dilute potassium carbonate solution until the salt is completely dissolved. The organic layer is then separated, washed with water and dried over magnesium sulfate. Evaporating the solution gives 1-[4-chloro-β-(4'-chlorophenylthio)phenethyl]
The imidazole is obtained as a gum. Analogously, the acid addition salts of all compounds of formula (I) can be converted into the corresponding basic forms of the compounds, e.g. 1-[2,4-dichloro-β-(3',4'-dichlorophenylthio) Phenethyl]imidazole, 1-[2,4-dichloro-β-(2',4'-dichlorobenzylthio)phenethyl]imidazole, 1-[2,4-dichloro-β-(n-heptylthio)phenethyl]imidazole , 1-[2,4-dichloro-β-(4'-chlorophenylthio)phenethyl]imidazole, 1-[2,4-dichloro-β-(4'-chlorobenzylthio)phenethyl]imidazole, etc. Example 17 1-[4-chloro-β- in 40 ml of anhydrous ether
Nitric acid (70%; d=1.42) is added dropwise to a stirred solution of 2.5 g of (4'-chlorophenylthio)phenethyl]imidazole until precipitation is complete. The product is separated, washed with ether and dried. Recrystallization from ethyl acetate yields 1-[4-chloro-β
-(4'-Chlorphenylthio)phenethyl]imidazole nitrate, melting point 136.5-137.5°C is obtained. Similarly, all compounds of formula () in basic form can be converted into acid addition salts by treatment with a suitable acid in a conventional manner. The following Examples 18-20 demonstrate the fungal and bacterial growth inhibiting activity of the active ingredient compounds of the formula. EXAMPLE 18 The antibacterial activity of several compounds encompassed by the formula and of Keflin (sodium salt of 7-(thiophene-2-acetamido)cephalosporanic acid) is illustrated in the following manner. Streptococcus faecalis, Gram(+) bacteria in brain-heart infusion broth (Difco)
Incubate at 37°C. After 24 hours, the culture is diluted with this growth medium to a concentration of 1×10 ⁸ cells/ml. Add 0.05 ml of this suspension to various dilutions of the test compound. Test compounds are dissolved in dimethyl sulfoxide, ethanol or water at a concentration of 10 mg/ml and then diluted with sterile water to give a stock solution with a concentration of 100 μg/ml. Make an appropriate dilution from this stock solution. Approximately 4 ml of each dilution is added to sterile test tubes, then 0.05 ml of the inoculum prepared above is added to each tube. A 24 hour incubation is then carried out and the minimum inhibitory concentration (MIC) (this is the concentration at which no visible growth occurs) is determined.

[Table] Nitrate Example 19 Some compounds included in the formula and Miconazole (1-[2,4-dichloro-β-(2',4'-dichlorobenzyloxy)phenethyl]imidazole nitrate) The antifungal activity of is also illustrated in the following manner. Trichophyton rubrum is cultured on Sabouraud dextrose agar (Difco) for 14 days at room temperature. The fungal mats are then removed from the agar slant and homogenized into a fine suspension in Sabouraud's glucose broth. This suspension liquid was heated to a uniform concentration (at 600 nm).
OD 0.1) and add 0.05 ml to various dilutions of test compound. Test compounds are dissolved in dimethyl sulfoxide, ethanol or water at a concentration of 10 mg/ml and then diluted with sterile water to a concentration of 100 μg/ml. Make an appropriate dilution from this stock solution. Approximately 4 of each dilution
ml into sterile test tubes, then add 0.05 ml of the inoculum prepared above to each tube. Incubation is carried out for 7 to 14 days depending on development in the negative control. The minimum inhibitory concentration (MIC), which is the concentration at which no visible growth occurs, is then determined for each test compound and for miconazole. The results obtained are shown in the table.

Table: Oxate Example 19a The active ingredient compound of formula 19a was further tested for antifungal activity in vitro. The following microorganisms are used as test microorganisms: 1. Candida albicans (ATCC 10231)
[Ca#1] (Candida albicans) 2 Candida albicans (ATCC 14053)
[Ca#2] 3 Cryptococcus neoformans (ATCC 13690) [Cn] (Cryptococcus
neoformans) 4 Epidermophyton flotscosum (ATCC
15693) [Ef] (Epidermophyton floccosum) 5 Trichophyton Mentaglophytes (ATCC 11481) [Tm] (Tichophyton
mentagrophytes) 6 Microsporum gypseum (ATCC
14683) [Mg] (Microsporum gypseum) Microsporum odowinii (ATCC
10008) [Ma] (Microsporum audouini) Microorganisms 1, 2 and 3 are generally classified as yeast-like microorganisms, and 4, 5 and 6 are dermatophytes. Because of their different characteristics, their treatment in testing varies. Cultivation of all microorganisms is carried out in roller drum tubes containing 5 ml of culture medium incubated at 25°C. All fungal test evaluations are performed after 16 hours of incubation. Inhibition evaluation for microorganisms 1, 2 and 3 was measured after 3 days, and for microorganisms 5 and 6.
The evaluation for microorganisms was carried out after 5 days and
The evaluation will be done on the 7th day. Miconazole is used as a control in each test. Test compounds were dissolved in 0.6 ml of dimethyl sulfoxide, ethanol or sterile distilled water, and these solutions were supplemented with sterile Sabouraud dextrose broth.
Add 30 ml to make the first stage test compound sample. Appropriate amounts of these stock solutions are diluted with sterile Sabouraud dextrose broth (Difco) to the desired concentration. Dilution is generally a geometric series, e.g.
Performed at 300, 100, 30, 10, 3 and 1 μg/ml. Approximately 5 ml of each dilution is added to each sterile test tube (16 mm) and each tube is inoculated with 2 drops of inoculum. Each tube is incubated at 25° C. under aerobic conditions with roller drum agitation. For inoculation, yeast-like organisms were transferred from Sabouraud dextrose agar (Difco) slants to Sabouraud dextrose broth and incubated at 25°C.
Incubate overnight. 16 of these
Two drops of a 1/10 dilution of the time culture are used as the inoculum for each tube. Dermatophytes are cultured on Sabouraud dextrose agar or neutral walt agar slants incubated at 25°C for at least 4 weeks. Approximately 10 ml of 0.7% sodium chloride solution is added to this agar slant, and the agar surface is pulled and stirred to form a suspension. The suspension is passed through two layers of sterile stainless steel bowls (40 x 40 mesh and 100 x 100 mesh).
This operation separates the agar particles and fungal hyphae on the agar from the spores required in this test. After microscopic examination of the suitability of the inoculum, two drops of each of these suspensions are added to various dilutions of the test compound in Sabouraud dextrose broth. Antifungal activity is determined after incubating each broth dilution tube for 16 hours. Transfer one drop of broth to a suitable agar plate (Sabouraud dextrose agar for yeast-like bacteria and Mycocel agar [BBL] for dermatophytes). The minimum lethal concentration (MIC) is determined in μg/ml. These measurements were taken when each broth dilution tube was transferred to an agar plate at 16 hours and this agar plate was incubated (3 days for yeast-like bacteria, 5 days for microorganisms 5 and 6, and (day 7) represents the lowest concentration at which the growth of more than 10 pinpoint colonies or the development of solid growth does not occur. The bacteriostatic end point was determined visually and expressed as the minimum inhibitory concentration (MIC) in μg/ml. Yeast-like bacteria readings are taken after 3 days of incubation, organisms 5 and 6 after 5 days of incubation, and organisms 4 at 7 days of incubation. Microbial Preparation and Inoculation Media Fungi are grown on Sabouraud dextrose agar (Difco) to prepare inoculum. During the period of exposure to the test compound, these bacteria
Culture in dextrose broth (Difco). Preparation of cultures for inoculation Two yeast-like bacteria, Cryptococcus neoformans and Candida albicans, are grown for 48 hours at 37°C on agar media. The cells are then placed in Sabouraud dextrose broth at approximately 1 x 10 ⁸ cells/
Suspend to a concentration of ml. 0.05 ml of this suspension is used to inoculate each test compound dilution. The filamentous fungi are incubated at room temperature (22°C ± 2) for 14 days. The fungal "mat" is harvested from the agar medium and homogenized in Sabouraud dextrose broth to produce a fine suspension. This suspension is diluted to a uniform concentration (OD 0.1 at 600 nm) and 0.05 ml is used for inoculation of the test compound. Preparation of test compounds All test compounds are dissolved in an appropriate solvent to a concentration of 10 mg/ml. As a solvent, DMSO ethanol or water is usually used. After dissolving the compound,
Dilute with 9 ml of sterile distilled water to give a concentration of 100 μg/ml. Each dilution is made from this stock solution.
Test concentrations were 100, 50, 10, 5, 1 and 0.1μg/
ml. Approximately 4 ml of the diluted solution of each concentration is placed in sterile test tubes, and these test tubes are inoculated with the test microorganism. The maximum concentration of solvent that microorganisms are exposed to is 1%.
(e.g. in a 100 μg/ml test). Appropriate control experiments are performed to determine the effect of microorganisms on the solvent. If the compound precipitates out of solution when sterile distilled water is added, mix or sonicate to obtain a homogeneous suspension. The test microorganisms are exposed to dilutions of this suspension. If the compound is not soluble,
He indicated that. Results If the test compound is inoculated with the microorganism,
After incubation for the following periods, the minimum inhibitory concentration (MIC) is determined. Yeast-like fungi 48 hours Filamentous fungi 7-14 days depending on growth in negative control (untreated control) MIC refers to the concentration at which no visible growth occurs (bacteriostatic or fungistatic concentration). Samples are taken from tubes with no growth and added to fresh medium containing no test compound. In this case, the concentration at which no growth occurs is the bactericidal or fungicidal concentration. These samples are incubated for at least 7 days in case any potential growth can be detected. The results obtained are shown in the following table:

【table】

【table】

[Table] Example The acute toxicity of the active ingredient compound of formula 19b was determined after oral administration. As a test compound, ():1-[2,4-dichloro-β-(4'-chlorobenzylthio)phenethyl]imidazole nitrate (Example 2; Table and ) ():1-(2,4-dichlor-β -n-heptylthiophenethyl)imidazole oxalate (Example 2; Table and ) was used. The test compound is suspended in 2% corn starch and administered orally once to a group of 10 mice. The observation period after administration is one week, during which the number of dead animals is determined. The results are shown in the table below.

[Table] From the above results, it was determined that the acute oral toxicity LD ₅₀ value of compound () in mice was greater than 4050 mg/Kg body weight, and
LD ₅₀ value is Profit Analysis by DJ Finney, 3
2710 mg/Kg (95% confidence interval: 2250-3320)
mg/Kg). Example 20 The following examples illustrate topical, oral, and parenteral dosage forms of compositions according to the invention. Example Cream: Compound of formula 1.0g Stearic acid 10.0g Span 60 (trade name of commercially available surfactant)
5.2g Span 80 (trade name of commercially available surfactant) 1.0g Propylene glycol 5.0g Methylparaben 0.05g Propylparaben 0.01g Distilled water Amount to make 100.0g Mix the ingredients at 60℃ and cool while stirring to make a smooth cream. to make. Example Tablet: Compound of Formula 100 mg Lactose (US Pharmacopoeia) 80 mg Corn Stitch 16 mg Polyvinylpyrrolidone 5.6 mg Magnesium Stearate 0.4 mg 200.0 mg Ingredients are mixed, granulated in a suitable solvent, such as methanol, dried, and then granulated in a suitable solvent. Form into tablets using tabletting equipment. Example Suppository: Compound of formula 0.1g Polyethylene Glycol 1000 1.0g Polyethylene Glycol 4000 0.1g 1.2g The ingredients are mixed together at 50°C, then poured into a mold,
Cool to room temperature. Example Injection: Compound of the formula 0.5 g Propylene glycol 30.0 g Sodium chloride 0.8 g Distilled water Amount to make 100 ml A solution of the active compound in propylene glycol is mixed with an aqueous sodium chloride solution and the final volume is filtered through a 02μ membrane filter; Pack under sterile conditions.

Claims (1)

[Claims] 1 Formula: [Here, R is alkyl, phenyl or phenyl-C ₁
~ C ₄ alkyl, these phenyl groups may be substituted by halo, lower alkyl, lower alkoxy or trifluoromethyl, R ₁ is halo, lower alkyl, lower alkoxy,
lower alkylthio or trifluoromethyl; and p is 1 or 2] or an acid addition salt thereof, for inhibiting fungal growth in humans and animals. 2. The composition according to claim 1, which comprises a pharmaceutically acceptable non-toxic carrier as a carrier. 3. A composition according to claim 2, containing a compound of formula () in an amount of 0.1 to 10.0 percent by weight of the composition. 4. The composition according to claim 1, containing 1-[2,4-dichloro-β-(4'-chlorobenzylthio)phenethyl]imidazole and its acid addition salt. 5 Formula: (In the formula, R is phenyl substituted with halogen-
phenyl substituted by lower alkyl or halogen; R ¹ is halogen; and p
is 1 or 2) or an acid addition salt thereof, for inhibiting the growth of bacteria in humans and animals. 6. The composition according to claim 5, which comprises a pharmaceutically acceptable non-toxic carrier as a carrier. 7. A composition according to claim 6, containing a compound of formula (') in an amount of 0.1 to 10.0 percent by weight of the composition.