JPS6234758B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a method for producing a novel imidazole derivative, more specifically, the present invention relates to a method for producing a novel imidazole derivative, and more specifically, [Here, R is alkyl having 1 to 20 carbon atoms, 2
Alkenyl with ~12 carbon atoms, alkynyl with 2 to 12 carbon atoms, aryl with one or more aromatic rings with 6 to 10 carbon atoms, 5 to 8 carbon atoms cycloalkylalkyl, in which a cycloalkyl group as defined above is attached to an unbranched alkyl group having 1 to 3 carbon atoms; an aryl group as defined above is attached to an unbranched alkyl group having 1 to 4 carbon atoms; aralkyl bonded to an alkyl group having an atom;
Aralkenyl, or substituted aryl, substituted aralkyl or substituted aralkenyl, in which the aryl group as defined above is attached to an alkenyl group having 2 to 4 carbon atoms, and the substituted aralkenyl and substituted aralkyl are , at least one substituent selected from the group consisting of halogen, lower alkyl having 1 to 6 carbon atoms, lower alkoxy having 1 to 6 carbon atoms, trifluoromethyl, nitro and cyano on the aryl moiety, and the substituted aryl includes halogen, lower alkyl having 1 to 6 carbon atoms,
contains at least one substituent selected from the group consisting of lower alkoxy, trifluoromethyl, nitro, amino, acylamino and cyano having 1 to 6 carbon atoms; R ¹ is halogen, 1 to 6 carbon atoms; lower alkyl, lower alkoxy having 1 to 6 carbon atoms, trifluoromethyl, nitro, cyano or the group -S-R ² in which R ² is a lower alkyl group, and p is an integer zero, 1 or 2] or an acid addition salt thereof. As used herein and in the claims, the term "alkyl" refers to a saturated unbranched or branched acyclic hydrocarbon radical containing from 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 "cycloalkyl" as used herein refers to a saturated monocyclic hydrocarbon radical having 5 to 8 ring carbon atoms, such as cyclopentyl, cyclohexyl, cycloheptyl, and the like. The term "cycloalkylalkyl" means
Refers to a cycloalkyl group as described above attached to an unbranched acyclic hydrocarbon group containing 1 to 3 carbon atoms, such as cyclopentylpropyl, cyclohexylmethyl, cyclohexylethyl, cycloheptylmethyl, and the like. The term "alkenyl" refers to unbranched or branched acyclic hydrocarbon groups having carbon-carbon double bond unsaturation and containing 2 to 12 carbon atoms, such as allyl, 2-hexenyl, 3-octenyl, 2
- Refers to octenyl, 2-decenyl, etc. The term "aralkenyl" refers to a hydrocarbon moiety in which the alkenyl moiety containing 2 to 4 carbon atoms consists of one or more aromatic rings and is attached to a hydrocarbon radical containing 6 to 10 ring carbon atoms, e.g. Refers to phenyl-2-propenyl, 4-phenyl-3-butenyl, styryl, 3-naphthyl-2-propenyl, etc. The term "alkynyl" refers to an unbranched or branched acyclic hydrocarbon group having carbon-carbon triple bond unsaturation and containing from 2 to 12 carbon atoms, e.g.
Refers to propynyl, 3-hexynyl, 2-octyl, etc. The term "aryl" refers to a hydrocarbon group consisting of one or more aromatic rings and containing 6 to 10 ring carbon atoms, such as phenyl and naphthyl. The term "aralkyl" means that the alkyl portion contains 1 to 4 carbon atoms and the aryl portion is as defined above. Refers to the hydrocarbon part. Representative examples of aralkyl groups include benzyl, 3-phenylpropyl, and the like. The term acylamino, i.e. R-C
(O)-NH-, refers to a substituent containing up to 12 carbon atoms, where R in the substituent is methyl, ethyl, i-propyl, n-butyl, pentyl, octyl, etc. . The term "halo" as used herein refers to chloro, fluoro and brome. The term "acid addition salt" refers to inorganic acids such as hydrochloric, hydrobromic, sulfuric, nitric, and phosphoric acids, or organic acids,
For example, 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-toluesulfonic acid,
Refers to the salt of the subject compound made with 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. The compounds according to the invention can therefore be prepared either in optically active form or in the form of racemic mixtures. 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 meant to encompass the individual optical isomers of the subject compounds. If necessary, the racemic intermediates or final products made herein are described, for example, in U.S. Pat.
3717655 and 3839574, or by conventional dividing means known in the art;
For example, a diastereomeric salt produced by the reaction of a racemic compound of formula () with an optically active acid, or a diastereomeric ester produced by the reaction of a racemic alcohol precursor of a compound of formula () with an optically active acid. It can be resolved into its optical antipodes by separation, for example by fractional crystallization. Such a good example of optical activated acids include shyonou -10 -sulfonic acid, α -brom -shyonou -π -sulfonic acid, shyonuic acid, mentate acetic acid, and tartar acid.
These are optically active forms such as malic acid, diacetylacetic acid, and pyrrolidone-5-carboxylic acid. 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 group of compounds of the above formula are those in which R ¹ is halo and R is alkyl, alkenyl, aralkenyl, halo-substituted alkenyl, aralkyl, halo-substituted aralkyl, aryl and halo-substituted aryl. Particularly suitable compounds in the group mentioned in the above paragraph are [R ¹ ] _p is monohalo or dihalo;
alkyl containing 1 to 12 carbon atoms, 2-
alkenyl, phenyl-2-alkenyl, chloro-substituted phenyl-2-alkenyl, benzyl, chlor- or fluoro-substituted benzyl, phenyl and chloro-substituted phenyl. In particular, the most preferred compound is [R ¹ ] _p is 2,4-dichlor;
It represents 2,4-dibrome or 2,4-difluoro. The subject compounds of formula () exhibit antifungal and antibacterial activity. For example, the compounds according to the invention may be used against human and animal pathogens, such as Microsporum audouini, Microsporum gypseum, Microsporum gypseum Canis, Epidermophyton floccosum, Trichophyton mentha. Trichophyton mentagrophytes, Trichophyton rubrum, Trichophyton tonsurans, Candida albicans
It exhibits antifungal activity against Cryptococcus albicans) and Cryptococcus neoformans. The compounds according to the invention may also be used primarily for fungi of agricultural importance, such as Aspergillus flavus (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 according to the invention are suitable for human and animal pathogens, such as Staphylococcus aureus, Streptococcus faecalis, Corynebacterium acnes, Erysipelothrix insidiosa, Escherichia coli ( Escherichia coli, Proteus vulgaris
vulgaris), Salmnella choleraesuis, Pasteurella multocida
It exhibits antibacterial activity against Pseudomonas multocida and Pseudomonas aeruginosa. Because of the aforementioned activities, the subject compounds prove to be useful antimicrobial agents that have not only pharmaceutical applications, but also agricultural and industrial applications. Therefore, another aspect of the present invention is for pharmaceutical use,
It relates to compositions for agricultural and industrial use, which compositions have the formula () in combination with a suitable carrier.
It consists of thematic compounds. Yet another aspect of the invention provides that a host subject containing or susceptible to attack by fungi or bacteria is treated with a suitable drug containing a fungicidally or bactericidalally effective amount of a compound according to the invention or the same. The present invention relates to a method for inhibiting the growth of fungi and bacteria by applying a composition. 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. can give. Pharmaceutical compositions containing compounds according to the invention may be subjected to conventional pharmaceutical expedients such as sterilization and may be subjected to conventional pharmaceutical auxiliaries such as preservatives, stabilizers,
Emulsifiers, osmotic salts and buffers may be included. The composition may also include other therapeutically active substances. For pharmaceutical applications, the subject compounds and compositions can be administered to humans and animals in a conventional manner, eg, topically, orally, parenterally, and the like. For oral administration, the compound may be administered alone or in admixture with a suitable carrier at a dosage of about 12.5 mg to about 1000 mg per dose (assuming a 70 kg host subject) once or more daily. can be administered 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 subject compound or composition, for example by powdering, liquid spraying, spraying, washing, brushing, dipping, smearing, coating, soaking, etc.
Pharmaceutical compositions containing compounds according to the invention can be used over a wide range of concentrations, for example from about 0.1 to 10.0 of the composition.
exerts antifungal and antibacterial activity over % by weight. In any case, the composition to be administered will contain a certain amount of the subject compound in an amount effective for alleviating or preventing the particular condition being treated.
The precise control over the drug administration of the compounds or compositions described herein will necessarily depend on the individual subject being treated, the type of treatment, e.g., prophylactic or therapeutic, the type of organism involved, and, of course, the It will depend on the judgment of the attending physician. In agricultural applications, the subject compounds can be applied directly to plants (eg, seeds, leaves) or to the soil. For example, the compounds according to the invention can be applied alone or as a mixture with powdered solid carriers. Typical powder carriers are various mineral silicates such as mica, talc, pyrophyllite, and clay. The subject compounds can also be applied to seeds as 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 subject compounds can be mixed with sand, earth or powdered solid carriers, such as mineral silicates, and applied as a powder, with or without additional surfactants, or the subject compounds can be applied as a powder, with or without additional surfactants. can be applied as an aqueous spray, optionally containing a surface-active dispersant and a powdered solid carrier. As a foliar treatment, the subject compounds 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, the subject compounds can be used to control bacteria and fungi by linking the compounds with pathogens in known manner.
Materials capable of harboring bacteria and fungi can be protected by contacting, mixing with, or impregnating these materials with the subject compounds. To enhance their effectiveness, the subject compounds can be combined with other pest control agents, such as fungicides, fungicides, insecticides, acaricides, and the like. A particularly important industrial/agricultural use for the subject compounds according to the invention is as food preservatives against bacteria and fungi that cause food deterioration and spoilage. The compound of the above formula () can be produced by the following reaction formula: where R, R ¹ and p are as defined above and X is a conventional leaving group, such as chloro, bromo or a reactive ester group, such as CH ₃ -S(O)
₂ -O- or p- _CH3 - _C6H4 - _S (O) _2-
Represents O-. 1-[β-(R-thio)phenethyl] of formula-A
Imidazoles can be prepared by condensing compounds of the formula with thiols. In the condensation, the starting materials and reactants are brought into contact by any convenient method and maintained at a temperature for a time sufficient to drive the reaction to completion. Furthermore, the reaction products may be affected by methods commonly used or known in the art for carrying out such or similar reactions, as well as by the reaction conditions themselves. can be isolated and collected from the reaction mixture by using 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. In general, compounds of formula
aralkyl and substituted aralkyl) in the presence of an inert organic solvent such as tetrahydrofuran, ether, menthanol, etc. and in the presence of sodium hydride or other suitable base at 20 to 66°C. 30 minutes at a temperature of
This will be done for 24 hours. The reaction of a compound of formula with a compound of formula where R is aryl or substituted aryl 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. under reflux conditions in the presence of 30
Do this for a period of minutes to 12 hours. Although the subject compounds according to the invention can be isolated as free bases, since many of the basic forms of the compounds are oils or gums, 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 was potassium carbonate, sodium carbonate, or sodium or potassium hydroxide. It can be easily converted into a basic compound by treatment with an alkali. Starting materials of the formula (where R ¹ is methyl, methoxy, halo, or nitro) are described in US Pat. No. 3,679,697, along with methods for their preparation. Compounds of formula (wherein R ¹ is other than the group described in the above patent) can be prepared in a similar manner, i.e. by bromination of the appropriate acetophenone, resulting in 2-
By reaction of the bromoacetophenone compound and imidazole, reduction of the obtained 2-(1-imidazolyl)acetophenone compound with sodium tetrahydroporate, and finally reaction of the obtained 1-imidazole ethanol and compound with thionyl halide. , can be produced by producing a 1-(β-halofenethyl)imidazole compound of the formula. An acetophenone containing the group -S-R ² (wherein R ² is as above) has the formula, i.e. (wherein R ² and X are as defined above), these acetophenones can be prepared by the following methods: Alkyl- or arylphenyl sulfide
Friedel-Crafts acylation with acetyl chloride or acetic anhydride in the presence of AlCl ₃ to form the corresponding alkylthio-, cycloalkylthio-
Create aralkylthio or arylthioacetophenone. These methods are described in the Journal of American Chemical Society.
Society) 74 , 5475-81 (1952) and U.S. Pat. No. 2,763,692. (B) diazotized aminoatophenone with arylthio or substituted arylthiol (the substituted thiol is halo, lower alkyl, lower alkoxy,
containing at least one substituent selected from the group consisting of trifluoromethyl, nitro, and cyano) to obtain a substituted arythioacetophenone. Alternatively, a diazotized arylamino compound substituted with at least one of the above substituents can be combined with a mercaptoacetophenone to obtain a substituted arylthioacetophenone. These methods are Boll.sci . fac ．
chim ． ind ． Bologna 17 , 33-43 (1959). (C) O-, m-, or p-mercaptoacetophenone is converted into a known alkyl, cycloalkyl, aralkyl, or substituted aralkylnahalide (the substituted aralkylhalide has halo, lower alkyl, or lower alkoxy in the aryl moiety). , trifluoromethyl, nitro and cyano) to obtain the corresponding alkyl-, cycloalkyl-, aralkyl- or substituted aralkylthioacetophenone. This method is described in The Journal of American Chemical Society 78 , 4792-7.
(1956). The following specific description is presented to enable those skilled in the art to more clearly understand and practice the method of the invention. This should not be considered a limitation on the scope of the invention, but merely as an illustration and representative example thereof. Preparation A A mixture of 1.52 g of 4-mercaptoacetophenone, 1.72 g of 4-methoxybenzyl chloride and 1.5 g of anhydrous potassium carbonate in 50 ml of acetone is stirred to reflux under nitrogen. After 4 hours, the solvent and excess 4-methoxybenzyl chloride were evaporated under vacuum,
Add water 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 was recrystallized from cyclohexane to give 4-
(4'-Methoxybenzylthio)-acetophenone is obtained. Similarly, 4-methoxybenzyl chloride is replaced by other aralkyl halides or at least one substitution selected from the group consisting of halo, lower alkyl, lower alkoxy, trifluoromethyl, nitro and cyano on the aryl moiety. Substituted aralkyl halides containing groups can be used to make the corresponding substituted aralkylthioacetophenones. The starting compound of formula is prepared from the substituted alkylthiacetophenones described above according to the method of US Patent No. 367,997. Example 1 (A) 1 g of 1-(2.4.β-trichlorophenethyl)imidazole in 50 ml of acetone, 3.4-
A mixture of 1.8 g dichlorothiophenol and 1.5 g potassium carbonate 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 was dried over magnesium sulfate and evaporated to give 1-[2.4-
Dichloro-β-(3'·4'-dichlorophenylthio)phenethyl]imidazole is obtained. The free base oxalate salt is prepared by adding ethereal oxalic acid to the free base in ether until precipitation ceases. The product was filtered 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, other starting materials in place of 1-(2.4.β-trichlorophenethyl)imidazole, 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, 1-(β-chloro-4-cyanophenethyl)
Imidazole, 1-(β-chloro-4-nitrophenethyl)
imidazole, and 1-(β-chloro-2-thiocyanatophenethyl)imidazole, such as the following 1-[β-(3′·4′-
Dichlorophenylthio)phenethyl]imidazole can be prepared; the product is identified as an acid addition salt by treatment with a suitable 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-difluoro-β-(3',4'-dichlorophenylthio)phenethyl] Rolfenylthio)phenylthyl]imidazole, oxalate, 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 are prepared and these are identified as acid addition salts by treatment with the appropriate acid in a conventional manner: 1-[β-(4'-chlorophenethyl) nilthio)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, 4-[2,4-dichloro-β-(4 '-Chlorphenylthio)phenethyl]imidazole, nitrate, melting point 165.5-170℃, 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, oxalate decomposes at 169-171.5℃. Example 2 (A) 1-(2.4.
β-Trichlorophenethyl)imidazole 1g
A solution of 2.4 in 40 ml of tetrahydrofuran
- 1 g of dichlorobenzyl mercaptan and 56
% sodium hydride dispersion to the mixture. After stirring for 12 hours at room temperature, the solvent is evaporated under reduced pressure and 10 ml of water is 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,
Upon evaporation, 1-[2,4-dichloro-β-
(2',4'-dichlorobenzylthio)phenethyl]imidazole is obtained. The nitrate of free chlorine 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 give 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
By substituting those listed in paragraph B of , for example, the following 1-[β-(2',4'-dichlorobenzylthio)phenethyl]imidazole can be prepared, which can be prepared by conventional treatment with a suitable acid. Identified as the acid addition salt by: 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 starting materials of the formula listed in paragraph B of Example 1, the following 1-[β-(R-thio)phenethyl]imidazoles can be prepared, for example: , and these are identified as acid addition salts by treatment with the appropriate acid in a conventional manner: 1-[4-tert-butyl-β-(4'-chlorobenzylthio)phenethyl]imidazole, oxalate; Decomposes at 156-158.5°C, 1-[4-n-butoxy-β-(4'-chlorobenzylthio)phenethyl]imidazole, nitrate, decomposes at 113-114°C, 1-[4-n-butoxy-β- (n-heptylthio)phenethyl]imidazole, oxalate, decomposed at 124.5-130°C, 1-[4-chloro-β-(4'-chlorobenzylthio)phenethyl]imidazole, oxalate, decomposed at 148-149.5°C Decomposition, nitrate, melting point 103.5
−105.5℃. 1-[2,4-dichloro-β-(4'-chlorobenzylthio)phenethyl]imidazole, nitrate, melting point 130.5-132℃, 1-[2,4-dichloro-β-(3',4'-dichloride) Chlorbenzylthio)phenethyl]imidazole, nitrate, decomposed at 95-96.5°C, 1-[2,4-dichloro-β-(n-heptylthio)phenethyl]imidazole, oxalate, melting point 106-109°C, 1-[ 3,4-dichloro-β-(4'-chlorobenzylthio)phenethyl]imidazole, oxalate, decomposed at 174-175℃, 1-[3,4-dichlor-β-(3',4'-dichlor Benzylthio)phenethyl]imidazole, oxalate, decomposed at 176-177.5℃, 1-[2,4-dibromo-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.
By repeating the method described in paragraph A of Example 1 using 4,5-trichlorothiophenol and pentachlorothiophenol, the following 1-[β-(R-thio)phenethyl]imidazoles can be prepared, for example: , 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, sulfur Acid acid, 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'-trochlorphenylthio) Phenethyl]imidazole, nitrate, decomposed at 178-185.5℃, 1-[2,4-dichloro-β-(pentachlorphenylthio)phenethyl]imidazole, nitrate, decomposed at 201-202.5℃, 1-[3,4-dichlor -β-(4'-trifluoromethylphenylthio)phenethyl]imidazole, oxalate, decomposed at 170-171℃, 1-[3,4-dichloro-β-(4'-chloro-
3'-Trifluoromethylphenylthio)phenethyl]imidazole, oxalate, decomposed at 165-166°C. Example 4 The method described in paragraph A of Example 2 is repeated, except that instead of 2,4-dichlorobenzyl mercaptan, starting materials of the formula, such as ethyl mercaptan, pentyl mercaptan, octyl mercaptan, nonyl mercaptan, dodecyl mercaptan, Octadecyl mercaptan, 3-phenylpropyl mercaptan, cyclopentylpropyl mercaptan, cyclohexyl mercaptan, cyclohexyl methyl mercaptan, cyclohexylethyl mercaptan, cycloheptyl methyl mercaptan, allyl mercaptan, 2-octenyl mercaptan, 3-phenyl-2-propenyl mercaptan, 3- (4-Chlorphenyl)-2-propenyl mercaptan, 3-hexynyl mercaptan, 2-octynyl 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, 4-fluorobenzyl mercaptan, 4-nitrobenzyl Using mercaptan and 4-cyanobenzyl mercaptan, the following 1-[2,4-dichloro-β-(R-thio)phenethyl]imidazoles can be prepared, for example, and these can be prepared using appropriate methods in a conventional manner. Treatment with acid identifies the acid addition salt: 1-[2,4-dichloro-β-(n-pentylthio)phenethyl]imidazole, oxalate, 99
1-[2,4-dichloro-β-(n-octylthio)phenethyl]imidazole, oxalate, melting point 101.5-103.5°C, 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°C, 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, melting point 87.5-90°C, 1-[2,4-dichloro- 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, decomposed at 104-108.5°C, 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, 123 Decomposed at -126℃, 1-[2,4-dichloro-β-(3-hexynylthio)phenethyl]imidazole, oxalate,
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, decomposed at 162.5-163℃, 1-[2,4-dichloro-β- (4'-Trifluoromethylbenzylthio)phenethyl]imidazole, nitrate, decomposed at 112-114℃, 1-[2,4-dichloro-β-(4'-methoxybenzylthio)phenethyl]imidazole, nitrate, 118-119.5 °C decomposition, 1-[2,4-dichlor-β-(3',4',5'-trimethoxybenzylthio)phenethyl]imidazole, oxalate, 147 °C gelation, 1-[2,4-dichlor -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 172.5-73.5℃, 1-[2,4 -dichloro-β-(4'-brombenzylthio)phenethyl]imidazole, nitrate,
Decomposed at 137-138℃, 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,
Decomposed at 129.5-132℃, 1-[2,4-dichloro-β-(4'-cyanobenzylthio)phenethyl]imidazole, nitrate,
Decomposed at 119.5−123℃. Example 5 1-[4.beta.-dichlorophenyl ether)imidazole and 1-[2.
4-β-trichlorophenethyl)imidazole and instead of 3,4-dichlorothiophenol other starting materials of the formula, such as thiophenol, β-thionaphthol, 4-methylthiophenol, 4-methoxythio Phenol, 3-methoxythiophenol, 2-chlorothiophenol, 3-chlorothiophenol, 2,5-dichlorothiophenol, 4-bromothiophenol, 4-fluorothiophenol, 4-nitrothiophenol, 4-aminothio Repeating the method described in paragraph A of Example 1 using phenol, 4-acetamidothiophenol, and 4-cyanothiophenol yields, for example, the following 1-[4-chloro-β-(R-thio) Phenethyl]imidazoles and 1-[2,4-dichloro-β-(R-thio)phenethyl]imidazoles can be prepared and identified as acid addition salts by treatment with the appropriate acid in a conventional manner. Decomposed: 1-[4-chloro-β-(phenylthio)phenethyl]imidazole, oxalate, decomposed at 166-167°C, 1-[4-chloro-β-(2-naphthylthio)phenethyl]imidazole, oxalate , melting point
193.5-194℃, 1-[4-chloro-β-(4'-methylphenylthio)phenethyl]imidazole, oxalate,
Decomposed at 199.5-200℃, 1-[4-chloro-β-(4'-methosyphenylthio)phenethyl]imidazole, oxalate,
Decomposed at 177-178℃, 1-[4-chloro-β-(3'-methoxyphenylthio)phenethyl]imidazole, oxalate,
Melting point 164.5-165.5℃, 1-[4-chloro-β-(2'-chlorophenylthio)phenethyl]imidazole, oxalate, melting point 177-178℃, 1-[4-chloro-β-(3') -Chlorferthio)phenethyl]imidazole, oxalate, melting point 169.5-171.5°C, 1-[4-chlor-β-(2',5'-dichlorophenylthio)phenethyl]imidazole, oxalate, melting point 181.5-183.5 °C, 1-[4-chloro-β-(4'-bromphenylthio)phenethyl]imidazole, oxalate,
Decomposed at 185-186.5℃, 1-[4-chloro-β-(4'-fluorophenylthio)phenethyl]imidazole, oxalate,
Melting point 182.5-183℃, 1-[4-chloro-β-(4'-nitrophenylthio)phenethyl]imidazole, oxalate, melting point 203-204.5℃, 1-[4-chloro-β-(4') -acetamidophenylthio)phenethyl]imidazole, oxalate, melting point 149.5-152°C. Example 6 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. β-chloro-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-chlor-4- phenylthiophenethyl)imidazole, 1-[β-chloro-4-(4'-chlorophenylthio)phenethyl]imidazole, 1-(β-chloro-4-methylsulfinylphenethyl)imidazole, 1-(β-chloro-4-t-butylsulfenylphenethyl)imidazole, 1-(β-chloro-4-benzylsulfenylphenethyl)imidazole, 1-[β-chloro-4-( 4'-chlorobenzylsulfinyl)phenethyl]imidazole, 1-[β-chloro-4-(4'-methoxybenzylsulfenyl)phenethyl]imidazole, 1-[β-chloro-4-phenylsulfinyl] enethyl]imidazole, 1-[β-chloro-4-(4'-chlorophenylsulfinyl)phenethyl]imidazole, 1-(β-chloro-4-methylsulfonylphenethyl)imidazole, 1-(β- Chlor-4-tert-butylsulfonylphenethyl)imidazole, 1-(β-chloro-4-benzylsulfonylphenethyl)imidazole, 1-[β-chloro-4-(4'-chlorbezylsulfonyl)phenethyl ] imidazole, 1-[β-chloro-4-(4′-methoxybenzylsulfonyl)phenethyl]imidazole, 1-[β-chloro-4-phenylsulfonylphenethyl]imidazole, and 1-[β-chloro- Repeating the procedure described in paragraph A of Example 1 using 4-(4'-chlorophenylsulfonyl)phenethyl]imidazole yields the corresponding 1-[β-(3'·4'-dichlorophenylthio ) Phenethyl] imidazoles are produced. 1-[4-Methylthio-β-(3'·4'-dichlorophenylthio)phenethyl]imidazole, oxalate, melting point 146-148.5°C. Example 7 The following compounds can be made by repeating the method described in Example 1 using the desired specific 1-[β-R-thio)phenethyl]imidazole specified reactants, and which are 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℃ decomposition, 1-[4-methoxy-β-(3',4'-dichlorophenylthio)phenethyl]imidazole, oxalate, melting point 145.5℃, 1-[4-methoxy-β-(4') -tert-butylphenylthio)phenethyl]imidazole, oxalate, melting point 139.5-141.5°C, 1-[2,4-dimethoxy-β-(3',4'-dichlorophenylthio)phenethyl]imidazole,
Nitrate, decomposed at 155.5-158℃, 1-[4-nitro-β-(pentachlorophenylthio)phenethyl]imidazole, nitrate,
163.5-165.5℃ decomposition, 1-[2,4-dichloro-β-(n-butoxyphenylthio)phenethyl]imidazole, oxalate, melting point 143-144℃ 1-[4-cyano-β-(pentachlor) Phenylthio)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 8 By repeating the procedure described in Example 2 using the specified reactant with the desired specific 1-[β-(R-thio)phenethyl]imidazole, one can make e.g. These are identified as acid addition salts by treatment with the appropriate acid in a conventional manner: 1-[2,4-difluoro-β-(n-nonylthio)phenethyl]imidazole, oxalate, mp 79.5-84 °C, 1-[2,4-dimethyl-β-(4'-chlorobenzylthio)phenethyl]imidazole, oxalate, decomposed at 80.5-83 °C, 1-[4-methoxy-β-(3-phenylpropyl) thio)phenethyl]imidazole, oxalate, melting point 75-83°C, 1-[4-methoxy-β-(n-dodecylthio)
Phenethyl imidazole, oxalate, melting point 90
−93°C, 1-[2,4-dichloro-β-(1′-naphthylmethylthio)phenethyl]imidazole, oxalate, fused at 86°C, foamed at 86-121.5°C, 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)prop-2-ylthio)phenethyl]imidazole, nitrate, Melting point 133.5-137℃, 1-[2,4-dichloro-β-(3-(4'-tert
-butylphenyl)prop-2-ylthio)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, decomposes at 122-124°C. Example 9 1-[4-chloro-β- in 100 ml 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. When the solvent is evaporated, 1-[4
-Chlor-β-(4'-chlorophenylthio)phenethyl]imidazole is obtained as a gum. In a similar manner, the acid addition salts of all compounds of formula () 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, and the like. Example 10 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 filtered off, 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. Example 11 Some compounds obtained by the method of the present invention,
and Keflin [7-(thiophene-2
The antibacterial activity of -acetamido)cephalosporanic acid sodium salt] is explained 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 oxide, 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] Imidazole nitrate Example 12 Some compounds obtained by the method of the present invention,
and Miconazole [1-[2.
The antifungal activity of 4-dichloro-β-(2'·4'-dichlorobenzyloxy)phenethyl imidazole nitrate will be explained 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 determined for each test compound and for miconazole. The results obtained are shown in the table.

Table: Midazole Oxalate Example 13 The following formulation is typical of topical, oral, and parenteral dosage forms for compounds obtained by the process of the invention: Cream: Compound of the invention 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. Tablets: Compound of the invention 100 mg Lactose (US Pharmacopoeia) 80 mg Corn starch 16 mg Polyvinylpyrrolidone 5.6 mg Magnesium stearate 0.4 mg 200.0 mg Ingredients are mixed, granulated with a suitable solvent such as methanol, dried, and then granulated with a suitable solvent such as methanol. Form into tablets using tabletting equipment. Suppositories: Compound of the invention 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. Injection solution: Compound of the invention 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, brought to final volume and passed through a 0.2μ membrane filter. Filter and package under sterile conditions. The present invention includes the following embodiments: Compounds of the formula wherein R is 4'-chlorobenzyl, R ¹ is chloro in the 2 and 4 positions, p is 2, and the acid addition salt is a nitrate salt. Claimed method of manufacturing.

Claims (1)

[Claims] 1 formula [Wherein R ¹ is halogen, lower alkyl having 1 to 6 carbon atoms, lower alkoxy having 1 to 6 carbon atoms, trifluoromethyl, nitro,
cyano or the following group -S-R ² (wherein R ² is a lower alkyl group);
is alkyl having 1 to 20 carbon atoms, 2 to 12
alkenyl having 5 to 8 carbon atoms, alkynyl having 2 to 12 carbon atoms, aryl having one or more aromatic rings having 6 to 10 carbon atoms, having 5 to 8 carbon atoms Cycloalkyl, cycloalkylalkyl in which a cycloalkyl group as defined above is attached to an unbranched alkyl group having 1 to 3 carbon atoms, an aryl group as defined above having 1 to 4 carbon atoms aralkyl or substituted aryl, substituted aralkyl or substituted aralkenyl in which an aryl group as defined above is bonded to an alkenyl group having 2 to 4 carbon atoms; and the substituted aralkenyl and substituted aralkyl include halogen in the aryl moiety, lower alkyl having 1 to 6 carbon atoms, lower alkoxy having 1 to 6 carbon atoms, trifluoromethyl, nitro and cyano. The substituted aryl contains at least one substituent selected from the group consisting of halogen, 1
lower alkyl having ~6 carbon atoms, 1-6
contains at least one substituent selected from the group consisting of lower alkoxy, trifluoromethyl, nitro, amino, acylamino and cyano having 5 carbon atoms; and p is an integer zero, 1 or 2. A method for producing an acid addition salt of a compound, the method comprising: (wherein R ¹ , R and p are as defined above) is reacted with an inorganic or organic acid to obtain the corresponding formula A method comprising forming an acid addition salt of a compound of the formula (R ¹ , R and p are as defined above). 2. The method according to claim 1 for producing 1-[2,4-dichloro-β-(4'-chlorobenzylthio)phenethyl]imidazole nitrate. 3 formulas [Wherein R ¹ is halogen, lower alkyl having 1 to 6 carbon atoms, lower alkoxy having 1 to 6 carbon atoms, trifluoromethyl, nitro,
cyano or the following group -S-R ² (wherein R ² is a lower alkyl group);
is alkyl having 1 to 20 carbon atoms, 2 to 12
alkenyl having 5 to 8 carbon atoms, alkynyl having 2 to 12 carbon atoms, aryl having one or more aromatic rings having 6 to 10 carbon atoms, having 5 to 8 carbon atoms Cycloalkyl, cycloalkylalkyl in which a cycloalkyl group as defined above is attached to an unbranched alkyl group having 1 to 3 carbon atoms, an aryl group as defined above having 1 to 4 carbon atoms aralkyl or substituted aryl, substituted aralkyl or substituted aralkenyl in which an aryl group as defined above is bonded to an alkenyl group having 2 to 4 carbon atoms; and the substituted aralkenyl and substituted aralkyl include halogen in the aryl moiety, lower alkyl having 1 to 6 carbon atoms, lower alkoxy having 1 to 6 carbon atoms, trifluoromethyl, nitro and cyano. The substituted aryl contains at least one substituent selected from the group consisting of halogen, 1
lower alkyl having ~6 carbon atoms, 1-6
contains at least one substituent selected from the group consisting of lower alkoxy, trifluoromethyl, nitro, amino, acylamino and cyano having 5 carbon atoms; and p is an integer zero, 1 or 2. A method for producing a compound, the formula (wherein R ¹ , R and p are as defined above) is reacted with a base to obtain the corresponding formula (wherein R ¹ , R and p are as defined above).