KR790001843B1 - Process for producing 1-( -(r-thio)phenehtyl) imidazol and derivatives thereof - Google Patents

Abstract

Title compds. (I; R = alkyl, alkenyl, aralkenyl, alkinyl, cycloalkyl, aralkyl substituted aralkyl, R1 = H, halo, lower alkyl, lower alkoxy, trifluoromethyl, nitro, cyano thiocyanate or S(O)NR2, R2 = alkyl, aralkyl, P = 1 or 2, m,n and p=0-2, m<=o), useful as an antibacterial, were prepd. by condensating II with III, then oxidating 1 (β-(R-thiophenethyl) imidazole of 1-A to give the corresponding compd of 1-B.

Description

1- [β- (R-thio) phenethyl] imidazole and its preparation method

The present invention relates to novel imidazole derivatives. In particular 1- [β- (R-thio) phenethyl] -amidazole, 1- [β- (R-sulfinylphenethyl] imidazole and 1- [β- (R-sulfonyl) phenethyl having the following structural formula: ] Imidazole and its addition salt.

Wherein R is on an aryl moiety selected from the group consisting of alkyl, alkenyl, aralkenyl, substituted aralkenyl, ilkynyl, cycloalkyl, aralkyl, substituted aralkyl, aryl and substituted aryl, halo Aralkyl and halo, lower-alkyl, lower, substituted with at least one of the above-mentioned substituted aralkenyl and substituted aralkyl, lower alkyl, lower alkoxy, trifluoromethyl, nitro and cyano containing at least one substituent Aryl substituted with at least one of alkoxy, trifluoromethyl, nitro, amino, acylamino and cyano. R ¹ is hydrogen, halo, lower alkyl, lower alkoxy, trifluoromethyl, nitro, cyano, thiocyanato and the following groups

Wherein R ² is alkyl, cycloalkyl, aralkyl, substituted aralkyl, aryl and substituted aryl wherein the substituted aralkyl and substituted aryl are in the aryl moiety halo, lower alkyl, lower alkoxy, trifluoromethyl, At least one of nitro and cyano is substituted.

m, n, and P are integers from 0-2, where m must not be greater than n, with the exception that R ¹ is the next group

When R ² is aryl or substituted aryl.

가 있으나 또는 분지가 없는 C₁-C₂₀아실형 탄화수소로서, 메틸, 에틸, n-프로필, 이소프로필, n-부틸, 이소부틸, 3급-부틸, n-펜틸, n-옥틸, n-노닐, n-도데실, n-옥타데실 등이 있다. "저급알킬"이란 C₁-C₆의 알킬기이며, "저급알콕시"란 다음 구조의 기인데"Alkyl" as used herein is saturated or branched

Or branched C ₁ -C ₂₀ acyl hydrocarbon, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, n-octyl, n-nonyl , n-dodecyl, n-octadecyl and the like. "Lower alkyl" is an alkyl group of C ₁ -C ₆ , and "lower alkoxy" is a group having the structure

Lower alkyl-0-

Lower alkyl substituents are as described above. "Cycloalkyl" is a saturated C ₅ -C ₈ monocyclic saturated hydrocarbon, and examples thereof include cyclopentyl, cyclohexyl and cycloheptyl. "Cycloalkyl-alkyl" means a cycloalkyl group having a C ₁ -C ₃ branched acyl hydrocarbon attached thereto, for example cyclopentyl-propyl, cyclohexyl-methyl, cyclohexylethyl, cycloheptylmethyl, or the like. have.

"Alkenyl" group refers to carbon-2 and the unsaturated hydrocarbon with the bond between the carbon or the branches of the C ₂ -C ₁₂ acyl group or a hydrocarbon-free branched, e.g., allyl, 2-hexenyl, 3-oxide Tenyl, 2-decenyl and the like. "Aralkenyl" refers to a hydrocarbon moiety wherein a C ₂ -C ₄ alkenyl moiety is attached to one or more aromatic rings of C ₆ -C ₁₀ cyclic, 3-phenyl-2-propenyl, 4-phenyl-3-butenyl, styryl, 3-naphthyl-2-propenyl, and the like. "Alkynyl" means carbon-and the bond between carbon 3, or the branches of the C ₂ -C ₁₂ hydrocarbon or a cyclohexane rilseong with no branches, for example, 2-propynyl, 3-hexynyl, 2-oxide Tinyl and the like. "Aryl" is one or more aromatic rings and is a C ₆ -C ₁₀ cyclic hydrocarbon, for example phenyl and naphthyl. "Aralkyl" is a hydrocarbon consisting of an alkyl site and an aryl site of C ₁ -C ₄ . Typical examples of the aralkyl group are benzyl, 3-phenylpropyl and the like. Acylamino, RC (o) -NH-, is a C ₁₂ or greater substituent, of which R is methyl, ethyl, iso-propyl, n-butyl, pentyl, octyl and the like. "Halo" here is chloro-fluoro and bromo. By "acid addition salt" is meant an inorganic acid, i.e. hydrochloric acid, hydrochloric acid, sulfuric acid, nitric acid and phosphoric acid, or an organic acid, i.e. acetic acid, propionic acid, glycolic acid, citric acid, tartaric acid, benzoic acid, malic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, n-toluene It means a salt of sulfonic acid, salicylic acid and the like.

, RS(o)m, H 및

부위를 붙히는 것이다. 따라서, 본 발명의 화합물은 광학적으로 활성있는 형태 또는 라세미 혼합물로 제조된다. 여기서 언급하는 화합물은, 특별히 명시하지 않는 한 모두 라세미형이다. 그러나, 본 발명의 범위는, 라세미형에만 국한된 것은 아니며 각각의 광학 이성체를 포함한다.The preparation of the compound of formula (I) is carried out on at least one chiral center, i.e., a carbon atom.

, RS (o) m, H and

It is to paste the site. Thus, the compounds of the present invention are prepared in optically active forms or racemic mixtures. The compounds mentioned herein are all racemic unless otherwise specified. However, the scope of the present invention is not limited to the racemic type but includes each optical isomer.

If desired, racemic intermediates or end products can be partitioned into their optical colon by conventional cleavage methods. Conventional methods include, for example, diastereomercis produced by reacting racemic compounds of U.S. Pat.Nos. 3, 717, 655 and 3, 839, 574 or the structural formula (I) with an optically active acid. The separation of salts (e.g. fractional crystallization) or the separation of diastereo salts produced by reacting the racemic alcohol precursor of the compound of formula (I) with an optically active acid. Examples of such optically active acids include, but are not limited to, optically active camphor-10-sulfonic acid, n-bromo-camphor-π-sulfonic acid, camphoric acid, methoxy-acetic acid, tartaric acid, malic acid, diacetyltartaric acid, Pyrrolidone-5-carboxylic acid and the like. The separated pure diastereo salts or esters are ring-opened by standard methods to form optical compounds of the compound of formula (I) or the precursor alcohol.

Compounds of the present invention are general formula (I) compounds having the following structural formula and acid addition salts thereof.

R, R ¹ and P in the above structural formula are as defined above.

Suitable compounds of the compounds defined above are aryl wherein R ¹ is halo and R is alkyl, alkenyl, aralkenyl, aryl and halo substituted.

Suitable compounds included in the groups defined above are those in which [R ¹ ] p is mono-halo or di halo and R is C ₁ -C ₁₂ -alkyl, 2-alkenyl, phenyl-2-alkenyl, chloro substituted phenyl-2 -Alkenyl, benzyl, chloro or fluoro substituted benzyl, phenyl and chloro substituted phenyl. Most suitable compounds are those wherein [R ¹ ] p is 2,4-dibromo or 2,4-dichloro.

Structural formula (I) compounds have antifungal and antibacterial effects. For example, the compound of the present invention has an antifungal action against the following pathogenic bacteria in animals.

Microsporum Augustine,

Microsporum Jeepium,

Microsporum Jeepium-Canis,

Epidermophytom Flocosum,

Trico Phyton Mentagropides

Trico Phyton Louvroom

Tricot Phyton Tonnage Balance,

Candida albicans and Cryptocoke neoformans.

The compounds of the present invention also have antifungal action against the fungi of the following primary cultivated crops.

Aspergillus Flaves,

Cladosporium Ervarum,

Fusarium Graminea Room,

Penicillium Notatum,

Asper Gilus Niger

Penicillium Oxalicum

Penicillium spinurosum and

Phytomaises Cartageum

In addition, the inventive compound has an antibacterial action against pathogenic bacteria of humans and animals as follows.

Staphylococcus aureus

Streptocoke Pecalis

Corinbacterium Asnes

Ericipelotrix Insidiosa

Escherichia collie

Proteus Bulgari

Salmonella Correrasus

Paste Pasteurella and

Pseudomonas Eruginosa.

In view of the above-mentioned activity, the present invention is useful in agriculture and veterinary medicine as well as in pharmaceutical aspects as an antimicrobial agent. Accordingly, the present invention relates to compositions for use in pharmacy, agriculture and engineering, wherein the composition is prepared by combining the compound of formula (I) with a suitable carrier. The present invention is to inhibit the growth of fungi and bacteria by applying the compound to a host infected with fungi or bacteria, and obtain the effect of fungicidal or bactericidal using the compound of the present invention or a suitable composition thereof.

Pharmaceutically applied methods include solids, semi-solids or liquids, tablets, capsules, powders, suppositories, solutions, suspensions, creams, lotions, ointments, and the like. Pharmaceutically acceptable non-toxic carriers or excipients are used in solids, such as tricalcium phosphate, calcium carbonate, kaolin, bentonite, talc, gelatin, lactose, starch, and the like. , Polyalkylene glycols, petrolatum and other cream preparations, and liquids include water, cooking oil and low boiling point solvent, i.e., isopropanol, hydrogenated naphthalene and the like. Pharmaceutical compositions containing the compounds of the present invention include conventional pharmaceutical excipients such as fungicides and preservatives, stabilizers, emulsifiers, salts for buffering osmotic pressure and buffers. The composition may also contain other therapeutically active substances. The composition of the present invention can be administered to humans and animals locally, orally and parenterally. For oral administration, this compound alone or in admixture with an excipient is administered at about 12.5 mg-100 mg (assuming a 70 kg host) once or more per day, for days to weeks. Suppositories may contain about 1 mg-500 mg of active compound.

It is advisable to apply locally. Such treatment may include powder, sprinkle, spray, smear, immersion, coating, application, injection, or the like of a compound or composition in an area where fungi or bacteria are growing or to be prevented from being infected by fungi or bacteria. It is treated by a method such as rinsing. Pharmaceutical compositions containing a compound of the present invention have antifungal and antibacterial activity in a concentration range of about 0.1-10.0% per weight of the composition. The composition to be administered contains an amount of the compound effective for protecting or stabilizing the conditions of the species to be treated. The exact scope of application of the compounds and compositions will depend on the use of the individual to be treated, the form of treatment for prevention or treatment, infectious organisms, route of infection, and the like.

When applied to pesticides, the compounds may be applied to plants (eg seeds, leaves) or soil. For example, the compounds of the present invention may be applied only to seeds or mixed with a carrier of the powder. Typical powder carriers include several inorganic silicates, ie mica, talc, pyrophyllite and clay. The compounds of the present invention are applied to the seeds by mixing with conventional surface active humectants with or without a carrier. Surface active wetting agents are anionic, non-anionic or cationic. In the case of soil treatment on fungi or the like, the present compound can be applied well with a moist, soil surface active agent or mixed with a powder carrier such as inorganic silicate, or the compound contains a surface active dispersant and a powder solid carrier. It can be applied as an aqueous spray. The leaves can be applied to plants growing as an aqueous spray containing the surface active dispersant with or without powder solid carrier and hydrocarbon solvent.

For industrial use, this compound can be used for regulating bacteria and fungi so as not to be contaminated with pathogenic bacteria with the compound by a known method. Objects contaminated by bacteria or fungi can be protected by contacting, mixing or injecting the compound. In order to enhance such an effect, the compound may be used in combination with a fungicide, fungicide, insecticide, acaricide and the like. Of particular importance for the industrial / agricultural use of the present invention is that it can be used as a preservative against bacteria and fungi that cause food rot.

This invention relates to the manufacturing method of compound (I), The reaction is as follows.

Wherein R, R ₁ and P are as defined above and X is a chloro, bromo or active ether group, ie CH ₃ -S (O) ₂ -O-, P-CH ₃ -C ₅ H ₄ -S It is a well-known leaving group like (O) _2- O-.

Structural formula (I-A) -1- [β- (R-thio) phenethyl] imidazole is prepared by condensing a compound of formula (II) with a thiol of formula (III).

In the condensation reaction, the starting materials and the reagents are contacted by conventional methods and left for a sufficient time until the reaction is terminated at room temperature. The reaction product is also isolated and recovered. The nature of the leaving group X is not important. In general, compounds of formula III are substituted by compounds of formula III wherein R is alkyl alkenyl, aralkenyl, substituted aralkenyl, alkynyl, cycloalkyl, cycloalkyl, aralkyl and substituted Reaction with aralkyl) is carried out in an inert organic solvent, i.e. tetrahydrofuran, ether, methanol or the like, in the presence of sodium hydride or other suitable base for 30 minutes to 24 hours in the temperature range of 20 ° -66 ° C.

The reaction of the formula (II) compound with the formula (III) compound (R is aryl or substituted aryl) is refluxed for 30 minutes to 12 hours in the presence of potassium carbonate or other suitable base in an inert organic solvent, ie acetone, methanol It is performed on condition.

The 1- [β- (R-thio) phenethyl imidazole compound (1-A) thus produced was oxidized to form 1- [β- (R-sulfinyl) phenethyl- and 1- of Formulas I-B and IC. [Β- (R-sulfonyl) phenethyl] imidazole compounds are each obtained. The oxidation reaction is carried out by a known method using hydrogen peroxide, organic peroxides, such as acetic acid peroxide, P-nitro-per-benzoic acid and m-chloro perbenzoate or inorganic peroxides, i.e., peroxide. The oxidation reaction is preferably performed using m-chloro- and benzoic acid in a liquid reaction medium, ie, chlorinated hydrocarbon.

In the above oxidation reaction, the starting materials and the reagents are contacted by conventional methods and allowed to react for a sufficient time until the reaction is completed. In addition, the reaction products are isolated and recovered by conventional methods depending on the reaction conditions. Generally, the compound of formula (IA) is about 1 to 30 or 30 equivalents of an oxidizing agent such as m-chloro and benzoic acid in an organic solvent such as chloroform for about 30 minutes to about 6 hours. Reaction to give the corresponding sulfinyl compound of formula (IB). Similarly, the compound of formula (IA) is dissolved in about 2 equivalents or more equivalents of an oxidizing agent (e.g. m-chloro perbenzoic acid) at about 0 ° -60 ° C, in an organic solvent (e.g. chloroform), about 1-24 Reaction over time affords the corresponding sulfonyl compound of formula (IC).

The compounds of the present invention can be isolated in freebase form because the base form is oily or rubbery, which is more convenient for isolation and is characterized by acid addition salt compounds. Such salts are prepared by conventional methods (ie, reacting the base compound with a suitable inorganic or organic acid). If necessary, the salts can be converted to the base form by treatment with alkali, ie potassium carbonate, sodium carbonate or potassium hydroxide or the like.

Starting compounds of formula (II) which are hydrogen, methyl, methoxy, halo, nitro or lower alkyl sulfonyl are known from US Pat. No. 3, 679, 697. Compound (II) in which R ₁ is a group other than the groups mentioned above (except for R ₂ S (O)-) bromines the appropriate acetophenone, reacts the resulting 2-bromo acetophenone compound with imidazole, and In addition, the resultant 2- (1-imidazolyl) acetophenone den compound is reduced with sodium tetrahydroborate, and finally the produced 1-imidazole ethanol compound is reacted with thionyl halide to give 1- [ β-halofenethyl) -imidazole is formed. The compound of formula (II) wherein R ¹ is R ² S (O)-is obtained by oxidizing the compound of formula (II) wherein R ¹ is R ² S- by a conventional method.

Acetophenone having the next group

(R ² is the same as described above)

If necessary as a reactant for the preparation of starting materials of formula (II):

(R ² and X are as described above)

Acetophenone is prepared by the following procedure.

A) Known alkyl-, cycloalkyl-, aralkyl-, or aryl phenylsulfides are reacted with acetyl chloride or acetic anhydride in the presence of Alder _{3 to} give the corresponding alkylthio-, cycloalkylthio-, aralkyl Thio or arylthio-acetophenones are produced, which are oxidized with hydrogen peroxide in acetic acid to convert to the corresponding sulfonyl derivatives. This method is described in J, A, C, S 74, 5475-81 (1952) and US Pat. Nos. 2, 763, 692.

B) diazotized amino acetophenones substituted with aryl thiols or substituted arylthiols, (substituted aryl thiols being substituted with at least one substituent, ie halo, lower alkyl lower alkoxy, trifluoromethyl, nitro and cyano, etc. Coupling) gives a substituted arylthio acetophenone. In addition, a substituted arylthioacetophenone may be obtained by coupling a diazotized aryl amino compound substituted with at least one of the aforementioned substituents with mercapto acetophenone. This method is known from Boll, Sci, fac, chim, ind, Bologna 17, 33-43 (1959).

C) Aralkyl halides with known alkyl, cycloalkyl, aralkyl or substituted substituents for O-, m-, or P-mercaptoacetophenone (with at least one halo, lower alkyl, lower alkoxy, Alkylation with trifluoromethyl, nitro and cyano groups substituted aralkyl halides) yields the corresponding alkyl-, cycloalkyl-, aralkyl-, or substituted aralkyl-thioacephenones. This method is known from J, A, C, S 78, 4792-7 (1956).

Oxidation of the products of (B) and (C) by the method described in (A) yields the corresponding R ₂ -sulfonylacetophenone (R ² is as described above).

[Preparation A]

1.52 g of 4-mercaptoacetophenone, 1.72 g of 4-methoxybenzyl chloride and 1.5 g of potassium carbonate anhydride and 50 ml of acetone mixture are stirred and refluxed under nitrogen. After 4 hours, the solvent and excess 4-methoxybenzyl pullolide are evaporated in vacuo and water is added to the residue. The aqueous mixture is extracted with ether and the ether extract is washed with water, dried over magnesium sulfate and evaporated to dryness. Recrystallization of the resulting residue with cyclohexane affords 4- (4'-methoxybenzylthio) -acetophenone.

Similarly, aralkyl halides with substituents substituted for at least one halo, lower alkyl, lower alkoxy, trifluoromethyl, nitro and cyano to another aralkyl halide or aryl moiety instead of 4-methoxy benzyl chloride. The corresponding substituted aralkylthioacetophenones are obtained.

The starting material of formula (II) produces the above substituted aralkylchioacetophenones by US Pat. No. 3,679,697.

[Production B]

A mixture of 2 g of 4-methylthioacetophenone, 5 g of acetic acid and about 3.8 g of 30% hydrogen peroxide is heated to 85 ° -95 ° C. until the exotherm starts. Once the reaction is relaxed, 0.002 g of Pd-carbon is added and the reaction mixture is filtered through a divalent earth element. The precipitate produced by cooling the filtrate is filtered off and air dried to yield 4-methylsulfonyl acetophenone.

Similarly, using other thioacetophenones listed below instead of 4-methylthioacetophenone,

4-t-bumethioacetophenone,

4-benzylthioacetophenone,

4- (4'-chlorobenzylthio) acetophenone,

4- (4'-methoxybenzylthio) acetophenone,

4-phenylthioacetophenone, and

4- (4'-chlorophenylthio) acetophenone,

The following acetophenones are produced with sulfonyl.

4-t-butylsulfonyl acetophenone,

4-benzylsulfonyl acetophenone,

4- (4'-chlorobenzylsulfonyl) acetophenone,

4- (4'-methoxybenzylsulfonyl) acetophenone,

4-phenylsulfonylacetophenone and

4-('4-chlorophenylsulfonyl) acetophenone.

Starting materials of formula (II) are prepared from acetophenones substituted with the above sulfonyl by US Pat. No. 3, 679, 697.

Example 1

A) A mixture of 1 g 1- (2,4, β-trichlorophenethyl) imidazole, 1.8 g 3,4-dichlorothiophenol, 1.5 g potassium carbonate and 50 ml acetone is stirred and refluxed for 4 hours. The solvent is evaporated under reduced pressure and 20 ml of water are added. The aqueous mixture is extracted with ether and the ether extract is washed with 50 ml saturated brine. The organic layer was dried over magnesium sulfate and evaporated to yield 1- [2, 4-dichloro-β- (3 ', 4'-dichloro-phenethylthio) phenethyl] imidazole.

Hydroxides of the free base are produced by adding etheric hydroxyl acid of the free base in ether until the precipitation is completely complete. 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 ° C. do.

B) Similarly using the following 1 (2, 4, β-trichlorophenethyl) imidazole in place of the other starting materials of formula (II),

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-chlorophenethyl) imidazole,

1- (2,4-dibromo-β-chlorophenethyl) imidazole,

1- (β-chloro-4-fluorophenethyl) -imidazole,

1- (β-chloro-4-difluorophenethyl) imidazole,

1- (β-chloro-2-trifluoromethylphenethyl) imidazole,

1- (β-chloro-4--trifluoroethylphenethyl) imidazole,

1- (β-chloro-4--cyanophenethyl) imidazole,

1- (β-chloro-4-nitrophenethyl) imidazole, and

1- (β-chloro-2-thiocyanatophenethyl) imidazole,

The following 1- [β- (3 ', 4'-dichlorophenylthio) phenethyl] imidazole is produced, which can be converted to acid addition salts by treatment with acid.

1- [β- (3 ', 4'-dichlorophenylthio) phenethyl imidazole,

1- [4-ethyl-β- (3 ', 4'-dichlorophenylthio) phenethyl] imidazole,

1- (4-t-butyl-β- (3 ', 4'-dichlorophenylthio) phenethyl] imidazole nitrate, decomposed, 142.5 ° -146.5 ° C

1- [4-ethoxy-β- (3 ', 4'-dichlorophenethylthio) phenethyl] imidazole,

1- [4-n-butoxy-β- (3 ', 4'-dichlorophenethylthio) phenethyl] imidazole,

1- [4-t-butoxy-β- (3 ', 4'-dichlorophenethylthio) phenethyl] imidazole,

1- [3,4-dichloro-β- (3 ', 4'-dichlorophenethylthio) phenethyl] imidazole, nitrate, decomposition, 133 ° -137 ° C

1- [4-bromo-β- (3 ', 4'-dichlorophenylthio) phenethyl] imidazole,

1- [2,4-dibromo-β | (3 ', 4'-dichlorophenylthio) phenethyl] imidazole, nitrate, decomposition 132.5 ° -134.5 ° C

1- [4-fluoro-β- (3 ', 4'-dichlorophenylthio] phenethyl] imidazole,

1- [2,4-difluoro-β- (3 ', 4'-dichlorophenylthio) phenethyl] imidazole, oxalate, decomposition, 172.5-175 ° C

1- [2-trifluoromethyl-β)-(3 ', 4'-dichlorophenylthio) phenethyl] imidazole,

1- [4-trifluoromethyl-β (3 ', 4'-dichlorophenylthio] phenethyl] imidazole,

1- [4-cyano-β- (3 ', 4'-michloro phenyliophenethyl] imidazole,

1- [2-thiocyanate-β- (3 ', 4'-dichlorophenylthio) phenethyl] imidazole,

C) In this way, instead of the other starting materials of formula (III), 3, 4-dichlorothiophenol and 4-dichlorothiophenol and 2, 4-dichlorothiophenol and the starting of structural formula (II) mentioned above When the reaction is carried out using a substance, 1- [β- (R-thio) phenethyl] imidazole as listed below is produced, which is treated with an acid by a conventional method to prepare an acid addition salt.

1- [β-4'-chlorophenylthio) phenethyl] imidazole, oxalate, decomposition 147.5 ° -149 ° C

1- [β-2,4-dichlorophenylthio) phenethyl] imidazole,

1- [4-ethyl-β- (4'-chlorophenylthio) phenethyl] imidazole,

1- [4-ethyl-β- (2 ', 4'-dichlorophenylthio) phenethyl] imidazole,

1- [4-t-butyl-β- (4'-chlorophenylthio) phenethyl] imidazole,

1- [4-t-butyl-β- (2 ', 4'-dichlorophenylthio)] imidazole,

1- [4-ethoxy-β- (4'-chlorophenylthio) phenethyl] imidazole,

1- [4-ethoxy-β- (2 ', 4'-dichlorophenylthio) phenethyl] imidazole,

1- [4-n-butoxy-β- (4'-chlorophenylthio) phenethyl] imidazole,

1- [4-n-butoxy-β- (2 ', 4'-dichlorophenylthio) phenethyl] imidazole,

1- [4-t-butoxy-β- (4'-chlorophenylthio) phenethyl] imidazole,

1- [4-t-butoxy-β- (2 ', 4'-dichlorophenylthio) phenethyl] imidazole, hydroxide decomposition 190 ° -191 ° C

1- [4-chloro-β- (2 ', 4'-dichlorophenylthio) phenethyl] imidazole,

1- [2,4-dichloro-β- (4'-chlorophenylthio) phenethyl] imidazole, nitrate, melting point 169.5 ° -170 ° C

1- [2,4-dichloro-β- (2 ', 4'-dichlorophenylthio) phenethyl] imidazole, nitrate, melting point 150 ° -151 ° C

1- [3,4-dichloro-β- (2 ', 4'-dichlorophenylthio) phenethyl] imidazole, oxalate, decomposition 169 ° -171.5 ° C

1- [4-broro-β- (4'-chlorophenylthio) phenethyl] imidazole,

1- [4-bromo-β- (2'.4'-dichlorophenylthio) phenethyl] imidazole,

1- [2,4-dibromo-β- (4'-chlorophenylthio) phenethyl] imidazole,

1- [2,4-dibromo-β- (2 ', 4'-dichlorophenylthio) phenethyl] imidazole,

1- [4-fluoro-β- (4'-chlorophenylthio) phenethyl] imidazole,

1- [4-fluoro-β- (2 ', 4'-dichlorophenylthio) phenethyl] imidazole,

1- [2,4-difluoro-β- (4'-chlorophenylthio) phenethyl] imidazole,

1- [2,4-difluoro-β- (2 ', 4'-dichlorophenylthio) phenethyl] imidazole,

1- [2-trifluoromethyl-β- (4'-chlorophenylthio) phenethyl] imidazole,

1- [2-trifluoromethyl-β- (2 ', 4'-dichlorophenylthio) phenethyl] imidazole,

1- [4-trifluoromethyl-β- (4'-chlorophenylthio) phenethyl] imidazole

1- [4-trifluoromethyl-β- (2 ', 4'-dichlorophenylthio) phenethyl] imidazole,

1- [4-cyano-β- (4'-chlorophenylthio) phenethyl] imidazole,

1- [4-cyano-β- (2 ', 4'-dichlorophenylthio) phenethyl] imidazole,

1- [4-nitro-β- (4'-chlorophenylthio) phenethyl] imidazole,

1- [4-nitro-β- (2 ', 4'-dichlorophenylthio) phenethyl] imidazole.

Example 2

A) A solution of 1 g of 1- (2,4, β-trichlorophenethyl) imidazole and 10 ml of tetrahydrofuran, 40 ml of 1 g of 2,4-dichlorobenzylmercaptan and 220 mg of 56% sodium hydride Add to hydrofuran dispersion. After stirring for 12 hours at room temperature, the solvent is evaporated in vacuo and 10 ml water is added. The resulting soluble mixture is extracted with ether and the ether extract is washed with 50 ml of saturated brine. The organic layer was dried over sulfuric magnesium and evaporated to yield 1-2, 4-dichloro-β- (2 ', 4'-dichlorobenzylthio) phenethyl imidazole.

The free base nitrate is added dropwise with nitric acid to the free base in ether until complete precipitation is achieved. The product was collected and recrystallized with ethyl acetate to yield 1-2, 4-dichloro-β- (2 ', 4'-dichloro-benzylthio) phenethyl imidazole, nitrate. Decomposition, 133.5 ° -134.5 ℃

B) Similarly, reactions using the materials mentioned in Example 1 (B) instead of the other starting materials of formula (II) resulted in the following 1- [β- (2 ', 4'-dichlorobenzyl-thio ) Phenethyl] imidazole is produced and can be converted into an acid addition salt by treatment with an acid by conventional methods.

1- [β- (2 ', 4'-dichlorobenzylthio) phenethyl] imidazole,

1- [4-ethyl-β- (2 ', 4'-dichlorobenzylthio) phenethyl] imidazole,

1- [4-t-butyl-β- (2 ', 4'-dichlorobenzylthio) phenethyl] imidazole,

1- [4-ethoxy-β- (2 ', 4'-dichlorobenzylthio) phenethyl] imidazole,

1- [4-n-butoxy-β- (2 ', 4'-dichlorobenzylthio) phenethyl] imidazole,

1- [4-t-butoxy-β- (2 ', 4'-dichlorobenzylthio) phenethyl] imidazole,

1- [4-chloro-β- (2 ', 4'-dichlorobenzylthio) phenethyl] imidazole,

1- [3,4-dichloro-β- (2 ', 4'-dichlorobenzylthio) phenethyl] imidazole,

1- [3,4-dichloro-β- (2 ', 4'-dichlorobenzylthio) phenethyl] imidazole, nitrate, decomposition, 107 ° -110 ° C,

1- [4-bromo-β (2 ', 4'-dichlorobenzylthio) phenethyl] imidazole,

1- [2,4-dibromo-β- (2 ', 4'-dichlorobenzylthio) phenethyl] imidazole,

1- [4-fluoro-β (2 ', 4'-dichlorobenzylthio) phenethyl] imidazole,

1- [2,4-difluoro-β- (2 ', 4'-dichlorobenzylthio) phenethyl] imidazole,

1- [2-trifluoromethyl-β- (2 ', 4'-dichlorobenzylthio) phenethyl] imidazole,

1- [4-trifluoromethyl-β- (2 ', 4'-dichlorobenzylthio) phenethyl] imidazole,

1- [4-cyano-β- (2 ', 4'-dichlorobenzylthio) phenethyl] imidazole,

1- [4-nitro-β- (2 ', 4'-dichlorobenzylthio) phenethyl] imidazole,

1- [2-thiocyanato-β- (2 ', 4'-dichlorobenzylthio) phenethyl] imidazole,

C) As such, instead of the other starting materials of formula (III), 2,4-dichlorobenzylmercaptan, ie 4-chlorobenzylmercaptan, 3,4-dichlorobenzylmercaptan or heptylmercaptan and of Example 1 Using the starting material of formula (II) mentioned in (B), the following 1- [β- (R-thio) phenethyl] -imidazole was produced, which was added to the acid by treatment with acid by conventional methods. Convert to salt.

1- [β- (4'-chlorobenzylthio) phenethyl] imidazole,

1- [β- (3 ', 4'-dichlorobenzylthio) phenethyl] imidazole,

1- [β- (n-heptylthio) phenethyl] imidazole,

1- [4-ethyl-β- (4'-chlorobenzylthio) phenethyl imidazole

1- [4-ethyl-β- (3 ', 4'-chlorobenzylthio) phenethyl] imidazole,

1- [4-ethyl-β- (n-heptinthio) phenethyl] imidazole,

1- [4-t-butyl-β- (4'-chlorobenzylthio) phenethyl] imidazole, nitrate, decomposition 156-158.5 ° C

1- [4-t-butyl-β- (3 ', 4'-dichlorobenzylthio) phenethyl] imidazole,

1- [4-t-butyl-β- (n-heptylthio) phenethyl] imidazole,

1- [4-ethoxy-β- (4'-chlorobenzylthio) phenethyl] imidazole,

1- [4-ethoxy-β- (3 ', 4'-dichlorobenzylthio) phenethyl] imidazole,

1- [4-ethoxy-β- (n-heptylthio) phenethyl] imidazole,

1- [4-n-butoxy-β- (4'-chlorobenzylthio) phenethyl] imidazole, nitrate, decomposition 113 ° -114 ° C

1- [4-n-butoxy-β- (3 ', 4'-dichlorobenzylthio) phenethyl] imidazole,

1- [4-n-butoxy-β- (n-heptylthio) phenethyl] imidazole, oxalate, decomposition, 124.5-130 ° C.

1- [4-t-butoxy-β- (4'-chlorobenzylthio) phenethyl] imidazole,

1- [4-t-butoxy-β- (3 ', 4'-dichlorobenzylthio) phenethyl] imidazole,

1- [4-t-butoxy-β- (n-heptylthio) phenethyl] imidazole,

1- [4-chloro-β- (4'-chlorobenzylthio) phenethyl] imidazole, oxalate, decomposition 148 ° -149 ° C Nitrate melting point 103.5 ° -105.5 ° C

1- [4-chloro-β- (3 ', 4'-dichlorobenzylthio) phenethyl] imidazole,

1- [4-chloro-β- (n-heptylthio) phenethyl] imidazole,

1- [2,4-dichloro-β- (4'-chlorobenzylthio) imidazole, nitrate melting point 130.5 ° -132 ° C

1- [2,4-dichloro-β- (3 ', 4'-dichlorobenzylthio) phenethyl] imidazole, nitrate, decomposition 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, degradable 174-175 ° C

1- [3,4-dichloro-β- (3 ', 4'-dichlorobenzylthio) phenethyl] imidazole, oxalate, decomposition 176-177.5 ° C

1- [3,4-dichloro-β- (n-heptylthio) phenethyl] imidazole,

1- [4-bromo-β- (4'-chlorobenzylthio) phenethyl] imidazole,

1- [4-bromo-β- (3 ', 4'-dichlorobenzylthio) phenethyl] imidazole,

1- [4-bromo-β- (n-heptylthio) phenethyl] imidazole,

1- [2,4-dibromo-β- (4'-chlorobenzylthio) phenethyl] imidazole, nitrate, decomposition 126.5-128 ° C

1- [2,4-dibromo-β- (3 ', 4'-dichlorobenzylthio) phenethyl] imidazole,

1- [2,4-dibromo-β- (n-heptylthio) phenethyl] imidazole,

1- [4-fluoro-β- (4'-chlorobenzylthio) phenethyl] imidazole,

1- [4-fluoro-β- (3 ', 4'-dichlorobenzylthio) phenethyl] imidazole,

1- [4-fluoro-β- (n-heptylthio) phenethyl] imidazole,

1- [2,4-difluoro-β- (4'-chlorobenzylthio) phenethyl] imidazole,

1- [2,4-difluoro-β- (3 ', 4'-dichlorobenzylthio) phenethyl] imidazole, oxalate, decomposition 89.5-93.5 ° C

1- [2,4-difluoro-β- (n-heptylthio) phenethyl] imidazole,

1- [2-trifluoromethyl-β- (4'-chlorobenzylthio) phenethyl] imidazole,

1- [2-trifluoromethyl-β- (3 ', 4'-dichlorobenzylthio) phenethyl] imidazole, nitrate, decomposition 134.5-137 ° C

1- [2-trifluoromethyl-β- (n-heptylthio) phenethyl] imidazole,

1- [4-trifluoromethyl-β- (4'-chlorobenzylthio) phenethyl] imidazole,

1- [4-trifluoromethyl-β- (3 ', 4'-dichlorobenzylthio) phenethyl] imidazole,

1- [4-trifluoromethyl-β- (n-heptylthio) phenethyl] imidazole,

1- [4-cyano-β- (4'-chlorobenzylthio) phenethyl] imidazole,

1- [4-cyano-β- (3 ', 4'-dichlorobenzylthio) phenethyl] imidazole,

1- [4-cyano-β- (n-heptylthio) phenethyl] imidazole,

1- [4-nitro-β- (4'-chlorobenzylthio) phenethyl] imidazole,

1- [4-nitro-β- (3 ', 4'-dichlorobenzylthio) phenethyl] imidazole,

1- [4-nitro-β- (n-heptylthio) phenethyl] imidazole,

1- [2-thiocyanato-β- (4'-chlorobenzylthio) phenethyl] imidazole,

1- [2-thiocyanato-β- (3 ', 4'-dichlorobenzylthio) phenethyl] imidazole,

1- [2-thiocyanato-β- (n-heptylthio) phenethyl] imidazole,

Example 3

Example 1 using 1- (2, 4, β-trichlorophenethyl) imidazole and (1- (3, 4, β-trichlorophenethyl) imidazole as starting materials of formula (II) In the same manner as in A), 4-trifluoromethylthiophenol, 4-chloro-3-trifluoromethylthiophenol, 3, 4, 5-trichlorophenol and pentachlorothio as starting materials of formula (III) The use of phenol produces the following 1- [β- (R-thio) phenethyl] imidazole, which is converted to the acid addition salt by treatment with acid by conventional methods.

1- [2,4-dichloro-β- (4'-trifluoromethylphenylthio) phenethyl] imidazole, oxalate, decomposition 178-178.5 ° C

1- [2,4-dichloro-β- (4'-chloro-3'-trifluoromethyl-phenylthio) phenethyl] imidazole, hydroxide decomposition 186-187.5 ° C

1- [2,4-dichloro-β- (3 ', 4', 5'-trichlorophenylthio) phenethyl] imidazole, nitrate, decomposition 178-185 ° C

1- [2,4-dichloro- (pentachlorophenylthio) phenethyl] imidazole, nitrate, decomposition 201-202.5 ° C

1- [3,4-dichloro-β- (4'-trifluoromethylphenylthio) phenethyl] imidazole, oxalate, decomposition 170-171 ° C

1- [3,4-dichloro-β- (4'-chloro-3'trifluoromethyl-phenylthio) phenethyl] imidazole, oxalate, decomposition 165-166 ° C

1- [3,4-dichloro-β- (3 ', 4', 5'-trichlorophenylthio) phenethyl] imidazole,

1- [3,4-dichloro-β- (pentachlorophenylthio) phenethyl] imidazole,

Example 4

Description of Example 2 (A) The procedure enumerated was repeated and reacted using another material as in the following example instead of 2,4-diclobenzyl mercaptan of the structural formula III.

Ethyl mercaptan

Pentyl mercaptan

Octyl mercaptan

Nonyl Mercaptan

Dodecyl Mercaptan

Octadecyl mercaptan

3-phenylpropyl mercaptan

Cyclophenyl propyl mercaptan

Cyclohexyl mercaptan

Cyclohexyl methyl mercaptan

Cyclohexyl methyl mercaptan

Allyl Mercaptan

2-octyl mercaptan

3-phenyl-2-propenyl mercaptan

3- (4-chlorophenyl) -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-t-butoxybenzyl mercaptan

2, 4, 5-trichlorobenzyl mercaptan

4-bromobenzyl mercaptan

4-fluorobenzyl mercaptan

4-nitrobenzyl mercaptan

4-cyclobenzyl mercaptan

The following 1- [2,4-diclo-β (R-thio) phenethyl] imidazole was produced from the reaction described above, treated with an acid by a conventional method to give an acid addition salt as indicated below. Obtain a substance with characteristics

1- [2,4-dichloro-β- (ethylthio) phenylethyl] imidazole,

Solidification at 1- [2,4-dichloro-β- (n-fetylthio) phenethyl] imidazole, oxalate, 99 ° C.,

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, gels at 82.5 占 폚.

1- [2,4-dichloro-β- (3-dodecylthio) phenethyl] imidazole, oxalate, melting point 124.5 ° C

Gels at 1- [2,4-dichloro-β- (octadecylthio) phenethyl] imidazole, oxalate, 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- (cyclopentylpropylthio) phenethyl] imidazole,

1- [2,4-dichloro-β- (cyclohexylthio) phenethyl] imidazole, nitrate, melting point 114.5-117.5 ° C

1- [2,4-dichloro-β- (cyclohexylmethylthio) phenethyl] imidazole, oxalate, (decomposition) 122.5-140 ° C

1- [2,4-dichloro-β- (cyclohexylmethylthio) phenethyl] imidazole, oxalate (decomposition) 104-108.5 ° C

1- [2,4-dichloro-β- (cyclohexylmethylthio) phenethyl] imidazole,

1- [2,4-dichloro-β- (allylthio) phenethyl] imidazole, oxalate, melting point 84.5-123 ° C

1- [2,4-dichloro-β- (2-octenylthio) phenethyl] imidazole, melting point 112.5-116.5 ° C.

1- [2,4-dichloro-β- (3-phenyl-2-propenylthio) phenethyl] imidazole, (decomposition) 151-160.5 ° C

1- [2,4-dichloro-β- (4'-chlorophenyl)-(2-propenylthio) phenethyl] imidazole, oxalate, nitrate, (decomposition) 123-126 ° C

1- [2,4-dichloro-β- (2-octenylthio) phenethyl] imidazole, oxalate, (decomposition) 118-119.5 ° C

1- [2,4-dichloro-β- (benzylthio) phenethyl] imidazole, nitrate, melting point 110-112 ° C

1- [2,4-dichloro-β- (4-methylbenzylthio) phenethyl] imidazole, oxalate, melting point 110.5-112 ° C

1- [2,4-dichloro-β- (4'-t-butylbenzylthio) phenethyl] imidazole, nitrate, (decomposition) 162.5-163 ° C

1- [2,4-dichloro-β- (4'-trifluoromethylbenzylthio) phenethyl] imidazole, nitrate, (decomposition) 112-114 ° C

1- [2,4-dichloro-β- (4'-methoxybenzylthio) phenethyl] imidazole, oxalate (decomposition) 118-119.5 ° C

1- [2,4-dichloro-β- (3 ', 4', 5-trimethoxybenzylthio) phenethyl] imidazole, oxalate, gelled at 147 ° C.

1- [2,4-dichloro-β- (4'-n-butoxybenzylthio) phenethyl] imidazole,

1- [2,4-dichloro-β- (2 ', 4', 5'-trichlorobenzylthio) phenethyl] imidazole, nitrate, (decomposition) 172.5-173.5 ° C

1- [2,4-dichloro-β- (4'-bromobenzylthio) phenethyl] imidazole, nitrate, (decomposition) 137-138 ° C

1- [2,4-dichloro-β- (4'-fluorobenzylthio) phenethyl] imidazole, nitrate, (decomposition) 104.5-107.5 ° C

1- [2,4-dichloro-β- (4'-nitrobenzylthio) phenethyl] imidazole, nitrate, (decomposition) 129.5-132 ° C

1- [2,4-dichloro-β- (4'-cyanobenzylthio) phenethyl] imidazole, nitrate, (decomposition) 119.5-123 ° C

Example 5

Procedures listed in step A of Example 1 using 1- (4, β-dichloro-phenylethyl) imidazole and 1- (2, 4, β-trichlorophenylethyl) imidazole as starting materials of formula II Was repeated and the following material was reacted using starting material instead of 3, 4-dichlorothiophenol of Structural Formula III.

Thiophenol

β-thiophenol

4-methyl thiophenol

4-ethoxy thiophenol

3-methoxy thiophenol

2-chlorothiophenol

2,5-dichlorothiophenol

4-bromo thiophenol

5-fluoro thiophenol

4-nitro thiophenol

4-amino thiophenol

4-acetamido thiophenol and

4-cyano thiophenol.

From the reaction, the following 1- [4-chloro-β- (R-thio) phenylethyl] imidazole and 1- [2,4-dichloro-β- (R-thio) phenylethyl] imidazole are produced. When treated in a conventional manner, a substance characterized by acid addition salts is obtained.

1- [4-chloro-β- (phenylthio) phenethyl] imidazole, oxalate, (decomposition) 166-167 ° C

1- [4-chloro-β- (2-naphthylthio) phenethyl] imidazole, oxalate, melting point 193.5-194 ° C

1- [4-chloro-β- (4'-methylphenylthio) phenethyl] imidazole, oxalate, (decomposition) 199.5-200 ° C

1- [4-chloro-β- (4'-methoxyphenylthio) phenethyl] imidazole, oxalate, (decomposition) 177-178 ° C

1- [4-chloro-β- (3'-methoxyphenylthio) phenethyl] imidazole, oxalate, melting point 164.5-165.5 占 폚

1- [4-chloro-β- (2'-chlorophenylthio) phenethyl] imidazole, oxalate, melting point 177-178 ° C

1- [4-chloro-β- (3'-chlorophenylthio) phenethyl] imidazole, oxalate, melting point 169.5-171.5 deg.

1- [4-chloro-β- (2 ', 5'-dichlorophenylthio) phenethyl] imidazole, oxalate, melting point 181.5-183.5 ° C

1- [4-chloro-β- (4'-bromophenylthio) phenethyl] imidazole, oxalate, (decomposition) 185-186.5 占 폚

1- [4-chloro-β- (4'-fluorophenylthio) phenethyl] imidazole, oxalate, melting point, 182.5-183 占 폚

1- [4-chloro-β- (4'-nitrophenylthio) phenethyl] imidazole, oxalate, melting point 203-204.5 deg.

1- [4-chloro-β- (4'-aminophenylthio) phenethyl] imidazole,

1- [4-chloro-β- (4'-acetaminophenylthio) phenethyl] imidazole, oxalate, melting point 149.5-152 ° C

1- [4-chloro-β- (4'-cyanophenylthio) phenethyl] imidazole,

1- [2,4-dichloro-β- (phenylthio) phenethyl] imidazole,

1- [2,4-dichloro-β- (2-naphthylthio) phenethyl] imidazole,

1- [2,4-dichloro-β- (4'-methylphenylthio) phenethyl] imidazole,

1- [2,4-dichloro-β- (4'-methoxyphenylthio) phenethyl] imidazole,

1- [2,4-dichloro-β- (3'-methoxyphenylthio) phenethyl] imidazole,

1- [2,4-dichloro-β- (2'-chlorophenylthio) phenethyl] imidazole,

1- [2,4-dichloro-β- (3'-chlorophenylthio) phenethyl] imidazole,

1- [2,4-dichloro-β- (2 ', 5'-dichlorophenylthio) phenethyl] imidazole,

1- [2,4-dichloro-β- (4'-bromophenylthio) phenethyl] imidazole,

1- [2,4-dichloro-β- (4'-fluorophenylthio) phenethyl] imidazole,

1- [2,4-dichloro-β- (4'-nitrophenylthio) phenethyl] imidazole,

1- [2,4-dichloro-β- (4'-aminophenylthio) phenethyl] imidazole,

1- [2,4-dichloro-β- (4'-acetamidophenylthio) phenethyl] imidazole,

1- [2,4-dichloro-β- (4'-cyanophenylthio) phenethyl] imidazole

Example 6

Tetrahydrofuran containing 1 ml triethylamine, 0.5 ml hexanoyl chloride in a solution containing 400 mg of 1- [4-chloro-β- (4'-aminophenylthio) phenethyl] imidazole hydrate in 20 ml. Add. After shaking for 30 minutes at room temperature, the solvent is evaporated under vacuum and water soluble potassium carbonate is added to the residue. The reaction mixture is extracted with dichloromethane to acidify the organic phase with hydroxyl. The product forming the precipitate was filtered off and then recrystallized from acetone and ethyl acetate to give 1- [4-chloro-β- (4'-hexanoylaminophenylthio) phenethyl] imidazole hydrochloride, (melting point 98.5-102 ° C.) Get

Similarly, the reaction of hexanoyl chloride with other acid chlorides (propionyl chloride n-vareryl chloride, decanonyl chloride and the like) instead yields the following materials.

1- [4-chloro-β- (4'-propionyl aminophenylthio) phenethyl] imidazole oxalate,

1- [4-chloro-β- (4'-valeroyl aminophenylthio) phenethyl] imidazole oxalate,

1- [4-chloro-β- (4'-decanoylaminophenylthio) phenethyl] imidazole hydroxide,

Example 7

1- [4-Chloro-β- (4'-chlorophenylthio) phenethyl] imidazole nitrate was treated with water-soluble potassium carbonate until the pH reached 11 to give the free base of 1- [4-chloro-β- (4 '-Chlorophenylthio) phenethyl] imidazole is separated and extracted with dichloromethane. The extract is dried over magnesium sulfate and evaporated. The resulting residue was added to a solution in which 700 mg of 85% m-chlorobenzene acid was dissolved in 50 ml chloroform slowly while shaking in 50 ml chloroform at 0 ° C. Shaking is continued at 0 ° C. for about 3 hours when the addition process is complete. The reaction mixture is then washed with water soluble potassium carbonate and water soluble sodium chloride and then evaporated to dryness over magnesium sulfate. Crystallization of this residue in benzene yields 1- [4-chloro-β- (4'-chlorophenylsulfinyl) phenethyl] imidazole (melting point 139-140 ° C) and the hydroxide is characterized by a melting point of 167-167.5 ° C. .

Similarly, repeating the above procedure for 1- [β (R-thio) phenethyl] imidazole obtained in Examples 1 to 6 yields the corresponding 1- [β (R-sulfinyl) phenylethyl] imidazole. It is converted to a conventional method to obtain the acid addition salt as follows.

1- [2,4-dichloro-β- (m-dodecylsulfinyl) phenethyl] imidazole, oxalate, (decomposition) 134-138 ° C

1- [4-β- (4'-chlorobenzylsulfinyl) phenethyl] imidazole, nitrate, (decomposition) 161.5-162 占 폚, and the like.

Example 8

1- [4-chloro-β- (4'-chlorophenylthio) phenethyl] imidazole nitrate (1 g) was treated with water-soluble potassium carbonate until the pH reached 11, where 1- [4- Chloro-β- (4'-chlorophenylethyl) -phenethyl] imidazole was separated and extracted with dichloromethane. The extract is evaporated to dryness with magnesium sulfate. To the reaction mixture in 50 ml chloroform at room temperature is added slowly while shaking the solution of 1.7 g of 85% m-chloro-perbenzoic acid in 50 ml chloroform. When the addition is complete the shaking at room temperature is continued for almost 24 hours. The reaction mixture is then washed with water soluble potassium carbonate and sodium chloride and evaporated to dryness with magnesium sulfate.

The residue was crystallized from benzene to give 1- [4-chloro-β- (4'-chlorophenylsulfinyl) phenethyl] imidazole (melting point, 176-178.5 ° C).

Similarly, for the 1- [β- (R-thio) phenethyl] imidazole and acid addition salts obtained in Examples 1 to 6, the above procedure was continued for the corresponding 1- [β- (R-sulfonyl) -phene. Ethyl] imidazole is produced and converted to the conventional method to obtain the following acid addition salt.

1- [2,4-dichloro-β- (dodecylsulfonyl) phenethyl] imidazole, oxalate, (decomposition) 105.5-110 ° C

1- [4-chloro-β- (4'-chlorobenzylsulfonyl) phenethyl] imidazole nitrate (decomposition) 181 ° C

Example 9

2.53 g of 1- [β-chloro-methylthiophenylethyl] imidazole in 150 ml chloroform at 0 ° C. in a drop of 85% m-chloroperbenzoic acid solution in chloroform (2 g / 100 ml) over one hour or more. It is added to the dissolved shaking solution. After 6 hours, the reaction solution is washed with water-soluble potassium carbonate and water. The organic phase is separated and dried over magnesium sulfate. The solvent is evaporated to give 1- [β-chloro-4-methylsulfinylphenylethyl] imidazole.

Similarly, instead of 1- [β-chloro-4-methylthiophenethyl] imidazole, if reacted with another 1- [β-chloro-thiophenylethyl] imidazole, i.e., the following material, 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 and

1- [β-chloro-4- (4'-chlorophenylthio) phenethyl] imidazole,

The reaction produces the following compounds.

1- [β-chloro-4-t-butylsulfinylphenethyl] imidazole,

1- [β-chloro-4-benzylsulfinylphenethyl] imidazole,

1- [β-chloro-4- (4'-chlorobenzylsulfinyl) phenethyl] imidazole,

1- [β-chloro-4- (4'-methoxybenzylsulfinyl) phenethyl] imidazole,

1- [β-chloro-4-phenylsulfinylphenethyl] imidazole, and

1- [β-4- (4'-chlorophenylsulfinyl) phenethyl] imidazole

Example 10

The procedure listed in item A of Example 1 using 3, 4-dichlorothiophenol as starting material of Structural Formula III was repeated to produce 1- (2,4-β-trichlorophenethyl) as another starting material of Structural Formula II. Imidazoles, or reactions of

1- (β-chloro-4-methylthiophenethyl) imidazole,

1- (β-chloro-4-t-benzylthiophenethyl) 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-phenylthiophenethyl) 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-chlorobenzylsulfinyl) phenethyl] imidazole,

1- (β-chloro-4- (4'-methopybenzylsulfinyl) phenethyl] imidazole,

1- (β-chloro-4-phenylsulfinylphenethyl) imidazole,

1- (β-chloro-4- (4'-chlorophenylsulfinyl) phenethyl] imidazole,

1- (β-chloro-4-methylsulfonylphenethyl) imidazole,

1- (β-chloro-4-t-butylsulfonylphenethyl) imidazole,

1- (β-chloro-4-benzylsulfonylphenethyl) imidazole,

1- (β-chloro-4- (4'-chlorobenzylsulfonyl) phenethyl] imidazole,

1- (β-chloro-4- (4'-methoxybenzylsulfonyl) phenethyl] imidazole,

1- (β-chloro-4-phenylsulfonylphenethyl] imidazole and

1- (β-chloro-4- (4'-chlorophenylsulfonyl) phenethyl] imidazole,

From the reaction, the following 1- [β- (3 ', 4'-dichlorophenylthio) phenethyl] imidazole is produced.

1- [4-methylthio-β- (3 ', 4'-dichlorophenylthio) phenethyl] imidazole,

1- [4-t-butylthio-β- (3 ', 4'-dichlorophenylthio) phenethyl] imidazole,

1- [4-benzylthio-β- (3 ', 4'-dichlorophenylthio) phenethyl] imidazole,

1- [4- (4-chlorobenzylthio) -β- (3 ', 4'-dichlorophenylthio) phenethyl] imidazole,

1- [4- (4-methoxybenzylthio) -β- (3 ', 4'-dichlorophenylthio) phenethyl] imidazole,

1- [4-phenylthio-β- (3 ', 4'-dichlorophenylthio) phenethyl] imidazole,

1- [4-(4-chlorophenylthio) -β- (3 ', 4'-dichlorophenylthio) phenethyl] imidazole,

1- [4-methylsulfinyl-β- (3 ', 4'-dichlorophenylthio) phenethyl] imidazole,

1- [4-t-butylsulfinyl-β- (3 ', 4'-dichlorophenylthio) phenethyl] imidazole,

1- [4-benzylsulfinyl-β- (3 ', 4'-dichlorophenylthio) phenethyl] imidazole,

1- [4- (4-chlorobenzylsulfinyl) -β- (3 ', 4'-dichlorophenylthio) phenethyl] imidazole,

1- [4- (4-methoxybenzylsulfinyl) -β- (3 ', 4'-dichlorophenylthio) phenethyl] imidazole,

1- [4-phenylsulfinyl-β- (3 ', 4'-dichlorophenylthio) phenethyl] imidazole,

1- [4-phenylsulfinyl-β- (3 ', 4'-dichlorophenylthio) phenethyl] imidazole,

1- [4- (4-chlorophenylsulfinyl) -β- (3 ', 4'-dichlorophenylthio) phenethyl] imidazole,

1- [4-methylsulfonyl-β- (3 ', 4'-dichlorophenylthio) phenethyl] imidazole,

1- [4-butylsulfonyl-β- (3 ', 4'-dichlorophenylthio) phenethyl] imidazole,

1- [4-benzylsulfonyl-β- (3 ', 4'-dichlorophenylthio) phenethyl] imidazole,

1- [4- (4-chlorobenzylsulfonyl) -β- (3 ', 4'-dichlorophenylthio) phenethyl] imidazole,

1- [4- (4-methoxybenzylsulfonyl) -β- (3 ', 4'-dichlorophenylthio) phenethyl] imidazole,

1- [4-phenylsulfonyl-β- (3 ', 4'-dichlorophenylthio) phenethyl] imidazole,

1- [4- (4-chlorophenylsulfonyl) -β- (3 ', 4'-dichlorophenylthio) phenethyl] imidazole,

Example 11

The process listed in item A of Example 2 using 4-chlorobenzyl mercaptan as a starting material of Structural Formula III was repeated, and the starting material of Structural Formula II listed in Example 10, which is another starting material, was used as the starting material of Structural Formula II. The use of-(2, 4, β-trichlorophenethyl) imidazole produces the following 1- [3- (4'-chlorobenzylthio) phenethyl] imidazole.

1- [4-methylthio-β- (4'-chlorobenzylthio) phenethyl] imidazole,

1- [4-t-butylthio-β- (4'-chlorobenzylthio) phenethyl] imidazole,

1- [4-benzylthio-β- (4'-chlorobenzylthio) phenethyl] imidazole,

1- [4- (4-chlorobenzylthio) -β- (4'-chlorobenzylthio) phenethyl] imidazole,

1- [4- (4-methoxybenzylthio) -β- (4'-chlorobenzylthio) phenethyl] imidazole,

1- [4-phenylthio-β- (4'-chlorobenzylthio) phenethyl] imidazole,

1- [4- (4-chlorophenylthio) -β- (4'-chlorobenzylthio) phenethyl] imidazole,

1- [4-methylsulfinyl-β- (4'-chlorobenzylthio) phenethyl] imidazole,

1- [4-t-butylsulfinyl-β- (4'-chlorobenzylthio) phenethyl] imidazole,

1- (4'-benzylsulfinyl-β- (4'-chlorobenzylthio) phenethyl] imidazole,

1- [4- (4-chlorobenzylsulfinyl) -β- (4'-chlorobenzylthio) phenethyl] imidazole,

1- [4- (4-methoxybenzylsulfinyl) -β- (4'-chlorobenzylthio) phenethyl] imidazole,

1- [4-phenylsulfinyl-β- (4'-chlorobenzylthio) phenethyl] imidazole,

1- [4- (4-chlorophenylsulfinyl) -β- (4'-chlorobenzylthio) phenethyl] imidazole,

1- [4-methylsulfonyl-β- (4'-chlorobenzylthio) phenethyl] imidazole,

1- [4-t-butylsulfonyl-β- (4'-chlorobenzylthio) phenethyl] imidazole,

1- [4-benzylsulfonyl-β- (4'-chlorobenzylthio) phenethyl] imidazole,

1- [4-benzylsulfonyl-β- (4'-chlorobenzylthio) phenethyl] imidazole,

1- [4- (4-chlorobenzylsulfonyl) -β- (4'-chlorobenzylthio) phenethyl] imidazole,

1- [4- (4-methoxybenzylsulfonyl) -β- (4'-chlorobenzylthio) phenethyl] imidazole,

1- [4-phenylsulfonyl-β- (4'-chlorobenzylthio) phenethyl] imidazole,

1- [4- (4-chlorophenylsulfonyl) -β- (4'-chlorobenzylthio) phenethyl] imidazole,

Example 12

To the product obtained in the procedure of Examples 10 and 11, the procedure listed in Example 7 was repeated (using an appropriate amount of m-chloroperbenzoic acid) to give the following 1- [β-R-sulfinyl) phenethyl] Produces a dazole.

1- [4-phenylthio-β- (3 ', 4'-dichlorophenylsulfinyl) phenethyl] imidazole,

1- [4- (4-chlorophenylthio-β- (3 ', 4'-dichlorophenylsulfinyl) phenethyl] imidazole,

1- [4-methylsulfinyl-β- (3 ', 4'-dichlorophenylsulfinyl) phenethyl] imidazole,

1- [4-t-butylsulfinyl-β- (3 ', 4'-dichlorophenylsulfinyl) phenethyl] imidazole,

1- [4-benzylsulfinyl-β- (3 ', 4'-dichlorophenylsulfinyl) phenethyl] imidazole,

1- [4- (4-chlorobenzylsulfinyl) -β- (3 ', 4'-dichlorophenylsulfinyl) phenethyl] imidazole,

1- [4- (4-methoxybenzylsulfinyl) -β- (3 ', 4'-dichlorophenylsulfinyl) phenethyl] imidazole,

1- [4-phenylsulfinyl-β- (3 ', 4'-dichlorophenylsulfinyl) phenethyl] imidazole,

1- [4- (4-chlorophenylsulfinyl) -β- (3 ', 4'-dichlorophenylsulfinyl) phenethyl] imidazole,

1- [4-methylsulfonyl-β- (3 ', 4'-dichlorophenylsulfinyl) phenethyl] imidazole,

1- [4- (4-chlorophenylsulfonyl) -β- (3 ', 4'-dichlorophenylsulfinyl) phenethyl] imidazole,

1- [4-methylsulfonyl-β- (3 ', 4'-dichlorophenylsulfinyl) phenethyl] imidazole,

1- [4-t-butylsulfonyl-β- (3 ', 4'-dichlorophenylsulfinyl) phenethyl] imidazole,

1- [4-benzylsulfonyl-β- (3 ', 4'-dichlorophenylsulfinyl) phenethyl] imidazole,

1- [4- (4-chlorobenzylsulfonyl) -β- (3 ', 4'-dichlorophenylsulfinyl) phenethyl] imidazole,

1- [4- (4-methoxybenzylsulfonyl) -β- (3 ', 4'-dichlorophenylsulfinyl) phenethyl] imidazole,

1- [4-phenylsulfonyl-β- (3 ', 4'-dichlorophenylsulfinyl) phenethyl] imidazole,

1- [4- (4-chlorophenylsulfonyl) -β- (3 ', 4'-dichloro) phenethyl] imidazole,

1- [4--phenylthio-β- (4'-chlorobenzylsulfinyl) phenethyl] imidazole,

1- [4- (40chloro phenylthio) -β- (4'-chlorobenzyl sulfinyl) phenethyl] imidazole,

1- [4-methylsulfinyl-β- (4'-chlorobenzylsulfinyl) phenethyl] imidazole,

1- [4-t-butylsulfinyl-β- (4'-chlorobenzylsulfinyl) phenethyl] imidazole,

1- (4'-benzylsulfinyl-β- (4'-chlorobenzylsulfinyl) phenethyl] imidazole,

1- [4- (4-chlorobenzylsulfinyl) -β- (4'-chlorobenzylsulfinyl) phenethyl] imidazole,

1- [4- (4-methoxybenzylsulfinyl) -β- (4'-chlorobenzylsulfinyl) phenethyl] imidazole,

1- [4-phenylsulfinyl-β- (4'-chlorobenzylsulfinyl) phenethyl] imidazole,

1- [4- (4-chlorophenylsulfinyl) -β- (4'-chlorobenzylsulfinyl) phenethyl] imidazole,

1- [4-methylsulfonyl-β- (4'-chlorobenzylsulfinyl) phenethyl] imidazole,

1- [4-t-butylsulfonyl-β- (4'-chlorobenzylsulfinyl) phenethyl] imidazole,

1- [4-benzylsulfonyl-β- (4'-chlorobenzylsulfinyl) phenethyl] imidazole,

1- [4- (4-chlorobenzylsulfonyl) -β- (4'-chlorobenzylsulfinyl) phenethyl] imidazole,

1- [4- (4-methoxybenzylsulfonyl) -β- (4'-chlorobenzylsulfinyl) phenethyl] imidazole,

Example 13

The procedure listed in Example 8 was repeated on the compounds to be obtained in Examples 10 and 11 to produce the following 1- [β- (R-sulfonyl) phenethyl] imidazole.

1- [4-phenylthio-β- (3 ', 4'-dichlorophenylsulfonyl) phenethyl] imidazole,

1- [4- (4-chlorophenylthio) -β- (3 ', 4'-dichlorophenylsulfonyl) phenethyl] imidazole,

1- [4-phenylsulfinyl-β- (3 ', 4'-dichlorophenylsulfonyl) phenethyl] imidazole,

1- [4- (4-chlorophenylsulfinyl) -β- (3 ', 4'-dichlorophenylsulfonyl) phenethyl] imidazole,

1- [4-methylsulfonyl-β- (3 ', 4'-dichlorophenylsulfonyl) phenethyl] imidazole,

1- [4-t-butylsulfonyl-β- (3 ', 4'-dichlorophenylsulfonyl) phenethyl] imidazole,

1- [4-benzylsulfonyl-β- (3 ', 4'-dichlorophenylsulfonyl) phenethyl] imidazole,

1- [4- (4-chlorobenzylsulfonyl) -β- (3 ', 4'-dichlorophenylsulfonyl) phenethyl] imidazole,

1- [4-phenylsulfonyl-β- (3 ', 4'-dichlorophenylsulfonyl) phenethyl] imidazole,

1- [4- (4-chlorophenylsulfonyl) -β- (3 ', 4'-dichlorophenylsulfonyl) phenethyl] imidazole,

1- [4-phenylthio-β- (4'-chlorobenzylsulfonyl) phenethyl] imidazole,

1- [4- (4-chlorophenylthio) -β- (4'-chlorobenzylsulfonyl) phenethyl] imidazole,

1- [4--phenylsulfonyl-β- (4'-chlorobenzylsulfonyl) phenethyl] imidazole,

1- [4- (4-chlorophenylsulfinyl) -β- (4'-chlorobenzylsulfonyl) phenethyl] imidazole,

1- [4-methylsulfonyl-β- (4'-chlorobenzylsulfonyl) phenethyl] imidazole,

1- [4-t-butylsulfonyl-β- (4'-chlorobenzylsulfonyl) phenethyl] imidazole,

1- [4-benzylsulfonyl-β- (4'-chlorobenzylsulfonyl) phenethyl] imidazole,

1- [4- (4-chlorobenzylsulfonyl) -β- (4'-chlorobenzylsulfonyl) phenethyl] imidazole,

1- [4- (4-methoxybenzylsulfonyl) -β- (4'-chlorobenzylsulfonyl) phenethyl] imidazole,

1- [4-phenylsulfonyl-β- (4'-chlorobenzylsulfonyl) phenethyl] imidazole,

1- [4- (4-chlorophenylsulfonyl) -β- (4'-chlorobenzylsulfonyl) phenethyl] imidazole,

Example 14

Using the reactant represented by the special 1- [β- (R-thio) phenethyl] imidazole, the procedure listed in Example 1 was repeated to produce the following compound, as indicated below. Processing according to the method gives a substance characterized by acid addition salts.

1- [2,4-dichloro-β- (4'-nitro-3'-trifluoromethylphenylthio) phenethyl] imidazole, nitrate (decomposition) 127.5-130.5 ° C

1- [4-trifluoromethyl-β (4'-t-butylphenylthio) phenethyl] imidazole, oxalate, melting point 161-162 ° C

1- [2,4-dimethyl-β (3 ', 4'-dichlorophenylthio) phenethyl] imidazole, nitrate (decomposition) 165.5-166 ° C

1- [4-methoxy-β- (3 ', 4'-dichlorophenylthio) phenethyl] imidazole, oxalate, melting point 145.5 占 폚

1- [4-methoxy-β- (4'-t-butylphenylthio) phenethyl] imidazole, oxalate, melting point 139.5-141.5 ° C

1- [2,4-dimethoxy-β- [3 ', 4'-dichlorophenylthio) phenethyl] imidazole, nitrate, (decomposition) 155.5-158 ° C

1- [4-nitro-β- (pentachlorophenylthio) phenethyl] imidazole, nitrate, (decomposition) 163.5-165.5 ° C

1- [2,4-dichloro-β- (n-butoxyphenylthio) phenethylimidazole, oxalate melting point 143-144 ° C

1- [4-cyano-β- (pentachlorophenylthio) phenethyl) imidazole, nitrate, melting point 182.5-183.5 ° C. (bubble formation)

1- [4-n-butylthio-β- (4'-chlorophenylthio) phenethyl] imidazole, and

1- [4-methylthio-β- (3 ', 4'-dichlorophenylthio) phenethyl imidazole

Example 15

Reacting the reactants as indicated by the desired particular 1- [β- (R-thio) phenethyl] imidazole according to the method listed in Example 2 yields the following compounds, as indicated below. Treatment with an acid makes it a characteristic compound of acid addition salts.

1- [2,4-difluoro-β- (n-nonylthio) phenethyl] imidazole oxalate, melting point 79.5-84 ° C

1- [2,4-dimethyl-β- (4'-chlorobenzylthio) phenethyl] imidazole oxalate (decomposition)

1- [4-methoxy-β- (3-phenylpropylthio) phenethyl] imidazole hydrate, 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, solidifies at 86 ° C. and bubbles at 86-121.5 ° C.

1- [4-chloro-β- (ethylthio) phenethyl] imidazole, oxalate melting point 157-158 ° C

1- [2,4-dichloro-β- (n-undec-10-enylthio) phenethyl] imidazole, oxalate, melting point 82-107 ° C

1- [2,4-dichloro-β- (3- (4'-methylphenyl) prop-2-enylthio) phenethyl] imidazole, nitrate, melting point 133.5-137 ° C

1- [2,4-dichloro-β- (3- (4'-t-butylphenyl) prop-2-ethylthio) phenethyl] imidazole, nitrate, melting point 147-153.5 ° C

1- [2,4-dichloro-β- (4-phenylbut-3-enylthio) phenethyl] imidazole

1- [2,4-dichloro-β- (3- (4'-chlorophenyl) propylthio) phenethyl] imidazole, nitrate, melting point 111-113 ° C

1- [2,4-dichloro-β- (prop-2-aniylthio) phenethyl] imidazole

1- [4-methylthio-β- (3 ', 4'-dichloro-benzylthio) phenethyl] imidazole

1- [4-n-butylthio-β- (4'-chlorobenzylthio) phenethyl] imidazole

1- [2,4-dichloro-β- (n-hexylthio) phenethyl] imidazole

1- [2,4-dibromo-β- (n-hexylthio) phenethyl] imidazole

1- [2,4-dibromo-β- (n-octylthio) phenethyl] imidazole

1-2, 4-difluoro-β- (n-octylthio) phenethyl] imidazole

1- [2,4-difluoro-β- (n-decylthio) phenethyl] imidazole

Example 16

1- [4-Chloro-β-4'-chlorophenylthio) phenethyl] imidazole contained in 100 ml of dichloromethane is shaken with a considerably dilute carbocarbonate solution until the salt is completely dissolved. The organic layer is separated, washed with water and dried over magnesium sulfate. Evaporation of the solvent produces a gummy 1- [4-chloro-β-4'-chloro-phenylthio) phenethyl] imidazole.

In a similar manner the acid addition salts of formula (I) can be changed to the corresponding compounds in base form, as in the examples below.

1- [2,4-dichloro-β- (3 ', 4'-dichlorophenylthio) phenethyl] imidazole

1- [2,4-dichloro-β- (2 ', 4'-dichlorophenylthio) 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 17

Nitric acid (70%, d = 1.42) was added to the shaking solution of 2.5 g of 1- [4-chloro-β-4'-chlorophenylthio) phenethyl] imidazole dissolved in 40 ml anhydrous ether until complete precipitation. Add drops. Recrystallization from ethyl acetate gives 1- [4-chloro-β- (4'-chlorophenylthio) phenethyl] imidazole nitrate (melting point 136.5-137.5 ° C.)

In a similar manner the compounds of formula (I) in base form can be converted to acid addition salts by treatment with acids of conventional methods.

Example 18

The antimicrobial action of the compounds of the present invention and kephrin can be illustrated by the following procedure.

Streptococcus whicalis is a Gram-positive bacterium and is cultured at 37 ° C. in brain-hearted Huzonbros (Diffco) medium. After incubation for 24 hours, the culture solution is diluted to a concentration of 1 × 10 ⁸ cells / ml with medium. 6.05 milliliters are added to the test compound diluted in various dilutions in this suspension.

Test compounds are dissolved in dimethylsulfoxide, ethanol or water at a concentration of 10 μg / ml and then diluted with sterile water to make a stock solution containing 100 μg / ml. Proper dilution is made from this stock solution. Approximately 4 ml of each dilution is added to a sterile test tube and 0.05 ml of each of the above injections is added to each test tube. Incubate for 24 hours and determine the minimum inhibitory concentration, ie the concentration at which the bacteria have not grown at all.

TABLE 1

Example 19

Antifungal action of the compounds of the present invention and myconazole was illustrated by the following procedure.

Tricofiton rubrum is incubated for 14 days at room temperature in sabrod glucose KEPCO medium. The fungi formed on the agar slope medium are removed and homogenized in sabroglucose broth to form a fine suspension. The suspension is diluted to a constant concentration (OD of 600 mm to 0.1) and 0.05 ml of each test compound is added to the diluted solution.

The test compound is dissolved in dimethylsulfoxide, ethanol and water to a concentration of 10 μg / ml and then diluted with sterile water to a concentration of 100 μg / ml. Proper dilution is made from this stock solution. Approximately 4 ml of each dilution is added to a sterile test tube and 0.05 ml of the prepared infusion is added to each test tube. The culture is continued for 7-14 days depending on the extent of development of the control group. The minimum inhibitory concentration, the concentration at which no development occurs at all, is determined for the test compound and the micon azel, respectively. The results obtained are shown in Table 1.

TABLE 1

Example 20

The following formulation is representative of topical, dose and intravenous doses for the compounds of the present invention.

cream

1.0 g of the compound of the present invention

10.g stearic acid

5.2 g of spence 60 (brand name of the surface action product)

1.6 g of span 80 (brand name of surface action products)

Propylene Glycol 5.0g

0.05 g of methyl paraben

0.01 g propyl paraben

Distilled water 100.0 g

The blending ingredients are mixed at 60 ° C. and cooled with shaking to give a soft cream.

refine

100 mg of the compound of the present invention

Lactose 80mg

Soybean Starch 16mg

Polyvinylprolidone 5.6mg

Magnesium Stearate 0.4mg

The ingredients are mixed, granulated with an appropriate solvent such as methanol, and dried to form a tablet using a suitable tablet making machine.

Suppository

0.1 g of the compound of the present invention

Polyethylene glycol 1000 1.0 g

Polyethylene glycol 4000 0.1 g

1.2 g

The ingredients are mixed together at 50 ° C. and poured onto the mold and allowed to cool to room temperature.

Injection solution

0.5 g of a compound of the present invention

Propylene glycol 30.0 g

0.8 g of salt

Distilled water 100mℓ

A solution of the active compound in propylene glycol is mixed with a salt solution dissolved in water, adjusted to a final volume, filtered through a 0.2 μm membrane filter paper, and packaged in a sterile state.

Claims (1)

The following compound of formula (II) is condensed with the following compound of formula (III) to oxidize 1- [β- (R-thio) phenethyl] imidazole of formula (IA) to the corresponding compound of formula (IB). And converting the compound into an acid addition salt of the compound of formula (I) or converting the acid addition salt thereof into a free base.

Wherein R is alkyl, alkenyl, aralkenyl, substituted aralkenyl, alkynyl, cycloalkyl, aralkyl-substituted aralkyl, halo, lower-alkyl, lower alkoxy, trifluoromethyl in the aryl and aryl moieties Aralkyl substituted with at least one of nitro and cyano and aryl substituted with at least one of halo, lower-alkyl, lower alkoxy, trifluoromethyl, nitro, amino, acylamino and cyano. R ¹ is hydrogen, halo, lower alkyl, lower alkoxy, trifluoromethyl, nitro, cyano, thiocyanato and the following groups,

Wherein R ² is alkyl, cycloalkyl, aralkyl, substituted aralkyl, aryl and substituted aryl wherein the substituted aralkyl and substituted aryl are in the aryl moiety halo, lower alkyl, lower alkoxy, trifluoromethyl, At least one of nitro and cyano is substituted. q is 1 or 2. m, n and P are integers from 0-2, m must not be greater than n, e.g. R ¹ is the next group

When R ² is aryl or substituted aryl.