Imidazole derivatives,their preparation and antifungal and antibacterial compositions containing them

The present invention relates to novel imidazole derivatives and more particularly to 1-[β-(R-thio)phenethyl] imidazoles, 1-[β-(R-sulfinyl)phenethyl]imidazoles and 1-[β(R-sulfonyl)phenethyl]imidazoles having the formula

S(O)m

CH—CH £ (I) and the addition salts thereof, wherein:

• R is alkyl, alkenyl, aralkenyl or substituted aralkenyl haying 8 to 14 carbon atoms, alkynyl, cycloalkyl, cycloalkyl alkyl, aralkyl or substituted areIky1 helving 7 to 14 carbon atoms, aryl or substituted aryl having 6 to 10 carbon atoms, said substituted aralkenvl and substituted aralkyl containing at least one substituent _son the aryl moiety selected from the group consisting of halo, lower alkyl, lower alkoxy, trifluoromethyl, nitro and cyano and said substituted aryl containing at least one substituent selected from the group consisting of halo, lower alkyl, lower alkoxy, trifluoromethyl, nitro, amino, alkanoylamino and cyano;

R¹ is hydrogen, halo, lower alkyl, lower alkoxy, trifluoromethyl, nitro, cyano or alkylthio;

m and p are independently selected from the integers zero, 1 and 2.

U.S. Patents 3,658,813 and 3,717,655 disclose compounds related in structure to the compounds of formula (I) above, the closest known compounds bear an oxygenated group instead of the RS (0) - group in formula (I). The compounds according to the present invention ’nave been demonstrated to be unexpectedly superior to these prior art compounds, as shown in Example 16 herein.

47l^2׳

The term alkyl as used in the specification and appended claims refers to a saturated, unbranched or branched acylic hydrocarbon group containing 1 to 20 carbon atoms inelusive, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, i-butyl, t-butyl, n-pentyl, n-heptyl, n-octyl, n-nonyl, ndodecyl, n-octadecyl and the like. The term ״lower alkyl refers to an alkyl group as previously defined containing 1 to 6 carbon atoms, inclusive. The term lower alkoxy refers to groups of the formula lower alkyl-Owherein the lower alkyl substituent is as previously defined. The term cycloalkyl as used herein refers to a saturated, monocyclic hydrocarbon group having 5 to. 8 ring carbon atoms, such as cyclopentyl, cyclohexyl, cycloheptyl and the like. The term cycloalkyl alkyl refers to a cycloalkyl group as previously defined 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 an unbranched or ‘branched acyclic hydrocarbon group having carbon-carbon double bond unsaturation and containing 2 to 12 carbon atoms such as allyl, 2-hexenyl, 3-octenyl, 2-octenyl, 2-decenyl and the like.

The term aralkenyl refers to a hydrocarbon moiety in which the alkenyl portion containing 2 to 4 carbon atoms is attached to a hydrocarbon group consisting of one or more aromatic rings and containing 6 to 10 ring carbon atoms such as 35 phenyl-2-propenyl, 4-phenyl-3-butenyl, styryl, 3-naphthyl-2propenyl and the like. The term alkynyl refers to an unbranched or branched acyclic hydrocarbon group having carboncarbon triple bond unsaturation and containing 2 to 12 carbon • .

atoms, such as 2-propynyl, 3-hexynyl, 2-octynyl and the like.

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 refers to a hydrocarbon moiety in which the alkyl portion contains 1 to 4 carbon atoms and the aryl portion is defined

י as above. Representative examples of aralkyl groups include benzyl, 3-phenylpropyl and the like. The term alkanoylamino i.e., R-C(O)-NH-, refers to substituents containing up to 12 carbon atoms, wherein R in such substituents is methyl, ethyl, i-propyl, n-butyl, pentyl, octyl and the like. The term ”halo as used herein refers to chloro, fluoro and bromo.

The term acid addition salts refers to salts of the subject compounds formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid and the like, or organic acids such as acetic ?5 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, ptoluenesulfonic acid, salicylic acid and the like.

iO

I

All compounds of Formula (I) process at least one chiral center, i.e., the carbon atom to which ate attached the (r!)P—(O) , RS (0)^, H and moieties. Accordingly, the compounds of the present invention may be prepared in either optically active form, or as a racemic mixture. Unless otherwise specified, the compounds described herein are all in the racemic form. However, the scope of the subject invention herein is not to be considered limited to the racemic form, but to encompass the individual optical isomers of the subject compounds.

If desired, racemic intermediates or final products prepared herein may be resolved into their optical antipodes by conventional resolution means known per se, for example, as described in U.S. Patents 3,717,655 and 3,839,574 or by the separation (e.g., fractional crystallization) of the diastereomeric salts formed by reaction of, e.g., racemic compounds of Formula (I) with an optically active acid, or the diastereomeric esters formed by reaction of the racemic alcohol precursors of compounds of Formula (II) with an optically active acid. Exemplary of such optically active acids are the optically active forms of camphor-10-sulfonic acid, a-bromo-camphor-πsulfonic acid, camphoric acid, menthoxy-acetic acid, tartaric acid, malic acid, diacetyltartaric acid, pyrrolidone-5-carboxylic acid, and the like. The separated pure diastereomeric salts or esters may then be cleaved by standard means to afford the respective optical isomers of the compounds of Formula (I) or the precursor alcohols.

a. 47885/L

A preferred subclass of compounds within the class defined by Formula (I) are those compounds having the formula and the acid addition salts thereof, wherein R, R and p are as defined above,

A preferred group of compounds within the above defined subclass are those wherein R^ is halo and R is alkyl alkenyl, aralkenyl or halo-substituted aralkenyl having 8 to 14 carbon atoms, aralkyl or halo-substituted aralkyl having 7 to 14 carbon atoms, aryl and halo-substituted aryl having 6 to 10 carbon atoms.

Particularly preferred compounds within the group described in the previous paragraph are those wherein [R^lp is mono, halo or dihalo and R is alkyl containing 1 to 12 carbon atoms, 2-alkenyl, phenyl-2-alkenyl, chloro substituted phenyl-2-alkenyl, benzyl, chloro or fluoro substituted benzyl, phenyl and chloro substituted phenyl. Most particularly preferred compounds are those wherein [R^J represents 2,4dichloro, 2,4-dibromo or 2,4-difluoro.

The subject compounds of Formula (I) exhibit anti-fungal and anti-bacterial activity. For example, compounds of the present invention exhibit anti-fungal activity against human and animal pathogens such as

Microsporum audouini,

Microsporum gypseum,

Microsporum gypseum - canis,

Epidermophyton floccosum,

Trichophyton mentagrophytes,

Trichophyton rubrumj

Trichophyton tonsurans,

<td></td><td> Candida albicans, and Cryptococcus neoformans. The compounds of the present invention also exhibit anti-fungal activity against fungi of primarily agricultural</td>

<td> 5</td><td> importance such as Aspergillus flavus, Cladosporium herbarum, Fusarium graminearum,</td>

<td> ׳ •</td><td> Penicillium notatum, Aspergillus niger,</td>

<td> 10</td><td> • Penicillium oxalicum, Penicillium spinulosum, and Pithomyces chartarum. In addition, the compounds of the present invention exhibit anti-bacterial activity against human and animal</td>

<td> 15</td><td> pathogens, such as Staphylococcus aureus, Streptococcus faecalis,</td>

<td></td><td> Corynebacterium acnes, Erysipelothrix insidiosa,</td>

<td> 20</td><td> Escherichia coli, Proteus vulgaris, Salmonella choleraesuis, ... Pasteurella multocida, and Pseudomonas aeruginosa.</td>

<td> 25</td><td></td>

- . . -647885/2 4P

In view of the aforementioned activities, the subject compounds are found to be useful antimicrobials, having not only pharmaceutical but also agricultural and industrial application. '

Accordingly, a further aspect of the present invention relates to compositions for pharmaceutical, agricultural, and industrial use, which compositions comprise the subject compounds of Formula (I) m combination with a suitable carrier., A still further aspect of the present invention relates to methodsof inhibiting the growth of fungi and bacteria by applying to a non human host or object containing, or subject to attack by ’fungi or bacteria, a fungicidally or bacteriocidally effective amount of a compound of the present invention or a suitable composition containing same.

In pharmaceutical applications, compositions may be solid, semi-solid or liquid in form such as tablets, capsules, powders, suppositories, liquid solutions, suspensions, creams, lotions, ointments and the like. Pharmaceutically acceptable non-toxic carriers, or excipients normally employed for solid formulations include tricalcium phosphate, calcium carbonate, kaolin, bentonite, talcum, gelatin, lactose, starch and the like; for semisolid formulations there may be mentioned, for example, polyalkylene glycols, vaseline and other cream bases; for liquid formulations there may be mentioned, for example, water, oils of vegetable origin and low boiling solvents such as isopropanol, hydrogenated naphthalenes and the like. The pharmaceutical compositions containing the compounds of the present invention may be subjected to conventional pharmaceutical expedients such as sterilization and can contain conventional pharmaceutical excipients such as preservatives, stabilizing agents, emulsifying agents, salts for the adjustment of osmotic pressure and buffers. The compositions may also contain other therapeutically active materials. In pharmaceutical applications, the subject compounds and compositions may be administered to humans and animals by conventional methods, e.g., topically, orally, parenterally and the like. When given orally the compounds, alone or in admixture with a suitable carrier, may be administered at a dosage of from about 12.5 mg. to about 1000 mg. per dose (assuming a 70 kg. host subject), one or more times daily, extending over a period of several days to many weeks. Suppositories may contain from about 1 mg. to 500 mg. of active compounds.

Topical application is preferred. For such treatment, an area having an existing fungal or bacterial growth, or to be protected against attack by fungi or bacteria, may be treated with the subject compounds or compositions by, for example, dusting, sprinkling, spraying, rinsing, brushing, dipping, smearing, coating, impregnating and the like. Pharmaceutical compositions containing the compounds of the present invention exhibit anti-fungal and anti-bacterial activity over a wide range of concentration, for example, from about 0.1 to 10.0% by weight of the composition. In any event, the composition to be administered will contain a quantity of the subject compound in an amount effective for relief or prevention of the specific condition being treated. The exact regimen for pharmaceutical administration of the compounds and compositions disclosed herein will necessarily be dependent upon the needs of the individual subject being treated, the type of treatment e.g., whether preventative or curative, the type of organism involved and, of course, the judgment of the attending practitioner.

In agricultural applications, the subject compounds may be applied directly to plants (e.g., seeds, foliage) or to soil. For example, compounds of the present invention may be applied to seeds alone or in admixture with a powdered solid carrier. Typical powdered carriers are the various mineral silicates, e.g. mica, talc, pyrophyllite, and clays. The subject compounds

<img file="IL47885A_D0001.tif" />

ain admixture with a conventional surface-active wetting agent with or without additional solid carrier. Surface-active wetting agents that can be used are any of the conventional anionic, non-anionic or cationic types. As a soil treatment for fungi and the like, the subject compounds can be applied as a dust in admixture with sand, soil or a powdered solid carrier such as a mineral silicate with or without additional surface-active agent, or the subject compounds can be applied as an aqueous spray optionally containing a surface-active dispersing agent and a powdered solid carrier. As a foliage treatment, the subject compounds may be applied to growing plants as an aqueous spray which contains a surface-active dispersing agent with or without a powdered solid carrier and hydrocarbon solvents .

In industrial applications, the subject compounds may be used to control bacteria and fungi by contacting the pathogens with the compounds in any known matter. Materials capable of supporting bacteria and fungi may be protected by contacting miving or impregnating these materials with the subject compounds. In order to increase their effect, the subject compounds may be combined with other pesticidal control agents such as fungicides, bactericides, insecticides, miticides and the like. A particularly important industrial/agricultural use for the subject compounds of the present invention is as a food preservative against bacteria and fungi which cause deterioration and spoilage of foods.

Detailed Description

The present invention, in a still further aspect, is directed to methods for the preparation of the subject compounds of Formula (I) according to the following reaction sequence!

<img file="IL47885A_D0002.tif" />

wherein R, R and p are as previously described and X represents a conventional leaving group such as chloro, bromo or a reactive ester group such as CH₇-S(0)₉־O״ or (0)_-0-.

The 1-[β-(R-thio)phenethyl]imidazoles of Formula I-A are prepared by condensing a compound of Formula II with a thiol of

Formula III,

In said condensation, the starting materials and reagents may be contacted in any convenient manner and maintained at a temperature and for a period of time sufficient to complete the reaction. Furthermore, the reaction products may be isolated and recovered 30 from the reaction using,asin the case of the reaction conditions themselves, procedures conventional or known in the art for conducting such reactions or analogous reactions. The nature of the leaving group (X) is not critical, its selection being predicated on relative reactivity rates known for reactions of this type. Chloro, bromo, and the two ester groups noted above are given by way of typical examples only.

Generally, the reaction of compounds of Formula II with compounds of Formula III wherein R in Formula III is alkyl, alkenyl, aralkenyl, substituted aralkenyl, alkynyl, cycloalkyl, cycloalkyl alkyl, aralkyl and substituted aralkyl is carried out in the presence of an inert organic solvent, e.g. tetrahydrofuran, ether, menthanol and the like in the presence of sodium hydride or other suitable base at a temperature of 20 to 66°C for a period of 30 minutes to 24 hours.

The reaction of compounds of Formula II with compounds of Formula III wherein R in Formula III is aryl or substituted aryl is carried out in the presence of an inert organic solvent, e.g. acetone, methanol, and the like and in the presence of potassium carbonate or other suitable base under reflux conditions for a period of 30 minutes to 12 hours.

The thus obtained 1-[β-(R-thio)phenethyl]imidazole compounds of Formula I-A are then optionally oxidized to obtain the 1-[β(R-sulfinyl)phenethyl]-and the 1- (β-(R-sulfonyl)phenethyl]imidazole compounds of Formulas I-B and I-C, respectively. Oxidation is conducted by methods well-known in the art using hydrogen peroxide, an organic peracid such as peracetic acid, p-nitroperbenzoic acid and m-chloroperbenzoic or an inorganic peracid such as periodic acid. The oxidation reaction is preferably conducted using mchloroperbenzoic in a liquid reaction medium, such as a chlorinated hydrocarbon.

In said oxidation, the starting materials and reagents may be contacted in any convenient manner and maintained at a temperature and for a period of time sufficient to complete the reaction. Furthermore, the reaction products may be isolated and recovered from the reaction using, as in the case of the reaction conditions themselves, procedures conventional or known in the art for conducting such reactions or analogous reactions.

In general, when the compounds of Formula I-A are contacted with about one or more equivalents of oxidizing agent, such as m-chloroperbenzoic acid, at a temperature of from about -30°C to about 30°C, perferably in an organic medium, such as chloroform, and for a period of about 30 minutes to about 6 hours, the corresponding sulfinyl products of Formula I-B are obtained. Similarly, when the compounds of Formula I-A are contacted with about two or more equivalents of oxidizing agent, such as m-chloroperbenzoic acid, at a temperature of from about 0°C to about 60°C, preferably in an organic medium, such as chloroform, and for a period of about 1 to about 24 hours, the corresponding sulfonyl products of Formula I-C are obtained.

The subject compounds of the instant invention can be isolated as free bases, however, since many of the compounds in base form are oils or gums, it is more convenient to isolate and characterize the compounds as acid addition salts. These salts are prepared in the usual manner, i.e., by reaction of the base compound with suitable inorganic or organic acid. If desired, the salts can be readily converted to the compounds in base form by treatment with alkali, such as potassium carbonate, sodium carbonate or sodium or potasslum hydroxide.

־The starting compounds of Formula II, wherein is hydrogen, methyl, methoxy, halo or nitro, disclosed together with a method for their preparation m U.S. Patent 3,679,697. Compounds of Formula II wherein R¹ is other than those groups disclosed in the above-identified patent, can be analogously prepared, i.e'., by bromination of the appropriate acetophenone, reaction of the resultant 2-bromo acetophenone compound with imidazole, reduction of the resultant 2-(1-imidazolyl)acetophenone compound with sodium tetrahydroborate, and finally, reaction of the resultant l-imidazoleethanol compound with a thionyl halide to yield the 1-(β-halophenethyl)imidazole compounds of Formula II. ין

When acetophenones containing the group R’ = alkylthio are required as reactants for the preparation of starting compounds of formula II, these acetophenones may be prepared by the following processes:

(A) Friedel-Crafts Acylation of a known alkylthiophenyl with acetyl chloride or with acetic anhydride in the presence of AlCl^ to yield the corresponding alkylthioacetophenone. These methods are described in the Journal of American Chemical Society 74, 5475-81, (1952) and U.S. 2,763,692.

(B) Alkylation of an 0-, m- or p- mercaptoacetophenone with a known alkyl halide, to obtain the corresponding alkylthioacetophenone. This procedure is described in the Journal of American Chemical Society 78, 4792-7 (1956).

DESCRIPTION OF SPECIFIC EMBODIMENTS

The following specific description is given to enable those skilled in the art to more clearly understand and practice the present invention. It should not be considered as a limitation upon the scope of the invention but merely as being illustrative and representative 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 and refluxed under nitrogen. After 4 hours the solvent and excess 4-methoxybenzyl chloride are evaporated under vacuum and water is added to the residue. The resultant aqueous mixture is extracted with ether and the ether extract washed with water, dried over magnesium sulfate and evaporated to dryness. The resulting residue is recrystallized from cyclohexane to yield 4-(4*-methoxybenzylthio)-acetophenone.

Similarly, replacing 4-methoxy benzyl chloride with other aralkyl halides or substituted aralkyl halides containing at ' least one substituent on the aryl moiety selected from the 15 group consisting of halo, lower alkyl, lower alkoxy, tri* fluoromethyl, nitro and cyano is productive of the corresponding substituted aralkylthioacetophenones.

The starting compounds of Formula II are prepared from the above substituted aralkylthioacetophenones according to 20 the procedure in U.S. 3,679,697.

PREPARATION B

A mixture of 2 g. of 4-methylthioacetophenone, 5 g. of acetic acid, and approximately 3,8 g. of 30% hydrogen peroxide is heated.at 85° - 95°C. until an exothermic reaction is ini25 tiated. When the reaction subsides, .002 g. of palladium-oncarbon is introduced and the reaction mixture is filtered through diatomaceous earth. The filtrate is chilled to pre-, pipitate the product which is isolated by filtration and air dried to yield 4-methylsulfonyl acetophenone.

Similarly, replacing 4-methylthioacetophenone with other thioacetophenones, for example,

4-t-butyIthioacetophenone,

4-benzyIthioacetophenone,

4-(4 *-chlorobenzylthio)acetophenone,

4-(4’-methoxybenzylthio)acetophenone,

4-phenyIthioacetophenone, and

4-(4'-chlorophenylthio)acetophenone is productive of the following sulfonyl substituted acetophenones: ׳ י ׳ .

4-t-butylsulfony!acetophenone,

4-benzylsulfonylacetophenone,

4-(4’-chlorobenzylsulfonyl)acetophenone,

4-(4’-methoxybenzylsulfonyl) acetophenone,

4-phenyIsulfonylacetophenone, and

4-(4^,-chlorophenylsulfonyl)acetophenone.

The starting compounds of Formula II are prepared from the above sulfonyl substituted acetophenones according to the procedure in U.S. 3,679,697.

EXAMPLE 1

A) A mixture of 1 g. of 1-(2,4,3־trichlorophenethyl) imidazole, 1.8 g. of 3,4-dichlorothiophenol and 1.5 g. of potassium carbonate in 50 ml. of acetone is stirred and refluxed for 4 hours. The solvent is evaporated under vacuum and 20 ml. of water is added to the residue. The resultant aqueous mixture is extracted with ether and the ether extract washed with 50 ml. of a saturated sodium chloride solution. The organic phase is dried over magnesium sulfate and evaporated to yield 1-[2,4-dichloro-g-(3',4'-dichlorophenylthio)phenethyl] imidazole. __.. ... . .-.---- ‘... :י-The oxalate salt of the free base is prepared by the dropwise addition of ethereal oxalic acid to the free base in ether until precipitation is complete. The product is collected by filtration and recrystallized from a mixture of acetone and ethyl acetate to yield 1-[2,4-dichloroβ- (3’:, 4 ^,.-dichlorophenylthio)phenethyl]imidazole oxalate, m.p. 161.5-163.5°C.

B) Similarly, substituting other starting materials of Formula II for 1-(2,4,β-trichlorophenethyl)imidazole, for example,

1-,( β-chlorophenethyl) imidazole;

1-(p-chloro-4-ethylphenethyl)imidazole;

1-(B-chloro-4-t-buty!phenethyl)imidazole;

1-(β-chloro-4-ethoxyphenethyl)imidazole;

' 1-(B-chloro-4-n-butoxyphenethyl)imidazole;

1-(p-chloro-4-t-butoxyphenethyl)imidazole;

. 1-(4,β-dichlorophenethyl)imidazole;

ί- (3,4,β-trichlorophenethyl)imidazole;

1-(4-bromo-B־chlorophenethyl)imidazole;

1-(2,4-dibromo־B-chlorophenethyl)imidazole;

1-(B־chloro-4-fluorophenethyl)imidazole;

1- (8־-chloro-2,4-difluorophenethyl)imidazole;

‘ 1-(8-chloro-2-trifluoromethylphenethyl)imidazole;

1-(B־chloro-4-trifluoromethy!phenethyl)imidazole; «

1־ (B־chlord-4-cyanophenethyl) imidazole,

-(g-chloro-4-nitrophenethyl)imidazole, and 1-(β-chloro-2-thiocyanatophenethyl)imidazole is productive of the following 1-[β-(3',4'-dichlorophenylthio)phenethyl]imidazoles which, where indicated, are further characterized as the acid addition salts by treatment in the conventional manner with the appropriate acid:

1- [04,'3)־'-dichlorophenylthio)phenethyl]imidazole;

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

1-(jl-t-butyl-β4, '3) ־'-dichlorophenylthio)phenethyl]imidazole, nitrate salt, decomp. 142.5-146.5°C.

1-[4-ethoxy-B-(3',4'-dichlorophenyIthio)phenethyl]imidazole;

1-[4-n-butoxy4¹,'3)-3־-dichlorophenyIthio)phenethyl]im15 idazole;

1-[4-t-butoxy-$-(3',4'-dichlorophenylthio)phenethyl]imidazole;

1-[4-chloro-B4¹,'3)־-dichlorophenylthio)phenethyl]imidazole;

1-[3,4-dichloro-B-(3',4״'-dichlorophenyIthio) phen־ ethyl]imidazole, nitrate salp decomp. 133-137’C.; 1-[4-bromo-g-(3¹,4' -dichlorophenylthio) phenethyl] !!!!idazole;

1-[2,4-dibromo-iJ-(3', 4 ¹-dichlorophenylthio) phen25 ethyl]imidazole, nitrate salt decomp. 132.5-134.5°C.;

1-[4-fluoro-p-(3',4’-dichlorophenylthio)phenethyl]im* idazole;

1-[2,4-difluoro-B-(3';4'-dichlorophenylthio)phen’ ethyl]imidazole, oxalate salt, decomp. 172.5-175°C.;

1-l2-trifluoromethyl־B-(3',4^,-dichlorophenylthio)phenethyl]imidazole;

-[4-trifluoromethyl-β- (3’,4'-dichlorphenylthio)phenethyl]imidazole;

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

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

1-[2-thiocyanato-β-(3',4¹-dichlorophenylthio)phenethyl]imidazole.

C) In like manner, substituting other starting materials of Formula III for 3,4-dichlorothiophenol, for example, 4-chlorothiophenol and 2,4-dichlorothiophenol and using the above recited starting compounds of Formula II is productive of the following 1-[β-(R-thio)phenethyl]imidazoles which,where indicated, are further characterized as the acid addition salts by treatment in the conventional manner with the appropriate acid:

[β_(4׳-chlorophenylthio)phenethyl]imidazole, oxalate salt, decomp. 147.5-149°C.ן

1- [34,י2) ־'-dichlorophenylthio)phenethyl]imidazole;

1-[4-ethyl-3-(4'-chlorophenylthio)phenethyl]imidazole;

1-[4-ethyl4,'2)-3־'-dichlorophenylthio)phenethyl]imidazole;

1- [4-t-butyl-5-(4'-chlorophenylthio)phenethyl]imidazole;

1-[4-t-butyl-3-(2',4'-dichlorophenylthio)phenethyl]imidazole;

1-[4-ethoxy-&amp;-(4'-chlorophenylthio)phenethyl]imidazole;

1-[4-ethoxy-6-(2',4'-dichlorophenylthio)phenethyl]imidazole

-[4-n-butoxy-p-(4'-chlorophenylthio)phenethyl]imidazole;

1-[4-n-butoxy-g-(2‘,4^,-dichlorophenylthio)phenethyl]imidazole;

1-[4-t-butoxy-$-(4’-chlorphenylthio)phenethyl]imidazole;

1-[4-t-butoxy-34,'2)־^,-dichlorophenylthio)phenethyl]imidazole; . 1- [4-chloro-£-(4^,-chlorophenylthio)phenethyl]imidazole, oxalate salt, decomp. 190-191°C.;

1-[4-chloro-g-(2',4'-dichlorophenylthio)phenethyl]imidazole; .1-[2,4-dichloro־iJ-(4¹-chlorophenylthio)phenethyl]imidazole, nitrate salt,M.P. 169.5-170°C.; 1-[2,4-dichloro-g-(2',4'-dichlorophenylthio)phen15 ethyl]imidazole, nitrate salt, M.P. 150-151°C.;

. . 1-[3,4-dichloro-{j-(4 ^,-chlorophenylthio)phenethyl]imidazole, nitrate salt,decomp. 123-125.5°C.;

1- [3,'4-dichloro4, '2) -8־ ^,-dichlorophenylthio) phenethyl]imidazole, oxalate salt, decomp. 169-171.5°C.;

l־r I4-bromo-g-(4 ^,-chlorophenylthio)phenethyl]imidazole;

1-[4-bromo-g-(2',4'-dichlorophenylthio)phenethyl]imidazole;

1-[2,4-dibromo-p-(4’-chlorophenylthio)phenethyl]imidazole;

1-[2,4-dibromo4,'2)-8־'-dichlorophenylthio)phenethyl]imidazole;

r 4] -1: ־: .־ ־ .־-f luoro-β- (4' -chlorophenyIthio) phenethyl ] imidazole; 1-[4-fluoro-p-(2',4^,-dichlorophenylthio)phenethyl]im':. - - .. idazole; :

1-[2,4-difluoro-g-(4¹-chlorophenylthio)phenethyl]imidazole;

-[2,4-difluoro-β-(2 4,י'-dichlorophenyIthio)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;

[4-cyano־B-(4’-chlorophenylthio)phenethyl]imidazole; 1-[4-cyano-3~(2',4'-dichlorophenylthio)phenethyl]imidazole;

1-[4-nitro-g-(4'-chlorophenylthio)phenethyl]imidazole; and

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

EXAMPLE 2 (A) A solution of 1 g. of 1-(2,4^-trichlorophenethyl)imidazole in 10 ml. of tetrahydrofuran is added to a mixture of 1 g. of 2,4-dichlorobenylmercaptan and 220 mg. of 56% sodium hydride dispersion in 40 ml. of tetrahydrofuran.

After stirring for 12 hours at room temperature, the solvent is evaporated under vacuum and 10 ml. of water is added to the residue. The resultant aqueous mixture is extracted with ether and the ether extract washed with 50 ml. of a saturated sodium chloride solution. The organic phase is dried over magnesium sulfate and evaporated to yield 1[2,4-dichloro4,'2)-8־'-dichlorobenzylthio)phenethyl]imidazole.

The nitrate salt of the free base is prepared by the dropwise addition of nitric acid to the free base in ether until precipitation is complete. The product is collected by filtration and recrystallized from ethyl acetate to yield 1[2,4-dichloro-f?-(2',4'-dichlorobenzylthio)phenethyl]imidazole nitrate, decomp. 133.5-134.5°C.

‘ (B) Similarly, substituting other starting materials of Formula II, i.e., those recited in paragraph B of Example 1, is productive of the following 1-[β-(2',4'-dichlorobenzylthio) phenethyl]imidazoles which, where indicated, are further characterized as the acid addition salts by treatment in the conventional manner with the appropriate acid:

1־I(2¹,4’-dichlorobenzylthio)phenethyl]imidazole ן • 1-(4-ethyl־B-(2',4'-dichlorobenzylthio)phenethyl]imidazole;

1-[4-t-butyl-β-(2',4'-dichlorobenzylthio)phenethyl]im15 idazole;

1-[4-ethoxy4,'2)־3־'-dichlorobenzylthio)phenethyl]imidazole;

1-[4-n-butoxy-g-(2',4'-dichlorobenzylthio)phenethyl]im. idazole;

1-[4-t-butoxy4,'2)-3־'-dichlorobenzylthio)phenethyl]imidazole;

1-[4-chloro-B-(2',4'-dichlorobenzylthio)phenethyl]im' idazole;

1-[3,4-dichloro4,'2)-3־'-dichlorobenzylthio)phenethyl]im.

. idazole, nitrate salt, decomp. 107-110’C.;

. 1-[4-bromo4,'2)-3־^,-dichlorobenzylthiojphenethyl]imidazole;

1-[2,4-dibromo־B-(2',4'-dichlorobenzylthio)phenethyl]im' idazole;

1-[4-fluoro-3~(2',4'-dichlorobenzylthio)phenethyl]imidazole;

-(2,4-difluoro-β-(2 4, י'-dichlorobenzylthio)phenethyl]imidazole;

1-[2-trifluoromethyl-β-(2', 4 '-dichlorobenzylthio)phenethy1]imidazole;

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

1-[4-cyano-g-(2',4’-dichlorobenzylthio)phenethyl]im. . idazole;

1-[4-nitro4,'2)-8־'-dichlorobenzylthio)phenethyl]im10 . _# idazole; and

1-(2-thiocyanato־B-(2¹,4'-dichlorobenzylthio)phenethy1]imidazole.

(C) In like manner, substituting other starting materials of Formula III for 2,4-dichlorobenzy!mercaptan, for example, 4-chlorobenzylmercaptan, 3,4-dichlorobenzy1 mercaptan or heptylmercaptan and using the starting materials of Formula II recited in paragraph B of Example 1 is productive of the following1־-(β-(R-thio)phenethyl]imidazoles which, where indicated, are further characterized as the acid addition salts by treatment in the conventional manner with the appropriate acid:

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

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

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

1-[47ethyl-B-(4’-chlorobenzylthio)phenethyl]imidazole;

1-[4-ethyl־B-(3’,4’-dichlorobenzylthio)phenethyl]imidazole;

1- [4-ethyl-f3- (n-heptylthio) phenethyl] imidazole;

1-(4“t-butyl4)-3־'-chlorobenzylthio)phenethyl]imidazole, . oxalate salt; decomp. 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-(4¹-chlorobenzylthio)phenethyl]imidazole;

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

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

1-[4-n-butoxy־B4¹)־-chlorobenzylthio)phenethyl]imidazole, nitrate salt, decomp. 113-114^0.,10 1-[4-n-butoxy4,'3)-3־'-dichlorobenzylthio)phenethyl]imidazole;

1-[4־n-butoxy3־-(n-heptylthio)phenethyl]imidazole, oxalate salt, decomp. 124.5-130°C.;

1-[4-t-butoxy-$-(4-chlorobenzylthio)phenethyl]imidazole;

1-[4-t-butoxy-B-(3',4'-dichlorobenzylthio)phenethyl]im• idazole; 7־-. .—.־.־

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

1-[4-chloro-B-(4¹-chlorobenzylthio)phenethyl]imidazole, oxalate salt, decomp. 148-149.5°C., nitrate salt,

m.p . 103.5-105.5°C.;

1-[4-chloro-B~(3’,4'-dichlorobenzylthio)phenethyl]imidazole;

. . :. 1- [4-chloro־B- (n-heptylthio)phenethyl] imidazole;

1-[2,4-dichloro־B-(4^,-chlorobenzylthio)phenethyl]im25 idazole, nitrate salt, M.P. 130.5-132°C.;

1-[2,4-dichloro~B-(3',4'-dichlorobenzylthio)phen- ־ethyl]imidazole, nitrate salt, decomp. 95-96.5°C.;

1-[2,4-dichloro־B־(n-heptylthio)phenethyl]imidazole, oxalate salt, M.P. 106-109°C.;

1-[3,4-dichloro־B-(4'-chlorobenzylthio)phenethyl]imidazole, oxalate salt, decomp. 174-175°C.;

-(3,4-dichloro-β- (34,י'-dichlorobenzylthio)phenethyl]imidazole, oxalate salt, decomp. 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^,-dichlorobenzylthiojphenethyl]imidazole;

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

1-(2,4-dibromo-β-(4'-chlorobenzylthio)phenethyl]imidazole, nitrate salt, decomp. 126.5-128°C.;

1-[2,4-dibromo-β-(3',4^,-dichlorobenzylthio)phenethyl]im־ idazole;

1-[2,4-dibromo-8-(n-heptylthio)phenethyl]imidazole;

1-[4-fluoro-8-(4^,-chlorobenzylthio)phenethyl]imidazole;

1-[4-fluoro-8-(3',4'-dichlorobenzylthio)phenethyl]imidazole;

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

1-[2,4-difluoro-3-(4'-chlorobenzylthio)phenethyl]imidazole; *

1-[2,4-difluoro-ft-(3',4^,-dichlorobenzylthio)phenethyl]imidazole, oxalate salt, decomp. 89.5-93.5°C.;

,4]-1 ־-’־-difluoro-8-(n-heptylthio)phenethyl]imidazole;

-[2-trifluoromethyl-8-(4^,-chlorobenzylthio)phenethyl]imidazole;

1-[2-trifluoromethyl-β-(3',4^,-dichlorobenzylthio)phenethyl]imidazole, nitrate salt, decomp. 134.5-137°C.;

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

1-[4-trifluoromethyl-β-(4¹-chlorobenzylthio)phenethyl]imidazole;

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

-[4-trifluoromethyl-B-(n-heptylthio)phenethyl]imidazole;

1-[4-cyano-B-(4'-chlorobenzylthio)phenethyl]imidazole; 1-[4-_Cyano-B-(3',4'-dichlorobenzylthio)phenethyl]imidazole;

1-[4-_Cyano-6-(n-heptylthio)phenethyl]imidazole;

1-[4-nitro-3-(4'-chlorobenzylthio)phenethyl]imidazole;

1- [4-nitro-g-(3'.,4 '-dichlorobenzylthio)phenethyl]imidazole;

1-[4-nitro-B-(n-heptylthio)phenethyl]imidazole;

1-[2-thiocyanato4)-8־^,-chlorobenzylthio)phenethyl]imidazole;

1-[2-thiocyanato-$-(3',4¹-dichlorobenzylthio)phenethyl]imidazole; and . . 1—[2-thiocyanato-B-(n-heptylthio)phenethyl]imidazole.

.. EXAMPLE 3

Repeating the procedure recited in paragraph A of Example 1 using 1-(2,4,β-trichlorophenethyl)imidazole and 1-(3,4,3-trichlorophenethyl)imidazole as starting materials of Formula II and using 4-trifluoromethylthiophenol, 4-chloro3-trifluoromethylthiophenol, 3,4,5-trichlorothiophenol and pentachlorothiophenol as starting materials of Formula III is productive of the following 1-[3(R-thio)phenethyl]imidazoles which, where indicated, are further characterized as the acid addition salts by .treatment in the conventional manner with the appropriate acid:

.9-

1-[2,4-dichloro-8-(4'-trifluoromethylphenylthio)phenethyl]imidazole, oxalate salt, decomp. 178-178.5°C.;

1-[2,4-dichloro-8-(4^,-chloro-3’-trifluoromethylphenylthio) phenethyl]imidazole, oxalate salt, decomp. 186-187.5®C.;

1-[2,4-dichloro-8-(3',4¹,5'-trichlorophenylthio)phenethyl]imidazole, nitrate salt, decomp. 178-185.5°C.;

1-[2,4-dichloro8־-(pentachlorophenylthio)phenethyl]imidazole, nitrate salt, decomp. 201-202.5 °C.;

1-[3,4-dichloro-8-(4^,-trifluoromethylphenylthio)phenethyl]imidazole, oxalate salt, decomp. 170-171°C.;

. 1—[3,4-dichloro-8-(4^,-chloro-3'-trifluoromethylphenylthio)phenethyl]imidazole, oxalate salt, decomp.

165-166°C.;

1- [ 3,4-dichloro- 8-(3^4^5¹ - trichlorophenylthio) phenethyl]imidazole; and

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

Repeating the procedure recited in paragraph A of Example but substituting other starting materials of Formula III for

2,4-dichlorobenzyl mercaptan, for example

EXAMPLE 4 ethyl mercaptan, pentyl mercaptan, octyl mercaptan, nonyl mercaptan, dodecyl mercaptan octadecyl mercaptan, 3-phenylpropy1. mercaptan, cyclopentylpropyl mercaptan, cyclohexyl mercaptan, cyclohexylmethyl mercaptan, cyclohexylethyl mercaptan, cycloheptylmethyl mercaptan, allyl mercaptan,

2- octenyl 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-b)1tylbenzyl mercaptan, 4-trifluoromethylbenzyl mercaptan, 4-methoxybenzyl mercaptan,

3.4.5- trimethoxybenzyl mercaptan, 4-n-butoxybenzyl mercaptan,

2.4.5- trichlorobenzyl mercaptan.

-bromobenzyl mercaptan,

4-fluorobenzyl mercaptan,

4-nitrobenzyl mercaptan, and 4-cyanobenzyl mercaptan, is productive of the following 1-[2,4-dichloro~3~(R-thio)phenethyl]imidazoles which, where indicated, are further characterized as the acid addition salts by treatment in the conventional manner with the appropriate acid:

. 1-[2,4-dichloro-3-(ethylthio)phenethyl]imidazole;

j₅ . 1-[2,4-dichloro-3-(n-pentylthio)phenethyl]imidazole, oxalate salt, coalesces 99°C.;

1-[2,4-dichloro-3-(n-octylthio)phenethyl]imidazole, oxalate salt, M.P. 101.5-103.5°C-;

1-[2,4-dichloro-3־(n-nonylthio)phenethyl]imidazole, oxalate salt, gels 82.5°C.;

ל1-[2,4-dichloro-β-(n-dodecylthio) phenethyl ]imidazole , oxalate salt, M.P. 124.5°C.;

1-[2,4-dichloro-3-(octadecylthio)phenethyl]imidazole, oxalate salt, gels 91.5-150°C.;

1-(2,4-dichloro-3-(3-phenylpropylthio)phenethyl]imidazole, oxalate salt, M.P. 87.5-90°C.;

1-[2,4-dichloro3־-(cyclopentylpropylthio)phenethyl]imidazole;

1- [2,4-dichloro-3-(cyclohexylthio)phenethyl]imidazole nitrate salt, M.P. 114.5-117.5⁰¢.;

1-[2,4-dichloro3־~(cyclohexylmethylthio)phenethyl]imidazole, oxalate salt, decomp. 122.5-140°¢.;

1-[2,4-dichloro3־-(cyclohexylethylthio)phenethyl]imidazole, oxalate s^lt, decomp. 104-108.5°C;

1-[2,4-dichloro3־-(cycloheptylmethylthio)phenethyl]imidazole;

12,4]־-dichloro-g-(allylthio)phenethyl]imidazole oxalate salt, M.P. 84.5-123°C.;

1-[2,4-dichloro2)-3־-octenylthio)phenethyl]imidazole, oxalate salt, M.P. 112.5-116.5°C.;

1- [2,4-dichloro-il.-(3-phenyl-2-propenylthio)phenethyl]imidazole, oxalate salt, decomp. 151-160.5°C.;

1-[2,4-dichloro- β-(4’-chlorophenyl)-2-propenylthio)phenethyl]imidazole, nitrate salt, decomp. 123-126°C.;

1-[2,4-dichloro-β-(3-hexynylthio)phenethyl]imidazole, oxalate salt, M.P. 90.5-95°C.;

1-[2,4-dichloro-8-(2-octynylthio)phenethyl]imidazole, oxalate salt, decomp. 118-119.5°C.;

1-[2,4-dichloro-8-(benzylthio)phenethyl]imidazole;

:. nitrate salt, m.p. 110-112°C.;

4.,2]-1 ן-dichloro-84) ־ ^,-methylbenzylthio) phenethyl] imidazole, nitrate salt, M.P. 110.5-112°C.;

1— [2,4-dichloro-β-(4^,-t-butylbenzylthio)phenethyl]imidazole, nitrate salt, decomp. 162.5-163°C.;

1—[2,4-dichloro-8-(4'-trifluoromethylbenzylthio)phenethyl]imidazole, nitrate salt, decomp. 112-114°C.;

1-[2,4-dichloro-B-(4'-methoxybenzylthio)phenethyl]imidazole, nitrate salt, decomp. 118-119.5°C.;

1-[2,4-dichloro-85,'4,'3)־'-trimethoxybenzylthio)phenethyl]imidazole, oxalate salt, gels 147°C.;

1-[2,4-dichloro-8-(4^,-n-butoxybenzylthio)phenethyl]im. idazole;

1- [2,4-dichloro-8-(2’,4',5’-trichlorobenzylthio)phenethyl]imidazole, nitrate salt, decomp. 172.5-173.5?C.;

1-[2,4-dichloro-8-(4'-bromobenzylthio)phenethyl]imidazole, nitrate salt, decomp. 137-138°C.;

1- [2,4-dichloro-8-(4'-fluorobenzylthio)phenethyl]imidazole, nitrate salt, decomp. 104.5-107.5°C.;

-[2,4-dichloro- β- (4'-nitrobenzylthio)phenethyl]imidazole, nitrate salt, decomp. 129.5-132°C.;

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

. .EXAMPLE 5

Repeating the procedure recited in paragraph A of Example 1 using 1-(4,β-dichlorophenylethyl)imidazole and 1-[2,4,β-trichlorophenethyl)imidazole as starting materials of Formula II and using other starting materials of Formula III for 3,4-dichlorothiophenol for example, thiophenol, β-thionaphthol,

4-methylthiophenol, 4-methoxythiophenol,

3-methpxythiophenol,

2- chlorothiophenol,

3- chlorothiophenol,

2,5־dichlorothiophenol,

4- bromothiophenol,

4-fluorothiophenol, 4-nitrothiophenol, 4-aminothiophenol, 4-acetamidothiophenol, and 4-cyanothiophenol, is productive of the following 1-[4-0Η10Γ0-β-(R-thio)phenethyl] imidazoles and 1- [2,4-άΐσ1110Γ0-β- (R-thio)phenethyl] imidazoles which, where indicated, are further characterized as the acid addition salts by treatment in the conventional manner with the appropriate,acid:

1- [4-chloro-B-(phenylthio)phenethyl]imidazole, oxalate salt, decomp. 166-167°C.;

-[4-chloro-β-(2-naphthylthio)phenethyl]imidazole, oxalate salt, M.P. 193.5-194°C.;

1-[4-chloro-β-(4'-methylphenylthio)phenethyl]imidazole, oxalate salt, decomp. 199.5-200°C.;

1-[4-chloro-B4)־^,-methoxyphenylthio)phenethyl]imidazole, oxalate salt, decomp. 177-178°C.;

1- [4-chloro3)־8־'-methoxyphenylthio)phenethyl]imidazole, oxalate salt, M.P. 164.5-165.5⁰¢.;

1-[4-chloro2)־8־'-chlorophenylthio)phenethyl]imidazole, oxalate salt, M.P. 177-178°¢.;

. 1-[4-chloro3)־8־^,-chlorophenylthio)phenethyl]imidazole, oxalate salt, M.P. 169.5-171.5⁰¢.;

1-[4-chloro2¹,5)־8־'-dichlorophenylthio)phenethyl]imdazble, oxalate salt, M.P. 181.5-183.5⁰¢.;

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

«. oxalate salt, decomp. 185-186.5⁰¢.;

1- [4-chloro4)-8־^,-fluorophenylthio)phenethyl]imidazole, oxalate salt, M.P. 182.5-183⁰¢^

1-[A-chloro-β-(4¹-nitrophenylthio)phenethyl]imidazole, oxalate salt, M.P. 203-204.5⁰¢.;

1-[4-chloro4)-3־^,-aminophenylthio)phenethyl]imidazole;

1-[4-chloro־B-(4^,-acetamidophenylthio)phenethyl]imidazole, oxalate salt, M.P. 149.5-152⁰¢.;

1-[4-chloro־B-(4¹-cyanophenylthio)phenethyl]imidazole;

1- [2,4-dichloro~B-(phenylthio)phenethyl]imidazole;

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

1-[2,4-dichloro4)- 8־'-methylphenylthio)phenethyl]imidazole;

1- [2,4-dichloro-4¹) - 8־-methoxyphenylthio) phenethyl] im30 idazole;

- [2,4-dichloroי3)-6־-methoxyphenylthio)phenethyl]imidazole;

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

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

1- [2,4~di chloro-β- (2', 5 ’-dichlorophenylthio) phenethyl] imidazole;

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

1-(2,4-dichloro-B-(4'-fluorophenyIthio)phenethyl]imidazole;

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

1-[2,4-dichloro-β-(4’-aminophenyIthio)phenethyl]imidazole;

1-(2,4-dichloro-β-(4¹-acetamidophenylthio)phenethyl]imidazole; and

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

EXAMPLE 6

To a solution of 400 mg. of l-[4-chloro-p-(4'-aminophenylthio)phenethyl]imidazole oxalate in 20 ml. of tetrahydrofuran containing 1 ml. of triethylamine is added 0.5 ml. of hexanoy1 chloride. After stirring for 30 minutes at room temperature, the solvent is evaporated under vacuum and aqueous potassium carbonate is added to the residue. The resuitant aqueous mixture is extracted with dichloromethane and the organic phase is acidified with oxalic acid. The product which precipitates is filtered off and recrystallized from a mixture of acetone and ethyl acetate to yield 1-[4-chloroβ- (4^,-hexanoylaminophenylthio)phenethyl]imidazole oxalate, M.P. 98.5-102 °C.

Similarly, substituting other, acid chlorides for hexanoyl chloride, for example propionyl chloride, n-valeryl chloride, decanoyl chloride and the like is productive of the corresponding

1-[4-chloro-β-(4'-propionylaminophenylthio)phenethyl]imidazole oxalate;

1-[4-chloro-p-(4^,-valeroylaminophenylthio)phenethyl]imidazole oxalate;

1-[4-chloro-B-(4^,-decanoylaminophenylthio)phenethyl]imidazole oxalate, and so forth.

EXAMPLE 7

1-[4-chloro-p-(4'-chlorophenylthio)phenethyl]imidazole nitrate ( 1’g.) is treated with aqueous potassium carbonate until a pH of approximately 11 is obtained, whereupon the 5 free base, i.e., 1-[4-chloro-p-(4¹-chlorophenylthio)phenethyl] imidazole, which separates is extracted with dichloromethane. The extract is dried with magnesium sulfate and evaporated. To the resulting residue, in 50 ml. of chloroform at 0°C. is slowly added with stirring, a solution of 700 mg. of 85/ m-chloroperbenzoic acid in 50 ml. of chloroform. When the addition is complete, stirring at 0°C. is continued for approximately 3 hours. Thereafter, the reaction mixture is washed with aqueous potassium carbonate and aqueous sodium chloride, dried over magnesium sulfate and evaporated. The residue is crystallized from benzene to yield 1-[4-chloro-£:.(4'-chlorophenylsulfinyl)phenethyl] imidazole, M.P. 139-140°C., which is further characterized as the oxalate salt, M.P.

167-167.5°C.

Similarly, repeating the above procedure on the 1-[β20 (R-thio)phenethyl]imidazole salts obtained in Examples 1 thru is productive of the corresponding 1-[β-(R-sulfinyl)phenethyl]imidazoles which can be further characterized by conversion in the usual manner to the indicated acid addition salts, e.g., _ ..... ..

1-[2,4-dichloro-0-(n-dodecylsulfinyl)phenethyl]imidazole, oxalate salt, decomp. 134-138°C.;

1- (4-chloro-g-(4¹-chlorobenzylsulfinyl)phenethyl]imidazole, nitrate salt, decomp. 161.5-162°C.; and so forth.

κ.

• *

EXAMPLE 8

1- [4-(chloro-β-(4'-chlorophenylthio)phenethyl]imidazole nitrate (1 g.) is treated with aqueous potassium carbonate until a pH of approximately 11 is obtained whereupon the free base, i.e. 1-[4-chloro-&amp;-(4'-chlorophenylthio)phenethyl]imidazole, which separates is extracted with dichloromethane. The extract is dried with magnesium sulfate and evaporated. To the resulting residue in 50 ml. of chloroform at room temperature is slowly added with stirring a solution of 1.7 g. of 85% m-chloroperbenzoic acid in 50 ml. of chloroform. When the addition is complete, stirring at room temperature is continued for approximately 24 hours. Thereafter, the reaction mixture is washed with aqueous potassium carbonate and aqueous sodium chloride, dried over magnesium sulfate and evaporated. The residue is crystallized from benzene to yield 1-[4-chloro-B-[4'chlorophenylsulfonyl)phenethyl]imidazole, M.P. 176-178.5°C.

Similarly, repeating the above procedure on the 1-[β(R-thio)phenethyl]imidazoles or acid addition salts obtained in Examples 1 thru 6 is productive of the corresponding 1[β-R-sulfonyl)-phenethyl]imidazoles which can be further characterized by conversion in the usual manner to the indicated acid addition salts, e.g., ' 1- [2,4-dichloro-g-(dodecylsulfonyl)phenethyl]imidazole, oxalate salt, decomp. 105.5-110°C.;

1- [4-chloro4¹)-8־-chlorobenzylsulfonyl)phenethyl]imidazole, nitrate salt, decomp. 181 °C.; and so forth.

. 47885/2 . EXAMPLE 9

Repeating the procedure recited in paragraph A of Example 1 using 3,4-dichlorothiophenol as the starting material of Formula III and using other starting materials of Formula II for 1-(2,4,β-trichlorophenethyl)imidazole, for example,

1- (3-chloro-4-methylthiophenethyl)imidazole ן l-(p-chloro-4-t-butylthiophenethyl)imidazole;

is productive of the following 1-[β-(3',4’-dichlorophenylthi0) — phenethyl]imidazoles:

‘ . 1-(4-methylthio-p-(3' ,4’-dichlorophenylthio)phenethyl]imidazole;

1-[4-t-butylthip-8-(3',4'-dichlorophenylthio)phenethyl]imidazole;

]_ [4-b_enzylthio-8-(3',4^,-dichlorophenylthio)phenethyl]imidazole ;

EXAMPLE 10

Repeating the procedure recited in paragraph A of Example .2 using 4-chlorobenzyl mercaptan as the starting material of Formula III and using other starting materials of Formula II for 1-(2,4,β-trichlorophenethyl)imidazole, i.e., those starting materials of Formula II recited in Example 9'¹ , is productive of the following 1-[β-(4'-chlorobenzylthio)phen ethyl]imidazoles:

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

1-(4-t-butylthio4)-3־'-chlorobenzylthio)phenethyl]imidazole;

1-[4-benzylthio-g4)־'-chlorobenzylthio)phenethyl]imidazole;

EXAMPLE 11

Repeating the procedure recited in Example 1, using reactants as dictated by the particular 1-[β-(R-thio)phenethyl]imidazole desired, is productive of the following

47885/2' .

compounds which, where indicated, are further characterized as the acid addition salts by treatment in.the conventional manner with the appropriate acid.

1-[2,4-dichloro-B-(4'־'nitro-S'-trifluoromethyIphenyl- 5 thio)phenethyl]imidazole, nitrate salt, decomp.

127.5-130.5°C.;

1-[4-trifluoromethyl-B-(4'-tert-butylphenylthio)phenethyl]imidazole, oxalate salt, M.P. 161-162°C.;

1-[2,4-dimethyl-β-(3',4'-dichlorophenylthio)phen10 ethyl]imidazole, nitrate salt, decomp. 165.5166°־C.;

. , l-[4-methoxy־B4,’3)־'-dichlorophenylthio)phen. . ethyl]imidazole, oxalate salt, M.P. 145.5°C.;

. 1-[4-methoxy-B-(4^,-tert-butylphenylthio)phenethyl]imidazole, oxalate salt, M.P. 139.5-141.5°C.;

1- [2,4-dimethoxy-B4,'3)־'-dichlorophenylthio)phenethyl]imidazole, nitrate salt, decomp. 155.5-158°C.;

1- [4-nitro־B-(pentachlorophenylthio)phenethyl]imidazole, nitrate salt, decomp. 163.5-165.5°C;

.1-[2,4-dichloro-β-(n-butoxyphenylthio)phenethyl]im20 idazole, oxalate salt, m.p. 143-144°C.j

1- [4-cyano-B-(pentachlorophenylthio)phenethyl]imidazole., nitrate salt, m.p. 182.5-183,5°C. (foaming);

14] ־-n-butylthio־B4). ־ '-chlorophenylthio) phenethyl] imidazole oxalate, m.p. 159-162°C. dec.; and

1-[4-methylthio-B-(3',4'-dichlorophenylthio)phenethyl]imidazole oxalate, m.p. 146-148.5°C. dec.

EXAMPLE •±5־

<td></td><td> Repeating the procedure recited in Example 2, using</td>

<td> -</td><td> reactants as dictated by the particular 1-[β-(R-thio)phenethyl]imidazole desired, is productive of the following com-</td>

<td> 5</td><td> pounds which, where indicated, are further characterized as the acid addition salts by treatment in the conventional manner with the appropriate acid: 1- [2,4-difluoro-β- (n-nonylthio)phenethyl]imidazole, oxalate salt, M.P. 79.5-84°C.;</td>

<td> 10</td><td> 1-[2,4-dimethyl-β-(4'-chlorobenzylthio)phenethyl]imidazole, oxalate salt, decomp. 80.5-83°C.; 1-[4-methoxy-β-(3-phenylpropylthio)phenethyl]imidazole, oxalate salt, M.P. 75-83°C; 1-[4-methoxy-β-(n-dodecylthio)phenethyl]imidazole;</td>

<td> 15</td><td> oxalate salt, m.p. 90-93°C.; 2,4]-1 ׳-dichloro-β-(I’-naphthyImethylthio)phen- ethyl] imidazole, oxalate salt, coalesces 86°C., foams 86-121.5⁰¢.;</td>

<td> •</td><td> 1-[4-chloro-8-(ethylthio)phenethyl]imidazole, oxalate</td>

<td> 20</td><td> salt, M.P. 157-158⁰¢.; . 1-[2,4-dichloro-8-(n-undec־dO-enylthio)phenethyl]imidazole, oxalate salt, M.P. 82-107°C.; 1- [2,4-dichloro-3-(3-(4¹-methylphenyl)prop-2-enylthio)phenethyl]imidazole, nitrate salt, m.p. 133.5-137⁰¢.;</td>

<td> 25 i</td><td> 1- [•2,4-dichloro-B- (3- (4' -tert-butylphenyl) prop-2-enyl thio)phenethyl]imidazole, nitrate salt, m.p. 147-153.5°C.; 1-[2,4-dichloro-B-(4-phenylbut-3-enylthio)phen- ethyl]imidazole; 1- [2,4-dichloro-8-(3-(4¹-chlorophenyl)propylthio)phen-</td>

<td> 30</td><td> ethyl]imidazole, oxalate salt, m.p. 111-113⁰¢.; 1- [2,4-dichloro-8-(prop-2־ynylthio)phenethyl]imidazole;</td>

. ’ 47885/2 .. ־

1- [4-methylthio4, '3)-8־ ' -dichl.orobenzylthio) phen ethyl]imidazole;

1-[4-n-butylthio-8-(4י-chlorobenzylthio)phenethyl]imidazole nitrate,, m.p. 122-124°C. dec.;

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-άΐί1η0Γ0-β-(n-octylthio)phenethyl]imidazole; and

1-[2,4-difluoro-8-(n-decylthio)phenethyl]imidazole.

־ . 15

EXAMPLE -tfr

1-[4-chloro-p-(4'-chlorophenylthio)phenethyl]imidazole nitrate (1 g.) in 100 ml. of dichloromethane is shaken 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.

Evaporation of the solvent yields 1-[4-chloro-£5- (4 ^,-chlorophenylthio)phenethyl]imidazole as a gum.

In similar manner, the acid addition salts of all compounds of Formula (I) can be converted to the corresponding compounds in base form, for example,

1-[2,4-dichloro-β-(3¹,4¹-dichlorophenylthio)phenethyl]imidazole;

1- [2,4-dichloro-£3- (2' , 4¹ -dichlorobenzylthio)phenethyl]imidazole; .1- [2, 4-dichloro-f3- (n-heptylthio)phenethyl] imidazole;

1-[2,4-dichloro-B-(4¹-chlorophenylthio)phenethyl]imidazole.

1- [2,4-dichloro-f3- (4¹ -chlorobenzylthio)phenethyl] imidazole, and so forth.

—52q.* t

EXAMPLE -ΗNitric acid (70%; d=1.42) is added dropwise to a stirred solution of 2.5 g. of 1-[4-chloro4)-6־'-chlorophenylthio)phenethyl]imidazole in 40 ml. anhydrous ether until precipitation is complete. The product is filtered off, washed with ether and dried. Recrystallization from ethyl acetate yields 1-[4-chloro-£-(4'-chlorophenylthio)phen ethyl]imidazole nitrate, m.p. 136.5-137.5°C.

In similar manner, all compounds of Formula (I) in base form can be converted to the acid addition salts by treatment in the conventional manner with the appropriate acid.

EXAMPLE +&amp;

The anti-bacterial activity of certain compounds of the present invention and of Keflin* is illustrated in the following procedure.

Streptococcus faecalis, a gram(+) bacteria, is cultured at 37°C. in Brain-Heart Infusion Broth (Difco). After 24 hours the culture is diluted to a concentration of IxlO⁸ cells/ml. with the growth medium. Of this suspension, 0.05 ml. is added to various dilutions of the test compounds.

The test compounds are dissolved in dimethyl sulfoxide, ethanol or water at a concentration of 10 mg./ml. and thereafter diluted with sterile water to give a stock solution having a concentration of 100 yg./ml. From this stock 15 > solution, appropriate dilutions are made. Approximately

4״ ml. of each dilution is added to a sterile test tube and 0.05 ml. of the above prepared inoculum is then added to each tube. Incubation is then carried out for 24 hours and the minimal inhibitory concentration (MIC), which is the concentration at which no visible growth occurs, is then determined.

* sodium salt of 7-(thiophene-2-acetamido) cephalosporanic acid.

־⁴⁷־ . 30

ף— *A

Table I

Minimal Inhibitory ConcenCompound tration pg./ml.

<td> Keflin</td><td> 33</td>

<td> 1-[3,4-dichloro-B-(3',4^,-dichloro. phenylthio)phenethyl]imidazole nitrate</td><td> 10</td>

<td> 1-[2,4-dichloro-g-(4'-chlorobenzyl. thio)phenethyl]imidazole nitrate</td><td> 10</td>

<td> 1-[4-chloro-&amp;-(4'-chlorophenylthio)phenethyl]imidazole nitrate</td><td> 3.3</td>

-53b16

EXAMPLE 4+־.

The anti-fungal activity of certain compounds of the present invention and of Miconazole* is illustrated in the following procedure.

Trichophyton rubrum is cultured on Sabourad Dextrose agar (Difco) at room temperature for 14 days. The fungi mat is then removed from the agar slant and homogenized to a fine suspension in Sabouraud Dextrose Broth. This suspension is diluted to a uniform concentration (OD of 0.1 at 600 nm) and 0.05 ml. is added to various dilutions of the test compounds.

The test compounds are dissolved in dimethyl sulfoxide, ethanol or water at a concentration of 10 mg./ml. and thereafter diluted with sterile water to give a concentration of 100 |1g/ml. From this stock solution appropriate dilutions were made. Approximately 4 ml. of each dilution is added to a sterile test tube and 0.05 ml. of the above prepared inoculum is then added to each tube. Incubation is carried out for 7 to 14 days depending on the growth in the negative control.

The minimal inhibitory concentration (MIC), which is the concentration at which no visible growth occurs, is then determined for each test compound and for Miconazole.

The results obtained are listed in Table I.

* 1-[2,4-dichloro-B-(2',4¹-dichlorobenzyloxy)phenethyl)imidazole nitrate.

-:

eTable I

Minimal Inhibitory ConcenCompound tration pg./ml.

Miconazole IQ

1-[2,4-dichloro-B-(2',4'-dichloro-3 benzylthio)phenethyl]imidazole nitrate

1-[2,4-dichloro-B-(4'-chlorobenzyl-3 thio)phenethyl]imidazole nitrate

1-[2,4-dichloro-B-(n-heptylthio)phen-3 ethyl]imidazole oxalate

Example -gfr

The following formulations are typical of topical, oral and parenteral dosage forms for the compounds of the present

<td colspan="2"> invention:</td>

<td> Cream:</td><td></td>

<td> a compound of the present invention</td><td> 1.0 g.</td>

<td> stearic acid</td><td> 10.0 g.</td>

<td> Span 60 (Tradename for commercial</td><td> 5.2 g.</td>

<td> surfactant)</td><td></td>

<td> Span 80 (Tradename for commercial</td><td> 1.0 g.</td>

<td> surfactant)</td><td></td>

<td> propylene glycol</td><td> 5.0 g.</td>

<td> . methyl paraben</td><td> 0.05 g.</td>

<td> propyl paraben</td><td> 0.01 g.</td>

<td> distilled water gs. to</td><td> 100.0 g.</td>

<td> The constituents are mixed at 60°C. and cooled</td><td> with agitation</td>

<td> to produce a smooth cream. Tablet:</td><td></td>

<td> a compound of the present invention</td><td> 100 mg.</td>

<td> lactose USP</td><td> 80 mg.</td>

<td> cornstarch</td><td> 16 mg.</td>

<td> polyvinylpyrrolidone</td><td> 5.6 mg.</td>

<td> magnesium stearate</td><td> 0.4 mg. 200.0 mg.</td>

<td> The constituents are mixed and granulated with</td><td> an appropriate</td>

<td colspan="2"> solvent, e.g. methanol, dried, then formed into tablets using</td>

<td> suitable tableting equipment. Suppository:</td><td></td>

<td> a compound of the present invention</td><td> 0.1 g.</td>

<td> polyethylene glycol 10.00</td><td> 1.0 g.</td>

<td> polyethylene glycol 4000</td><td> 0.1 g. 1.2 g.</td>

<td>- -53c-</td><td></td>

The constituents are mixed together at 50°C., then poured into molds and allowed to cool to room temperature.

Injectable Solution:

a compound of the present invention 0.5g.

propylene glycol 30.0g.

sodium chloride 0.8g.

distilled water qs. to 100 ml.

A solution of the active compound hereof in the propylene glycol is mixed with the sodium chloride in water, brought to final volume, and filtered through 0.2μ membrane filter and packaged under sterile conditions.