Derivatives of substituted N-alkyl imidazoles

Compounds of the formula ##STR1## wherein R.sup.1 and R.sup.2 are each independently phenyl, phenyl straight chain lower alkyl or phenyl straight chain lower alkenyl or one of the above substituted in the phenyl ring with one or more substituents independently selected from the group consisting of lower alkyl of from one to four carbon atoms, halo and trifluoromethyl; X is oxygen or sulfur; n is an integer of from 1 to 8 with the proviso that n is not 1 when R.sup.1 is phenyl or substituted phenyl; and the antimicrobial acid addition salts thereof are useful as antifungal, antibacterial and antiprotozoal agents.

DETAILED DESCRIPTION OF THE INVENTION 
The present invention relates to novel chemical compounds which are 
derivatives of substituted N-alkyl imidazoles. More particularly, the 
compounds of the present invention are represented by the formula 
##STR2## 
wherein R.sup.1 and R.sup.2 are each independently phenyl, phenyl straight 
chain lower alkyl, or phenyl straight chain lower alkenyl; or one of the 
above substituted in the phenyl ring with one or more substituents 
independently selected from the group consisting of lower alkyl of from 
one to four carbon atoms, halo and trifluoromethyl; X is oxygen or sulfur; 
n is an integer of from 1 to 8 with the proviso that n is not 1 when 
R.sup.1 is phenyl or substituted phenyl; and the antimicrobial acid 
addition salts thereof. 
In a second aspect the present invention is concerned with a method of 
combatting fungi, bacteria and protozoa by administering a compound of the 
present invention or a composition containing same. 
As used in the specification and the appended claims, unless specified to 
the contrary, the following terms have the meaning inidicated. The term 
"lower alkyl" refers to a straight or branched chain monovalent 
substituent consisting solely of carbon and hydrogen, containing no 
unsaturation, and having from one to eight carbon atoms. Examples of lower 
alkyl groups are methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, 
pentyl, n-hexyl, and n-octyl. The term "lower alkenyl" refers to a 
straight or branched chain monovalent substituent consisting solely of 
carbon or hydrogen containing mono-olefinic unsaturation, and having from 
2 to 8 carbon atoms. Examples of lower alkenyl groups are ethenyl, 
prop-1-enyl, prop-2-enyl, but-1-enyl, but-2-enyl, pent-1-enyl, 
pent-3-enyl, hex-1-enyl, hex-3-enyl, hex-5-enyl, hept-1-enyl, hept-4-enyl, 
hept-6-enyl, oct-1-enyl, oct-5-enyl, and oct-7-enyl. The term "styryl" 
refers to .alpha.-styryl. The term "halo" refers to fluoro, chloro and 
bromo. "Antimicrobial acid addition salts" of the subject bases refers to 
those salts which retain the antimicrobial properties of the free bases 
and which are neither biologically or otherwise undesirable, formed with, 
for example, inorganic acids such as hydrochloric acid, hydrobromic acid, 
sulfuric acid, nitric acid or phosphoric acid; or inorganic acids such as 
acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, 
oxalic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric 
acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic 
acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, 
salicylic acid, and the like. It is also understood, for purposes of this 
invention, that the phenyl rings of R.sup.1 and R.sup.2 cannot be 
substituted with three or more adjacent branched alkyl and/or 
trifluoromethyl groups. 
All compounds of formula (I) possess at least one chiral center, i.e., the 
carbon atom to which are attached the R.sup.1, X, (CH.sub.2).sub.n and H 
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. Additionally, those compounds 
possessing a substituted or unsubstituted phenyl straight chain lower 
alkenyl group can have geometric (cis and trans) isomers about the double 
bond. Both isomers as well as mixtures thereof are intended to be included 
within the scope of the present invention. 
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, 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 by the 
separation of the diastereomeric salts or esters formed by reaction of 
racemic compounds of formula (II), infra, with an optically active acid. 
Exemplary of such optically active acids are optically active forms of 
camphor-10-sulfonic acid, .alpha.-bromo-camphor-.pi.-sulfonic 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 (II). 
The subject compounds of formula (I) exhibit anti-fungal, anti-bacterial 
and anti-protozoal 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 rubrum 
Trichophyton tonsurans 
Candida albicans, and 
Cryptococcus neoformans. 
The compounds of the present invention also exhibit anti-fungal activity 
against the following fungi primarily of agricultural significance 
Aspergillus flavus, 
Cladosporium herbarum, 
Fusarium graminearum, 
Penicillium notatum, and 
Aspergillus niger 
Penicillium oxalicum, 
Penicillium spinulosum, 
Pithomyces chartarum. 
In addition, the compounds of the present invention exhibit anti-bacterial 
activity against human and animal pathogens, such as 
Staphylococcus aureus, 
Streptococcus faecalis, 
Corynebacterium acnes, 
Erysipelothrix insidiosa, 
Escherichia coli, 
Proteus vulgaris, 
Salmonella choleraesuis, 
Pasteurella multocida, and 
Pseudomonas aeruginosa. 
Moreover, the compounds of the present invention exhibit anti-protozoal 
activity against protozoa such as Trichomonas vaginalis. 
In general, the subject compounds of the instant invention exhibit a low 
level of toxicity. Moreover, these compounds demonstrate good solubility 
in the stratum corneum. Since dermatophyte (i.e., parasitic fungal) 
infections are usually localized in the dead tissue of the stratum 
corneum, solubility of anti-fungal agents in this tissue significantly 
enhances their effectiveness. 
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) in combination 
with a suitable carrier. A still further aspect of the present invention 
relates to methods of inhibiting the growth of fungi, bacteria and 
protozoa by applying to a host object containing, or subject to attack by, 
fungi, bacteria or protozoa, an 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 semi-solid formulations there may be mentioned, for example, 
poly-alkylene 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. Parenteral 
administration includes intramuscular as well as subcutaneous and 
intravenous administration. Intravenous injection of imidazole-type 
anti-fungals has been demonstrated to be effective in the treatment of 
systemic mycoses (see for example, Drugs, 9, pp. 419-420, 1975, which 
describes the intravenous administration of miconazole, i.e. 
1-[2,4-dichloro-.beta.-(2',4'-dichlorobenzyloxy)phenethyl]-imidazole 
nitrate, to patients with systemic candidiasis). Topical application is 
the preferred method of administration for pharmaceutical applications. 
For such treatment, an area having an existing fungal, bacterial or 
protozoal growth, or to be protected against attack by fungi, bacteria or 
protozoa, may be treated with the subject compounds or compositions by, 
for example, dusing, sprinkling, spraying, rinsing, brushing, dipping, 
smearing, coating, impregnating and the like. Topical pharmaceutical 
compositions containing the compounds of the present invention exhibit 
anti-fungal anti-bacterial and anti-protozoal 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 pharmaceutical compositions hereof typically comprise one or more 
subject compounds of Formula (I) and a pharmaceutically acceptable, 
non-toxic carrier, and are preferably formulated in unit dosage form to 
facilitate administration (unit dosage being the amount of active 
ingredient administered on one occasion). 
In general, or systemic (e.g., oral or parenteral) administration it is 
expedient to administer the active ingredient in amounts between about 1 
and 100 mg./kg. body weight per day, preferably between about 5 and 50 
mg./kg. body weight per day, preferably distributed over several 
applications (e.g., in 3 individual doses) in order to achieve most 
effective results. For localized (e.g. topical) administration, however, 
proportionately less of the active ingredient is required. 
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 may also be applied to the seeds in 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 
bacterial and fungi by contacting the pathogens with the compounds in any 
known manner. Materials capable of supporting bacteria and fungi may be 
protected by contacting, mixing 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. 
The compounds of formula (I) may be considered to consist of two 
subclasses, those of formulas (Ia) and (Ib) shown below 
##STR3## 
wherein R.sup.1, R.sup.2, and n are as defined above. 
Both groups of compounds may be prepared from common intermediates having a 
free hydroxyl group which is then converted to the ether or thioether, as 
the case may be, and which may be prepared by a variety of methods, 
depending upon the length of the (CH.sub.2).sub.n chain, i.e., the value 
of n. 
One preferred subgenus of compounds of formula I are those wherein n is 1, 
2 or 3. 
Within this subgenus one group of preferrred compounds are those wherein 
R.sup.1 is substituted or unsubstituted phenethyl, phenylpropyl or styryl, 
with compounds wherein n is 1 being most preferred. Within the above group 
(n is 1, 2 or 3), preferred compounds are those wherein R.sup.1 is 
halo-substituted phenethyl or styryl. Halo substitution at the 4-position 
is preferred and, when there is more than one halo substituent, it is 
preferred that all halo groups be the same, most preferably chloro. 
Particularly preferred is 4-chloro substitution. Within the above group of 
compounds, preferred R.sup.2 groups are substituted or unsubstituted 
phenyl or benzyl, most preferably halo-substituted phenyl or benzyl. One 
particularly preferred sub-group of compounds are those wherein R.sup.2 is 
phenyl having a halo substituent in the ortho position. When there is more 
than one halo substituent it is preferred that all halo groups be the 
same, most preferably chloro. Preferred chloro substitution patterns for 
R.sup.2 are 2,3-, 2,4-, 2,5-, 2,6-, 2-, 2,4,5- and 2,4,6-, especially 
2,4-dichloro, 2,5-dichloro, 2,6-dichloro and 2-chloro. When R.sup.2 is 
halo substituted phenyl it is preferred that X be sulfur. Another 
preferred sub-group of compounds are those wherein R.sup.2 is halo 
substituted benzyl, most preferably chloro-substituted benzyl. Especially 
preferred are 2-chloro, 4-chloro, 2,4-dichloro and 2,6-dichlorobenzyl. 
Another preferred group of compounds within the above mentioned subgenus 
are those wherein n is 2 or 3 and R.sup.1 is phenyl, benzyl or halo 
substituted phenyl or benzyl, preferably 4-chloro-, 4-bromo-, 4-fluoro, 
2,4-dichloro-, 2,4-difluoro- or 2,4-dibromo-substituted and R.sup.2 is 
independently phenyl or benzyl, or halo (preferably chloro)-substituted 
derivatives thereof (preferably those having 2-, 4-, 2,4-, 2,5-, or 
2,6-substitution. Within this group of compounds of a first sub-group of 
compounds are those wherein R.sup.1 is phenyl or halo-substituted phenyl, 
and a second sub-group of compounds are those wherein R.sup.1 is benzyl or 
halo-substituted benzyl. 
For all the above described preferred groups of compounds of Formula I, 
most preferred compounds have, for each of R.sup.1 and R.sup.2, no more 
than 2 substituents except when all substituents for R.sup.1 and/or 
R.sup.2 are halo. 
As mentioned above, compounds of Formula (I) may be prepared by forming an 
ether or thioether from a suitable alcohol of formula (II) 
##STR4## 
wherein R.sup.1 and n are as defined above. Compounds of formula (II) may 
be prepared by a variety of rection sequences, depending on the size of n. 
For example, when n is 1, certain compounds of formula (IIa) may be 
prepared by reaction scheme A shown below. 
##STR5## 
In this reaction scheme the imidazole alcohol of formula (IIa) is formed by 
opening of a terminal epoxide of formula (III) with imidazole. This 
reaction is generaly carried out using at least one mole and preferably an 
excess of imidazole relative to epoxide. The reaction may either be 
carried out in the absence of solvent or, preferably, in an inert organic 
solvent, for example, a solvent such as dimethylformamide, 
hexamethylphosphoramide, acetonitrile, and the like. The temperature 
normally employed for such epoxide opening is in the range of from about 
-20.degree. to about 100.degree. C. most preferably from about 20.degree. 
to about 60.degree. C. 
Epoxides of formula (III), insofar as they may not be known or readily 
available, may be prepared by a variety of well known methods, for example 
epoxidation of a terminal olefin (e.g., (V)) with, for example, a peracid, 
or by reaction of an aldehyde having one fewer carbon atoms (e.g., (IV)) 
with the ylide prepared from trimethylsulfoxonium iodide as described, for 
example, in J. Am. Chem. Soc., 84, p. 867 (1962); ibid, 87, p. 1353 
(1965). 
Another reaction scheme for preparing certain compounds of formula (IIa) is 
shown in reaction scheme B presented below 
##STR6## 
wherein Y is chloro or bromo. 
In this reaction scheme the hydroxy compound of formula (IIa) is prepared 
by reduction of the corresponding ketone (VI), which in turn is prepared 
by reaction of an .alpha.-halo ketone (VII) with imidazole. 
.alpha.-Halo ketones are generally available, or may be readily prepared 
by, for example, halogenation of the corresponding methyl ketone. When 
R.sup.1 is styryl or substituted styryl, a particularly useful method of 
bromination is described in Tetrahedron, 29, p. 1625 (1973) and Can. J. 
Chem. 47, p. 706 (1969). 
The .alpha.-halo ketone is contacted with imidazole in an inert organic 
solvent to afford the keto imidazole of formula (VI). The reaction is 
carried out utilizing at least a molar amount and, preferably, an excess 
of imidazole relative to halo ketone. The reaction may be carried out in 
the absence of solvent or, preferably, in an inert organic solvent such as 
for example dimethylformamide, hexamethylphosphoramide, acetonitrile, and 
the like. The reaction is suitably carried out at a temperature initially 
between about -10.degree. and 100.degree. C. most preferably between about 
0.degree. and 25.degree. C. 
In the next step the keto imidazole of formula (VI) is reduced to the 
hydroxy imidazole of formula (IIa) utilizing a conventional metal hydride 
reducing agent such as, for example, sodium borohydride. The reaction is 
suitably carried out in an alcoholic solvent such as, for example, 
methanol or ethanol at a reduced temperature, for example, between about 
-10.degree. and +25.degree. C., most preferably about 0.degree. C. 
When n is 2 compounds of formula (IIb) may be prepared according to a 
variety of synthetic methods. One convenient method for the preparation of 
certain compounds of formula (IIb) is shown in reaction scheme C presented 
below. 
##STR7## 
This scheme involves the reaction of imidazole with a vinyl ketone of 
formula (VIII) (or Mannich base quaternary intermediate) followed by 
reduction of the resulting keto imidazole of formula (IX) to the hydroxy 
imidazole of formula (IIb). 
Vinyl ketones of formula (VIII), insofar as they may not be known or 
generally available, may be prepared by a variety of methods well known in 
the synthetic organic chemistry art, for example, by the addition of vinyl 
lithium to the corresponding carboxylic acid; by the addition of vinyl 
lithium to the corresponding aldehyde followed by oxidation of the allylic 
alcohol thus produced to the vinyl ketone (e.g., J. Chem. Soc. (C), 1966, 
p. 1972; J. Chem. Soc. (London), 1956, p. 3070); or by Mannich reaction of 
the corresponding methyl ketone, quaternization and elimination. 
The first step of the conversion, the reaction of vinyl ketone of formula 
(VIII) to keto imidazole of formula (IX), is accomplished by contacting 
the vinyl ketone (or a Mannich quaternary base precursor) with imidazole 
in an inert organic solvent. The reaction is conveniently carried out 
utilizing at least a molar amount, and preferably an excess, of imidazole 
relative to vinyl ketone or Mannich quaternary base in an inert organic 
solvent, for example, diethyl ether, dichloromethane or dimethylformamide, 
at a temperature between about 0.degree. and 40.degree. C. preferably 
about ambient temperature. 
The reduction of the keto imidazole of formula (IX) to the hydroxy imidazo 
le of formula (IIb) is carried out in the same manner as described above 
for the conversion of compound of formula (VI) to that of formula (IIa). 
When n is 2 (or greater) certain compounds of formula (II) are conveniently 
prepared as illustrated in reaction scheme D presented below 
##STR8## 
wherein Y is chloro or bromo. 
In this reaction scheme an .omega.-halo (preferably chloro) ketone of the 
formula (X) is converted to the corresponding keto imidazole of formula 
(XI) and then to the hydroxy imidazole of the formula (II). 
The starting .omega.-halo ketones, insofar as they may not be known or 
generally available, may be suitably prepared by the well known 
Friedel-Crafts reaction involving the aromatic hydrocarbon R.sup.1 H and 
an .omega.-halo acylhalide. 
The conversion from compound (X) to compound (XI) is carried out using 
imidazole in the same manner as described above for the conversion of 
(VII).fwdarw.(VI). When n is 3 or greater, the reaction temperature is 
between about 0 and 100.degree. C., preferably between 25.degree. and 
80.degree. C. 
The reduction of the keto imidazole of formula (XI) to the hydroxy 
imidazole of formula (II) is carried out as previously described for the 
conversion of (VI).fwdarw.(IIa). 
Certain compounds of formula (IIc) may also be prepared by an alternate 
procedure depicted in reaction scheme E 
##STR9## 
involving the conversion of the previously described vinyl ketone of the 
formula (VIII) to the corresponding cyclopropyl ketone of the formula 
(XII), followed by conversion to the .gamma.-halo ketone of formula (X), 
n=3, and then, as described above, to the hydroxy imidazole of formula 
(IIc). 
The cyclopropanation of the vinyl ketone of formula (VIII) may be 
accomplished by methods known per se, for example as disclosed in J. Am. 
Chem. Soc., 87, p. 1353 (1965). The resulting cyclopropyl ketone is then 
opened to afford the .gamma.-halo ketone by treatment with a hydrohalic 
acid such as, for example, hydrobromic acid. 
Certain compounds of formula (II) may also be prepared according to 
reaction scheme F below 
##STR10## 
wherein Y is chloro or bromo. 
This reaction scheme is particularly useful for preparing compounds wherein 
n is 4 or greater, but may also be used to prepare compounds where n is 2 
or 3. In this scheme, the previously described aldehyde of formula (IV) is 
reacted with an .omega.-halo terminal alkene of formula (XIII), readily 
prepared, for example, by halogenation of the corresponding alcohol, in a 
free radical addition reaction to afford the previously described halo 
ketone of formula (X), which is then converted as previously described 
through the keto imidazole of formula (XI), to the hydroxy imidazole of 
formula (II). The conversion (IV) + (XIII).fwdarw.(X) is conveniently 
carried out using a free radical source such as, for example, diacetyl 
peroxide, di-tert-butyl peroxide, dibenzoyl peroxide, 
azobisisobutyronitrile; or photochemically, at a temperature between about 
50.degree. and 150.degree. C., most preferably between about 60.degree. 
and 80.degree. C., using an excess of the aldehyde as a solvent medium. 
Certain compounds of formula (III) may be also prepared as demonstrated 
below in reaction scheme G 
##STR11## 
wherein Y is chloro or bromo. 
This reaction scheme is conveniently utilized where compounds having n 
equal to or greater than 4 are desired. 
In this reaction scheme an acid halide of formula (XIV), readily prepared 
from the corresponding carboxylic acid, is reacted with the previously 
described .omega.-halo terminal alkene of formula (XIII) to afford the 
halo ketone of the formula (X), which is then converted, as shown above, 
to the hydroxy imidazole of formula (II). The addition reaction between 
compounds of formulas (XIV) and (XIII) is conveniently carried out under 
conditions as described in G. Olah, "Friedel Crafts and Related 
Reactions", Vol. 3, Part 2, Interscience Publishers, New York, (1964). 
In yet another reaction sequence certain compounds of formula (II) wherein 
n is 1 or greater may be prepared. This is illustrated below in reaction 
scheme H 
##STR12## 
wherein R.sup.1 is R.sup.o CH.sub.2 CH.sub.2 and Y is chloro or bromo. 
In this scheme the .omega.-halo ketone of formula (X), described above, is 
prepared starting with a terminal olefin of formula (XV) and an 
.omega.-halo acyl halide of formula (XVI), readily prepared, for example, 
from the corresponding hydroxyacid. This reaction is carried out under the 
conditions described above for Reaction Scheme G. 
In reaction scheme I shown below there are illustrated alternative methods 
for preparing certain compounds of formula (II) wherein n is 1, 
##STR13## 
R.sup.1 is R.sup.0 --CH=CH-- or R.sup.0 CH.sub.2 CH.sub.2 -- and Y is 
chloro or bromo. 
In this scheme an aldehyde of formula (XVII) is reacted, in a Wittig 
reaction, with an ylide of formula (XIX) or (XXI) to afford the 
corresponding olefin of formula (XX) or (XXII). The ylide (XXI) is formed, 
according to methods known per se, from the corresponding phosphonium salt 
(XVIII), prepared in turn from triphenylphosphine and the corresponding 
dihalo acetone. To form the ylide of formula (XIX) the phosphonium salt is 
reacted with an excess of imidazole, in an inert organic solvent such as 
acetonitrile, dimethylformamide at a temperature between about 25.degree. 
and 100.degree. C., preferaly between about 50.degree. and 80.degree. C., 
thus affording the imidazole substituted ylide of formula (XIX) which, 
upon reaction with the aldehyde of formula (XVII) under standard Wittig 
conditions, (e.g., in acetonitrile at 80.degree. C.) affords the 
unsaturated keto imidazole of formula (XX). 
Alternatively, reaction of the aldehyde of formula (XVII) with the ylide of 
formula (XXI), prepared in the normal manner from phosphonium salt (XVIII) 
by treatment with a base such as an alkali metal carbonate, affords the 
halo unsaturated ketone of formula (XXII). This compound may then be 
converted to the corresponding imidazole compound of formula (XX) by 
treatment with imidazole as described above the conversion (VII).fwdarw. 
(VI). Reduction of the keto group of compound (XX) affords the hydroxy 
imidazole of formula (IIa). The double bond adjacent to the hydroxy moiety 
may be hydrogenated to afford a compound of formula (IIa) having a phenyl 
lower alkyl or substituted phenyl lower alkaly moiety as R.sup.1. Such 
hydrogenation may be carried out using standard conditions, for example, 
using a palladium on charcoal catalyst in a solvent such as methanol. 
Alternatively, hydrogenation may be performed prior to reduction of the 
ketone. 
The compounds of formula (II) are converted to the final products of 
formula (I) wherein X is O and R.sup.2 is substituted or unsubstituted 
phenyl straight chain lower alkyl or phenyl straight chain lower alkenyl, 
by O-alkylation with the appropriate R.sup.2 Y wherein Y is a leaving 
group such as halide (chloride, bromide or iodide) or sulfonate ester 
(e.g., p-toluenesulfonate or methanesulfonate). 
The alkylation is carried out by converting the hydroxy group of the 
compound of formula (II) to its alkali metal salt by treatment with a 
strong base such as, for example, an alkali metal hydride such as sodium 
hydride; and alkali metal amide such as sodium amide or potassium amide; 
and the like. This is preferably done in an inert organic solvent such as, 
for example, dimethylformamide, hexamethylphosphoramide, tetrahydrofuran, 
and the like. The alkali metal salt is then contacted with the R.sup.2 Y, 
preferably in the same solvent system, at a temperature between about 
0.degree. and 80.degree. C., most preferably between about 0.degree. and 
60.degree. C. 
Compounds of formula (I) wherein R.sup.2 is substituted or unsubstituted 
phenyl (i.e., phenolic ethers or thioethers) may be prepared from the 
compounds of formula (II) by a two-step sequence involving conversion of 
the hydroxy group to a suitable leaving group such as a halide (e.g., a 
chloride or bromide) or a sulfonate ester (e.g., methanesulfonate or 
p-toluenesulfonate) which is then reacted with a metal salt of the 
corresponding phenol R.sup.2 OH or thiophenol R.sup.2 SH. 
The conversion from the alcohol to the halide or sulfonate ester is carried 
out by means well known in the art. For example, the alcohol may be 
halogenated using a halogenating agent such as thionyl chloride or thionyl 
bromide, either neat, or in an inert organic solvent such as 
dichloromethane or chloroform, at a temperature between about 0.degree. 
and 80.degree. C., preferably between about 20.degree. and 80.degree. C. 
The halogenation reaction may be carried out in the presence of a molar 
equivalent of a base (e.g., pyridine) if desired. Alternate halogenation 
procedures include, for example, the use of triphenylphosphine with either 
carbon tetrachloride, carbon tetrabromide, or N-chloro (or N-bromo) 
succinimide. When utilizing thionyl chloride or thionyl bromide without 
the use of added base, the hydrochloride or hydrobromide salt of the 
corresponding halo compound is produced. This salt may be neutralized 
(e.g., with potassium carbonate) prior to its use in the alkylation step, 
or the salt may be used directly if excess phenol or thiophenol salt is 
utilized. 
Sulfonate esters may be prepared by the standard procedure of treating the 
alcohol with an excess of, for example, methanesulfonyl chloride or 
p-toluenesulfonyl chloride, in the presence of a base, for example 
pyridine or triethylamine. This reaction is carried out at a temperature 
from about -20.degree. to +50.degree. C., preferably between about 
0.degree. and 20.degree. C. 
The halide or sulfonate ester prepared as described above, is then treated 
with a metal salt, preferably an alkali metal salt such as the sodium or 
potassium salt, of the corresponding phenol or thiophenol, in the presence 
of an inert organic solvent solvent such as acetone, methanol, and the 
like, at a temperature of about 20.degree. to about 80.degree. C. If 
desired, the metal salt of the phenol or thiophenol may be preformed prior 
to addition of the halide. 
Compounds of formula (I) wherein X is S and R.sup.2 is substituted or 
unsubstituted phenyl straight chain lower alkyl or phenyl straight chain 
lower alkenyl, may be prepared by reacting the above mentioned halide or 
sulfonate ester with the metal salt, preferably an alkali metal salt such 
as the sodium or potassium salt, of a thiol R.sup.2 SH. This reaction is 
carried out in an inert organic solvent such as for example, 
tetrahydrofuran, diethylether, methanol, and the like. The salt is formed 
with a strong base such as for example, sodium hydride, sodium amide, 
sodium methoxide and the like, at a temperature between about 20.degree. 
and 80.degree. C. 
Compounds of formula (I) wherein n is 1, X is S and R.sup.1 is substituted 
or unsubstituted phenyl straight chain lower alkyl may also be prepared as 
depicted in reaction scheme J below. 
##STR14## 
wherein Y is a leaving group. 
In this scheme the epoxide of formula (III) described earlier, is open with 
a thiol or thiophenol or a metal salt thereof, to afford the compound of 
formula (XXIII). This reaction is carried out utilizing, preferably, an 
alkali metal salt of the thiol or thiophenol, most preferably the sodium 
salt, in an inert organic solvent such as, for example, tetrahydrofuran or 
acetone at a temperature of between about 0.degree. and 67.degree. C., or 
using the free thiol or thiophenol in the presence of an acid catalyst, 
e.g., perchloric acid, under similar conditions. 
In the next step the hydroxy group of the compound of formula (XXIII) is 
converted to a leaving group such as a halide (e.g., chloro or bromo) or 
sulfonate ester (e.g., p-toluenesulfonate or methanesulfonate) by 
treatment with, e.g., a halogenating agent such as, for example, thionyl 
chloride, neat, or preferably in an inert solvent such as dichloromethane, 
or with, for example, p-toluenesulfonyl chloride, in a solvent such as 
pyridine. The product of formula (XXIV) may exist in either or both forms 
depicted, and may be interconvertible through an episulfonium 
intermediate. 
In the final step, the compound of formula (XXIV) is converted to the final 
product of formula (I) by treatment with imidazole. This reaction is 
carried out in an inert organic solvent such as for example acetonitrile, 
dimethylformamide, and the like, at a temperature of about 0.degree. to 
about 80.degree. C. 
Alternatively, certain compounds of formula (I) may be formed, in a final 
step, by hydrogenation of a compound of the formula 
##STR15## 
or an acid addition salt thereof wherein R.sup.1' and R.sup.2' are 
identical with R.sup.1 and R.sup.2, respectively, except that R.sup.1' 
and/or R.sup.2' contains aliphatic olefinic unsaturation, i.e., wherein 
R.sup.1' and/or R.sup.2' is a substituted or unsubstituted phenyl lower 
alkenyl group. Such hydrogenation may be carried out using conditions well 
known in the art. For example, the hydrogenation may be carried out at 
about atmospheric pressure or at higher pressure, and at temperatures from 
about 0.degree. to about 100.degree. C., in the presence of a suitable 
supported, unsupported or soluble metal catalyst such as palladium, 
platinum or tris (triphenylphosphine) chlororhodium, in an inert solvent 
such as benzene, acetone, methanol, and the like, for a time sufficient to 
allow the uptake of the required amount of hydrogen. 
The subject compounds of the instant invention can be isolated as free 
bases; however, since many of the compounds in base form are oils, 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 a suitable inorganic or organic acid, described 
above. Salts formed with dibasic acids (e.g., oxalic acid) may contain one 
or two molecules of base per molecule of acid. All oxalates described 
herein contain one molecule of oxalic acid per molecule of imidazole base. 
If desired, the salts can be readily converted to the free base form by 
treatment with alkali, such as potassium carbonate, sodium carbonate or 
sodium or potassium hydroxide.

For following specific examples are illustrative of the present invention 
and should not be considered as limitative thereof in any manner. 
PREATION 1 
This preparation illustrates the process in reaction scheme A. 
3-Phenylpropionaldehyde (26.8 g.) is added under nitrogen to the ylide 
prepared from trimethylsulfoxonium iodide (48.4g.) and sodium hydride (55% 
dispersion in oil; 9.6 g.) in dry dimethylsulfoxide (200 ml.), according 
to the procedure in Journal of the American Chemical Society, Vol. 84, 
page 867 (1962) and Vol. 87, page 1353 (1965). After one hour, the 
solution was poured into 1 liter of water and the product extracted with 
ether (3 .times. 300 ml.). The extract was washed with water (2 .times. 
150 ml.) dried (MgSO.sub.4) and evaporated to give an oil, 
1,2-epoxy-4-phenylbutane, used directly in the next step. 
The oil from above in 50 ml. of dimethylformamide was treated with 
imidazole (70 g.) and the mixture stirred at 40.degree. C. overnight. The 
resulting solution was poured into a mixture of 700 ml. water and 200 ml. 
hexane, stirred until crystallization was complete, and the product was 
filtered off as buff granules (28.2 g.). Recrystallization from ethyl 
acetate gave 1-(2-hydroxy-4-phenylbutyl)imidazole as colorless crystals, 
m.p. 106.degree.-107.degree. C. 
Similarly, proceeding as above, substituting the appropriate aldehyde for 
3-phenylpropionaldehyde, there may be prepared, for example, the following 
compounds of formula (IIa): 
1-[2-hydroxy-4-(4-chlorophenyl)butyl]imidazole 
1-[2-hydroxy-4-(2,4-dichlorophenyl)butyl]imidazole 
1-[2-hydroxy-4-(4-tert-butylphenyl)butyl]imidazole 
1-[2-hydroxy-4-(4-fluorophenyl)butyl]imidazole 
1-[2-hydroxy-4-(4-bromophenyl)butyl]imidazole 
1-[2-hydroxy-4-(4-trifluoromethylphenyl)butyl]imidazole 
1-2-hydroxy-5-(4-chlorophenyl)pentyl]imidazole 
and 
1-[2-hydroxy-4-(2,4-dimethylphenyl)butyl]imidazole 
PREATION 2 
This preparation illustrates the process in reaction scheme B. 
Bromomethyl styryl ketone (22.5 g., reference Tetrahedron, Vol. 29, page 
1625-8, 1973) in a few ml. of dimethylformamide was added dropwise to a 
well-stirred, ice cooled solution of imidazole (35 g.) in 
dimethylformamide (25 ml.), keeping the temperature below 13.degree. C. 
The mixture was stirred for three hours at 0.degree. C., then overnight at 
25.degree. C., and poured into 1 liter of water. The solution was 
extracted successively with benzene (600 ml.) and ether (600 ml.) and the 
combined extracts were dried (MgSO.sub.4) and evaporated. Addition of 
benzene to the residue gave lemon-yellow granules (12 g.). Treatment of a 
solution of this product in methanol with ethereal hydrogen chloride, 
removal of the solvent and trituration of the residue with ethyl acetate 
(100 ml.) gave 5.75 g. of 1-(4-phenylbut-3-en-2-onyl) imidazole 
hydrochloride as a white solid, m.p. 208.degree.-210.degree. C. 
The above ketone (5.50 g.) in 50 ml. of methanol at 0.degree. C. was 
treated with stirring with excess sodium borohydride. When the reaction 
was complete, the solvent was evaporated and the residue treated with 
ice-cold water (10 ml.). Filtration and washing with a small quantity of 
ice water gave an off-white powder (5.40 g.), recrystallized from benzene 
to give 1(2-hydroxy-4-phenylbut-3-enyl)imidazole (5.20 g.), m.p. 
125.degree.-127.5.degree. C. 
Similarly proceeding as above, substituting the appropriate halo ketone for 
bromomethyl styryl ketone, there may be prepared, for example, the 
following compounds of formula (IIa): 
1-(2-hydroxy-3-phenylpropyl)imidazole 
1-[2-hydroxy-3-(4-chlorophenyl)propyl]imidazole 
and 
1-[2-hydroxy-4-(4-chlorophenyl)but-3-enyl]imidazole 
PREATION 3 
This preparation illustrates the process in reaction scheme C. 
A. 7.0 g. of 2,4-dichlorophenyl vinyl ketone (prepared by Jones oxidation 
of 2,4-dichlorophenyl vinyl carbinol using the general method described in 
J. Chem Soc. (C), 1966, p. 1972) in 350 ml. of anhydrous ether was treated 
with 3.5 g. of imidazole, the solution stirred overnight and then washed 
with water (3 .times. 30 ml.). The solution is dried (MgSO.sub.4) and 
evaporated to give 2,4-dichloro-.beta.-(1-imidazolyl)propiophenone as an 
amber gum (8.65 g.). The hydrochloride salt may be precipitated from ether 
and recrystallized from methanol/acetone as colorless rods, m.p. 
105.5.degree.-110.degree. C. 
B. 13.1 g. of 2,4-dichlorobenzoylethyl trimethylammonium iodide (prepared 
by Mannich reaction of 2,4-dichloroacetophenone with paraformaldehyde and 
dimethylamine hydrochloride, followed by quaternization with methyl iodide 
in ether) and 12 g. of imidazole in dimethylformamide (50 ml.) was stirred 
overnight at room temperature and poured into 500 ml. of water. The 
product was extracted with ether (3 .times. 300 ml.), the extracts washed 
with water (3 .times. 75 ml.) and dried. Addition of ethereal hydrogen 
chloride precipitated the hydrochloride of 
2,4-dichloro-.beta.-(1-imidazolyl) propiophenone, which was recrystallized 
from methanol/acetone, m.p. 105.degree.-109.degree. C. 
C. The ketone prepared in part A or part B above may be reduced to the 
corresponding alcohol, 
1-[3-hydroxy-3-(2,4-dichlorophenyl)propyl]imidazole, m.p. 
112.degree.-114.5.degree. C. following the procedure described in 
Preparation 2. 
D. Similarly proceeding as above, substituting the appropriate vinyl ketone 
or Mannich quaternary salt for those indicated in Part A or B, there may 
be prepared, for example, the following compounds of formula (IIb): 
1-[3-hydroxy-3-(4-chlorophenyl)propyl]imidazole, m.p. 
95.degree.-100.degree. C. 
1-[3-hydroxy-3-(4-tert-butylphenyl)propyl]imidazole, m.p. 
139.5.degree.-140.5.degree. C. 
1-[3-hydroxy-3-(4-fluorophenyl)propyl]imidazole, m.p. 
104.5.degree.-110.degree. C. 
1-[3-hydroxy-3-(2,4-dimethylphenyl)propyl]imidazole 
1-(3-hydroxy-4-phenylbutyl)imidazole 
1-[3-hydroxy-4-(4-chlorophenyl)butyl]imidazole 
1-[3-hydroxy-4-(4-methylphenyl)butyl]imidazole 
1-[3-hydroxy-5-(4-chlorophenyl)pentyl)imidazole 
and 
1-[3-hydroxy-3-(2-trifluoromethylphenyl)propyl]imidazole 
1-[2-hydroxy-3-(2,4-dibromophenyl)propyl)]imidazole 
1-[3-hydroxy-3-(2,4-difluorophenyl)propyl]imidazole 
PREATION 4 
This preparation illustrates the process of reaction scheme D. 
A. .beta.-Chloropropiophenone (16.8 g.) and imidazole (35 g.) in 
dimethylformamide (25 ml.) were stirred at 0.degree. C. for three hours 
and poured into 700 ml. water. The product was filtered off as buff flakes 
(15.9 g.) and recrystallized from cyclohexane as colorless flakes of 
.beta.-(1-imidazolyl)propiophenone, m.p. 96.degree.-99.5.degree. C. 
The above material (5.60 g.) in 70 ml. of methanol was treated at 0.degree. 
C. with excess sodium borohydride. When the reaction was complete, the 
solvent was evaporated, 100 ml. of water was added and the product (4.90 
g.) was filtered off. Recrystallization from ethyl acetate gave 
1-(3-hydroxy-3-phenylpropyl)imidazole as colorless rods, m.p. 
106.5.degree.-108.degree. C. 
B. To a 0.degree. C. slurry of 8.24 g. of imidazole in 15 ml. dry 
dimethylformamide was added 5.79 g. of 
p-t-butyl-.gamma.-chlorobutyrophenone and the mixture was stirred 
overnight at room temperature, then one day at 60.degree. C. The above 
solution was poured into 400 ml. of water and extracted three times with 
ethyl acetate. The combined extracts were washed with water, dried over 
magnesium sulfate and the solvent evaporated to afford 5.25 g. of 
1-[4(4-t-butylphenyl)butan-4-onyl]imidazole as a golden oil. 
To a 0.degree. C. solution of 5.0 g. of the above ketone in 150 ml. of 
anhydrous methanol was added excess sodium borohydride, and the mixture 
stirred for one hour. After removal of the solvent, a small quantity of 
water was added and the mixture was extracted with ethyl acetate. The 
combined extracts were dried over magnesium sulfate and evaporated to 
afford 1[4-hydroxy-4-(4-t-butylphenyl)butyl]imidazole, which was converted 
to the oxalate salt and recrystallized from ethyl acetate/ethanol, m.p. 
205.degree.-207.degree. C. (foaming). 
Similarly, proceeding as above, substituting the appropriate haloketone for 
those indicated in part A or B, there may be prepared, for example, the 
first four compounds of formula (IIb) listed in Preparation 3, as well as 
the following compounds of formula (II): 
1-[4-hydroxy-4-(4-chlorophenyl)butyl]imidazole 
1-[4-hydroxy-4-(2,4-dichlorophenyl)butyl]imidazole 
1-[4-hydroxy-4-(4-fluorophenyl)butyl]imidazole, m.p. 
91.5.degree.-94.degree. C. 
1-[4-hydroxy-4-(2,4-dimethylphenyl)butyl]imidazole 
1-[4-hydroxy-4-(4-bromophenyl)butyl]imidazole, m.p. 
113.5.degree.-115.degree. C. 
1-(4-hydroxy-5-phenylpentyl)imidazole 
1-[4-hydroxy-5-(4-chlorophenyl)pentyl]imidazole 
1-[4-hydroxy-6-(4-chlorophenyl)hexyl]imidazole 
1-(6-hydroxy-6-phenylhexyl)imidazole 
1-[6-hydroxy-6-(4-chlorophenyl)hexyl]imidazole 
1-[6-hydroxy-7-(4-chlorophenyl)heptyl]imidazole 
1-(6-hydroxy-8-phenyloctyl)imidazole 
1-(6-hydroxy-10-phenyldecyl)imidazole 
1-(9-hydroxy-9-phenylnonyl)imidazole 
1-[9-hydroxy-9-(4-chlorophenyl)nonyl]imidazole 
1-[9-hydroxy-10-(4-chlorophenyl)decyl]imidazole 
1-(9-hydroxy-11-phenylundecyl)imidazole 
and 
1-(9-hydroxy-13-phenyltridecyl)imidazole 
PREATION 5 
This preparation illustrates the process of reaction scheme I. 
7.3 g. of chloroacetylmethyl triphenylphosphonium chloride and 7.3 g. of 
imidazole in acetonitrile (60 ml.) were stirred and heated at 80.degree. 
C. for two days. The resulting solution was evaporated and the residue 
treated with water, extracted with benzene, and the extract washed with 
water, dried (MgSO.sub.4) and evaporated. Recrystallization from ethyl 
acetate/cyclohexane afforded 
1-imidazolylacetylmethylenetriphenylphosphorane, as colorless blades, m.p. 
154.5.degree.-158.degree. C. 
The above phosphorane (3.85 g.) and p-tolualdehyde (2.4 g.) were stirred in 
30 ml. of acetonitrile and refluxed overnight. After evaporation to 
dryness, the residue was chromatographed on silica gel eluting with 
acetone/dichloromethane to afford 
1-[4-(4-methylphenyl)but-3-en-2-onyl]imidazole as a colorless solid. 
This material was reduced with sodium borohydride, following the procedure 
in Preparation 2 to afford 
1-[2-hydroxy-4(4-methylphenyl)but-3-enyl]imidazole. 
In a similar manner, substituting benzaldehyde for p-tolualdehyde, there 
was prepared 1-(2-hydroxy-4-phenylbut-3-enyl) imidazole, m.p. 
125.degree.-127.5.degree. C. 
2.5 g. of this material in 30 ml. of methanol was hydrogenated at ambient 
temperature and pressure over a 10% palladium on charcoal catalyst. When 
the uptake of hydrogen ceased, the solution was filtered, and the residue 
was recrystallized from benzene/cyclohexane to give white microcrystals 
(2.37 g.) of 1-(2-hydroxy-4-phenylbutyl)imidazole, m.p. 
108.degree.-109.5.degree. C. 
Similarly proceeding as above, substituting the appropriate aldehyde for 
those indicated, there may be prepared, for example, the following 
compounds of formula (Ia): 
1-[2-hydroxy-4-(4-chlorophenyl)but-3-enyl]imidazole 
1-[2-hydroxy-4-(4-chlorophenyl)butyl]imidazole 
1-[2-hydroxy-4-(2,4-dichlorophenyl)but-3-enyl]imidazole 
1-[2-hydroxy-4-(2,4-dichlorophenyl)butyl]imidazole 
1-[2-hydroxy-4-(4-tert-butylphenyl)but-3-enyl]imidazole 
1-[2-hydroxy-4-(4-tert-butylphenyl)butyl]imidazole 
1-[2-hydroxy-4-(4-fluorophenyl)but-3-enyl]imidazole 
1-[2-hydroxy-4-(4-fluorophenyl)butyl]imidazole 
1-[2-hydroxy-4-(2,4-dimethylphenyl)but-3-enyl]imidazole 
and 
1-[2-hydroxy-4-(2,4-dimethylphenyl)butyl]imidazole 
EXAMPLE 1 
A. A mixture of 430 mg. of 1-(2-hydroxy-4-phenylbutyl)imidazole and 96 mg. 
of sodium hydride (56% dispersion in mineral oil) in 3 ml. of dry 
hexamethylphosphoramide was stirred under nitrogen at room temperature for 
one hour and at 45.degree. C. for one hour. After the evolution of 
hydrogen ceased, the solution was cooled in an ice bath and a solution of 
430 mg. of 2,4-dichlorobenzyl chloride in 2 ml. hexamethylphosphoramide 
added dropwise keeping the temperature below 10.degree. C. The solution 
was stirred for one hour at room temperature, 2 hours at 45.degree. C. and 
let stand overnight. The resulting mixture was then poured into water, 
extracted with ether, the ether extracts washed with water, dried and 
evaporated. The oily product, 
1-[2-(2,4-dichlorobenzyloxy)-4-phenylbutyl]imidazole, was converted to its 
nitrate salt by treatment of an ethereal solution with concentrated nitric 
acid, which salt was recrystallized from ethyl acetate as large colorless 
flakes, m.p. 121.degree.-124.degree. C. 
B. trans-1-[2-Hydroxy-4-phenylbut-3-enyl]imidazole (430 mg.) in 5 ml. dry 
tetrahydrofuran was treated under nitrogen with stirring with 96 mg. of 
sodium hydride (56% dispersion in mineral oil) and the mixture heated 
under reflux for 30 minutes. After cooling in an ice bath the mixture was 
treated with stirring with 430 mg. of .alpha.,2,4-trichlorotoluene in 5 
ml. tetrahydrofuran for 30 minutes at 0.degree. C., one hour at 25.degree. 
C. and overnight under reflux. The resulting mixture was evaporated to 
dryness, ether (150 ml.) added and the ether extract washed with water, 
dried over magnesium sulfate and evaporated to afford 
trans-1-[2-(2,4-dichlorobenzyloxy)-4-phenylbut-3-enyl]imidazole. The 
nitrate salt precipitated from ether and was crystallized from ethyl 
acetate, m.p. 133.5.degree.-134.5.degree. C. (foaming). 
A solution of 1.00 g. of 1-(2-hydroxy-4-phenylbutyl) imidazole in 40 ml. of 
dichloromethane was treated with 1 ml. of thionyl chloride with stirring 
and the solution heated to gentle reflux for one hour. Evaporation to 
dryness afforded 1-(2-chloro-4-phenylbutyl) imidazole hydrochloride as a 
white solid. 
The free base may be obtained for use in the subsequent alkylation steps, 
if desired, by shaking the hydrochloride in dichloromethane with excess 
aqueous potassium carbonate solution, washing the organic layer with 
water, drying over magnesium sulfate and evaporating to dryness. 
EXAMPLE 3 
600 Mg. of 1-(2-chloro-4-phenylbutyl) imidazole hydrochloride was added to 
a fully reacted mixture of 1.1 g. of 3,4-dichlorobenzylmercaptan and 400 
mg. of 56% sodium hydride dispersion in mineral oil in 30 ml. of 
tetrahydrofuran. After stirring under reflux for 12 hours the solvent was 
evaporated under vacuum and 150 ml. of ether was added. The resulting 
mixture was washed twice with water and the ethereal solution dried and 
evaporated to afford 
1-[2-(3,4-dichlorobenzylthio)-4-phenylbutyl]imidazole, as an oil. This 
material was converted to the oxalate salt by treatment of an ethereal 
solution wih oxalic acid in ether until precipitation was complete, which 
salt was recrystallized from acetone/ethyl acetate as colorless flakes 
(660 mg.), m.p. 143.5.degree.-146.degree. C. 
EXAMPLE 4 
A mixture of 600 mg. of 1-(2-chloro-4-phenylbutyl)imidazole hydrochloride, 
1.2 g. of 3,4-dichlorothiophenol and 800 mg. of potassium carbonate in 40 
ml. of acetone was stirred and refluxed for 4 hours. The solvent was 
evaporated under vacuum and 50 ml. of water was added. The resulting 
mixture was extracted with ether and the ether extract was washed with 
saturated sodium chloride solution, dried and evaporated to afford 
1-[2-(3,4-dichlorophenylthio)-4-phenylbutyl]imidazole as an oil. This 
material was converted to the oxalate salt by treatment with oxalic acid 
in ether, which salt was recrystallized from acetone/ethyl acetate as 
colorless flakes (850 mg.), m.p. 145.degree.-147.degree. C. 
EXAMPLE 5 
1,2-Epoxy-4-phenylbutane (1.48 g.) in dry tetrahydrofuran (10 ml.). was 
added to the clear solution obtained from the reaction of 50 mg. of 56% 
sodium hydride dispersion in mineral oil with 2.25 g. of 
3,4-dichlorobenzylmercaptan in 50 ml. of dry tetrahydrofuran. 
After stirring for four hours at 60.degree. C. the solvent was removed, the 
residue treated with water and extracted with ether. The ether extract was 
dried and evaporated to afford a colorless oil. 
The above oil in 30 ml dichloromethane was treated with 2 ml. of thionyl 
chloride at room temperature for 30 minutes, and the solution evaporated 
to dryness. The residue was treated with 4 g. of imidazole and 15 ml. of 
acetonitrile and stirred overnight at room temperature and for one day at 
50.degree. C. The solvent was evaporated and after the addition of 50 ml. 
water the residue was extracted with ether. The ether extract was washed 
with water, dried and evaporated to afford 
1-[2-(3,4-dichlorobenzylthio)-4-phenylbutyl]imidazole as an oil, which was 
further characterized as its oxalate salt, m.p. 143.5.degree.-146.degree. 
C. 
EXAMPLE 6 
Following the procedures in Preparations 1, 2 or 5, and Examples 1; 2,3; 
2,4; or 5, using equivalent amounts of the appropriate starting materials, 
there may be obtained the following compounds. Where indicated, the 
compounds may be further characterized by conversion to the indicated acid 
addition salt. 
1-[2-(3,4-dichlorobenzylthio)-3-phenylpropyl]imidazole 
1-[2-(4-chlorophenylthio)-3-phenylpropyl]imidazole 
1-[2-(2,4-dichlorophenoxy)-3-phenylpropyl]imidazole 
1-[2-(3,4,5-trichlorophenylthio)-3-phenylpropyl]imidazole 
1-[2-(2,4-dichlorobenzyl)-3-(4-chlorophenyl)propyl]imidazole 
1-[2-(4-fluorophenylthio)-3-(4-chlorophenyl)propyl]imidazole 
1-[2-(4-tert-butylphenoxy)-3-(4-chlorophenyl)propyl]imidazole 
1-[2-(3,4-dichlorophenylpropylthio)-3-(4-chlorophenyl)propyl]imidazole 
1-[2-(2,4-dichlorobenzylthio)-4-phenylbutyl]imidazole 
1-[2-(3,4-dichlorobenzyloxy)-4-phenylbutyl]imidazole 
1-[2-(3,4-dichlorophenoxy)-4-phenylbutyl]imidazole 
1-[2-(2,3,4,5,6-pentachlorophenylthio)-4-phenylbutyl]imidazole 
1-[2-(4-bromobenzylthio)-4-phenylbutyl]imidazole 
1-[2-(4-fluorophenoxy)-4-phenylbutyl]imidazole 
1-[2-(4-methylphenylthio)-4-phenylbutyl]imidazole 
1-[2-cinnamyloxy-4-phenylbutyl]imidazole 
1-[2-(4-chlorophenylthio)-4-(4-chlorophenyl)butyl]imidazole-nitrate salt, 
m.p. 116.degree.-119.degree. C. 
1-[2-(4-chlorophenoxy)-4-(4-chlorophenyl)butyl]imidazole 
1-[2-(4-chlorobenzylthio)-4-(4-chlorophenyl)butyl]imidazole-oxalate salt, 
m.p. 143.degree.-144.degree. C; nitrate salt, m.p. 120.degree.-121.degree. 
C 
1-[2-(4-chlorobenzyloxy)-4-(4-chlorophenyl)butyl]imidazole 
1-[2-(2,4-dichlorobenzyloxy)-4-(4-chlorophenyl)butyl]imidazole - nitrate 
salt, m.p. 152.degree.-153.5.degree. C 
1-[2-(2,4-dichlorobenzylthio)-4-(4-chlorophenyl)butyl]imidazole - nitrate 
salt, m.p. 101.degree.-108.degree. C. 
1-[2-(3,4-dichlorobenzyloxy)-4-(4-chlorophenyl)butyl]imidazole 
1-[2-(3,4-dichlorophenylthio)-4-(4-chlorophenyl)butyl]imidazole - nitrate 
salt, m.p. 87.5.degree.-89.5.degree. C. 
1-[2-(3,4-dichlorobenzylthio)-4-(4-chlorophenyl)butyl]imidazole 
1-[2-(2,4,5-trichlorophenylthio)-4-(4-chlorophenyl)butyl]imidazole 
1-[2-cinnamyloxy-4-(4-chlorophenyl)butyl]imidazole 
1-[2-(2,4-dichlorophenylthio)-4-(4-chlorophenylbutyl]imidazole -- nitrate 
salt, m.p. 115.degree.-116.degree. C 
1-[2-(4-chlorocinnamyloxy)-4-(4-chlorophenyl)butyl]imidazole 
1-[2-(4-fluorocinnamylthio)-4-(4-chlorophenyl)butyl]imidazole 
1-[2-(4-trifluoromethylphenylthio)-4-(4-chlorophenyl)butyl]imidazole 
1-[2-(4-chloro-3-trifluoromethylphenylthio)-4-(4-chlorophenyl)butyl]imidazo 
le 
1-[2-(4-trifluoromethylbenzyloxy)-4-(4-chlorophenyl)butyl]imidazole 
1-[2-(benzylthio)-4-(2,4-dichlorophenyl)butyl]imidazole 
1-[2-(4-chlorobenzyloxy)-4-(2,4-dichlorophenyl)butyl]imidazole 
1-[2-(2,4-dichlorobenzylthio)-4-(2,4-dichlorophenyl)butyl]imidazole 
1-[2-(3,4-dichlorobenzylthio)-4-(2,4-dichlorophenyl)butyl]imidazole 
1-[2-(4-tert-butylbenzyloxy)-4-(2,4-dichlorophenyl)butyl]imidazole 
1-[2-cinnamyloxy-4-(2,4-dichlorophenyl)butyl]imidazole 
1-[2-(4-chlorocinnamylthio)-4-(2,4-dichlorophenyl)butyl]imidazole 
1-[2-(4-phenylbutylthio)-4-(2,4-dichlorophenyl)butyl]imidazole 
1-[2-(4-chlorophenylthio)-4-(4-tert-butylphenyl)butyl]imidazole 
1-[2-(2,4-dichlorobenzyloxy)-4-(4-tert-butylphenyl)butyl]imidazole 
1-[2-(3,4-dichlorophenylthio)-4-(4-fluorophenyl)butyl]imidazole 
1-[2-(2,4-dichlorobenzyloxy)-4-(4-fluorophenyl)butyl]imidazole 
1-[2-(3,4-dichlorobenzylthio)-4-(4-fluorophenyl)butyl]imidazole 
1-[2-(3,4-dichlorobenzylthio)-4-(2,4-dimethylphenyl)butyl]imidazole 
1-[2-(4-chlorophenoxy)-4-(2,4-dimethylphenyl)butyl]imidazole 
trans-1[2-(3,4-dichlorophenylthio)-4-phenylbut-3-enyl]imidazole - oxalate 
salt, m.p. 171.5.degree.-175.5.degree. C. (dec.). 
trans-1-[2-(3,4-dichlorobenzylthio)-4-phenylbut-3-enyl]imidazole -- nitrate 
salt, m.p. 138.degree.-139.degree. C. (foaming) 
trans-1-[2-(2,4-dichlorobenzyloxy)-4-phenylbut-3-enyl]imidazole -- nitrate 
salt, m.p. 133.5.degree.-134.5.degree. C. (foaming) 
1-[2-(4-chlorobenzylthio)-4-phenylbut-3-enyl]imidazole 
1-[2-(4-chlorophenylthio)-4-phenylbut-3-enyl]imidazole 
1-[2-(4-chlorophenoxy)-4-phenylbut-3-enyl]imidazole 
1-[2-(4-bromobenzylthio)-4-phenylbut-3-enyl]imidazole 
1-[2-(4-fluorophenoxy)-4-phenylbut-3-enyl]imidazole 
1-[2-(3-phenylpropyloxy)-4-phenylbut-3-enyl]imidazole 
1-[2-cinnamyloxy-4-phenylbut-3-enyl]imidazole 
1-[2-(4-chlorocinnamyloxy)-4-phenylbut-3-enyl]imidazole 
1[2-(4-phenylbutylthio)-4-phenylbut-3-enyl]imidazole 
1-[2-(3,4-dichlorophenylthio)-4-(4-chlorophenyl)but-3-enyl]imidazole 
1-[2-(4-chlorophenoxy)-4-(4-chlorophenyl)but-3-enyl]imidazole 
1-[2-(2,4,5-trichlorophenylthio)-4-(4-chlorophenyl)but-3-enyl]imidazole 
1-[2-(2,3,4,5,6-pentachlorophenylthio)-4-(4-chlorophenyl)but- 
3-enyl]imidazole 
1-[2-(cinnamylthio)-4-(4-chlorophenyl(but-3-enyl]imidazole 
1-[2-(4-chlorocinnamyloxy)-4-(4-chlorophenyl)but-3-enyl]imidazole 
1-[2-(4-chlorophenylthio)-4-(4-chlorophenyl)but-3-enyl]imidazole 
1-[2-(4-chlorobenzyloxy)-4-chlorophenyl)but-3-enyl]imidazole 
1-[2-(4-chlorobenzylthio)-4-(4-chlorophenyl)but-3-enyl]imidazole 
1-[2-(2,4-dichlorobenzyloxy)-4-(4-chlorophenyl)but-3-enyl]imidazole 
1-[2-(2,4-dichlorophenylthio)-4-phenylbutyl]imidazole 
1-[2-(4-chlorobenzylthio)-4-phenylbutyl]imidazole 
1-[2-(4-chlorobenzyloxy-4-phenylbutyl]imidazole 
1-[2-(4-chlorobenzylthio)-4-(4-fluorophenyl)butyl]imidazole 
1-[2-(2,4-dichlorobenzylthio)-4-(4-fluorophenyl)butyl]imidazole 
1-[2-(2,4-dichlorophenylthio)-4-(4-fluorophenyl)butyl]imidazole -- nitrate 
salt, m.p. 92.degree.-93.5.degree. C 
1-[2-(2,6-dichlorophenylthio)-4-(4-chlorophenyl)butyl]imidazole -- nitrate 
salt, m.p. 162,5.degree.-164.5.degree. C 
1-[2-(2,5-dichlorophenylthio)-4-(4-chlorophenyl)butyl]imidazole -- nitrate 
salt, m.p. 155.5.degree.-157.degree. C. 
1-[2-(2,3-dichlorophenylthio)-4-(4-chlorophenyl)butyl]imidazole 
1-[2-(2-chlorophenylthio)-4-(4-chlorophenyl)butyl]imidazole -- nitrate 
salt, m.p. 134.5.degree.-135.5.degree. C. 
1-[2-(3-chlorophenylthio)-4-(4-chlorophenyl)butyl]imidazole 
1-[2-(2-bromophenylthio)-4-(4-chlorophenyl)butyl]imidazole 
1-[2-(4-bromophenylthio)-4-(4-chlorophenyl)butyl]imidazole 
1-[2-(2,6-dibromophenylthio)-4-(4-chlorophenyl)butyl]imidazole 
1-[2-(2,4-dibromophenylthio)-4-(4-chlorophenyl)butyl]imidazole 
1-[2-(2,4,6-trichlorophenylthio)-4-(4-chlorophenyl)butyl]imidazole 
1-[2-(2,6-dichlorophenylthio)-4-(4-fluorophenyl)butyl]imidazole -- nitrate 
salt, m.p. 131.5.degree.-132.5.degree. C. 
1-[2-(2,5-dichlorophenylthio)-4-(4-fluorophenyl)butyl]imidazole 
1-[2-(2,3-dichlorophenylthio)-4-(4-fluorophenyl)butyl]imidazole 
1-[2-(2-chlorophenylthio)-4-(4-fluorophenyl)butyl]imidazole 
1-[2-(4-chlorophenylthio)-4-(4-fluorophenyl)butyl]imidazole 
1-[2-(2-bromophenylthio)-4-(4-fluorophenyl)butyl]imidazole 
1-[2-(4-bromophenylthio)-4-(4-fluorophenyl)butyl]imidazole 
1-[2(2,6-dibromophenylthio)-4-(4-fluorophenyl)butyl]imidazole 
1-[2-(2,4-dibromophenylthio)-4-(4-fluorophenyl)butyl]imidazole 
1-[2-(2,4,5-trichlorophenylthio)-4-(4-fluorophenyl)butyl]imidazole 
1-[2-(2,4,6-trichlorophenylthio)-4-(4-fluorophenyl)butyl]imidazole -- 
nitrate salt, m.p. 163.degree.-164.degree. C. 
1-[2-(2,6-dichlorophenylthio)-4-(4-bromophenyl)butyl]imidazole 
1-[2-(2,5-dichlorophenylthio)-4-(4-bromophenyl)butyl]imidazole 
1-[2-(2,4-dichlorophenylthio)-4-(4-bromophenyl)butyl]imidazole 
1-[2-(2,3-dichlorophenylthio)-4-(4-bromophenyl)butyl]imidazole 
1-[2-(3,4-dichlorophenylthio)-4-(4-bromophenyl)butyl]imidazole 
1-[2-(2-chlorophenylthio)-4-(4-bromophenyl)butyl]imidazole 
1-[2-(3-chlorophenylthio)-4-(4-bromophenyl)butyl]imidazole 
1-[2-(4-chlorophenylthio)-4-(4-bromophenyl)butyl]imidazole 
1-[2-(2-bromophenylthio)-4-(4-bromophenyl)butyl]imidazole 
1-[2-(4-bromophenylthio)-4-(4-bromophenyl)butyl]imidazole 
1-[2-(2,6-dibromophenylthio)-4-(4-bromophenyl)butyl]imidazole 
1-[2-(2,4-dibromophenylthio)-4-(4-bromophenyl)butyl]imidazole 
1-[2-(2,4,5-trichlorophenylthio)-4-(4-bromophenyl)butyl]imidazole 
1-[2-(2,4,6-trichlorophenylthio)-4-(4-bromophenyl)butyl]imidazole 
1-[2-(2,6-dichlorophenylthio)-4-(4-trifluoromethylphenyl)butyl]imidazole 
1-[2-(2-chlorophenylthio)-4-(4-trifluoromethylphenyl)butyl]imidazole 
1-[2-(2,5-dichlorophenylthio)-4-(4-trifluoromethylphenyl)butyl]imidazole 
1-[2-(2,4-dichlorophenylthio)-4-(4-trifluoromethylphenyl)butyl]imidazole 
1-[2-(2,6-dichlorobenzyloxy)-4-(4-chlorophenyl)butyl]imidazole 
1-[2-(2,6-dichlorobenzylthio)-4-(4-chlorophenyl)butyl]imidazole 
1-[2-(2-chlorobenzyloxy)-4-(4-chlorophenyl)butyl]imidazole 
1-[2-(2-chlorobenzylthio)-4-(4-chlorophenyl)butyl]imidazole 
1-[2-(2,3,6-trichlorophenoxy)-4-(4-chlorophenyl)butyl]imidazole 
1-[2-(2,4,6-trichlorophenoxy9-4-(4-chlorophenyl)butyl]imidazole -- nitrate 
salt, m.p. 173.5.degree.-174.5.degree. C. 
1-[2-(2,5-dichlorophenoxy)-4-(4-chlorophenyl)butyl]imidazole 
1-[2-(2,4-dichlorophenoxy)-4-(4-chlorophenyl)butyl]imidazole -- nitrate 
salt, m.p. 130.degree.-131.5.degree. C. 
1-[2-82,6-dichlorophenoxy)-4-(4-chlorophenyl)butyl]imidazole -- nitrate 
salt, m.p. 145.5.degree.-148.degree. C. 
1-[2-(2-chlorophenylthio)-5-(4-chlorophenyl)butyl]imidazole 
1-[2-(2,6-dichlorophenylthio)-5-(4-chlorophenyl)butyl]imidazole 
1-[2-(2,5-dichlorophenylthio)-5-(4-chlorophenyl)pentyl]imidazole 
1-[2-(2,4-dichlorophenylthio)-5-(4-chlorophenyl)pentyl]imidazole 
1-[2-(2-bromophenylthio)-5-(4-chlorophenyl)pentyl]imidazole 
1-[2-(2,6-dichlorophenylthio)-4-(4-chlorophenyl)but-3-enyl]imidazole 
1-[2-(2,5-dichlorophenylthio)-4-(4-chlorophenyl)but-3-enyl[imidazole 
1-[2-(2-chlorophenylyhio)-4-(4-chlorophenyl)but-3-enyl]imidazole 
1-[2-(2-bromophenylthio)-4(4-chlorophenyl)but-3-enyl]imidazole 
1-[2-(2,6-dichlorophenoxy)-4-(4-chlorophenyl)but-3-enyl]imidazole 
1-[2-(2,4-dichlorophenylthio)-4-(4-chlorophenyl)but-3-enyl]imidazole -- 
nitrate salt, m.p. 149.degree.-150.5.degree. C (foams) 
1-[2-(2,4,6-trichlorophenoxy)-4-(4-chlorophenyl)but-3-enyl]imidazole -- 
nitrate salt, m.p. 156.degree.-157.degree. C (foams) 
1-[2-(2-chlorophenylthio)-4-(2,4-dichlorophenyl)butyl]imidazole -- nitrate 
salt, m.p. 112.degree.-112.5.degree. C. 
1-[2-(4-chlorophenylthio)-4-(2,4-dichlorophenyl)butyl]imidazole -- nitrate 
salt, m.p. 124.degree.-125.5.degree. C. (foams) 
1-[2-(2,4-dichlorophenylthio)-4-(2,4-dichlorophenyl)butyl]imidazole -- 
nitrate salt, m.p. 130.degree.-131.5.degree. C. 
1-[2-(2-chlorophenoxy)-4-(2,4-dichlorophenyl)butyl]imidazole -- nitrate 
salt, m.p. 116.5-117.5.degree. C. 
EXAMPLE 7 
Following the procedures in Preparations 3 or 4, and Examples 1; 2,3; or 
2,4, using equivalent amounts of the appropriate starting materials, there 
may be obtained the following compounds. Where indicated, the compounds 
may be further characterized by conversion to the indicated acid addition 
salt. 
1-[3-(4-chlorophenylthio)-3-(4-chlorophenyl)propyl]imidazole -- oxalate 
salt, m.p. 108.degree.-112.degree. C. 
1-[3-(4-chlorobenzylthio)-3-(4-chlorophenyl)propyl]imidazole -- oxalate 
salt, m.p. 115.degree.-156.degree. C. 
1-[3-(4-chlorobenzyloxy)-3-(4-chlorophenyl)propyl]imidazole -- oxalate 
salt, m.p. 105.degree.-106.degree. C. 
1-[3-(4-bromo-3-methylphenylthio)-3-(4-chlorophenyl)propyl]imidazole -- 
nitrate salt, m.p. 107.degree.-108.degree. C. (dec.) 
1-[3-(4-tert-butylphenylthio)-3-(4-chlorophenyl)propyl]imidazole -- oxalate 
salt, m.p. 127.5.degree.-129.degree. C. (dec.) 
1-[3-(4-fluorophenylthio)-3-(4-chlorophenyl)propyl]imidazole 
1-[3-(4-bromobenzyloxy)-3-(4-chlorophenyl)propyl]imidazole 
1-[3-(2,4-dichlorophenylthio)-3-(4-chlorophenyl)propyl]imidazole 
1-[3-(3,4-dichlorophenylthio)-3-(4-chlorophenyl)propyl]imidazole 
1-[3-(4-trifluoromethylphenylthio)-3-(4-chlorophenyl)propyl]imidazole 
1-[3-(4-trifluoromethylbenzyloxy)-3-(4-chlorophenyl)propyl]imidazole 
1-[3-(4-chlorocinnamyloxy)-3-(4-chlorophenyl)propyl]imidazole 
1-[3-(2,4-dichlorocinnamylthio)-3-(4-chlorophenyl)propyl]imidazole 
1-[3-(4-phenylbutyloxy)-3-(4-chlorophenyl)propyl]imidazole 
1-[3-(4-methylbenzylthio)-3-(2,4-dichlorophenyl)propyl]imidazole -- nitrate 
salt, m.p. 69.5.degree.-75.degree. C. (dec.) 
1-[3-(4-chlorobenzylthio-3-(2,4-dichlorophenyl)propyl]imidazole -- nitrate 
salt, m.p. 63.degree.-66.5.degree. C. (dec.) 
1-[3-(4-chlorophenylthio)-3-(2,4-dichlorophenyl)propyl]imidazole -- nitrate 
salt, m.p. 123.5.degree.-125.5.degree. C. (dec.) 
1-[3-(2,4-dichlorophenylthio)-3-(2,4-dichlorophenyl)propyl]imidazole 
1-[3-(3,4-dichlorophenylthio)-3-(2,4-dichlorophenyl)propyl]imidazole 
1-[3-(4-trifluoromethylphenylthio)-3-(2,4-dichlorophenyl)propyl]imidazole 
1-[3-(4-trifluoromethylbenzyloxy)-3-(2,4-dichlorophenyl)propyl]imidazole 
1-[3-(4-tert-butylphenylthio)-3-(2,4-dichlorophenyl)propyl]imidazole 
1-[3-(4-methylbenzyloxy)-3-(2,4-dichlorophenyl)propyl]imidazole 
1-[3-(4-chlorocinnamyloxy)-3-(2,4-dichlorophenyl)propyl]imidazole 
1-[3-(3,4-dichlorobenzyloxy)-3-(2,4-dichlorophenyl)propyl]imidazole 
1-[3-(2,4,5-trichlorophenylthio)-3-(2,4-dichlorophenyl)propyl]imidazole 
1-[3-(4-phenylbutylthio)-3-(2,4-dichlorophenyl)propyl]imidazole 
1-[3-(4-chlorobenzyloxy)-3-(2,4-dichlorophenyl)propyl]imidazole 
1-[3-(2,4-dichlorobenzyloxy)-3-(2,4-dichlorophenyl)propyl]imidazole 
1-[3-(4-chlorophenylthio)-3-(4-tert-butylphenyl)propyl]imidazole 
1-[3-(2,4-dichlorobenzylthio)-3-(4-tert-butylphenyl)propyl]imidazole 
1-[3-(2,4,5-trichlorophenylthio)-3-(4-fluorophenyl)propyl]imidazole -- 
oxalate salt, coalesces 76.degree. C. final m.p. 99.degree. C. 
1-[3-(4-chlorobenzylthio)-3-(4-fluorophenyl)propyl]imidazole 
1-[3-(4-tert-butylphenylthio)-3-(4-fluorophenyl)propyl]imidazole 
1-[3-(4-chlorocinnamyloxy)-3-(4-fluorophenyl)propyl]imidazole 
1-[3-(4-chlorocinnamyloxy)-3-(2,4-dimethylphenyl)propyl]imidazole 
1-[3-(2,4-dichlorobenzylthio)-3-(2,4-dimethylphenyl)propyl]imidazole 
1-[3-(4-bromophenylthio)-3-(2,4-dimethylphenyl)propyl]imidazole 
1-[3-(4-methylbenzylthio)-3-(4-tert-butylphenyl)propyl]imidazole -- nitrate 
salt, m.p. 132.degree.-134.degree. C. (dec.) 
1-[3-cinnamyloxy-3-(4-tert-butylphenyl)propyl]imidazole 
1-[3-(4-chlorophenylthio)-4-phenylbutyl]imidazole 
1-[3-(2,4-dichlorobenzylthio)-4-phenylbutyl]imidazole 
1-[3-(4-tert-butylphenylthio)-4-phenylbutyl]imidazole 
1-[3-(4-chlorocinnamyloxy)-4-phenylbutyl]imidazole 
1-[3-(2,4-dichlorophenylthio)-4-(4-chlorophenyl)butyl]imidazole 
1-[3-(4-methylbenzylthio)-4-(4-chlorophenyl)butyl]imidazole 
1-[3-(4-chlorobenzylthio)-4-(4-methylphenyl)butyl]imidazole 
1-[3-(2,4-dichlorophenoxy)-4-(4-methylphenyl)butyl]imidazole 
1-[3-(4-chlorocinnamyloxy)-4-(4-methylphenyl)butyl]imidazole 
1-[3-(2,4-dichlorobenzylthio)-5-(4-chlorophenyl)pentyl]imidazole 
1-[3-(4-bromobenzyloxy)-5-(4-chlorophenyl)pentyl]imidazole 
1-[3-(4-chlorobenzylthio)-5-(4-chlorophenyl)pentyl]imidazole 
1-[3-(2,4,5-trichlorophenylthio)-5-(4-chlorophenyl)pentyl]imidazole 
1-[3-(4-tert-butylbenzylthio)-5-(4-chlorophenyl)pentyl]imidazole 
1-[3-(3,4-dichlorophenylthio)-3-(2-trifluoromethylphenyl)propyl]imidazole 
1-[3-(3,4-dichlorobenzylthio)-3-(2-trifluoromethylphenyl)propyl]imidazole 
1-[3-(4-chlorophenylthio)-3-(2,4-dibromophenyl)propyl]imidazole 
1-[3-(4-chlorophenylthio)-3-(2,4-difluorophenyl)propyl]imidazole 
1-[3-(4-fluorophenylthio)-3-(2,4-dichlorophenyl)propyl]imidazole 
1-[3-(4-fluorobenzylthio)-3-(2,4-dichlorophenyl)propyl]imidazole 
1-[3-(2-chlorophenylthio)-4-(4-chlorophenyl)butyl]imidazole 
1-[3-(2,6-dichlorophenylthio)-4-(4-chlorophenyl)butyl]imidazole 
1-[3-(2,5-dichlorophenylthio)-4-(4-chlorophenyl)butyl]imidazole 
1-[3-(2,4-dichlorophenylthio)-4-(4-chlorophenyl)butyl]imidazole 
1-[3-(2-bromophenylthio)-4-(4-chlorophenyl)butyl]imidazole 
1-[3-(2,6-dibromophenylthio)-4-(4-chlorophenyl)butyl]imidazole 
1-[3-(2-chlorophenylthio)-5-(4-chlorophenyl)pentyl]imidazole 
1-[3-(2,6-dichlorophenylthio)-5-(4-chlorophenyl)pentyl]imidazole 
1-[3-(2,5-dichlorophenylthio)-5-(4-chlorophenyl)pentyl]imidazole 
1-[3-(2,4-dichlorophenylthio)-5-(4-chlorophenyl)pentyl]imidazole 
1-[3-(2-bromophenylthio)-5-(4-chlorophenyl)pentyl]imidazole 
EXAMPLE 8 
Following the procedures in Preparation 4, and Examples 1; 2,3; or 2,4, 
using equivalent amounts of the appropriate starting materials, there may 
be obtained the following compounds. Where indicated, the compounds may be 
further characterized by conversion to the indicated acid addition salt. 
1-[4-(3,4-dichlorophenylthio)-4-(4-(4-chlorophenyl)butyl]imidazole -- 
nitrate salt, m.p. 100.degree.-104.5.degree. C., oxalate salt m.p. 
118.degree.-123.degree. C. (foaming) 
1-[4-(3,4-dichlorophenoxy)-4-(4-chlorophenyl)butyl]imidazole -- nitrate 
salt, m.p. 128.degree.-130.5.degree. C. 
1-[4-(4-chlorobenzylthio)-4-(4-chlorophenyl)butyl]imidazole -- nitrate 
salt, m.p. 123.degree.-125.degree. C. (foaming) 
1-[4-(2,4-dichlorobenzyloxy)-4-(4-chlorophenyl)butyl]imidazole -- nitrate 
salt, m.p. 91.degree.-114.degree. C. 
1-[4-(3,4-dichlorobenzyloxy-4-(4-chlorophenyl)butyl]imidazole 
1-[4-(4-bromobenzylthio)-4-(4-chlorophenyl)butyl]imidazole 
1-[4-(4-fluorophenylthio)-4-(4-chlorophenyl)butyl]imidazole 
1-[4-(4-methylbenzyloxy)-4-(4-chlorophenyl)butyl]imidazole 
1-[4-(4-chlorophenylthio)-4-(2,4-dichlorophenyl)butyl]imidazole -- oxalate 
salt, m.p. 69.degree.-75.degree. C. (foaming) 
1-[4-(4-methylphenylthio)-4-(2,4-dichlorophenyl)butyl]imidazole 
1-[4-(4-chlorobenzylthio)-4-(2,4-dichlorophenyl)butyl]imidazole -- oxalate 
salt, m.p. 62.5.degree.-65.degree. C. (foaming) 
1-[4-benzylthio-4-(2,4-dichlorophenyl)butyl]imidazole 
1-[4-(2,4-dichlorobenzyloxy)-4-(2,4-dichlorophenyl)butyl]imidazole 
1-[4-(4-chlorobenzyloxy)-4-(2,4-dichlorophenyl)butyl]imidazole -- nitrate 
salt, coalesces 98.5.degree. C., final m.p. 108.degree. C. 
1-[4-(4-phenylbutylthio)-4-(2,4-dichlorophenyl)butyl]imidazole 
1-[4-(4-fluorobenzylthio)-4-(2,4-dichlorophenyl)butyl]imidazole -- oxalate 
salt, m.p. 95.degree.-101.5.degree. C. 
1-[4-(4-tert-butylphenylthio)-4-(4-fluorophenyl)butyl]imidazole 
1-[4-(3,4-dichlorophenylthio)-4-(4-fluorophenyl)butyl]imidazole 
1-[4-(4-tert-butylbenzyloxy)-4-(4-fluorophenyl)butyl]imidazole -- oxalate 
salt, m.p. 49.5.degree.-51.degree. C. 
1-[4-phenylpropylthio-4-(4-fluorophenyl)butyl]imidazole -- oxalate salt, 
m.p. 97.degree.-99.degree. C. 
1-[4-phenylthio-4-(4-tert-butylphenyl)butyl]imidazole nitrate salt, m.p. 
121.5.degree.-123.5.degree. C. (dec.) 
1-[4-(4-chlorophenylthio)-4-(4-tert-butylphenyl)butyl]imidazole 
1-[4-(2,4-dichlorobenzylthio)-4-(4-tert-butylphenyl)butyl]imidazole 
1-[4-(4-fluorophenylthio)-4-(2,4-dimethylphenyl)butyl]imidazole 
1-[4-cinnamyloxy-4-(2,4-dimethylphenyl)butyl]imidazole 
1-[4-(4-methylbenzylthio)-4-(4-bromophenyl)butyl]imidazole -- nitrate salt, 
m.p. 93.degree.-95.degree. C. (dec.) 
1-[4-(4-bromobenzyloxy)-4-(4-bromophenyl)butyl]imidazole -- nitrate salt, 
m.p. 117.degree.-123.5.degree. C. 
1-[4-(4-chlorophenylthio)-5-phenylpentyl]imidazole 
1-[4-(2,4-dichlorobenzylthio)-5-phenylpentyl]imidazole 
1-[4-(4-tert-butylphenoxy)-5-phenylpentyl]imidazole 
1-[4-(4-chlorocinnamyloxy)-5-phenylpentyl]imidazole 
1-[4-(2,4-dichlorophenylthio)-5-(4-chlorophenyl)pentyl]imidazole 
1-[4-(4-methylbenzylthio)-5-(4-chlorophenyl)pentyl]imidazole 
1-[4-(2,4-dichlorobenzylthio)-6-(4-chlorophenyl)hexyl]imidazole 
1-[4-(4-bromobenzyloxy)-6-(4-chlorophenyl)hexyl]imidazole 
1-[4-(4-chlorobenzylthio)-6-(4-chlorophenyl)hexyl]imidazole 
1-[4-(2,4,5-trichlorophenylthio-6-(4-chlorophenyl)hexyl]imidazole 
1-[4-(4-tert-butylbenzylthio)-6-(4-chlorophenyl)hexyl]imidazole 
1-[4-(4-trifluoromethylphenylthio)-6-(4-chlorophenyl)hexyl]imidazole 
1-[4-(4-trifluoromethylbenzyloxy)-6-(4-chlorophenyl)hexyl]imidazole 
1-[6-(2,4-dichlorobenzyloxy)-6-phenylhexyl]imidazole 
1-[6-(4-chlorobenzylthio)-6-phenylhexyl]imidazole 
1-[6-(4-methylphenylthio)-6-phenylhexyl]imidazole 
1-[6-(4-chlorophenylthio)-6-phenylhexyl]imidazole 
1-[6-(4-chlorobenzyloxy)-6-(4-chlorophenyl)hexyl]imidazole 
1-[6-benzylthio-6-(4-chlorophenyl)hexyl]imidazole 
1-[6-(4-fluorobenzylthio)-6-(4-chlorophenyl)hexyl]imidazole 
1-[6-(3,4-dichlorobenzyloxy)-6-(4-chlorophenyl)hexyl]imidazole 
1-[6-cinnamyloxy-6-(4-chlorophenyl)hexyl]imidazole 
1-[6-(2,4-dichlorobenzyloxy)-7-(4-chlorophenyl)heptyl]imidazole 
1-[6-(2,4-dichlorobenzylthio)-8-phenyloctyl]imidazole 
1-[6-(4-chlorobenzyloxy)-10-phenyldecyl]imidazole 
1-(9-benzyloxy-9-phenylnonyl)imidazole 
1-[9-(4-fluorophenylthio)-9-phenylnonyl]imidazole 
1-[9-phenoxy-9-(4-chorophenyl)nonyl]imidazole 
1-[9-(2,4,5-trichlorobenzylthio)-9-(4-chloropheny) nonyl]imidazole 
1-[9-cinnamyloxy-9-(4-chlorophenyl)nonyl]imidazole 
1-[9-(2,4-dichlorobenzyloxy)-10-(4-chorophenyl)decyl]imidazole 
1-[9-(2,4-dichlorobenzylthio)-11-phenylundecyl]imidazole 
1-[9-(4-chlorobenzyloxy)-13-phenyltridecyl]imidazole 
1-[4-(4-fluorophenylthio)-4-(2,4-dichlorophenyl)butyl]imidazole. 
EXAMPLE 9 
Nitric acid (70%; d = 1.42) was added dropwise to a stirred solution of 2.0 
g. of 1-[2-(2,4-dichlorobenzyloxy)-4-phenylbutyl]imidazole in 30 ml. of 
anhydrous ether until precipitation was complete. The product was filtered 
off, washed with ether, air dried, and recrystallized from ethyl acetate 
to yield 1-[2-(2,4-dichlorobenzyloxy)-4-phenylbutyl]imidazole nitrate, 
m.p. 121.degree.--124.degree. C. 
In similar manner, all compounds of Formula (I) in base form can be 
converted to their antimicrobial acid addition salts by treatment with the 
appropriate acid, for example, hydrochloric acid, hydrobromic acid, 
sulfuric acid, nitric acid, phosphoric acid, acetic acid, propionic acid, 
glycolic acid, lactic acid, pyruvic acid, oxalic acid, malonic acid, 
succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, 
citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic 
acid, ethanesulfonic acid, p-toluenesulfonic acid or salicyclic acid. 
EXAMPLE 10 
1-[2-(2,4-Dichlorobenzyloxy)-4-phenylbutyl]imidazole nitrate (2.0 g.) in 
100 ml. of dichloromethane was shaken with excess dilute potassium 
carbonate solution until the salt was completely dissolved. The organic 
layer was then separated, washed twice with water, dried over magnesium 
sulfate and evaporated to yield 
1-[2-(2,4-dichlorobenzyloxy-4-phenylbutyl]imidazole as an oil. 
In similar manner, the antimicrobial acid addition salts of all compounds 
of Formula (I) can be converted to the corresponding compounds in base 
form. 
EXAMPLE 11 
The following illustrates the preparation of representative pharmaceutical 
formulations which may be used for controlling fungi, bacteria and 
protozoa, utilizing an active compound such as salt of 
1-[2-(3,4-dichlorophenylthio)-4-phenylbutyl]imidazole. 
______________________________________ 
A. Topical Formulation grams 
______________________________________ 
Active compound 0.2 - 2 
Span 60 2 
Tween 60 2 
Mineral oil 5 
Petrolatum 10 
Methyl paraben 0.15 
Propyl paraben 0.05 
BHA (butylated hydroxy anisole) 
0.01 
Water qs 100 
______________________________________ 
All of the above ingredients, except water, are combined and heated at 
60.degree. C. with stirring. A sufficient quantity of water at 60.degree. 
C. in then added with vigorous stirring to provide 100 g. of the cream 
formulation which is then cooled to room temperature. 
______________________________________ 
B I.V. Formulation 
______________________________________ 
Active compound 0.5 g. 
Propylene glycol 20 g. 
Polyethylene glycol 400 
20 g. 
Tween 80 1 g. 
0.9 Saline solution qs 
100 ml. 
______________________________________ 
The active compound is dissolved in propylene glycol, polyethylene glycol 
400 and Tween 80. A sufficient quantity of 0.9% saline solution is then 
added with stirring to provide 100 ml. of the I.V. solution which is 
filtered through a 0.2 micron membrane filter and packaged under sterile 
conditions. 
______________________________________ 
C. Oral Formulation parts by weight 
______________________________________ 
Active compound 200 
Magnesium stearate 3 
Starch 30 
Lactose 116 
PVP (polyvinylpyrrolidone) 
3 
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The above ingredients are combined and granulated using methanol as the 
solvent. The formulation is then dried and formed into tablets (containing 
200 mg. of active compound) with an appropriate tabletting machine.