Acylated imidazolyl-O,N-acetals, their pharmaceutically acceptable salts and metal complexes

Acylated imidazolyl-O,N-acetals of the formula ##STR1## and their pharmaceutically acceptable salts and metal complexes wherein R is alkyl, alkenyl, alkinyl, cycloalkyl, halogenoalkyl, optionally substituted phenyl, optionally substituted phenoxyalkyl, alkylamino, dialkylamino or optionally substituted phenylamino; PA1 X is halogen, alkyl, cycloalkyl, alkoxy, halogenoalkyl, alkylthio, alkoxycarbonyl, optionally substituted phenyl, optionally substituted phenoxy, optionally substituted phenylalkyl, amino, cyano or nitro; and PA1 N is 0 or an integer of from 1 to 5; are useful as antimicrobial agents, particularly for their use in treating mycotic infectins in humans and animals.

The present invention relates to the use of new acylated 
imidazolyl-O,N-acetals, pharmaceutically-acceptable, nontoxic salts 
thereof and metal complexes thereof as antimicrobial agents, particularly 
as antimycotic agents. It is known that imidazolyl-O,N-acetals, and 
especially 1-imidazolyl-1-phenoxy-3,3-dimethylbutan-2-ols, exhibit good 
antimycotic activity (see German OLS No. 2,333,355). However, the action 
of those compounds is not entirely satisfactory, particularly against 
dermatophytes. 
We have now discovered that acylated imidazolyl-O,N-acetals of the formula 
##STR2## 
pharmaceutically acceptable salts thereof and metal complexes thereof, 
wherein 
R is alkyl, especially of 1 to 18 carbon atoms, and particularly 1 to 12 
carbon atoms; alkenyl, especially of 2 to 4 carbon atoms; alkinyl, 
especially of 2 to 4 carbon atoms; cycloalkyl, especially of 5 to 7 carbon 
atoms; halogenoalkyl, especially of 1 to 4 carbon atoms in the alkyl 
moiety and 1 to 5 halogen atoms; phenyl unsubstituted or substituted by 
halogen, cyano, nitro or alkyl, especially of 1 to 4 carbon atoms; 
phenoxyalkyl, especially of 1 or 2 carbon atoms in the alkyl moiety, 
unsubstituted or nuclear-substituted by halogen, amino, cyano, nitro or 
alkyl of 1 to 4 carbon atoms; alkylamino, especially lower alkylamino; 
dialkylamino, especially di-lower alkylamino; or phenylamino unsubstituted 
or nuclear-substituted by halogen, nitro or cyano; 
X is halogen; alkyl, especially lower alkyl; cycloalkyl, especially of 5 to 
7 carbon atoms; alkoxy, especially of 1 to 4 carbon atoms; halogenoalkyl, 
especially of 1 to 4 carbon atoms in the alkyl moiety and 1 to 5 halogen 
atoms; alkylthio, especially of 1 to 4 carbon atoms in the alkyl moiety; 
alkoxycarbonyl, especially of 1 to 4 carbon atoms in the alkoxy moiety; 
phenyl unsubstituted or substituted by halogen, amino, cyano, nitro or 
alkyl, especially of 1 or 2 carbon atoms; phenoxy unsubstituted or 
nuclear-substituted by halogen, amino, cyano, nitro or alkyl, especially 
of 1 or 2 carbon atoms; amino; cyano; or nitro; and 
n is 0 or an integer from 1 to 5; 
exhibit good antimicrobial properties and are particularly useful as 
antimycotics. In the above-referred-to formula, when n is an integer from 
2 to 5 and therefore there is more than one X present in the phenyl 
moiety, the X's may be the same or different. 
According to one embodiment of the present invention 
R is alkyl of 1 to 8 carbon atoms; alkenyl of 2 to 4 carbon atoms; alkinyl 
of 2 to 4 carbon atoms; halogenoalkyl of 1 or 2 carbon atoms in the alkyl 
moiety and 1 to 5 halogen atoms selected from the group consisting of 
fluorine or chlorine; cycloalkyl of 5 to 7 carbon atoms; phenyl 
unsubstituted or substituted by halogen, cyano, nitro or alkyl of 1 or 2 
carbon atoms; phenoxyalkyl of 1 or 2 carbon atoms in the alkyl moiety 
unsubstituted or nuclear-substituted by halogen, amino, cyano, nitro or 
alkyl of 1 or 2 carbon atoms; alkylamino of 1 to 4 carbon atoms in the 
alkyl moiety; dialkylamino of 1 to 4 carbon atoms in each alkyl moiety; or 
phenylamino unsubstituted or nuclear-substituted by halogen, nitro or 
cyano; 
X is halogen; amino; cyano; nitro; alkyl of 1 to 4 carbon atoms; cycloalkyl 
of 5 to 7 carbon atoms; halogenoalkyl of 1 or 2 carbon atoms in the alkyl 
moiety and 1 to 5 halogen atoms selected from the group consisting of 
fluorine and chlorine; alkoxycarbonyl of 1 to 4 carbon atoms in the alkoxy 
moiety; alkoxy of 1 or 2 carbon atoms; alkylthio of 1 or 2 carbon atoms; 
phenyl unsubstituted or substituted by halogen, amino, cyano, nitro or 
alkyl of 1 or 2 carbon atoms; phenoxy unsubstituted or substituted by 
halogen, amino, cyano, nitro or alkyl of 1 or 2 carbon atoms; or 
phenylalkyl of 1 or 2 carbon atoms in the alkyl moiety unsubstituted or 
substituted in the alkyl portion by alkylcarbonyl of up to 3 carbon atoms 
in total and unsubstituted or substituted in the phenyl portion by 
halogen, nitro or cyano; and 
n is 0 or an integer from 1 to 3. 
According to another embodiment of the present invention 
R is alkyl of 1 to 6 carbon atoms; alkenyl of 2 to 4 carbon atoms; alkinyl 
of 2 to 4 carbon atoms; halogenoalkyl of 1 or 2 carbon atoms in the alkyl 
moiety and 1 to 5 halogen atoms selected from the group consisting of 
fluorine or chlorine; cyclohexyl; phenyl unsubstituted or substituted by 
halogen, cyano, nitro or alkyl of 1 or 2 carbon atoms; phenoxyalkyl of 1 
or 2 carbon atoms in the akyl moiety unsubstituted or nuclear-substituted 
by halogen, amino, cyano, nitro or alkyl of 1 or 2 carbon atoms; 
alkylamino of 1 or 2 carbon atoms in the alkyl moiety; dialkylamino of 1 
to 4 carbon atoms in each alkyl moiety; or phenylamino unsubstituted or 
nuclear-substituted by halogen, nitro or cyano; 
X is halogen; amino; cyano; nitro; alkyl of 1 to 4 carbon atoms; 
cyclohexyl; halogenoalkyl of 1 or 2 carbon atoms in the alkyl moiety and 1 
to 5 halogen atoms selected from the group consisting of fluorine and 
chlorine; alkoxycarbonyl of 1 to 4 carbon atoms in the alkoxy moiety; 
alkoxy of 1 or 2 carbon atoms; alkylthio of 1 or 2 carbon atoms; phenyl 
unsubstituted or substituted by halogen, amino, cyano, nitro or alkyl of 1 
or 2 carbon atoms; phenoxy unsubstituted or nuclear-substituted by 
halogen, amino, cyano, nitro or alkyl of 1 or 2 carbon atoms; or 
phenylalkyl of 1 or 2 carbon atoms in the alkyl moiety unsubstituted or 
substituted in the alkyl portion by alkylcarbonyl of up to 3 carbon atoms 
in total and unsubstituted in the phenyl portion or substituted in the 
phenyl portion by halogen, nitro or cyano; and 
n is 0 or an integer from 1 to 3. 
According to another embodiment of the present invention 
R is alkyl of 1 to 4 carbon atoms; alkenyl of 2 to 4 carbon atoms; alkinyl 
of 2 to 4 carbon atoms; cycloalkyl of 5 or 6 carbon atoms; phenyl 
unsubstituted or substituted by chlorine; phenoxyalkyl of 1 or 2 carbon 
atoms in the alkyl moiety; alkylamino of 1 or 2 carbon atoms; dialkylamino 
of 1 or 2 carbon atoms; or phenylamino unsubstituted or 
nuclear-substituted by chlorine; 
X is halogen; alkyl of 1 to 4 carbon atoms; cycloalkyl of 5 or 6 carbon 
atoms; trifluoromethyl; alkylthio of 1 or 2 carbon atoms; alkoxycarbonyl 
of 1 or 2 carbon atoms in the alkoxy moiety; phenyl unsubstituted or 
substituted by halogen; phenoxy unsubstituted or substituted by halogen; 
phenylalkyl of 1 or 2 carbon atoms in the alkyl moiety; or nitro; and 
n is 0 or an integer from 1 to 3. 
According to another embodiment of the present invention 
R is alkyl of 1 to 4 carbon atoms, allyl, cyclohexyl, phenyl unsubstituted 
or substituted by chlorine, phenoxymethyl, alkylamino of 1 or 2 carbon 
atoms, dimethylamino or chlorophenylamino; 
X is chlorine, alkyl of 1 to 4 carbon atoms, cyclopentyl, cyclohexyl, 
trifluoromethyl, methylthio, alkoxycarbonyl of 1 or 2 carbon atoms in the 
alkoxy moiety, phenyl unsubstituted or substituted by halogen, phenoxy 
unsubstituted or substituted by halogen, benzyl or nitro; and 
n is 0 or an integer from 1 to 3. 
According to another embodiment of the present invention 
R is alkyl of 1 to 18 carbon atoms, halogenoalkyl of 1 to 4 carbon atoms in 
the alkyl moiety and 1 to 3 halogen atoms, alkylamino of 1 to 4 carbon 
atoms in the alkyl portion or phenylamino unsubstituted or 
nuclear-substituted by chlorine; 
X is halogen, cycloalkyl of 5 or 6 carbon atoms, phenyl or chlorophenyl; 
and 
n is 0 or an integer from 1 to 3. 
According to another embodiment of the present invention 
R is methyl, butyl, heptadecyl, methylamino, tert.-butylamino, phenylamino 
or chlorophenylamino; 
X is fluorine, chlorine, bromine, iodine, cyclohexyl, phenyl or 
chlorophenyl; and 
n is 0 or an integer from 1 to 3. 
The compounds of formula (I) have two asymmetric carbon atoms and can, 
therefore, be in the erythro or the threo form. Preferably, they are 
racemic. 
The compounds of the present invention may be prepared by reacting an 
imidazole derivative of the formula (II) 
##STR3## 
wherein X and n are as above defined, according to the four Process 
Variants A to D set forth below. The imidazole derivatives of the formula 
(II) are known from German OLS No. 2,333,355. 
PROCESS VARIANT A 
Imidazole derivatives of the formula (II) may be reacted with acid halides 
according to procedures per se known; for example, in molar amounts in the 
presence of an inert organic solvent, such as ethyl acetate, at 
temperatures of between 0.degree. C. and 100.degree. C. The compounds of 
formula (I) are obtained in the form of their hydrohalides and can be 
isolated as such by precipitating them utilizing an organic solvent, such 
as hexane, filtering them off and optionally purifying them by 
recrystallization. The compounds of formula (I) can also be isolated in 
the form of their free bases by adding aqueous sodium bicarbonate solution 
to the reaction mixture and isolating the base according to procedures per 
se known. 
PROCESS VARIANT B 
Imidazole derivatives of the formula (II) may be reacted with acid 
anhydrides according to procedures per se known; such as, for example, in 
molar amounts in the presence of an inert organic solvent, such as acetone 
or an excess of the acid anhydride, and in the presence of an acidic or 
basic catalyst, such as sodium acetate, at a temperature of from 0.degree. 
C. to 105.degree. C., followed by isolation of the compounds of formula 
(I) according to procedures per se known. 
PROCESS VARIANT C 
Imidazole derivatives of the formula (II) may be reacted with ketenes 
according to procedures per se known; for example, in molar amounts in the 
presence of an inert organic solvent, such as ethyl acetate, and in the 
presence of an acidic or basic catalyst, such as sodium acetate, at 
temperatures of from -10.degree. C. to +70.degree. C., followed by 
isolation of the compounds of formula (I) according to the procedures per 
se known. 
PROCESS VARIANT D 
Imidazole derivatives of the formula (II) may be reacted with isocyanates 
according to procedures per se known; for example, in molar amounts in the 
presence of an inert organic solvent, such as ethyl acetate, and in the 
presence of a catalyst, such as triethylamine, at temperatures of from 
0.degree. C. to 100.degree. C., followed by isolation of the compounds of 
formula (I) according to procedures per se known. 
The compounds of formula (I) form salts with pharmaceutically acceptable 
acids. These acids include the hydrogen halide acids such as hydrochloric 
acid and hydrobromic acid, especially hydrochloric acid, and phosphoric 
acid, nitric acid and monofunctional and bifunctional carboxylic acids and 
hydroxycarboxylic acids such as, for example, acetic acid, maleic acid, 
succinic acid, formaric acid, tartaric acid, citric acid, salicyclic acid, 
sorbic acid, lactic acid and 1,5-naphthalene disulphonic acid. 
The salts of compounds of the formula (I) can be obtained in a simple 
manner by procedures per se known for forming salts, such as by dissolving 
the base in an ether, such as diethyl ether, and adding the appropriate 
acid, isolating the salt according to procedures per se known, such as by 
filtering off, and, optionally, purifying the salt. 
Compounds of the formula (I) may also be present in the form of complexes 
with metal salts. Metals which may be mentioned for these complexes are 
preferably metals of main groups II to IV and of sub-groups I, II and IV 
to VIII of the periodic table, especially copper, zinc, manganese, 
magnesium, tin, iron and nickel. Suitable salts include the 
pharmaceutically acceptable salts which are formed with acids such as 
those set forth above. Preferred acids include the hydrogen halide acids 
such as hydrochloric acid and hydrobromic acid, and phosphoric acid, 
nitric acid and sulphuric acid. 
The metal complexes of the present invention can be obtained in a simple 
manner by procedures per se known; for example, by dissolving the metal 
salt in an alcohol, for example, ethanol, and adding the solution to the 
base. Isolation is accomplished in a manner per se known; for example, by 
filtering off, and, optionally, purifying by recrystallization. 
Representative compounds according to the present invention include the 
following: 
2-acetoxy-1-phenoxy-1-imidazol-1-yl-3,3-dimethyl-butane, 
2-acetoxy-1-(4-chlorophenoxy)-1-imidazol-1-yl-3,3-dimethyl-butane, 
2-acetoxy-1-(2-chlorophenoxy)-1-imidazol-1-yl-3,3-dimethyl-butane, 
2-acetoxy-1-(2,4,5-trichlorophenoxy)-1-imidazol-1-yl-3,3-dimethyl-butane, 
2-acetoxy-1-(4-nitrophenoxy)-1-imidazol-1-yl-3,3-dimethyl-butane, 
2-acetoxy-1-(2-cyclopentylphenoxy)-1-imidazol-1-yl-3,3-dimethyl-butane, 
2-acetoxy-1-(3-trifluoromethylphenoxy)-1-imidazol-1-yl-3,3-dimethyl-butane, 
2-acetoxy-1-(4-methylphenoxy)-1-imidazol-1-yl-3,3-dimethyl-butane, 
2-acetoxy-1-(4-methoxycarbonylphenoxy)-1-imidazol-1-yl-3,3-dimethyl-butane, 
2-acetoxy-1-(3-ethoxyphenoxy)-1-imidazol-1-yl-3,3-dimethyl-butane, 
2-acetoxy-1-(4-methylthiophenoxy)-1-imidazol-1-yl-3,3-dimethyl-butane, 
2-acetoxy-1-(4,4'-chlorophenylphenoxy)-1-imidazol-1-yl-3,3-dimethyl-butane, 
2-acetoxy-1-(4-chloro-2-methylphenoxy)-1-imidazol-1-yl-3,3-dimethyl-butane, 
2-acetoxy-1-(4-phenoxyphenoxy)-1-imidazol-1-yl-3,3-dimethyl-butane, 
2-acetoxy-1-(3,4-dimethylphenoxy)-1-imidazol-1-yl-3,3-dimethyl-butane, 
2-acetoxy-1-(4,4'-iodobiphenoxy)-1-imidazol-1-yl-3,3-dimethyl-butane, 
2-acetoxy-1-(4-benzylphenoxy)-1-imidazol-1-yl-3,3-dimethyl-butane, 
2-ethylcarbonyloxy-1-phenoxy-1-imidazol-1-yl-3,3-dimethyl-butane, 
2-ethylcarbonyloxy-1-(4-chlorophenoxy)-1-imidazol-1-yl-3,3-dimethyl-butane, 
2-ethylcarbonyloxy-1-(2-phenylphenoxy)-1-imidazol-1-yl-3,3-dimethyl-butane, 
2-isopropylcarbonyloxy-1-phenoxy-1-imidazol-1-yl-3,3-dimethyl-butane, 
2-isopropylcarbonyloxy-1-(4-fluorophenoxy)-1-imidazol-1-yl-3,3-dimethyl-but 
ane, 
2-tert.-butylcarbonyloxy-1-phenoxy-1-imidazol-1-yl-3,3-dimethyl-butane, 
2-butylcarbonyloxy-1-(4-bromophenoxy)-1-imidazol-1-yl-3,3-dimethyl-butane, 
2-propenylcarbonyloxy-1-(2,5-dichlorophenoxy)-1-imidazol-1-yl-3,3-dimethyl- 
butane, 
2-allylcarbonyloxy-1-(4-tert.-butylphenoxy)-1-imidazol-1-yl-3,3-dimethyl-bu 
tane, 
2-propynylcarbonyloxy-1-(4-cyclohexylphenoxy)-1-imidazol-1-yl-3,3-dimethyl- 
butane, 
2-cyclohexylcarbonyloxy-1-phenoxy-1-imidazol-1-yl-3,3-dimethyl-butane, 
2-phenylcarbonyloxy-1-(5-chloro-2-methylphenoxy)-1-imidazol-1-yl-3,3-dimeth 
yl-butane, 
2-(4-chlorophenylcarbonyloxy)-1-(2-chlorophenoxy)-1-imidazol-1-yl-3,3-dimet 
hyl-butane, 
2-phenoxymethylcarbonyloxy-1-(4-phenylphenoxy)-1-imidazol-1-yl-3,3-dimethyl 
-butane, 
2-phenoxymethylcarbonyloxy-1-(4-chlorophenoxy)-1-imidazol-1-yl-3,3-dimethyl 
-butane, 
2-ethylcarbamoyloxy-1-(2,4-dichlorophenoxy)-1-imidazol-1-yl-3,3-dimethyl-bu 
tane, 
2-dimethylcarbamoyloxy-1-(4-nitrophenoxy)-1-imidazol-1-yl-3,3-dimethyl-buta 
ne, 
2-methylcarbamoyloxy-1-(2,4,5-trichlorophenoxy)-1-imidazol-1-yl-3,3-dimethy 
l-butane, 
2-methylcarbamoyloxy-1-(2-phenylphenoxy)-1-imidazol-1-yl-3,3-dimethyl-butan 
e, 
2-methylcarbamoyloxy-1-(3,4-dimethylphenoxy)-1-imidazol-1-yl-3,3-dimethyl-b 
utane, 
2-methylcarbamoyloxy-1-(2-methyl-5-chlorophenoxy)-1-imidazol-1-yl-3,3-dimet 
hyl-butane, 
2-methylcarbamoyloxy-1-(4-chloro-3,5-dimethylphenoxy)-1-imidazol-1-yl-3,3-d 
imethyl-butane, 
2-phenylcarbamoyloxy-1-phenoxy-1-imidazol-1-yl-3,3-dimethyl-butane, and 
2-(4-chlorophenylcarbamoyloxy)-1-(4-phenylphenoxy)-1-imidazol-1-yl-3,3-dime 
thyl-butane. 
The compounds of formula (I), their pharmaceutically acceptable salts and 
metal complexes display a broad antimycotic spectrum of activity, 
especially against dermatophytes and blastomyces and also biphase fungi, 
for example, against Candida species such as Candida albicans, 
Epidermophyton species such as Epidermophyton floccosum, Aspergillus 
species such as Aspergillus niger, Trichophyton species such as 
Trichophyton mentagrophytes, Microsporon such as Microsporon felineum, and 
Penicillium species such as Penicillium commune. 
The compounds of the present invention, their pharmaceutically acceptable 
salts and metal complexes are thus particularly useful for treating 
dermatomycoses, systemic mycoses caused by Trichophyton mentagrophytes and 
other Trichophyton species, Microsporon species, Epidermophyton floccosum, 
blastomyces and biphase fungi, as well as molds, in humans and in treating 
dermatomycoses, systemic mycoses and especially those caused by the 
abovementioned pathogens in animals. 
The pharmaceutical compositions of the present invention contain a major or 
minor amount, e.g., 0.1% to 99.5%, preferably 0.5% to 90% of at least one 
active compound as above defined in combination with a pharmaceutically 
acceptable, nontoxic, inert diluent or carrier, the carrier comprising one 
or more solid, semi-solid or liquid diluent, filler and formulation 
adjuvant which is nontoxic, inert and pharmaceutically acceptable. Such 
pharmaceutical compositions are preferably in dosage unit form; i.e., 
physically discrete units containing a predetermined amount of the drug 
corresponding to a fraction or multiple of the dose which is calculated to 
produce the desired therapeutic response. The dosage units can contain 
one, two, three, four or more single doses, or, alternatively, one half, 
third or fourth of a single dose. A single dose preferably contains an 
amount sufficient to produce the desired therapeutic effect upon 
administration at one application of one or more dosage units according to 
a predetermined dosage regimen, usually a whole, half, third or quarter of 
the daily dosage administered once, twice, three or four times a day. 
Other therapeutic agents can also be present. 
Although the dosage and dosage regimen must in each case be carefully 
adjusted, utilizing sound professional judgment and considering the age, 
weight and condition of the recipient, the route of administration and the 
nature and gravity of the illness, generally the dosage will be from 10 
mg/kg to 300 mg/kg of body weight per day and preferably from 50 mg/kg to 
200 mg/kg of body weight per day. In some instances a sufficient 
therapeutic effect can be obtained at a lower dose, while in others a 
larger dose will be required. 
Oral administration can be effected utilizing solid and liquid dosage unit 
forms such as powders, tablets, dragees, capsules, granulates, 
suspensions, solutions and the like. 
Powders are prepared by comminuting the compound to a suitable fine size 
and mixing with a similarly comminuted pharmaceutical carrier such as an 
edible carbohydrate as, for example, starch, lactose, sucrose, glucose or 
mannitol. Sweetening, flavoring, preservative, dispersing and coloring 
agents can also be present. 
Capsules are made by preparing a powder mixture as described above and 
filling formed gelatin sheaths. Glidants and lubricants such as colloidal 
silica, talc, magnesium stearate, calcium stearate or solid polyethylene 
glycol can be added to the powder mixture before the filling operation. A 
disintegrating or solubilizing agent such as agar-agar, calcium carbonate 
or sodium carbonate can also be added to improve the availability of the 
medicament when the capsule is ingested. 
Tablets are formulated, for example, by preparing a powder mixture, 
granulating or slugging, adding a lubricant and disintegrant and pressing 
into tablets. A powder mixture is prepared by mixing the compound, 
suitably comminuted, with a diluent or base as described above and, 
optionally, with a binder such as carboxymethyl cellulose, an alginate, 
gelatin or polyvinyl pyrrolidone, a solution retardant such as paraffin, a 
resorption accelerator such as a quaternary salt and/or an absorption 
agent such as bentonite, kaolin or dicalcium phosphate. The powder mixture 
can be granulated by wetting with a binder such as syrup, starch paste, 
acacia mucilage or solutions of cellulosic or polymeric materials and 
forcing through a screen. An an alternative to granulating, the powder 
mixture can be run through the tablet machine and the resulting 
imperfectly formed slugs broken into granules. The granules can be 
lubricated to prevent sticking to the tablet-forming dies by means of the 
addition of stearic acid, a stearate salt, talc or mineral oil. The 
lubricated mixture is then compressed into tablets. The medicaments can 
also be combined with free-flowing, inert carriers and compressed into 
tablets directly without going through the granulating or slugging steps. 
A clear or opaque protective coating consisting of a sealing coat of 
shellac, a coating of sugar or polymeric material and a polish coating of 
wax can be provided. Dyestuffs can be added to these coatings to 
distinguish different unit dosages. 
Oral fluids such as solutions, syrups and elixirs can be prepared in dosage 
unit form so that a given quantity contains a predetermined amount of the 
compound. Syrups can be prepared by dissolving the compound in a suitably 
flavored aqueous sucrose solution while elixirs are prepared through the 
use of a nontoxic alcoholic vehicle. Suspensions can be formulated by 
dispersing the compound in a nontoxic vehicle. Solubilizers and 
emulsifiers, such as ethoxylated isostearyl alcohols and polyoxyethylene 
sorbitol esters, preservatives, flavor additives such as peppermint oil or 
saccharin, and the like, can also be added. 
Where appropriate, dosage unit formulations for oral administration can be 
microencapsulated. The formulation can also be prepared to prolong or 
sustain the release as, for example, by coating or embedding particulate 
material in polymers, wax, or the like. 
Parenteral administration can be effected utilizing liquid dosage unit 
forms such as sterile solutions and suspensions intended for subcutaneous, 
intramuscular or intravenous injection. These are prepared by suspending 
or dissolving a measured amount of the compound in a nontoxic liquid 
vehicle suitable for injection such as an aqueous or oleaginous medium and 
sterilizing the suspension or solution. Alternatively, a measured amount 
of the compound is placed in a vial and the vial and its contents are 
sterilized and sealed. An accompanying vial or vehicle can be provided for 
mixing prior to administration. Nontoxic salts and salt solutions can be 
added to render the injection isotonic. Stabilizers, preservatives and 
emulsifiers can also be added. 
Rectal administration can be effected utilizing suppositories in which the 
compound is admixed with low-melting, water-soluble or insoluble solids 
such as polyethylene glycol, cocoa butter, higher esters as, for example, 
myristyl palmitate, or mixtures thereof. 
Topical administration can be effected utilizing solid dosage unit forms 
such as powders or liquid or semi-liquid dosage unit forms such as 
solutions, suspensions, ointments, pastes, creams and gels. The powders 
are formulated utilizing such carriers as talc, bentonite, silicic acid, 
polyamide powder and the like. Liquid and semi-liquid formulations can 
utilize such carriers, in addition to those described above, as 
polyethylene glycol, vegetable and mineral oils, alcohols such as 
isopropanol, and the like. Other excipients such as emulsifiers, 
preservatives, colorants, perfumes and the like can also be present. 
Formulations can also be administered as an aerosol, utilizing the usual 
propellants such as the chlorofluorohydrocarbons. 
While the routes of administration include oral, parenteral (i.e., 
intramuscular, intraperitoneal and intravenous), rectal and topical, 
parenteral administration, especially intravenous, is particularly 
preferred. 
Examples A and B, set forth below, illustrate the antimycotic activity of 
the compounds of the present invention. 
EXAMPLE A 
Antimycotic in vitro activity 
Description of the experiment: 
The in vitro tests were carried out in a series dilution test using germ 
inocula with an average of 5.times.10.sup.4 germs/ml of substrate. The 
nutrient medium used was (a) for dermatophytes and molds: Sabouraud's 
milieu d'epreuve and (b) for yeasts: meat extract/glucose broth. 
The incubation temperature was 28.degree. C. and the incubation time was 24 
to 96 hours. 
Table A 
__________________________________________________________________________ 
Antimycotic in vitro activity 
MIC values in .gamma./ml of nutrient medium 
with 
Trichophyton 
Microsporum 
Penicillium 
Aspergillus 
Candida 
Active Compound mentagrophytes 
felinum 
commune 
niger albicans 
__________________________________________________________________________ 
##STR4## 64 -- &gt;64 -- 32 
(known) 
##STR5## 32 -- &gt;64 -- 64 
(known) 
##STR6## 32 &gt;64 &gt;64 &gt;64 32 
(known) 
##STR7## (2) 
4 32 32 64 32 
##STR8## (4) 
&lt;1 8 8 &lt;1 64 
##STR9## (5) 
4 32 32 64 64 
##STR10## (13) 
4 32 64 64 32 
##STR11## (9) 
&lt;1 32 64 64 32 
##STR12## (6) 
8 -- 32 -- 64 
__________________________________________________________________________ 
example b 
antimycotic in vivo activity on candidosis in mice 
Description of the experiment: 
Mice of the SPF-CF.sub.1 type were infected intravenously with 
1-2.times.10.sup.6 logarithmically-growing Candida cells, which were 
suspended in physiological sodium chloride solution. One hour before and 
seven hours after the infection the aninals were treated orally with, in 
each case, 100 mg of the formulations per kg of body weight. 
Untreated animals died of the infection 3 to 6 days after infection. The 
survival rate on the 6th day after infection was about 5% in the case of 
the untreated control animals. 
Table B 
______________________________________ 
Antimycotic in vivo activity on candidosis in mice 
Active compound Action 
______________________________________ 
##STR13## + 
(known) 
##STR14## NA 
(known) 
##STR15## (2) ++++ 
##STR16## (5) ++ 
##STR17## (1) ++ 
##STR18## (9) ++++ 
##STR19## (3) +++ 
##STR20## (13) + 
______________________________________ 
++++ = good action = .gtoreq.80% survivors on the 6th day after infection 
+++ = action = .gtoreq.60% survivors on the 6th day after infection 
++ = weak action = .gtoreq.40% survivors on the 6th day after infection 
+ = trace action = &lt;40% survivors on 6th day after infection 
NA = no action

The following non-limitative examples more particularly illustrate the 
present invention: 
EXAMPLE 1 
##STR21## 
(Process variant A) 
8.0 g (0.1 mol) of acetyl chloride are added to 20.6 g (0.1 mol) of 
1-imidazol-1-yl-1-phenoxy-3,3-dimethyl-butan-2-ol in 100 ml of ethyl 
acetate at room temperature. The mixture is then heated under reflux for 4 
hours. It is allowed to cool and concentrated by distilling off the 
solvent in vacuo. The residue is taken up in benzene and the solution is 
washed with aqueous sodium bicarbonate solution and dried over sodium 
sulphate. The solvent is distilled off under a water pump vacuum and the 
residue is recrystallized from petroleum ether. 20.6 g (45% of theory) of 
2-acetoxy-1-phenoxy-1-imidazol-1-yl-3,3-dimethyl-butane are obtained as a 
mixture of isomers with a melting point of 114.degree.-121.degree. C. 
Starting material 
##STR22## 
25.8 g (0.1 mol) of 1-imidazol-1-yl-1-phenoxy-3,3-dimethyl-butan-2-one are 
dissolved in 250 ml of methanol and 5.9 g (0.15 mol) of sodium borohydride 
are introduced in portions into this solution, at 5.degree. to 10.degree. 
C., while stirring and with reflux cooling. After stirring for 15 hours at 
room temperature, 20 ml of concentrated hydrochloric acid are added and 
the reaction mixture is stirred for a further 15 hours at room temperature 
and poured into 300 ml of saturated sodium bicarbonate solution. The 
mixture is extracted with twice 100 ml of methylene chloride, the organic 
phase is washed with twice 100 ml of water and dried over sodium sulphate 
and the solvent is distilled off under a water pump vacuum. The residue is 
ground with 30 ml of petroleum ether. 21.6 g (83% of theory) of 
1-imidazol-1-yl-1-phenoxy-3,3-dimethyl-butan-2-ol are obtained as a 
mixture of isomers with a melting point of 99.degree.-105.degree. C. 
EXAMPLE 2 
##STR23## 
(Process variant B) 
8.0 g (0.027 mol) of 
1-(4-chlorophenoxy)-1-imidazol-1-yl-3,3-dimethyl-butan-2-ol are heated in 
40 ml of acetic anhydride with 0.15 g of sodium acetate for 10 hours at 
100.degree. C. The solution is then cooled and stirred into 400 ml of ice 
water, the temperature being kept at 20.degree.-25.degree. C. The mixture 
is left to stand overnight. A smeary crystalline mass precipitates out and 
is taken up in chloroform. The chloroform solution is washed several times 
with water and sodium bicarbonate solution, dried over sodium sulphate and 
concentrated in vacuo by distilling off the solvent. The crystalline 
residue is boiled up in petroleum ether and the product is filtered off 
cold and dried. 4.5 g (49% of theory) of 
2-acetoxy-1-(4-chlorophenoxy)-1-imidazol-1-yl-3,3-dimethyl-butane are 
obtained as a mixture of isomers with a melting point of 
81.degree.-91.degree. C. 
EXAMPLES 3-23 
The compounds below set forth in tabular form are produced in a manner 
analogous to that described in Examples 1 and 2. 
General formula: 
__________________________________________________________________________ 
##STR24## 
Melting point (.degree.C.) 
as a mixture of 
Example No. 
X.sub.n R isomers 
__________________________________________________________________________ 
3 4-F CH.sub.3 144-53 
##STR25## CH.sub.3 117-24 
5 4-Br CH.sub.3 78-89 
6 
##STR26## CH.sub.3 
##STR27## 
7 
##STR28## CH.sub.3 
##STR29## 
8 
##STR30## CH.sub.3 250-56, decomposition 
##STR31## 
9 
##STR32## CH.sub.3 118-29 
10 
##STR33## CH.sub.3 92-97 
11 3-Br CH.sub.3 
##STR34## 
12 
##STR35## CH.sub.3 
##STR36## 
13 4-J CH.sub.3 100-06 
14 2-F CH.sub.3 91-102 
15 4-Cl CH.sub.2 Cl 194 (x HCl) 
16 4-Cl CHCl.sub.2 105-07 (x HCl) 
17 4-Cl CH.sub.2CH(CH.sub.3).sub.2 
##STR37## 
18 4-Cl (CH.sub.2).sub.16 CH.sub.3 
##STR38## 
19 4-Cl NHC(CH.sub.3).sub.3 
111-15 
20 4-Cl NHCH.sub.3 183-190 
21 4-Cl 
##STR39## 170-173 
22 4-Cl 
##STR40## 177-185 
23 
##STR41## CH.sub.3 219-221 (x HCl) 
24 4-O NHCH.sub.3 187 
25 4-O NHC.sub.3 H.sub.7 
124-138 
26 4-O NHC.sub.2 H.sub.5 
98-120 
27 4-O NHC.sub.4 H.sub.9 
118-127 
__________________________________________________________________________