Imidazolylacetic acid amides, their production, antimycotic compositions comprising said compounds and their use as antimycotic agents

Imidazolylacetic acid amides of the formula: ##STR1## or pharmaceutically acceptable nontoxic salts thereof wherein either R.sup.1 is phenyl or cycloalkyl, unsubstituted or substituted by one or more substituents; and PA1 R.sup.2 is hydrogen; or PA1 R.sup.1 and R.sup.2, together with the nitrogen atom to which they are attached, form a saturated 5 to 7-membered heterocyclic ring which ring may contain an --SO.sub.2 -- or --NY-- moiety wherein Y is alkoxycarbonyl, dialkylaminocarbonyl, or phenyl or diphenylmethyl, unsubstituted or substituted by one or more substituents and wherein said 5 to 7-membered heterocyclic ring itself is otherwise unsubstituted or substituted by one or more substituents; and PA1 X.sup.1, x.sup.2, x.sup.3 and X.sup.4 are the same or different and are each hydrogen or halogen, Are produced by A. reacting a halodiphenylacetic acid amide of the formula: ##STR2## wherein R.sup.1, R.sup.2, X.sup.1, X.sup.2, X.sup.3 and X.sup.4 are as above defined, and Hal is halogen, With imidazole; or B. reacting a halodiphenylacetic acid halide of the formula- ##STR3## WHEREIN X.sup.1, X.sup.2, X.sup.3 and X.sup.4 are as above defined and Hal is halogen With imidazole to produce an imidazolide of the formula: ##STR4## wherein X.sup.1, X.sup.2, X.sup.3 and X.sup.4 are as above defined which in turn is transaminated by reaction with an amine of the formula: EQU NHR.sup.1 R.sup.2 wherein PA1 R.sup.1 and R.sup.2 are as above defined.

The present invention relates to imidazolylcarboxylic acid amides, their 
production, antimycotic compositions embodying said compounds of the 
active ingredient, and to their use as antimycotic agents. 
More particularly, the present invention is concerned with imidazolylacetic 
acid amides of the formula: 
##STR5## 
and pharmaceutically acceptable nontoxic salts thereof wherein either 
R.sup.1 is phenyl or cycloalkyl, unsubstituted or substituted by one or 
more substituents; and 
R.sup.2 is hydrogen; or 
R.sup.1 and R.sup.2, together with the nitrogen atom to which they are 
attached, form a saturated 5 to 7-membered heterocyclic ring which ring 
may contain an --SO.sub.2 -- or --NY-- moiety wherein Y is alkoxycarbonyl, 
dialkylaminocarbonyl, or phenyl or diphenylmethyl, unsubstituted or 
substituted by one or more substituents and wherein said 5 to 7-membered 
heterocyclic ring is itself either or otherwise unsubstituted or 
substituted by one or more substituents; and 
X.sup.1, x.sup.2, x.sup.3 and X.sup.4 are the same or different and are 
each hydrogen or halogen. 
The imidazolyacetic acid amides of formula (I) are produced by: 
(a) reacting a halodiphenylacetic acid amide of the formula: 
##STR6## 
wherein R.sup.1, R.sup.2, X.sup.1, X.sup.2, X.sup.3 and X.sup.4 are as 
above defined, and Hal is halogen, 
with imidazole; or 
(b) reacting a halodiphenylacetic acid halide of the formula: 
##STR7## 
wherein X.sup.1, X.sup.2, X.sup.3 and X.sup.4 are as above defined, and 
Hal is halogen 
with imidazole to produce an imidazolide of the formula: 
##STR8## 
wherein X.sup.1, X.sup.2, X.sup.3 and X.sup.4 are as above defined 
which in turn is transaminated by reaction with an amine of the general 
formula: 
EQU NHR.sup.1 R.sup.2 (V) 
wherein 
R.sup.1 and R.sup.2 are as above defined. 
The above two processes are hereinafter referred to as Process Variants (a) 
and (b). 
When R.sup.1 is cycloalkyl, it is preferably a cycloalkyl moiety of 5 to 7 
carbon atoms and especially 6 carbon atoms. Cyclopentyl, cyclohexyl and 
cycloheptyl are examples. 
When the phenyl or cycloalkyl moieties of R.sup.1 are substituted, they are 
preferably substituted by 1 to 3 of the same or different substituents, 
but especially one substituent. Preferred substituents are alkyl of 1 to 4 
carbon atoms, especially alkyl of 1 to 3 carbon atoms, i.e., methyl, 
ethyl, n- and i-propyl, halogen (preferably chlorine, fluorine and 
bromine, especially chlorine), haloalkyl of 1 or 2 carbon atoms and 2 to 5 
halogen atoms (preferably chlorine or fluorine and especially fluorine, 
the trifluoromethyl moiety being preferred), and nitro. 
When R.sup.1 and R.sup.2, together with the amide nitrogen atom to which 
they are attached, form a 5 to 7-membered heterocyclic ring, said ring may 
contain a --SO.sub.2 -- or --NY-- moiety. The preferred heterocyclic rings 
are those containing 5 or 6 ring members and especially 6 ring members. 
When --SO.sub.2 -- or --NY-- is contained in the 6-membered heterocyclic 
ring, it is preferably in the p-position to the amide nitrogen. When the 
ring contains a --NY-- moiety in the ring and Y is alkoxycarbonyl, it is 
preferred that the alkoxycarbonyl be of 2 to 4 carbon atoms and especially 
2 or 3 carbon atoms, i.e., methoxycarbonyl, ethoxycarbonyl and n- and 
i-propoxycarbonyl. When Y is a dialkylaminocarbonyl, each alkyl moiety may 
be the same or different and be of 1 to 4 carbon atoms and especially 1 or 
2 carbon atoms such as dimethyl, diethyl, methylethyl, methyl-n-propyl or 
ethylisobutyl. The phenyl and diphenylmethyl moieties of Y are either 
unsubstituted or substituted by preferably 1 to 3 of the same or different 
substituents selected from the group consisting of alkyl of 1 to 4 carbon 
atoms, especially alkyl of 1 to 3 carbon atoms, i.e. methyl, ethyl, n- and 
i-propyl, halogen, preferably chlorine, fluorine or bromine and especially 
chlorine, haloalkyl of 1 or 2 carbon atoms and 2 to 5 halogen atoms, 
preferably chlorine and fluorine and especially fluorine, for example 
trifluoromethyl, and nitro. When said 5 to 7 membered heterocyclic ring is 
substituted, it is substituted by one or more of the same or different 
substituents, and preferably one substituent selected from the group 
consisting of alkyl of 1 to 4 carbon atoms, i.e., methyl, ethyl, n- and 
i-propyl, and n-, i- and t-butyl, especially alkyl of 1 or 2 carbon atoms, 
or phenyl unsubstituted or substituted by a member selected from the group 
consisting of alkyl of 1 to 4 carbon atoms, especially alkyl of 1 to 3 
carbon atoms, i.e., methyl, ethyl, n- and i-propyl, halogen preferably 
chlorine, fluorine or bromine, especially chlorine, haloalkyl of 1 or 2 
carbon atoms and 2 to 5 halogen atoms, preferably chlorine and fluorine, 
and especially fluorine, for example, trifluoromethyl and nitro. 
X.sup.1, X.sup.2, X.sup.3 and X.sup.4 are the same or different hydrogen or 
halogen, for example, fluorine, chlorine, bromine or iodine and preferably 
fluorine, chlorine and bromine, especially chlorine. 
Hal in formulas II and III is preferably chlorine or bromine, and 
especially chlorine. 
According to one embodiment of the present invention, either 
R.sup.1 is phenyl or cycloalkyl of 5 to 7 carbon atoms, unsubstituted or 
substituted by 1 to 3 substituents selected from the group consisting of 
alkyl of 1 to 4 carbon atoms, halogen, haloalkyl of 1 or 2 carbon atoms 
and 2 to 5 halogen atoms and nitro, and 
R.sup.2 is hydrogen, or 
R.sup.1 and R.sup.2, together with the nitrogen atom to which they are 
attached, form a saturated 5 to 7-membered heterocyclic ring containing a 
--SO.sub.2 -- or --NY-- moiety wherein Y is alkoxycarbonyl of 2 to 4 
carbon atoms, dialkylaminocarbonyl of 1 to 4 carbon atoms in each alkyl 
moiety, phenyl or diphenylmethyl, unsubstituted or substituted by 1 to 3 
substituents selected from the group consisting of alkyl of 1 to 4 carbon 
atoms, halogen, haloalkyl of 1 or 2 carbon atoms and 2 to 5 halogen atoms, 
and nitro, said heterocyclic ring being otherwise unsubstituted or 
substituted by alkyl of 1 to 4 carbon atoms or phenyl unsubstituted or 
substituted by 1 to 3 substituents selected from the group consisting of 
alkyl of 1 to 4 carbon atoms, halogen, haloalkyl of 1 or 2 carbon atoms 
and 2 to 5 halogen atoms, and nitro, and 
X.sup.1, x.sup.2, x.sup.3 and X.sup.4 are the same or different and are 
each hydrogen or halogen. 
According to another embodiment of the present invention, either 
R.sup.1 is phenyl or cyclohexyl, unsubstituted or substituted by 1 or 2 
substituents selected from the group consisting of alkyl of 1 to 3 carbon 
atoms, chlorine, fluorine, bromine, trifluoromethyl and nitro, and 
R.sup.2 is hydrogen, or 
R.sup.1 and R.sup.2, together with the nitrogen atom to which they are 
attached, form a 6-membered heterocyclic ring containing a --SO.sub.2 -- 
or --NY-- moiety wherein Y is phenyl, diphenylmethyl, methoxycarbonyl, 
ethoxycarbonyl, dimethylaminocarbonyl or diethylaminocarbonyl, said 
heterocyclic ring containing a --SO.sub.2 -- moiety being either 
unsubstituted or substituted by methyl, ethyl or phenyl, and either 
X.sup.1, x.sup.2, x.sup.3 and X.sup.4 are each hydrogen, or 
X.sup.1 and X.sup.3 are each halogen and 
X.sup.2 and X.sup.4 are each hydrogen. 
According to another embodiment of the present invention, either 
R.sup.1 is cyclohexyl, or phenyl which phenyl is either unsubstituted or 
substituted by 1 or 2 substituents selected from the group consisting of 
alkyl of 1 to 3 carbon atoms, chlorine, fluorine, bromine and 
trifluoromethyl, and 
R.sup.2 is hydrogen, or 
R.sup.1 and R.sup.2, together with the nitrogen atom to which they are 
attached, form a 6-membered heterocyclic ring containing a --SO.sub.2 -- 
or --NY-- moiety wherein Y is phenyl, diphenylmethyl, methoxycarbonyl, 
ethoxycarbonyl, dimethylaminocarbonyl or diethylaminocarbonyl, said 
heterocyclic ring containing a --SO.sub.2 -- moiety being either 
unsubstituted or substituted by methyl, ethyl or phenyl, and 
X.sup.1, x.sup.2, x.sup.3 and X.sup.4 are each hydrogen, or 
X.sup.1 and X.sup.3 are chlorine and 
X.sup.2 and X.sup.4 are hydrogen. 
According to another embodiment of the present invention, either 
R.sup.1 is cyclohexyl or phenyl, unsubstituted or substituted by 1 or 2 
substituents selected from the group consisting of chlorine, methyl and 
trifluoromethyl; and 
R.sup.2 is hydrogen; or 
R.sup.1 and R.sup.2, together with the nitrogen atom to which they are 
attached, form a 6-membered heterocyclic ring selected from the group 
consisting of 
##STR9## 
and either X.sup.1, X.sup.2, X.sup.3 and X.sup.4 are each hydrogen, or 
X.sup.1 and X.sup.3 are chlorine and 
X.sup.2 and X.sup.4 are hydrogen. 
According to a further embodiment of the present invention, either 
R.sup.1 is cyclohexyl, chlorophenyl, tolyl, trifluoromethylphenyl, 
dichlorophenyl or chloromethylphenyl, and 
R.sup.2 is hydrogen, or 
R.sup.1 and R.sup.2, together with the nitrogen atom to which they are 
attached, form a 6-membered heterocyclic ring of the formula: 
##STR10## 
unsubstituted or substituted by methyl, ethyl or phenyl, or 
##STR11## 
wherein Y is COOC.sub.2 H.sub.5, chlorophenyl, CO-N(C.sub.2 H.sub.5).sub.2 
or diphenylmethyl, and 
X.sup.1, x.sup.2, x.sup.3 and X.sup.4 are each hydrogen, or 
X.sup.1 and X.sup.3 are chlorine and 
X.sup.2 and X.sup.4 are hydrogen. 
If for example 
[.omega.-(4,4'-dichlorodiphenyl)-.omega.-chloromethylcarbonyl-(4)]-1,4-thi 
azine dioxide and imidazole are used as the starting compounds, the course 
of the reaction can be represented by the following equation (Process 
Variant (a)): 
##STR12## 
If for example diphenylchloroacetic acid chloride, imidazole and 
o-methylaniline are used as starting compounds, the course of the reaction 
can be represented by the following equation (Process Variant (b)): 
##STR13## 
The halodiphenylacetic acid amides used as starting compounds of the 
formula II are not per se known but can be produced according to 
procedures per se known, for example, by reacting halodiphenylacetic acid 
halides of the formula III (some of which are known and can be produced by 
known methods) with amides of the formula V according to procedures 
described in Ber. 41, page 3593 (1908). Representative halodiphenylacetic 
acid amides of formula II include: 
.omega.,.omega.-diphenyl-.omega.-chloro-acetic acid p-chloroanilide; 
.omega.,.omega.-diphenyl-.omega.-chloro-acetic acid 
m-trifluoromethylanilide; 
.omega.,.omega.-diphenyl-.omega.-chloro-acetic acid 
2-methyl-4-chloroanilide; 
.omega.,.omega.-diphenyl-.omega.-chloro-acetic acid 2,4-dichloro-anilide; 
.omega.,.omega.-diphenyl-.omega.-chloro-acetic acid cyclohexylamide; 
.omega.,.omega.-di-(4-chlorophenyl)-.omega.-chloroacetic acid 
2-methylanilide; 
.omega.,.omega.-di-(4-chlorophenyl)-.omega.-chloro-acetic acid 
2,5-di-chloroanilide; 
[.omega.,.omega.-diphenyl-.omega.-chloro-methylcarbonyl-(4)]-1,4-thiazine 
dioxide; 
3-methyl-4-[.omega.,.omega.-di-(4-chlorophenyl)-.omega.-chloro-methylcarbon 
yl] -1,4 -thiazine dioxide; 
3-ethyl-4-[.omega.,.omega.-di-(4-chlorophenyl)-.omega.-chloro-methylcarbony 
l]-1,4-thiazine dioxide; 
[.omega.-phenyl-.omega.-4-chlorophenyl-.omega.-chloro-methylcarbonyl-(4)-3- 
phenyl]-1,4-thiazine dioxide; 
1-o-chlorophenyl- 
4-[.omega.,.omega.-diphenyl-.omega.-chloro-methylcarbonyl]-piperazine; 
1-diethylaminocarbonyl-4-[.omega.,.omega.-diphenyl-.omega.-chloro-methylcar 
bonyl]-piperazine and 
1-diphenylmethyl-4-[.omega.,.omega.-di-(4-chloro-phenyl)-.omega.-chlorometh 
ylcarbonyl]-piperazine. 
Representative halodiphenylacetic acid halides of the formula III include: 
.omega.,.omega.-diphenyl-.omega.-chloro-acetic acid chloride; 
.omega.,.omega.-di-(4-chlorophenyl)-.omega.-chloro-acetic acid chloride; 
.omega.-phenyl-.omega.-(2-chlorophenyl)-.omega.-chloro-acetic acid 
chloride; 
.omega.-phenyl-.omega.-(3-chlorophenyl)-.omega.-chloro-acetic acid 
chloride; and 
.omega.-phenyl-.omega.-(4-chlorophenyl)-.omega.-chloro-acetic acid 
chloride. 
Representative amines of the formula V include: 
aniline; 
o-methylaniline; 
o- and p-dichloroaniline; 
p-chloroaniline; 
m-trifluoroaniline; 
p-methylaniline; 
p-chloro-m-methylaniline; 
p-fluoroaniline; 
p-bromoaniline; 
o-ethylaniline; 
p-nitroaniline; 
o-nitroaniline; 
p-nitro-o-methylaniline; 
cyclohexylamine; 
cyclopentylamine and 
cycloheptylamine. 
The pharmaceutically acceptable nontoxic salts of the compound of the 
present invention include salts formed by the reaction between the 
imidazolylacetic acid amide as the free base and hydrohalic acids, such as 
hydrochloric and hydrobromic acids, especially hydrochloric acid, 
phosphoric acid, nitric acid, monofunctional and bifunctional carboxylic 
acids and hydroxycarboxylic acids, for example, acetic acid, maleic acid, 
succinic acid, fumaric acid, tartaric acid, citric acid, salicylic acid, 
sorbic acid and lactic acid, and 1,5 -naphthalenedisulphonic acid. 
Hydrochloric acid is especially preferred. 
The preferred salts are therefore the hydrohalides, for example, the 
hydrochloride and hydrobromide, especially the hydrochloride, the 
phosphate, nitrate, monofunctional and bifunctional carboxylates and 
hydroxycarboxylates, for example, the acetate, maleate, succinate, 
fumarate, tartrate, citrate, salicylate, sorbate and lactate, and 
1,5-naphthalenedisulphonate. The hydrochloride is especially preferred. 
The reaction of the halodiphenylacetic acid and imidazole in Process 
Variant (a) can be carried out in a diluent which is inert towards the 
reactants and products. Such diluents include all inert polar organic 
solvents. Preferred diluents are chlorinated hydrocarbons (especially 
aromatic chlorinated hydrocarbons, such as chlorobenzene); ketones 
(especially lower alkyl ketones, such as acetone and diethyl ketone); 
nitriles (especially those having up to 6 carbon atoms, such as 
acetonitrile); amides (especially lower dialkylformamides, such as 
dimethylformamide); and sulphoxides (especially lower dialkylsulphoxides, 
such as dimethylsulphoxide). 
As acid-binding agents, it is possible to use, in Process Variant (a), all 
the usual acid-binding agents. These include organic and inorganic bases 
(preferably alkali metal hydroxides, such as sodium hydroxide and 
potassium hydroxide) and tertiary organic bases (such as trialkylamines, 
for example triethylamine). In Process Variant (a) according to the 
invention, we prefer particularly to use an excess of imidazole instead of 
a separate acid-binding agent. 
In the Process Variant (a), the reaction temperatures can be varied over a 
substantial range. In general, the reaction is carried out at between 
50.degree. C. and 150.degree. C., preferably between 80.degree. C. and 
120.degree. C. 
The reaction in Process Variant (a) can be carried out under normal 
pressure but also under elevated pressure. The reaction is preferably 
carried out under normal pressure. 
In carrying out the process according to the invention Process Variant (a), 
1 to 5 (preferably 1 to 2) mols of imidazole and additionally 1 to 5 
(preferably 1 to 2) equivalents of the acid-binding agent (for example 
imidazole or triethylamine) are generally employed per 1 mol of the 
imidazolylcarboxylic acid amides of formula II. 
As an example, for the isolation of the free amides of the formula I 
according to the present invention carried out according to known methods, 
the solvent is distilled from the reaction mixture, the residue is 
digested with ice water and the undissolved solid is filtered off and 
purified by recrystallization. Thereafter any desired salts can be 
produced by generally customary methods, for example by dissolving the 
free amide of the formula I in an organic solvent and adding the requisite 
amount of acid. 
The solvents already mentioned in connection with Process Variant (a) can 
also be used as diluents in the reaction, according to the invention, of 
the halodiphenylacetic acid halides of the formula III with imidazole in 
Process Variant (b). 
The acid-binding agent used in the first reaction step in Process variant 
(b) (reaction of halodiphenylacetic acid halides of the general formula 
III with imidazole) is preferably an excess of imidazole, appropriately 
about 4 to 10, preferably 4 to 5, mols of imidazole per 1 mol of starting 
compound of the formula III. 
In the reaction of the compounds of the formula III with imidazole (Process 
Variant (b)), the reaction temperatures can be varied within a substantial 
range. In general, the reaction is carried out at between 50.degree. C. 
and 100.degree. C., preferably between 50.degree. C. and 100.degree. C. 
The imidazolides of the formula IV which are produced in the first reaction 
step are preferably reacted further without intermediate isolation. 
However, a prior isolation is possible within the scope of the invention. 
In the second reaction step of Process Variant (b) (reaction of the 
imidazolide of the formula IV with the amine of the formula V) the 
reaction temperatures can be varied within a substantial range. In 
general, the reaction is carried out between 50.degree. C. and 150.degree. 
C., preferably between 80.degree. C. and 150.degree. C. 
In carrying out the second reaction step in Process Variant (b), 1 to 5, 
more preferably 1 to 2, mols of amine of the formula V are preferably used 
per 1 mole of imidazolide of the formula IV. Using higher or lower than 
stoichiometric ratios does not adversely influence the outcome of the 
reaction. 
The working up and isolation of the imidazolylcarboxylic acid amides of the 
formula I can be carried out according to customary methods, for example 
as described in connection with Process Variant (a). Thereafter, the salts 
can be produced according to customary methods, for example as described 
above. 
The following compounds are representative of the imidazolylacetic acid 
amides of the present invention: 
4-[107 
,.omega.-di-(chlorophenyl)-.omega.-imidazolyl-(1)-methylcarbonyl]-1,4-thia 
zine dioxide; 
.omega.,.omega.-diphenyl-.omega.-imidazolyl-(1) -acetic acid 
3-trifluoromethylanilide; 
.omega.,.omega.-diphenyl-.omega.-imidazolyl-(1)-acetic acid 
2-methyl-4-chloro-anilide; 
.omega.,.omega.-diphenyl-.omega.-imidazolyl-(1)-acetic acid 
2,4-dichloroanilide; 
.omega.,.omega.-diphenyl-.omega.-imidazolyl-(1)-acetic acid 
cyclohexylamide; 
4-[.omega.,.omega.-di-(4-chlorophenyl)-.omega.-imidazolyl-(1) 
-methylcarbonyl]-3-phenyl-1,4-thiazine dioxide; 
4-[.omega.,.omega.-diphenyl-.omega.-imidazolyl-(1)-methylcarbonyl]-1-ethoxy 
carbonyl-piperazine and 
4-[.omega.,.omega.-diphenyl-.omega.-imidazolyl-(1)-methylcarbonyl]-1-o-chlo 
rophenyl-piperazine. 
The imidazolylacetic acid amides and the salts of the present invention 
exhibit strong antimycotic activity. They exhibit a broad spectrum of 
antimycotic activity especially against dermatophytes and blastomycetes, 
as well as biphase fungi, for example against species of Candida such as 
Candida albicans, species of Epidermophyton such as Epidermophyton 
floccosum, species of Aspergillus such as Aspergillus niger, species of 
Trichophyton such as Trichophyton mentagrophytes, species of Microsporon 
such as Microsporon felineum, and species of Penicillium such as 
Penicillium commune. 
The compounds of the present invention are deemed to be useful in the 
treatment of dermatomycoses and systemic mycoses in humans caused by 
Trichophyton mentagrophytes and other species of Trichophyton, species of 
Microsporon, Epidermophyton floccosum, blastomycetes and biphase fungi as 
well as moulds. 
The compounds of the present invention are useful in veterinary medicine 
and the treatment of dermatomycoses and systemic mycoses, especially those 
caused by the above mentioned pathogens. 
The present invention also includes pharmaceutical compositions comprising 
an imidazolylacetic acid amide of the present invention in combination 
with a pharmaceutically acceptable nontoxic, inert diluent or carrier. 
The pharmaceutical composition of the present invention contain a major or 
minor amount e.g. 99.5% to 0.1%, preferably 95% to 0.5% of at least one 
imidazolylacetic acid amide 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 30 to 
250, and preferably 50 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. As 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 semiliquid 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 semiliquid 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. 
The preferred daily dose is 1.5 to 22.5 g, preferably 2.5 to 18.0 g, of 
active agent. 
While the compounds of the present invention are suitable for oral, 
parenteral (for example intramuscular, intraperitoneal and intravenous 
administration), rectal, or topical application, oral administration and 
topical application are particularly preferred. 
The preferred pharmaceutical compositions are therefore those which are 
suitable for oral or topical administration, such as tablets, pills, 
granules, lotions and ointments. 
The following in vitro and in vivo experimental data illustrate the 
antimycotic activity of the compounds of the present invention. 
Determination of the anti-mycotic spectrum of action in vitro, by the 
series dilution test. 
Description of the experiments 
The nutrient substrates used were Sabouraud's milieu d'epreuve for 
dermatophytes and moulds, and meat broth-glucose bouillon for 
blastomycetes and biphase fungi. 
The incubation temperature was 28.degree. C. and the incubation time was 24 
to 96 hours. 
The experiment results are summarized in Table A. 
TABLE A 
__________________________________________________________________________ 
Minimum inhibitory concentration in .UPSILON./ml of nutrient medium 
Trichophyton 
Candida Aspergillus 
Compound from 
mentagrophytes 
albicans 
Pencillium 
niger Microsporon 
Example No. 
n.s. w.s. n.s. 
w.s. 
commune 
n.s. 
w.s. 
felineum 
__________________________________________________________________________ 
13 10 40 &gt;100 
-- &gt;100 1* 
100* 
100 
4 64 64 &gt;64 
&gt;64 
&gt;64 -- -- -- 
2 100 -- &gt;100 
-- &gt;100 -- -- -- 
12 64.sup.+ 
-- 64.sup.+ 
&gt;64 
&gt;64 -- -- -- 
7 32* &gt;64 4* 8 &gt;64 -- -- -- 
5 32 32 8.sup.+ 
64.sup.+ 
&gt;64 -- -- -- 
6 1* 8 1* 32* 
64* 4* 
8* 4* 
11 32 32 &gt;64 
&gt;64 
&gt;64 -- -- -- 
__________________________________________________________________________ 
Legend:- 
w.s. = with 30% serum added 
n.s. = no serum added 
* = 90% inhibition of growth 
.sup.+ = 50% inhibiton of growth 
Anti-mycotic action of the compounds according to the invention in animal 
experiments. 
(a) Action on Quinckeanum trichophytosis in white mice, on oral 
administration. 
With doses of 2.times. 100 mg/kg administered orally once daily up to the 
eighth day of the infection, it was possible to suppress the development 
of the Quinckeanum infection in mice. After administration of the 
compounds according to the invention, 0 to 2 out of 20 treated mice, in 
contrast to 19 out of 20 animals of the untreated control, showed scutula, 
which are to be regarded as a typical sign of infection of Quinckeanum 
trichophytosis, ten days after the infection. 
(b) Candidosis of mice. 
Mice of type SPF-CF.sub.1 were intravenously infected with 1 to 2.times. 
10.sup.6 Candida cells which were suspended in physiological sodium 
chloride solution. 
One hour before and seven hours after infection, the animals were treated 
orally with 50, 75, 100 and 150 mg of the compounds according to the 
invention/kg of body weight. Untreated control animals died of the 
infection, 3 to 6 days after infection. 
The experimental results are summarised in Table B. 
Table B 
______________________________________ 
Action in Candidosis of mice 
Compound from 
Action in the case of Candida 
Example No. albicans 
______________________________________ 
2 + 
12 + 
7 ++ 
______________________________________ 
Legend:- 
= 50% survivals on 6th day after 
+ = 60 to 80% survivals on 6th day after infection. 
The following Examples illustrate the invention.