Antifungal S-ethers of 2-aryl-3-mercapto-1-(1H-1,2,4-triazol-1-yl) propan-2-ols and corresponding sulfoxides and sulfones

Compounds of the general formula: ##STR1## wherein R is naphthyl, biphenylyl, phenyl or substituted phenyl; n is 0, 1 or 2; and R.sup.1 is H, C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl, C.sub.2-4 alkanoyl, or C.sub.1-2 alkyl substituted by C.sub.2-4 alkenyl with the provisos that when R.sup.1 is H or C.sub.2-4 alkanoyl, n is 0; and when n is 2, R.sup.1 is C.sub.1-3 alkyl; and their pharmaceutically acceptable salts are antifungal agents useful in combatting fungal infections in animals, including humans.

BACKGROUND OF THE INVENTION 
This invention relates to novel triazole derivatives which have antifungal 
activity and are useful in the treatment of fungal infections in animals, 
including humans. 
European Patent Application No. 82,300,888.3, published Oct. 6, 1982 as 
Publication No. 0,061,835, broadly describes a large series of S- and 
O-ethers of 2-aryl-3-mercapto (or 
3-hydroxy)-1-(1H-1,2,4-triazol-1-yl)propan-2-ols, and of the corresponding 
sulfoxides and sulfones of said mercapto derivatives, as antifungal 
agents. 
Related S-ethers of 2-aryl-3-mercapto-1-(1H-1,2,4-triazol-1-yl)propan-2-ols 
as antifungal agents are described in concurrently filed U.S. patent 
applications of Richardson and Whittle, entitled "Triazole Antifungal 
Agents"; and of Richardson, Whittle and Cooper, entitled "Antifungal 
S-Arylmethyl- and S-Heterocyclylmethyl Ethers of 
2-Aryl-3-Mercapto-1-(1H-1,2,4-Triazol-1-yl)Propan-2-Ols", said 
applications being Ser. Nos. 479,525 and 479,526, now U.S. Pat. No. 
4,505,919, filed Mar. 28, 1983. 
SUMMARY OF THE INVENTION 
According to the invention, there are provided compounds of the formula: 
##STR2## 
and their O-esters and O-ethers; wherein 
R is naphthyl, biphenylyl, phenyl, or substituted phenyl; 
R.sup.1 is H, C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.7 cycloalkyl, C.sub.2 
-C.sub.4 alkanoyl, or C.sub.1 -C.sub.2 alkyl substituted by C.sub.2 
-C.sub.4 alkenyl; and 
n is 0, 1 or 2, with the provisos and when 
n is 2, R.sup.1 is C.sub.1-3 alkyl; that when R.sup.1 is H or C.sub.2 
-C.sub.4 alkanoyl, n is 0; 
and their pharmaceutically acceptable salts. 
The O-ethers of the alcohols of the formula (I) include, for example, the 
C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.4 alkenyl, C.sub.2 -C.sub.4 
alkynyl, aryl (e.g. phenyl) and aralkyl (e.g. benzyl optionally ring 
substituted by halo, C.sub.1 -C.sub.4 alkyl or C.sub.1 -C.sub.4 alkoxy) 
ethers. 
The O-esters of the alcohols of the formula (I) include, for example, the 
C.sub.2 -C.sub.4 alkanoyl and aroyl (e.g. benzoyl, optionally substituted 
by halo, C.sub.1 -C.sub.4 alkyl or C.sub.1 -C.sub.4 alkoxy) esters. 
The preferred O-ester is the acetyl ester. 
"Substituted phenyl" is preferably phenyl substituted by 1 to 3 
substituents, more preferably 1 or 2 substituents, each independently 
selected from halo, CF.sub.3, C.sub.1 -C.sub.4 alkyl and C.sub.1 -C.sub.4 
alkoxy. 
More preferably, "substituted phenyl" is phenyl substituted by 1 to 3 
substituents, especially 1 or 2 substituents, each independently selected 
from halo or CF.sub.3. The most preferred individual groups represented by 
R are 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-iodophenyl, 
4-trifluoromethylphenyl, 2-chlorophenyl, 2,4-dichlorophenyl, 
2,4-difluorophenyl, 2,5-difluorophenyl, 2-fluoro-4-chlorophenyl, 
2,4,6-trifluorophenyl and 4-bromo-2,5-difluorophenyl. 
"Halo" means F, Cl, Br or I. 
Where appropriate, alkyl, alkoxy, alkenyl and alkynyl groups can be 
straight or branched chain. 
The preferred biphenylyl group is p-biphenylyl, of the formula: 
##STR3## 
R.sup.1 is preferably H, C.sub.1 -C.sub.4 alkyl, C.sub.3 -C.sub.6 
cycloalkyl (most preferably cyclohexyl), allyl, or acetyl. R.sup.1 is most 
preferably CH.sub.3. 
R is most preferably 2,4-dichlorophenyl, 2,4-difluorophenyl or 
2-chlorophenyl. 
The most preferred compound has the formula: 
##STR4## 
The invention also provides a pharmaceutical composition comprising a 
compound of the formula (I), or an O-ester, O-ether or pharmaceutically 
acceptable salt thereof, together with a pharmaceutically acceptable 
diluent or carrier. 
The invention yet further provides a method of treating a fungal infection 
in a human being, which comprises administering to the human an effective 
amount of a compound of the formula (I) or a pharmaceutically acceptable 
salt thereof. 
The invention further provides a compound of the formula (I), or an 
O-ester, O-ether or a pharmaceutically acceptable salt thereof, for use in 
treating a fungal infection in a human being. 
DETAILED DESCRIPTION OF THE INVENTION 
The compounds of the formula (I) can be obtained by a number of different 
processes: 
(1) The compounds of the formula (I) in which n is 0 can be prepared as 
follows: 
##STR5## 
It is preferred to carry out the reaction in an organic solvent in the 
presence of a base, e.g. sodium hydroxide, sodium hydride or potassium 
carbonate. Preferred base/solvent combinations are NaH/tetrahydrofuran, 
NaH/DMF and NaOH/dioxan. The reaction is typically achieved by mixing the 
reactants together in the organic solvent with, if necessary, heating at 
up to 120.degree. C., until the reaction is complete, generally in 24 
hours or less. The product can be isolated and purified by conventional 
procedures. 
When R.sup.1 is C.sub.2 -C.sub.4 alkanoyl, a mixture of the compound (IA) 
and its O-alkanoyl derivative may be formed. These can be separated by 
chromatography according to known techniques. 
The oxiranes (II) can be obtained by conventional methods, typically from 
the corresponding ketones: 
##STR6## 
by reacting them in a suitable solvent (e.g. dry dimethylsulphoxide) with 
dimethyloxosulphonium methylide prepared from trimethylsulphoxonium iodide 
and either sodium hydride or cetrimide/sodium hydroxide in toluene/water. 
The reaction using sodium hydride is typically achieved by adding dry 
powdered trimethylsulphoxonium iodide to a suspension of sodium hydride in 
dimethylsulfoxide. After stirring for, say, 30 minutes at room 
temperature, the ketone is added in an approximately equimolar amount in 
dimethylsulphoxide. The reaction mixture may be warmed to accelerate the 
reaction and after several hours at 50.degree.-80.degree. C., the product 
can be isolated by conventional procedures. 
The reaction utilizing cetrimide is typically achieved as follows. The 
ketone, trimethylsulphoxonium iodide and cetrimide are stirred vigorously 
in a mixture of toluene and sodium hydroxide solution for about an hour at 
up to about 100.degree. C. The oxirane product can then be isolated by 
conventional procedures. 
When R is a phenyl group containing no ortho substituent or biphenylyl, the 
cetrimide route should be used. 
The ketones are either known compounds or can be prepared by procedures 
analogous to those of the prior art. The preparation of 
2-(1H-1,2,4-triazol-1-yl)-2',4'-dichloroacetophenone from 
2-bromo-2',4'-dichloroacetophenone, 1,2,4-triazole and potassium carbonate 
is for example, described in Example 1 of British Patent Specification No. 
1,512,918, which utilizes acetonitrile as the solvent under reflux for 20 
hours. We have found that this type of reaction is generally best carried 
out in acetone at 0.degree.-20.degree. C., when it is generally complete 
in a shorter period of time, e.g. 4 hours or less. 
(2) Compounds of the formula (I) in which R.sup.1 is H (and thus n=0) can 
be prepared by the deacylation of the corresponding compounds in which 
R.sup.1 is C.sub.2 -C.sub.4 alkanoyl, preferably acetyl. The deacylation 
is preferably carried out using sodium ethoxide in ethanol, followed by 
acidification (e.g. with HCl) according to the following procedure: 
##STR7## 
The reaction is typically carried out by adding the alkanoyl derivative 
(IV) dropwise to a stirred and cooled solution of sodium ethoxide in 
ethanol. After about an hour the resulting mixture is poured into aqueous 
acid, e.g. 1N hydrochloric acid, followed by neutralization, e.g. by the 
addition of solid sodium bicarbonate. The thiol product (IB) can again be 
isolated and purified by conventional procedures. 
(3) The compounds of the formula (I) in which n is 0 and R.sup.1 is other 
than H can also be prepared as follows: 
##STR8## 
[Hal=Cl, Br or I, preferably Br or I]. 
The reaction is preferably carried out in the presence of a base, e.g. NaOH 
or K.sub.2 CO.sub.3. Typically, the thiol (IB), halide and base are 
stirred together at room temperature in a suitable organic solvent for a 
few hours. Preferred base/solvent combinations are K.sub.2 CO.sub.3 
/acetone and sodium hydroxide/aqueous ethanol. If necessary, the reaction 
mixture can be heated, e.g. to 70.degree. C., to accelerate the reaction. 
The product can be isolated and purified by conventional procedures. 
(4) The compounds of the formula (I) in which n is 1 (sulphoxides) and 2 
(sulphones) can be prepared by the controlled or strong oxidation, 
respectively, of the corresponding compounds in which n is 0. The 
compounds in which n is 2 can also be prepared by the oxidation of the 
compounds in which n is 1. 
The preferred oxidizing agent is m-chloroperbenzoic acid: approximately one 
equivalent should be used to prepare the sulphoxides and an excess to 
prepare the sulfones. 
In a typical procedure involving the preparation of a sulphoxide, the 
corresponding thio compound is dissolved in a mixture of isopropanol and 
chloroform (1:1, v/v) and the solution is cooled to below 5.degree. C. in 
an ice bath. Slightly less than 1 equivalent of m-chloroperbenzoic acid is 
added in portions over a few minutes. The mixture is then stirred for 
about 2 hours. If t.l.c. indicates unreacted starting material, a small 
further quantity of m-chloroperbenzoic acid (to approximately 1 
equivalent) is added. As stated hereinafter, the sulphoxides have two 
asymmetric centers and thus exist in two diastereoisomeric forms. Thus the 
sulphoxide product of the oxidation, which can be isolated by conventional 
procedures, will be a mixture of the two diastereoisomers. If desired, the 
diastereoisomers can be separated by column chromatography, e.g. on 
silica, since they differ markedly in polarity. The sulphones can be 
obtained simply by adding excess m-chloroperbenzoic acid to a solution of 
the crude sulphoxide (or sulphoxides) in e.g. chloforom, and stirring for 
a few hours, e.g. three hours, at room temperature. Alternatively the 
sulphones can be prepared by the oxidation of the thio compounds (n= 0) 
using excess m-chloroperbenozic acid. 
(5) The ethers can be made by treating an alkali metal salt of the alcohols 
of the formula (I), e.g. a lithium or sodium salt, with the appropriate 
halide, e.g. an alkyl, alkenyl, alkynyl, aryl or aralkyl halide. Esters 
can be made by treating an alkali metal salt of compound (I) with the 
appropriate acid chloride, bromide or anhydride. 
The sulphoxides of the formula (I) have two asymmetric centers, namely the 
carbon atom bearing the hydroxy group, and the sulphoxide sulphur atom. 
Consequently the sulphoxides exist in two diastereoisomeric forms, each of 
which is in fact a racemate consisting of a pair of enantiomers. The two 
diastereoisomeric forms can be readily separated by column chromatography, 
since they differ markedly in polarity. Each diastereoisomer can be 
resolved further into its individual optically active enantiomers by 
techniques known to those skilled in the art. In some cases, one 
diastereoisomer may predominate over the other. 
The invention includes both diastereoisomers whether resolved or not. 
All the compounds of the invention contain at least one chiral center, and 
the invention includes both resolved and unresolved forms. 
Pharmaceutically acceptable acid addition salts of the compounds of the 
formula (I) are those formed from strong acids which form non-toxic acid 
addition salts, such as hydrochloric, hydrobromic, sulphuric, oxalic and 
methanesulphonic acids. 
The salts may be obtained by conventional procedures, e.g. by mixing 
solutions containing equimolar amounts of the free base and desired acid, 
and the required salt is collected by filtration, if insoluble, or by 
evaporation of the solvent. 
The compounds of the formula (I) and their pharmaceutically acceptable 
salts are antifungal agents, useful in combatting fungal infections in 
animals, including humans. For example they are useful in treating topical 
fungal infections in man caused by, among other organisms, species of 
Candida, Trichophyton, Microsporum, or Epidermophyton, or in mucosal 
infections caused by Candida albicans (e.g. thrush and vaginal 
candidiasis). They may also be used systemically in the treatment of 
systemic fungal infections caused by, for example, Candida albicans, 
Cryptococcus neoformans, Aspergillus fumigatus, Coccidioides, 
Paracoccidioides, Histoplasma or Blastomyces. 
The in vitro evaluation of the antifungal activity of the compounds can be 
performed by determining the minimum inhibitory concentration (m.i.c.) of 
the test compounds in a suitable medium at which growth of the particular 
microorganism fails to occur. In practice, a series of agar plates, each 
having the test compound incorporated at a particular concentration are 
inoculated with a standard culture of, for example, Candida albicans and 
each plate is then incubated for 48 hours at 37.degree. C. The plates are 
then examined for the presence or absence of growth of the fungus and the 
appropriate m.i.c. value is noted. Other microorganisms used in such tests 
can include Cryptococcus neoformans, Aspergillus fumigatus, Trichophyton 
spp; Microsporum spp; Epidermophyton floccosum, Coccidioies immitis, and 
Torulopsis glabrata. 
The in vivo evaluation of the compounds can be carried out at a series of 
dose levels by intraperitoneal or intravenous injection or by oral 
administration, to mice which are inoculated with a strain of Candida 
albicans. Activity is based on the survival of a treated group of mice 
after the death of an untreated group of mice following 48 hours 
observation. The dose level at which the compound provides 50% protection 
against the lethal effect of the infection is noted. 
For human use, the antifungal compounds of the formula (I) can be 
administered alone, but will generally be administered in admixture with a 
pharmaceutical carrier selected with regard to the intended route of 
administration and standard pharmaceutical practice. For example, they may 
be administered orally in the form of tablets containing such excipients 
as starch or lactose, or in capsules or ovules either alone or in 
admixture with excipients, or in the form of elixirs or suspensions 
containing flavoring or coloring agents. They may be injected 
parenterally, for example, intravenously, intramuscularly or 
subcutaneously. For parenteral administration, they are best used in the 
form of a sterile aqueous solution which may contain other substances, for 
example, enough salts or glucose to make the solution isotonic. 
For oral or parenteral administration to human patients, the daily dosage 
level of the antifungal compounds of the formula (I) (and salts, O-esters 
and O-ethers thereof) will be from 0.1 to 5 mg/kg (in divided doses) when 
administered by either the oral or parenteral route. Thus tablets or 
capsules of the compounds can be expected to contain from 5 mg to 0.5 g of 
active compound for administration singly or two or more at a time as 
appropriate. The physician in any event will determine the active dosage 
which will be most suitable for an individual patient and it will vary 
with the age, weight and response of the particular patient. The above 
dosages are exemplary of the average case. There can, of course, be 
individual instances where higher or lower dosage ranges are merited, and 
such are within the scope of this invention. 
Alternatively, the antifungal compounds of formula (I) may be administered 
in the form of a suppository or pessary, or they may be applied topically 
in the form of a lotion, solution, cream, ointment or dusting powder. For 
example, they may be incorporated into a cream consisting of an aqueous 
emulsion of polyethylene glycols or liquid paraffin; or they may be 
incorporated, at a concentration between 1 and 10%, into an ointment 
consisting of a white wax or white soft paraffin base together with such 
stabilizers and preservatives as may be required.