2-Azolylmethyl-3-difluorobenzyloxy-2,3-dihydro-5- and 6-fluorobenzo[b]thiophen antifungally compounds, especially 2-(1H-imidazolylmethyl-3-(2',6'-difluorobenzyloxy)-2,3-dihydro-5-fluoroben zo[b]thiophene, pharmaceutical compositions containing them and their use in treating fungal infections in animals including humans are disclosed.

BACKGROUND OF THE INVENTION 
This invention relates to 
2-azolylmethyl-3-difluorobenzyloxy-2,3-dihydro-5-and-6-fluorobenzo[b]thiop 
hene, antifungal compounds, pharmaceutical compositions containing them, 
and their use in treating fungal infections in animals, including humans. 
U.S. Pat. No. 4,352,808 (Rane et al.) and the corresponding European patent 
application EP No. 54,233 disclose 
3-aralkyloxy-2,3-dihydro-2-(1H-imidazolylmethyl)benzo b]thiophene 
antifungal compounds. 
U.S. Pat. No. 4,431,816. (Rane et al.) discloses 
3-hydroxy-2,3-dihydro-2-(1H-imidazolylmethyl)benzo[b]thiophene antifungal 
compounds. U.S. Pat. No. 4,468,404 discloses 
3-arylalkoxy-2,3-dihydro-2-(1H-1,2,4-triazolymethyl)benzo[b]thiophene 
antifungal compounds. While U.S. Pat. Nos. 4,352,808 and 4,468,404 
disclose antifungal compounds that are generic to the compounds of this 
invention, there is no specific disclosure of the compound this invention 
and no indication that the trifluoro compounds of this invention would be 
expected to have properties superior compared to the trichoro-compounds, 
e.g., 
cis-5-chloro-3-(2',6'-dichlorobenzyloxy)-2,3-dihydro-2-(1H-imidazolymethyl 
)benzo[b] thiophene specifically disclosed in the above-identified U.S. 
patents. 
SUMMARY OF THE INVENTION 
The compounds of this invention are represented by the following formula I 
##STR1## 
or a pharmaceutically acceptable acid salts thereof, wherein Y is 
imidazolyl, 1,2,4-triazolyl or lower alkyl and aryl substituted 
derivatives thereof, said aryl being a memeber selected from the group 
consisting of phenyl, halophenyl; and lower alkylphenyl; in racemic or 
optically active form. 
The present invention also provides a pharmaceutical composition comprising 
an antifungally effective amount of a compound represented by formula I or 
a pharmaceutically acceptable acid salt thereof, together with a 
pharmaceutically acceptable carrier or diluent. 
The present invention further provides a method of treating susceptible 
fungal infections which comprises administering to a host in need of such 
treatment an antifungally effective amount of a compound represented by 
formula I or a pharmaceutically acceptable acid salt thereof, in racemic 
or optically active form, or a pharmaceutical composition comprising such 
a compound and a pharmaceutically acceptable carrier or diluent. 
A preferred method aspect of the present invention is a method of treating 
susceptible fungal infections which comprises administering to a host in 
need of such treatment an antifungally effective amount of 
cis-2-(1H-imidazolylmethyl)-3-(2',6'-difluorobenzyloxy)-2,3-dihydro-5-fluo 
robenzo[b]thiophene or a pharmaceutical composition comprising said 
compound and a pharmaceutically acceptable carrier or diluent. 
The most preferred compound of the present invention is 
cis-2-(1H-imidazolylmethyl)-3-(2',6'-difluorobenzyloxy)-2,3-dihydro-5-fluo 
robenzo[b]thiophene or a pharmaceutically acceptable acid salt thereof, 
e.g. HCl. 
The preferred pharmaceutical composition of the present invention comprises 
an antifungally effective amount of 
cis-2-(1H-imidazolymethyl)-3-(2',6'-difluorobenzyloxy-2,3-dihydro-5-fluoro 
benzo[b]thiophene or a pharmacetucially acceptable acid salt thereof 
together with a pharmaceutically acceptable carrier or diluent. 
DETAILED DESCRIPTION OF THE INVENTION AND THE PREFERRED EMBODIMENTS 
As used in the specification and claims, the term "lower alkyl" refers to 
straight and branched chain alkyl groups of 1 to 6 carbon atoms, such as 
methyl, ethyl, n- and iso-propyl, n-, sec- and tert-butyl, n-, sec-, 
tert-pentyl and n-, sec- and tert-hexyl. By the term "aryl" as used herein 
is meant phenyl and halophenyl, i.e., phenyl substituted by 1 to 3 
halogens (especially fluorine or chlorine) e.g., mono-, di- and 
trihalophenyl or loweralkyl phenyl, i.e., phenyl substituted by 1 to 3 
lower alkyl groups, mono-, di- and triloweralkyl phenyl, such as 4-chloro- 
or 4-fluorophenyl, 2,4-dichloro- or 2,4-difluorophenyl, 2,5-dichloro or 
2,5-difluorophenyl and 2,6-dichloro- or 2,6-difluorophenyl and 
2,4,6-trichloro- or 2,4,6-trifluorophenyl. 
Compounds of the present invention can exist in two isomeric forms, 
i.e.,(.+-.)-cis-2,3 and(.+-.)-trans-2,3. Both forms (each racemic 
mixtures) are within the scope of the present invention, as are the 
individual optical isomers e.g., (.+-.)- or (-)-cis-2,3 isomers of formula 
I. 
The compounds of the present invention may be prepared by reacting a 
compound of formula II with a difluorobenzyl halide in the presence of 
aqueous base in an organic solvent, e.g., 50% NaOH in 
tetrahydrofuran/water and in the presence of a suitable phase-transfer 
agent, or catalyst e.g., N,N,N- tricaprylyl-N-methylammonium chloride at 
0-30.degree. C. for 1-4 hrs. 
##STR2## 
Other phase-transfer catalysts useful for the invention are disclosed in 
Aldrichimica Acta, 9,35 (1976) and also U.S. Pat. No. 3,992,432. 
The product is isolated and purified in a conventional manner, e.g., by 
column chromatography. The most preferred compound of the present 
invention cis-2-(1H-imidazolylmethyl-3-(2',6'-difluorobenzyloxy)-2,3-dihyd 
ro-5-fluorobenzo[b]thiophene, was prepared in this manner from 
cis-2,3-dihydro-2-(1H-imidazolymethyl)-3-hydroxy-5-fluoro 
benzo[b]thiophene and 2,6-difluorobenzyl chloride. Compounds of formula II 
are prepared in accordance with the procedures of U.S. Pat. No. 4,352,808, 
4,318,816 and 4,468,404. The difluorobenzyl halides, e.g., chlorides or 
bromides are commerically available. 
The compounds of this invention exhibit broad spectrum antifungal activity, 
in conventional antifungal screening tests, against human and animal 
pathogens, such as the following: Aspergillus, Candida, Geotrichum, 
Microsporum, Monosporium, Rhodotorula, Saccharomyces, Trichophyton, and 
Torulopsis. In Sabourand broth medium, the most prefered compound of this 
invention, 
cis-2-(1H-imidazolylmethyl)-3-(2',6'-difluorobenzyloxy)-2,3-dihydro-5-fluo 
robenzo[b]thiophene had a mean Minimum Inhibitory Concentration (MIC) of 15 
mcg/mL in a 48 hour test; the MIC of this compound against Candida 
parapsilosis ,Trichophyton rubrum and Geotrichum candidum was 
.ltoreq.0.031 mcg/mL after 48 hours, and against Saccharomyces cerevisiae 
and Monosporium apiospermum was 0.125 mcg/mL after 48 hours and against 
various other strains of Candida was 32.0 mcg/mL after 48 hours. In Eagles 
medium, the mean MIC for the most prefered compound of this invention 
against six strains of Candida was 0.36 mcg/mL after 48 hours. 
The compounds of this invention also exhibited superior topical antifungal 
activity in in-vivo tests in animals compared to miconazole and 
clotrimazole, present commercial antifungal products. For example, in a 
hamster vaginal Candida C-60 topical infection model, the percent 
inhibition of infection for the most preferred compound of this invention 
was superior to those of miconazole and clotrimazole; in the guinea pig 
Trichophyton dermatophyte topical infection model, the percent inhibiton 
of infection for the most preferred compound of this invention was 
superior to that of miconazole. 
The present invention also provides a pharmaceutical composition comprising 
an effective antifungal amount of a compound represented by formula I or a 
pharmaceutically acceptable salt thereof and a pharmaceutically acceptable 
carrier or diluent. 
The preferred pharmaceutically acceptable salts are nontoxic acid addition 
salts formed by adding to the compound of the present invention about a 
stoichiometric amount of a mineral acid, such as HCl, HBr, H.sub.2 
SO.sub.4 or H.sub.3 PO.sub.4 or of an organic acid, such as acetic, 
propionic, valeric, oleic, palmitic, stearic, lauric, benzoic, lactic, 
para-toluene sulfonic, methane sulfonic, citric, maleic, fumaric, succinic 
and the like, respectively. 
The pharmaceutical compositions of the present invention may be formulated 
by combining the compound of this invention or a pharmaceutically 
acceptable salt thereof with any suitable, i.e., inert, pharmaceutical 
carrier or diluent adapted for administration orally, parentally or 
topically in a variety of formulations. The preferred mode of 
administration is topical. 
Examples of suitable compositions include solid or liquid compositions for 
oral administration such as tablets, capsules, pills, powders, granules, 
solutions, suspensions or emulsions. They may also be manufactured in the 
form of sterile solid compositions which can be dissolved in sterile 
water, physiological saline or some other sterile injectable medium 
immediately before use. 
Topical dosage forms may be prepared according to procedures well known in 
the art, and may contain a variety of ingredients excipients and 
additives. The formulations for topical use include ointments, creams, 
lotions, powders, aerosols, pessaries and sprays. Of these, ointments, 
lotions and creams may contain water, oils, fats, waxes, polyesters, 
alcohols, or polyols, plus such other ingredients as fragrances, 
emulsifiers and preservatives. Powders are made by mixing the active 
ingredient with a readily available, inert, pulverous distributing agent, 
such as talcum, calcium carbonate, tricalcium phosphate, or boric acid. 
Aqueous suspensions of the above powders may also be made. Solutions or 
emulsions may also be prepared using inert solvents which are preferably 
nonflammable, odorless, colorless and nontoxic, for example, vegetable 
oils, isopropanol, dimethyl sulfoxide, hydrogenated naphthalenes, and 
alkylated naphthalenes. Similarly, aerosol or non-aerosol sprays may be 
prepared using solutions or suspensions in appropriate solvents, e.g., 
difluorodichloromethane, for aerosols. 
Parenteral forms to be injected intravenously, intramuscularly, or 
subcutaneously are usually in the form of a sterile solution, and may 
contain salts or glucose to make the solution isotonic. 
Based on the greater in vivo topical activity for the compound of this 
invention compared to miconazole, the dosage of the compound of the 
present invention employed to combat a given fungal infection in animals, 
e.g., mammals, including humans be generally somewhat less than the dosage 
requirements of present commercial products such as miconazole. 
It will be appreciated that the actual preferred dosages of the compound of 
the present invention or pharmaceutically acceptable salts thereof will 
vary according to the particular composition formulated, the mode of 
application and the particular situs, host and disease being treated. Many 
factors that modify the action of the drug will be taken into account by 
the attending clinician, e.g., age, body weight, sex, diet, time of 
administration, rate of excretion, condition of the host, drug 
combinations, reaction sensitivities and severity of the disease. 
Administration can be carried out continuously or periodically within the 
maximum tolerated dose. Optimal application rates for a given set of 
conditions can be readily ascertained by the attending clinician using 
conventional dosage determination tests. 
In general, the dosage for man ranges from about 50 mg per day to about 800 
per day, with about 100 mg to 400 mg per day in single or divided doses 
being preferred.

The following Examples illustrate the invention. 
EXAMPLES 
PREATION 1 
(.+-.)-CIS-2-(1H-IMIDAZOLYLMETHYL)-3-HYDROXY-2,3-DIHYDRO-5-FLUOROBENZO[b]TH 
IOPHENE 
The procedure of Preparation 1 of U.S. Pat. No. 4,352,808, which is hereby 
incorporated by reference, is followed except that an equivalent quantity 
of 6-fluoro-thiocoumaran-4-one hydrochloride is substituted for 
7-chloro-thiocoumaran-3-one hydrochloride to give the title compound m.p. 
182.degree.-184.degree. C. 
PREATION 2 
(.+-.)-CIS-2-(1H-IMIDAZOLYLMETHYL)-3-HYDROXY-2,3-DIHYDRO-6-FLUOROBENZO[b]TH 
IOPHENE 
The procedure of Preparation 1 of U.S. Pat. No. 4,352,808 is followed 
except that an equivalent quantity of 7-fluorothiochroman-4-one is 
substituted for 7-chlorothiochroman-4-one to give the title compound, m.p. 
165.degree.-166.degree. C. 
PREATION 3 
(.+-.)-CIS-2-(1H-1,2,4-TRIAZOLYLMETHYL)-3-HYDROXY-2,3-DIHYDRO-5-FLUOROBENZO 
[b]THIOPHENE AND 
CIS-2-(1H-1,2,4-TRIAZOLYLMETHYL)-3-HYDROXY-2,3-DIHYDRO-6-FLUOROBENZO[b]THI 
OPHENE 
The procedures of Preparation 1 and 2 are followed except that an 
equivalent quantity of 1,2,4triazole is substituted for imidazole to give 
the title compounds. 
EXAMPLE 1 
(.+-.)-CIS-2-(1H-IMIDAZOLYLMETHYL)-3-(2',6'-DIFLUOROBENZYLOXY)-2,3-DIHYDRO- 
5-FLUOROBENZO[b]THIOPHENE 
##STR3## 
2.5 g(10 mmole) of 
(.+-.)-cis-2,3-dihydro-5-fluoro-3-hydroxy-2-(1H-imidazolymethyl)benzo[b]th 
iophene, 3.10 g (15 mmole) of 2,6-difluorobenzylbromide (Aldrich Chemical 
Co.), and 3 drops of methyltricaprylylammonium chloride were stirred in 25 
mL of 50% NaOH and 50 mL of THF at RT for 1 hr. The reaction mixture was 
poured into 500 mL of HCCl.sub.3 with another 500 mL of H.sub.2 O. The 
HCCl.sub.3 was dried over anhydrous MgSO.sub.4 and removed the CHCl.sub.3 
in vacuo. The residue was chromatographed on silica gel eluting with 
CHCl.sub.3 followed by recrystallization from cyclohexane to give 2.36 g, 
m.p. 167.degree.-168.degree., of 
(.+-.)-cis-3-(2',6'-difluorobenzyloxy)-2,3-dihydro-5-fluoro-2-(1H-imidazol 
ylmethyl)benzo[b]thiophene: Calculated: C,60.63; H,4.02; N,7.44; F,15.14; 
S,8.52. Found: C,60.73; H,3.99; N,7.17; F,15.08; S,8.55; .sup.1 H nmr (200 
MHZ, CDCl.sub.3) .delta.: 4:04 (m, 2H, 4.49 (m,1H), 4.85 (bs, 2H), 5.16 
(d, 1H, J=5.0), 6.93 (bs, 1H), 7.05 (bs, 1H), 7.50 (bs, 1H) and 6.95-7.4 
(m, 6H). 
EXAMPLE 2 
(.+-.)-cis-2-(1H-1,2,4-Triazolymethyl)-3-Difluorobenzyloxy 
-2,3-Dihydro-5-Fluorobenzo[b]Thiophenes and 
(.+-.)-cis-2-(1H-1,2,4-Triazolylmethyl)-3-Difluorobenzyloxy)-2,3-Dihydro-6 
-Fluorobenzo[b]Thiophenes 
The procedure of Example 1 is followed except that equivalent quantities of 
the title compounds of Preparation 3 are substituted for 
cis-2,3-dihydro-5-fluoro-3-hydroxy-2-(1H-imidazolylmethyl)benzo[b]thiophen 
e and equivalent quantities of 2,4- and 2,5-difluorobenzyl bromide (of 
Preparation 5) are substituted for 2,6-difluorobenzyl bromide to give: 
(a) 
(.+-.)-cis-2-(1H-1,2,4-triazolylmethyl)-3-(2',4'-difluorobenzyloxy)-2,3-di 
hydro-5-fluorobenzo[b]thiophene; 
(b) 
(.+-.)-cis-2-(1H-1,2,4-triazolylmethyl)-3-(2',4'-difluorobenzyloxy)-2,3-di 
hydro-6-fluorobenzo-[b]thiophene; 
(c) 
(.+-.)-cis-2-(1H-1,2,4-triazolylmethyl)-3-(2',5'-difluorobenzyloxy)-2,3-di 
hydro-5-fluorobenzo[b]thiopene; and 
(d) 
(.+-.)-cis-2-(1H-1,2,4-triazolylmethyl)-3-(2',5'-difluorobenzyloxy)-2,3-di 
hydro-6-fluorobenzo[b]thiophene The corresponding (.+-.)-trans compounds 
are prepared by using the (.+-.)-trans isomers corresponding to the above 
listed (.+-.)-cis isomers in Example 2. 
EXAMPLE 3 
(.+-.)-cis-2-(1H-Imidazolylmethyl)-3-Difluorobenzyloxy-2,3-Dihydro-5-Fluoro 
benzo[b]Tiophenes 
The procedure of Example 1 is followed except that equivalent quantites of 
2,3-difluorobenzyl bromide-2,4-difluorobenzyl bromide and 
2,5-difluorobenzyl bromide are substituted for 2,6-difluorobenzyl bromide 
to give: 
(a) 
(.+-.)-cis-2-(1H-imidazolylmethyl)-3-(2',3'-difluorobenzyloxy)-2,3-dihydro 
-5-fluorobenzo[b]thiophene; 
(b) 
(.+-.)-cis-2-(1H-imidazolylmethyl)-3-(2',4'-difluorobenzyloxy)-2,3-dihydro 
-5-fluorobenzo[b]thiophene; and 
(c) 
(.+-.)-cis-2-(1H-imidazolylmethyl)-3-(2',5'-difluorobenzyloxy)-2,3-dihydro 
-5-fluoro[b]thiopene. 
The corresponding (.+-.)-trans compounds are prepared by using the trans 
isomers corresponding to the above listed cis isomers in Example 3. 
EXAMPLE 4 
(.+-.)-cis-2-(1H-Imidazolylmethyl)-3-Difluorobenzyloxy-2,3-Dihydro-6-Fluoro 
benzo[b]Thiophene 
The procedure of Example 1 is followed except that about 1.5 mmoles of 
2,3-difluorobenzylbromide, 2,4-difluorobenzyl bromide, 2,5-difluorobenzyl 
bromide and 2,6-difluorobenzyl bromide are reached with about 1 mmole of 
(.+-.)-cis-2-(1H-imidazolymethyl)-3-hydroxy-2,3-dihydro-6-fluorobenzo[b]th 
iophene to give: 
(a) 
(.+-.)-cis-2-(1H-imidazolylmethyl)-3-(2',3'-difluorobenzyloxy)-2,3-dihydro 
-6-fluorobenzo[b]thiophene; 
(b) 
(.+-.)-cis-2-(1H-imidazolylmethyl)-3-(2',4'-difluorobenzyloxy)-2,3-dihydro 
-6-fluorobenzo[b]thiophene; 
(c) 
(.+-.)-cis-2-(1H-imidazolymethyl)-3-(2',5'-difluorobenzyloxy)-2,3-dihydro- 
5-fluoro[b]thiopene; and 
(d) 
(.+-.)-cis-2-(1H-imidazolylmethyl)-3-(2',6'-difluorobenzyloxy)-2,3-dihydro 
-6-fluoro[b]thiopene. 
The corresponding (.+-.)-trans isomers are prepared by using the 
(.+-.)-trans isomers corresponding to the above listed (.+-.)-cis isomers 
in Example 4. 
EXAMPLE 5 
The following are typical pharmaceutical formulations containing as the 
active ingredient (designated "Drug") a compound of this invention, e.g., 
cis-2-(1H-imidazolylmethyl)-3-(2',6'-difluorobenzyloxy)-2,3-dihydro-5-fluo 
robenzo[b]thiopene. It will be appreciated, however, that this preferred 
compound may be replaced by equally effective quantities of the other 
compounds of this invention represented by formula I. 
______________________________________ 
FORMULATION 1 
Tablet 125.00 mg. tab. 
______________________________________ 
Drug 125.00 mg. 
Polyethylene glycol 6000 
100.00 mg. 
Sodium lauryl sulfate 
6.25 mg. 
Corn starch 30.00 mg. 
Lactose, anhydrous 87.25 mg. 
Magnesium stearate 1.50 mg. 
______________________________________ 
Procedure: 
Heat the polyethylene glycol 6000 to 70.degree.-80.degree. C. Mix the drug, 
sodium lauryl sulfate, corn starch, and lactose into the liquid and allow 
the mixture to cool. Pass the solidified mixture through a mill. Blend 
granules with magnesium stearate and compress into tablets. 
______________________________________ 
FORMULATION 2 
Capsule 250 mg. tab. 
______________________________________ 
Drug 250.00 mg. 
Lactose, anhydrous 100.00 mg. 
Corn starch 50.00 mg. 
Microcrystalline cellulose 
95.00 mg. 
Magnesium stearate 5.00 mg. 
______________________________________ 
Procedure: 
Mix the first four ingredients in a suitable mixer for 10-15 minutes. Add 
the magnesium stearate and mix for 1-3 minutes. Fill the mixture into 
suitable two-piece hard gelatin capsules using an encapsulating machine.