CA1098036A

CA1098036A - Antimicrobial agents and their use

Info

Publication number: CA1098036A
Application number: CA296,584A
Authority: CA
Inventors: Wolfgang Kramer; Karl H. Buchel; Manfred Plempel
Original assignee: Bayer AG
Current assignee: Bayer AG
Priority date: 1977-02-11
Filing date: 1978-02-09
Publication date: 1981-03-24
Also published as: ES466868A1; DK61078A; CH633185A5; FI780433A7; IL54002A0; AT357154B; AU3324478A; GB1560366A; FR2380027A1; FR2380027B1; AU518192B2; IT7820131A0; SE7801528L; NL7801581A; DE2705679A1; ATA94578A; JPS53101537A; BE863853A; IL54002A

Abstract

"Antimicrobial agents and their use"

Abstract Of The Disclosure This invention relates to new 1-phenoxy 2-(2,4-dichlorophenyl)-1-(1,2,4-triazol-1-yl)-ethan-2-ones and -ols useful as antimycotic agents, especially as medicaments.
Le A 17 832-CA

Description

3~

The present invention relates to the use of 2,4-dichlorophenyl-triazolyl-ethan-ones and ols as antimicrobial agents, in particular as antimycotics.
It has already been disclosed that phenoxy-triazolyl derivatives have a good antimycotic action tcompare German Offenlegungsschriften (German Published Specifications)

2,247,18~ and 2,324,424). However, their action, in particular against dermatophytes, is not always completely satisfactory.
The present invention provides a pharmaceutical composition comprising an effective amount of an active ingredient which is a 2~4-dichlorophenyktriazolyl-ethan-one or ; ol compound of the following general formula or its salt Cl - O - ~H - A - ~ - Cl (I) ~n ~N
N

in which A is a keto group or a CH(OH) group, each X is independ-ently of any other X present, halogen, alkyl or optionally ~ substituted phenyl, and n is an integer having a value of `/ 0, 1, 2 or 3, together with a pharmaceutically acceptable carrier or diluent.
Those compounds of the formula (I) in which A repre-sents the CH(OH) ~roup have two asymmetric carbon atoms; theycan therefore exist in the form of the two geometric isomers (erythro form and threo form), which can be obtained in various proportions. In both cases, they exist in the form of optical isomers. All the isomers are included within the scope of the presenk invention.
Surprisingly, the 2,4~dichlorophenyl-triazolyI-ethan-:

~3~1~3~&i ones and -ols which can be used according to the invention exhibit a better antimycotic, therapeutically useful activity then the phenoxy-triazolyl derivatives known from the state o~ the art, which are the most closely related compounds chemically and from the point of view of their activity.
The ~ub~tances which can be u~ed according to the invention thus represent an enrichment of pharmacy.
Pre~erred compounds according to the invention include compo~ds o~ formula (I) in which each X is one of lG halogen e~pecially ~luorine 9 chlorine, bromine or iodine, straight-chain or branched alkyl having 1 to 4 carbon atoms and phenyl which is optionally substituted by halogen, especially chlorine; n is an inte~er having a value of 0, 1 or 2, and A has the 3ame meaning a~ defined hereinbefore.
~xamples which ~ay be mentioned of particularly active representatives o~ the active compounds according to the invention~ in addition to those of the preparation examples and the examples o~ Table 1, are the following: 1-(2-chlorophenoxy)-2-(2~4-dichlorophenyl)~ 1,2,4-tria~ol-1-yl)-ethan~2-one and ol, 1-(2-Isopropylphenoxy)-2-(2,4-dichloro phenyl)~ 294-triazol 1-yl3-ethan 2-one and -ol, 1-(2-methylphenoxy)D2-(2,4-dichlorophenyl)-1-(1,2,4-triazol-1-yl)-ethan-2 one and -ol, 1-(2~chloro-4-methylphenox~)-2-(274-dlc110rophenyl)w1-(172,4-triRzol-l-yl)-ethan-2 one and -ol, 1-(4~bromophenoxy)~2-(2,~-dichlorophenyl)-1-(1,2,4-triazol~l-yl)-ethan-2-one and -ol 9 1- ~ 4-iodophenoxy) 2~(2,4~dichloro-phenyl)-l-(l 9 2,4-triazol-l~yl) ethan~2-one and -ol, 1-(2, 6-dichlorophenoxy)-2-(2,4-dichlorophenyl)-1-(1,2,4-triazol 1-yl~-ethan-2-one and -ol 9 1-( 2,5-dichlorophenoxy)-2-(2 9 4-dichlorophenyl)-1~(1,2,4-triazol~l-yl)-ethan-2-one and ~ol, ~ - 3 -1,(5 fluorophenoxy)-2 (2,4-dichlorophenyl) 1-(192,4-triazol_ l-yl)-ethan-2-one and -ol~ 1-(3-~romopheno~y3-2-(2,4-dich-lorophenyl)-1-(1,2~4 triazol-1-yl)-ethan-2-one and -ol, 1-(4-methylphenoxy)-2-(2,4-dichlorophenyl)-1-(ly2,4-triazol l-yl)~ethan 2~one and -ol, 1-(4-ethylphenoxy~-2-(2 9 4-dichloro-phenyl)-1~(192,4-triazol-l-yl)-ethan-2 one and -ol, 1-(3-methylphenoxy~-2-(2~4-dichlorophenyl)-1-(1,2,4-triazol-1-yl~-ethan-2-one and -ol, 1-(2-methylphenoxy)-2-(2,4-dichlorophen-~ 2,4-triazol l yl)-ethan-2-one and -ol, 1~(4-chloro-2-methylphenoxy)-2-(2g4-dichlorophenyl)-1-(1~2,4-triazol-1-yl)-ethan-2-one and -ol~ 1-(4-bromo-2-methylphenoxy)-2-(2,4 dichlorophenyl)~ 2,4-triazol-1-yl)-ethan-2-one and ol, 1~(4-fluoro-2-methylphenoxy)-2-(2,4-dichlorophenyl) 1-(1,2,4-triazol 1-yl)-ethan-2~one and -ol~ 1-(4-iodo-2~methyl-phe~o2y)~2-(2,4-dichlorophenyl)-1-(1,2,4 triazol-l yl~-eth~n-2-one and ol, 1-(2,~dimethylphenoxy);2-(2,4-dichloro- .
phenyl~ (1,2,4-triazol-1-yl)-ethan~-2-one and -ol, 1-(4-2', 4'-dlchlorobiphenylyloxy)-2-(2,4-dichlorphenyl3-1-(1,2,4- -~ : triazol-l-yl)-ethan-2-one and -ol, 1-(4-2,4'-dichlorobipheny~
20~ ~loxy)-2-(2~4-dichlorophenyl)-1-(1,2,4-triazol-1-yl3-ethan-2-one and -ol, 1-(4-4'-bromobiphenylyloxy)-2-(294-dichloro-. phenyl)~ 2,4 triazol-1-yl~-ethan~2-one and -ol and~l ~4~2-chlorobiphenylyloxy~-2-(2,4-dichloro~hen~ 1,2~4-~:~ triazol-l~yl) ethan-2-one and -ol~
: However~ they can be prepared accor~ing to our own proposal, by reacting 1-bromo-2-(2~4-dichlorophenyl)-1-phenoxy-ethan-2~ones o the formula , ~ - .

3~

- 0 - CH - C0 - ~ - Cl ~I' ' (II) in which X and n have the same meaning as defined hereinbefore in form~la (I~ with 19294-triazole in the presence of an inert organic solvent, for example acetonitrile, and in the presence of an acid-billding agent, for example potassium carbonate or an excess o~ 1,2,4-triazole, at a temperature of from 0 to 150C, preferably at 60 to 1~0C~ and where necessary reducing the 1,2,4-triazolyl-ethanones, thereby obtained, with a complex borohydride~ for example sodium borohydride, in a manner which is in itself known in the presence of a polar organic solvent, for example methanol, at temperature of from 0 to 30C so as to produce the corres-pond m g 1,2~4-triazolyl-ethanols. The compounds of the formula (I) may be isolated b;y conventional techniques.
~he l-bromo-2-(2,4~dichlorophenyl)-1-phenoxy-ethan-2-ones of the ~ormula `(II) to be used as starting substances :20~ are not yet known~ However, -they can be prepared by known : processes~ by reacting ~ppropriate phenols wlth ~bromo-2,

4-diohlorQscetophenone and~subsequently replaclng the~active hydrogen~atom which still remains bY brcmine by conventional~
techniques O
~ : ~Preferred salts o~ the compounds cf the formula (I~
are salts with physiologically acceptable acids~ Thess :: include, preferably~ ~alts~wlth hydrogen halide aclds, such~;
as, for example, hydrochloric acid and hydrobromic acid, in~
particular h~drochloric acid, phcsphoric acid, nitric~acid,~
monofunctional and bi~unctional carboxylic acids and hydrcxy_ ~ 5 3~

carboxylic acids, such as, -for example, acetic acid, citric acid, sorbic acid and lactic acid, and 1,5-naphthalene-di-sulphonic acid.
The new compounds of formula (I) and their salts can ~e interconverted in any suitable manner; methods for such in-terconversion are known in the art.
The compounds of the formula (I)~ which can be used according to the invention, and their salts, exhibit anti-microbial, in particular powerful antimycotic9 effec~s. The~
1~ possess a ver~ broad spectrum of antimyco~ic activity, especi-ally agains~ dermatophytes and blastomyces as well as bi-phase fungi, for example against varieties of Candida, such as Candida albicans, varieties of Epidermophyton, such Epidermophyton floccosum, varieties of Aspergillus, such as Aspergillus niger and Aspergillus fumigatus, varieties of Trichop~yton, such as Trichophyton mentagrophytes, varieties of Microsporon, such as Microsporon felineum and varieties of Penicillium, such as Penicillium communc. The recital of these micro-organisms in no way implies a limitation of t~e 2~ germs which can be combated but is only of illustrative character.
The following may be mentioned as examples of fields ; of indication in human medicine: dermatomycoses and systemic mycoses caused by Trichophyton mentagrophytes and other varie-ties of Trichlophyton, varieties of Microsporon, Epidermophyton floccosum, blastomyces and biphase fungi as well as moulds.
The following may be mentioned as examples of fields of indication in veterinary medicine: generally all dermato-mycoses and systemic mycoses, especially those caused by the 3Q above mentioned pathogens.

,~ "
".~", As stated above, the invention also ~lates to the use in human and veterinary medicine of the compounds of the invention.
The present invention pro~ides a pharmaceutical compo-sition containing as active ingredient a compound of the invention in admixture with a solid or liquefied gaseous diluent) or in admixture with a liquid diluent other than a solvent of a molecular weight less than 200 (preferably less than 350) e~cept in the presence of a sur~ace active agent.
The invention further provides a pharmaceutical composition containing as active ingredient a compound of the invention in the form of a sterile and/or isotonic aqueous solution.
The invention also provides a medicament in dosage unit form comprising a compound of the invent~on.
~he invention also provides a medicament in the form of tablets (including lozenges;and granules~, dragees, cap-sules 9 pills ~ ampoules or suppositories comprising a com-pound of the inventionO
2~ "Medicament" as used in this Specifica~ion means : ~ :
ph~sically discrete coherent portions suitable for medlcal ;administration. "Medicament in dosage unit~form" as used :
in this Specification means physically discrete coherent units suitable for medical administration each containing~a daily dose~or a multiple (up to ~our times) or sub-multiple (down to a ~orbieth) of a daily dose of the compound of~ the ~; invention in association with a carrier and/or enclosed wibhin ;an envelope~ Whether the medicament contains a dally dose or7 ~or example, a hal~9 a third9 or a quarter of a daily dose~
7~ill depend on whether~the medicament is to be administered :

once or, for example, twice, three times or four times a day respectlvely.
The pharmaceutical compositions according to the invention may, for example, take the form of ointments, gels, pastes, creams, sprays (including aerosols), lotions, suspensions, solutions and emulsions of the active ingred ient in aqueous or non-aqueous diluents, syrups, granulates or powders~
~he diluents to be used in pharmaceutical compositions (e.g. granulates) adapted to be formed into tablets, dragees7 capsules and pills include the following:
(a) fillers and extenders, e.gt starch, sugars, mannitol, and silicic acid; (b) bindin~ agents, e~g. carboxymethyl cellulose and other cellulose derivatives, alginates, gela-tine and polyvinyl pyrrolidone; (c) moisturizing a~ents, e.~. glycerol; (d) disintegrating agents, e.g. agar-agar, calcium carbonate and ~odium bicarbonate; (e~ agents ~or retarding di~solution e.g. par~ffin; (f) resorption accelera-tors, e.g. quaternary ammonium compounds3 (g) sur~ace ; 20 active agents, e.g. cetyl alcohol, glycerol monostearate;
(h) adsorptive carriers, e.gO kaolin and bentonite; (i~ lub-~
ricants, e.g~ talc, calcium and magnesium stearate and solid polyethylene glycols~
The tablets ? dragees, oapsules and pills formed ~rom the pharmaceutical compositions of the invention can have the customary coatings, e~velopes and protectiye matrices, which may contain opaoi~iers. They can be so constituted that they release the active ingredient only or preferably in a particular part of the intestinal tract, possibly over ~0 a period o~ timeO The coatings, envelopes and proteotive :
, ' . ' .

3~

matrices may be made~ for e~ample 7 of polymeric substances or waxes The ingredient can also be made up in microencapsula-ted form together with one or several of the above men-tioned diluent~.
~he diluents to be used in pharmaceutical compositions adapted to be formed into suppositories can, for example, be the usual water-soluble or water-insoluble diluents, such as polyethylene glycols and fats (e~g. cocoa oil and high esters Le.g~ nl4 -alcohol with C16-fatty acid]~ or mixtures of these diluents.
The pharmaceutical compositions which are ointments, pastea, creams and gels can, for example, contain the usual diluents9 eOg animal and vegetable fats9 waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and 2inc oxide or mixtures of these substances.
The pharmaceutical compositions which are powders and sprays can~ for example? contain the usual diluents, e.g.
: ~
~ 20 lactose9 talc, silicic ~cid? aluminium hydro~ide, calcium :
silicate, and polyamide powder or mixtures o~ these substances~
Ae~osol sprays~can, for example9 contai:n the usual propel-~
lants, e~g.~chlorofluorohydrocarbonsO
~he pharmaceutioal compositions which are solutions and emulsions can, for example, contain the customar~ diluents~
(with~ of course, the above~mentioned exclusion of solvents having a molecular weight below 200 except in the presence o~ a ~ur~ace-active agen~), such as solvents~ dissolving agents and ~emulsi~iers; specific eæamples of such diluents ~
are water? ethyl alcohol, isopropyl aloohol, ethyl carbooate, _ g _ eth;yl acetate, benzyl alcohol5 benzyl benzoate, propylene glycolt 1,3-butylene glycol, dimethylformamide, oils Lfor e~ample ground nut oil], glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitol or mixtures thereof.
For parenteral administration, solutions and emul-sions should be sterile, and, if appropriate, blood-isotonic.
~he pharmaceutical compositions which are suspensions can contain the usual diluents, such as liquid diluents, e,g.
water~ ethyl alcohol, propylene glycol9 surface-active a~nt~
(e,~ ethoxvlated isostearyl alcohols, polyoxyeth~lene sorbite and sorbitane esters), microcr~stalline cellulose, aluminium metahydro~ide, bentonite, agar-agar and tragacanth or mixtures thereof~
All the pharmaceutical compositions according to the invention can also contain colouring agents and preservatives as well as perfumes and flavouring additions (e.g. peppermint oil and eucalyptus oil) and sweetening agents (e.g. saccharin).
The pharmaceutical compositions according to the invention generally contain from 0.1 to 9995 usually from 0.5 to 95% of -the active ingredient by weight of the total composition.
In addition to a compound of the invention, the pharma-ceutical compositions and medicaments according to the invention can also contain other pharmaceutically active compounds. ~hey may also ccntain a plurality of compounds of the invention, Any diluent in the medicaments of the present in~ention may be any of those mentioned above in relation to the pharma-ceutical compositions of the present invention. Such medioa;

~e A ~ - 10 -3~i ment~ may include solvents of molecular weight less ~han 200 as 301e diluent.
The discrete coherent portions constituting the medicament according to the invention will generally be adapted, by virtue of their shape or packaging, for medical admini~tration and may be, for example7 any of the following:
tablets, (including lozenges and granulates), pills, dragees, capsules, suppositories and ampoule~. Some of these ~orms may be made up for delayed release of the active ingredient~
Some, such as capsules, include a protective envelope which - renders the portion~ of the medicament physically discrete and coherent.
'rhe pre~erred daily dose for admini~tration of the medicaments o~ the invention is from 0.5 to 15 g preferably from 2.5 to 10 g o~ ac-tive ingredientO
~he production of the above mentioned pharmaceutical compositions and medicaments i~ carried out by any method known in the art, for example, by mixing the active ingred-ient(s3 with the diluent(s) to form a pharmaceutical compo-2G sition (e.g. a granulate) and then fol~ing the composition into the medicament (e.g~ tablets).
~his invention further provides a method of combating (including prevention, relief and cure of) the above mentioned di~eases in human and non-human animals~, which comprises administering to the animals a compound of the invention alone or in admixture with a diluent or in the form of a ~ medicament according to the lnvention.
O It is envisaged that these active compounds will be administered perorally, parenterally (for e~ample intra-muscularly, intraperitoneally, or intravenously)~ rectally e~ a~
:

or locally, pre~erably parenterally, especially intravenously.
Pre~erred pharmaceutical compositions and medicaments are therefore those adapted for intravenous administration, such as sterile and blood-isotonic solutions and emulsions and ampoules containing them. Administration in the method of the invention is pre~erably intravenously.
In general it has proved advantageous to administer amol~ts of from 10 mg to 300 mg/kg of body weight most pre~erably from 50 to 200 mg/kg of body weight per day to achieve e~ective results. Nevertheless, it can at times be necessary to deviate from those dosage rates, and in partic~ar to do so as a function of the nature and body weight of the human or animal subject to be treated, the individual reaction of this subject to the treatment, the type of formulation in which the active ingredient is admini-stered and the mode in which the administration is carried out, and the point in the progress o~ the disease or interval at which it is to be administered. Thus it may in some case suffice to use less than the above mentioned minimum dosage ratej whilst other cases the upper limit mentioned must be e~ceeded to achieve the desired results. Where larger amounts are administered it can be advlsable to divide these into several individual administrations o~er the course o~ the day.
~ 3~_~

Description of the e~periment:
The in vitro tests were carried out in a series diluN
tion test with germ inocula o~ an average o~ 5 ~ 104 germs/ml o~ substrateO The nutrient medium was (a) ~or dermato~h~tes ~ ~ a~ 12 -.

and moulds: Sabouraud's milieu d'épreuve and (b) for yeasts:
meat e~tract/glucose broth.
~ he incubation temperature was 28C and the duration of incubation was 24 to 96 hours.
The results of the tests o-f the activity o~ various compounds of t.l~e invention against diverse micro-organism are given in the following Table A, ::
: . ~ :

~: : : : :

~e A_L~ 13 -., . : ~ , ' . ' ' ' : ' .., 3~

o o ~
q~ rl h ~ ~ l l l h '~ o ~ O O
-rl O
o b~
rl ~
qD~ O *
.~ a) e) o 8 o ,, CQ

o ~ a) ~ O O O
~ ~` o . o o ~;
O ~d ~
~ ~,, o o ,., ~, O
,~
h !~ ~ ~
~a H C) h t~

¦ ~_ b~
~1 ~ ~ I ~) o \~;_ E~ D ~ D ~ ~9 D

I,.. ~ - 14 -03~

b~
.,, v~ ~d h o o ~
h I l I
0 ~
.,1 ~ bD

a h h s::
~1 a>
'Ho bO ~
H O

'~ H ,1 d ~ , ';~ ` d O /~
s~

~ ~ ~ o V

O
Z;
0~ h h d ~1~ æ ~ ~ æ

~P 1 Ç ~

~aL~ - 15 - ~

, . . . . , , ,i ~ ~1303~

O ~ ~ X ,~ Y
Z

.

~i ~, (D ;i3 H
J~, ~ p A r r ~y ~ C, `C H

P~
~ ~ ~ ''C t~
:' 00 v v v v a~ v ~o ~ .
~ -~ r ~ r ~ ~

c~ V ~
r r ~ (P oq 3 (n : b~

: . : ~ ~ ~
: ~ ~ ~ a ~ :

~ .

:
, .

, . .

PreP~3Sb~I:L
E~m~

Cl- ~ -0 CH-C0- ~ -Cl ~ I S03H
N--' x 1/2 ~
~o3~

24406 g (0~62 mol) of 1-bromo-1-(4-chlorophenoxy)-2-(2,4-dichlorophenyl)-ethan-2-one are added dropwise, at the boil, to 149 g (2.13 mols) of 1,2,4-triazole in 1,5G0 ml of acetonitrile. The mi~ture is heated under reflux for ~0 hours~ Thereafterp the solvent is distilled off in vaouo, the residue is taken up in 1,000 ml of methylene chloride and the methylene chloride i~s- extracted by shakin~ with three tirles 500 ml of water. '~he aqueous phase is again e~trac~-ted by shaking with 500 ml of methylene chloride. The com-bined methylene chloride phases are dried over sodium sulphate and concentrated by distilling off the solvent in vacuo.
he residue is dissolved in 300 ml of acetone and 100 g of ~lp5lnaphthalenedisulphonic acid hexahydrate in 200 ml of acetone are added. ~his gives 270 g (41~% of theory) of (4-chlorophenoxy)-2-(2,4 dichlorophenyl~ (1,2,4-triazol-yl) ethan~2~one na~halene-1,5-disulphonate of melting polnt 198C.
25 ~3~a~ ~ ~

~1 0-C~-~0 ~ -Cl Np:
~N J x HCl ~0 ~ :

The base is liberated from the 1-(4-chlorophenoxy)-2-(2,4~dichlorophenyl)-1-(1,2~4-triazol-1-yl~ethan-2-one naphthalene 1,5-disulphonate9 obtained according to Example 1, by adding sodium bicarbonate solution, and is taken up in ethyl acetate and converted with ethereal hydrochloric acid into the hydrochlo~ide, which crystallises out after standi~g in ether ~or a prolonged period, This gives 1-(4~chloro-phenoxy)-2-(2,4-dichlorophenyl)-1-(1,2,4-triazol-1 yl)-ethan-2-one hydrochloride of melting point 138~140a~ quantitatively.
~3a~
Cl Cl- ~ -0-CH-CH- ~ -Cl N. Il x HCl . .
226 g (0.42 mol) of 1-(4-chlorophenoxy)-2-t2,4-dichloro-phenyl)-1~ 2,4~triazol~1-yl)-ethan-2-one naphthalene-1,5-disulphonate (Example 1) are suspended in 500 ml of methylene : chloride, 1,000 ml of saturated sodium bicarbonate solution .
:20 ~ are added and the mixture is stirred for 5 hours. '~he isolated organic phase is dried over sodium sulphate and concentrated in vacuo. '~he residue is taken up in 1.5 1 o~
methanol, 17 g (0.45 mol) of sodium borohydride are added in portions of about 1 B at about 0 to 5C and the mixture is stirred ~or 15 hours at room temperature. 200 ml~of con~en-trated hydrochloric acid are then added dropwise at 0C
and the mixture is again stirred ~or 15 hours at room tempera~
ture. 'l'he reaction mixture is~then stirred into 1,000 ml G~ saturated sodium:bicarbonate solution, the aqueous phase is extracted by shaking with twice 500 ml o~methylene chloride `

~g~ ~9~ ~

and 1;he organic phase is extracted by shaking with -twice 200 ml o:~ water. The combined organic phases are dried over SOdil1m sulphate and concentrated by distilling off the solvent in vacuo. The oil which remains is dissolved in 800 ml of ether and dry hydrogen chloride is added in excess~ This gives 113.5 g (64% of theory) o~ 1-(4-chlorophenoxy)-2-(29 4~dichlorophenyl)-1 (1,2y4-triazol~l-yl)-ethan-2-ol hydrochlo-ride as an isomer mixture o~ melting point 157 - 172C.
The ~ollowing compounds in Table 1 are obtained by methods analog~us to tho3e of the example~ given above.

.

. .

:

,:

` : ' . ~ ~

`~

19- .

.
: - . . .,, :. , . . ' . ~

Tabl~s 1 ~ - O CH ~ A - ~ - Cl Xn ~N~N

Example Xn A Melting po nt (C) 4 2,4-C12 CO 173-83 (x HC1~
4 ~ CO 205~08 (~ ~Cl) 6 4 ~ -Ol ao 138 (decomposition) (x HCl) 7 4-~ ao 83-~6 8 2,6-al2 co 176 (~ Ha -Cl ao 140-42 (x HCl) , 11 4-CH~ CO 172 (x HCl) 12 4-Cl, 2-C~3 CO 138 ~ HCl) ~;~13 4~I ao 156 (x Ha 14 ~4-al2 CH(O~) 68-85 (x HCl)~ isomer 15: 4- ~~ CH(OH)~148-50 (x HaI)~ mlxture 16 ~4- ~ -ClCH(OH) 170-74 , "~
17~ ~ ~ 4-~oH(OH) 139-43: (~ H~
18 :~ CH(OH) 171-73 :~
~ l9~ 3-a~ CH(OH) 155-58 ~(x HCl), ; ~ ~ : : : ,' ~ :

- 20 _ :
:

.

Claims

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A pharmaceutical composition comprising an effective amount of an active ingredient which is a 2,4-dichlorophenyl-triazolyl-ethan-one or -ol compound of the following general formula or its salt (I) in which A is a keto group or a CH (OH) group, each X is independently of any other X present, halogen, alkyl or option-ally substituted phenyl, and n is an integer having a value of 0, 1, 2 or 3, together with a pharmaceutically acceptable carrier or diluent.

2. A composition according to claim 1 in which the active ingredient is a compound as defined in claim 1 in which each X
is one of fluorine, chlorine, bromine, iodine, straight-chain or branched alkyl having 1 to 4 carbon atoms and phenyl which is optionally substituted by halogen, or a salt thereof.

3. A pharmaceutical composition according to claim 1 in which the active ingredient is in admixture with a solid diluent or carrier or a liquefied normally gaseous diluent or carrier, or with a liquid diluent or carrier containing a sur-face active agent or preservative.

4. A pharmaceutical composition containing as an active ingredient a compound as defined in any of claims 1 to 3 in the form of a sterile or isotonic aqueous solution.

5. A composition according to any of claims 1 to 3 containing from 0.5 to 95% of the said active ingredient, by weight.

6. A medicament in dosage unit form comprising a composition as defined in any of claims 1 to 3.

7. A medicament in the form of tablets, pills, dragees, capsules, ampoules, or suppositories comprising a composition as defined in any of claims 1 to 3.

8. A pharmaceutical composition according to claim 1, 2 or 3 in which the active ingredient is 1-(4-chlorophenoxy)-2-(2,4-dichlorophenyl)-1-(1,2,4-triazol-1-yl)-ethan-2-one, 1-(4-chlorophenoxy)-2-(2,4-dichlorophenyl)-1-(1,2,4-triazol-1-yl)-ethan-2-ol, 1-(4-phenylphenoxy)-2-(2,4-dichlorophenyl)-1-(1,2,4-triazol-1-yl)-ethan-2-one, 1-(2,4-dichlorophenoxy)-2-12,4-dichloro-phenyl)-1-(1,2,4-triazol-1-yl)-ethan-2-ol, 1-(4-phenylphenoxy)-2-(2,4-dichloro-phenyl)-1-(1,2,4-triazol-1-yl)-ethan-2-ol, 1-[4-(p-chlorophenyl)phenoxy]-2-(2,4-dichlorophenyl)-1-(1,2,4-triazol-1-yl)-ethan-2-ol, or a hydrochloride thereof.

9. A pharmaceutical composition according to claim 1, 2 or 3 in which the active ingredient is 1-(4-chlorophenoxy)-2-(2,4-dichlorophenyl)-1-(1,2,4-triazol-1-yl)-ethan-2-one hydrochloride.

10. A pharmaceutical composition according to claim 1, 2 or 3 in which the active ingredient is 1-(4-chlorophenoxy)-2-(2,4-dichlorophenyl)-1-(1,2,4-triazol-1-yl)-ethan-2-ol hyrdrochloride.

11. A pharmaceutical composition according to claim 1, 2 or 3 in which the active ingredient is 1-(4-phenylphenoxy)-2-(2,4-dichlorophenyl)-1-(1,2,4-triazol-1-yl)-ethan-2-one hydrochloride.

12. A pharmaceutical composition according to claim 1, 2 or 3 in which the active ingredient is 1-(2,4-dichlorophenoxy)-2-(2,4-dichlorophenyl)-1-(1,2,4-triazol-1-yl)-ethan-2-ol hydrochloride.

13. A pharmaceutical composition according to claim 1, 2 or 3 in which the active ingredient is 1-(4-phenylphenoxy)-2-(2,4-dichlorophenyl)-1-(1,2,4-triazol-1-yl)-ethan-2-ol hydrochloride.

14. A pharmaceutical composition according to claim 1, 2 or 3 in which the active ingredient is 1-[4-(p-chlorophenyl)-phenoxy]-2-(2,4-dichlorophenyl)-1-(1,2,4-triazol-1-yl)-ethan-2-ol hydrochloride.