CA1097356A - 2,4-dichlorophenyl-imidazolyl-ethan-ones and -ols, a process for their preparation and their use as medicaments - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE
This invention relates to new 2,4-dichlorophenylimidazolyl-ethan-ones- and -ols useful as antimycotic agents, especially as medica-ments. The new compounds correspond to the formula:

Description

~3~73~

The p~e~ent invention relate~ to certain new imida?olyl compounds, to a process ~or their preparation and ~heir ~e as me~icaments, in particular a~ antimycotic~.
It ha~ already been disclosed that phenoxy-~midazolyl derivatives have a good antimycotic action (compare ~erman Of~enlegung~schriften (German Published ~pecifiaations)

2,1~5,490 ~e A 13 458] and 2,333,355 ~e A 15 145]). Ho~-P~er~ their actinn, in particular again~t dermatophyte~ and in vivo agai~t Csndida, i~ not always completely satis~acto~y.
It ha~ now been ~ound that the new eompound~ which ar~
2,4-dichlor~phenyli~idaz31yl-ethan-ones and -018 o~ th~
general formula a in which A i~ a keto group or a ~a~o~ ~roup, j X 18 halogen, ~traight-chain or branched alkyl with 1 to 4 car~on atom~ or phenyl optlonally sub~tituted by halog~n, prsfarably chlorine, and n i~ aa i~teger ~rom O to 3~ pre~arably ~rom O to 2, a~d th~ir 8~ ha~e po~er~ul a~tlmycotic propertie~
Among ~he ne~ ~mida~olyl ethanone a~d etha~ol ~alt3 o~ the inYention; those ~altG that are pharmaoeutically a~ceptable are particularly i~porta~t a~d prei~rred.
~ho~e co~pounds in whioh in ~ormula (I~ A repreaents the o~(OH~ group po~e~ two a~ymm~trio ca~bo~ QtomB; they can thereiore e~t ln the ~orm o~ both geometric isomer~ (e~ythro ~or~ ~nd threo ~orm)~ which c~n be obtalned in v~r~ou~ propor-tion~ both ca~e~, they e~ist in the ~orm of opti~al ~ 2 - ~

73~6 isomers. All the isomer~ are included within the scope o~
the present invention~
In a ~urther æEpect the present invention provide~ a process ~or the preparation of a compound according to the invention in which a 1-bromo-2-(2,4,-dichlorophenyl)-1-pheno~y-ethan-2-one o~ the general ~ormula Cl - O - oE - CO - ~ - ~1 (II) ~ ~r , in ~hich ~ and n have the ~me meaning a~ defined above ~n ~orm~
ula ~ reacted with imida~ole in the presence o~ a d~luent `. and an acld binding agent, and where nece~3ary the resulting lmidazolyl-ethanone compound i~ reduced with a comple~ boro-hyd~lde., optional~y in the presenoe o~ a d~luent ~o a~ t3 prod~oe the corre~ponding imidazolyl-ethanol compound o~
Formula I.
~he new 2,~-dlehlorophenyl i~ldaæolyl-ethan-one~ and -ol~ o~ the gelleral ~oTmula I a~d their ~alt~ can be i~te:r-con~erted in ~ny ~table ~ er; methods Ior ~uoh i~ter-con~ers~on are krlown i~ the art,, For es~mple salt~ r b~ pre pared b;sr ~eaction of th~ corr~spo~di~g iree compoland0 ~r~th ac:i ds ~
Surprl~ingly, the acti~e compounds acoordi~g to the ~n~en~ion 2i:hlbit a better a~tim3~¢otlc, therapeutically u~e-~ul acti~ty than ph~no:cy-~mid~zolyl der~vatiYes kno~n iro~
the ~tate oi the art, which are the mo~t clo~ely related compou~d~ ~hem~¢ally and ~rom tha poi~ OI vie~ ~ I;heir a~tlon. q~o ~ub~tax~es according to thc ln~e~tion thus ~ep~ent ~ e~rlohm~nt oi ph0.rmacy.

3~

If l-bromo-1-(4-chloropheno~y 3 -2-(2,4-dichlorophenylj-ethzn-2-one and imidazole are used as starting material~ the course o~ the reaction can ~e represented by the ~ollowin~
equation:

CO- ~-Cl + ~N~

Cl ~ C1- ~ -0-lE-C0- ~ -C1 If 1-(4-chlorophe 2-(2,4-dichlorophenyl)-~-imidazol-l-yl)-ethan-2-one a.nd sodium borohydride are used a~
~tarting ~ub~tances, the cour~e of the reaction can be repre~e~ted by the ~ollowing equation:
Cl Cl- ~ -O-I -C0 ~ -Cl ~o Cl ~ 9~4 ~ C1 ~ -0- ~-C~- ~ -Cl ~

, ~ amplea of ~tarting compounds o~ the ~ormula (II3 which may be mentioned ar~ bromo-l phenoxy-2-(2~4-di-chloropheny~)-e~han-2-one, 1-bromo-1-(4-~hlorophenoxy) 2-~2~A-dichlorophenyl)-athan-2-one, 1-bromo-1-(4-~luoropheno~y) ~0 ~ -2-(2,4~d~chloropheng1) ethan-2 one, 1-bromo-1-(4-bromophenoxy~

7;~

-2-(2,4-dichlorophenyl)-ethan-2-one, 1-bromo-(4-iodophenoxy) -2-(2,4-dichlorophenyl)-ethan-2-one, 1-bromo-1-(2,4-dichloro-phenoxy)-2-(2,4-dichlorophenyl)-ethan-2-one, 1-bromo-1-(2,6-dichlorophenoxy)-2-(2,4-dichlorophenyl)-ethan-2-one, l-bromo-1-(2,5-dichlorophenoxy)-2-(2,4-dichlorophenyl)-ethan-2-one, l-bromo-1-(3-fluorophenoxy)-2-(2,4-dichlorophenyl)-ethan-2-one, l-bromo-1-(3-chlorophenoxy)-2-(2,4-dichlorophenyl)-ethan -2-one, 1-bromo-1-(3-bromophenoxy)-2-(2,4-dichlorophenyl)-ethan-2-one, 1-bromo-1-(2-chlorophenoxy)-2-(2,4-dichlorophenyl) -ethan-2-one, 1-bromo-1-(4-methylphenoxy)-2-(2,4-dichlorophenyl ?
-ethan-2-one, 1-bromo-1-(4-ethylphenoxy)-2-(2,4-dichlorophenyl) -ethan-2-one, 1-bromo-1-(3-methylphenoxy)-2-(2,4-dichlorophenyl) -ethan-2-one, 1-bromo-1-(2-methylphenoxy)-2-(2,4-dichlorophen-yl)-ethan-2-one, 1-bromo-1-(2-isopropylphenoxy~-2-(2,4-dich-lorophenyl)-ethan-2-one, 1-bromo-1-(4-chloro-2-methylphenoxy) -2-(2,4-dichlorophenyl)-ethan-2-one, 1-bromo-1-(4-bromo-2-methylphenoxy~-2-(2,4-dichlorophenyl~-ethan-2-one, l-bromo-l-~4-fluoro-2-methylphenoxy)-2-(2,4-dichlorophenyl)-ethan-2-one, l-bromo-1(4-iodo-2-methylphenoxy)-2-(2,4-dichlorophenyl)-ethan-2-one, 1-bromo-1-(2,3-dimethylphenoxy)-2-(2,4-dichlo~o-phenyl)-ethan-2-one, 1-bromo-1-(4-biphenylyloxy)-2-(2,4-dichl-orophenyl)-ethan-2-one, 1-bromo-1-(4-4'-chlorobiphenylyloxy)-2-(2,4-dichlorophenyl)-ethan-2-one, 1-bromo-1-(4-2', 4'-dichlorobiphenylyloxy)-2-(2,4-dichlorophenyl)-ethan-2-one, l-bromo-1-(4-2,4'-dichlorophenylyloxy)-2-(2,4-dichlorophenyl3-ethan-2-one, 1-bromo-1-(4-4'-bromobiphenylyloxy)-2-(2,4-di-chlorophenyl)-ethan-2-one and 1-bromo-1-(4-2-chlorobipheny-lyloxy)-2-(2,4-dichlorophenyl)-ethan-2-one.
The l-bromo-2-(2,4-dichlorophenyl~-1-phenoxy-ethan-2-ones of the formula (II) to be used as starting compounds 735~i are ~ot yet ~n~n, but ~hey can be prepared by known proces-~es by reactin~ k~own phenols of the formula ~ ~ OH (III~

in which n X and n have the same meaning as de~ined above, in ~or-mula I with bromoacetophenone of the formula C~
~r ~I2 CO ~ - Cl (IV) The active hydrogen atom which still remains is then replaced by bromine in the cu~tomary manner~
Pre~erred ~alts of the compounds of the ~ormula (I~
are ~alts with ~hy~iologically acceptable acids~ The~e include, pre~erably, salts wlth the hydrogen halide acids, ~uch as, for e~ample, hydrochloric acid and hydrobromlc acid, in par~icular hydrochloric acid, phosphoric acid, nitric acid, mono~unctional and bifunctional carbo~ylic acids and hydro~y-carbQxylic acids, suc~ a~ ~or e~ample, acetic acid~ citric acid, ~orbic acld and lactic acidl and 1,5-naphthalenedisul-pho~i~ acid, Po~ible diluents ~or use in the process aocording to .
the in~ention ~or preparing the oompou~ds af ~ormula I, aro '~!
: prefer bly inert oreanic ~ol~ents. These include, pre~erably, ~
~5 ketone~, such as di~thyl ~eton~ and~ in partlcular, acetone and ii methyl ethyl ketone; nitriles, such as propionitrile and, in particular; acetonitrileD alcohol~ such as ethanol or isoprvp~nol; ether~, such as tetrahydro~urane or dioxane;
optionally substituted aromatic hydrocarbons, such as toluene and 1~3 dichloroben~ene and ben~ne; ~crmamide~, such a~ in I

~e ~

~3~7'~5~

particular, dimethyl~ormamide; and halogenated hydrocarbon~, such as methylene chloride, carbon tetrachloride or chloro-form.
The process for preparing the compounds o~ ~ormNla I
i~ carried out in the pre~ence o~ an acid-binding agent. It i9 possible to use any o~ the inorganic or organic acid-binding agents which can customarily be u~ed, such as alkali metal carbonates, for e~ample sodium carbonate, potaasium car-bonate and sodium bicarbonate7 or such as lower tertiary alkylaminss, cycloalkylamines or aralkylamines, ~or e~ampl~
triethyl~mine, N,~-dimethylcyclohe~ylamine, dicyolohexylmethy-lamine and ~ dimethylbsnzylamine, or furthermore pyridine and diazabicyclooctane. An excess of imidazole iB
I preferably used~
The reaction temperature used can be varied ~rithin a relatively wide range. In general~ the reaction i9 carried out at from about 0 to about 15QCt pre~erably at from 60 to 120C, u~ually in the presence o~ a Bolvent9 8uch ~S acetone or methyl ethyl keto~e.
In carrying out the above proce~ ~or preparing co~pou~d~
o~ ~ormula I, ~rom 1 to 2 m~l~ o~ a~ole and ~rom 1 to 2 mol~ of aoid--~indi~g agent are preferably employed per 1 mol o~ the compounds o~ the foxmula (II)~ IsolatiQn of the compounds oi ~
the formula (I)7 m2y be e~fecting b~ disti~ling o~ diluent9 2S takin~ up the residue i~ an or~anic solvent a~d washing with ~ate~ the re~ulting solution. ~he organic pha~e may then be dried over sodium sulphate and ~reed ~rom the solvent in vacuo.
~he residue may be puri~lsd by distillation or recrystalli~a- i ~io~
In the os~e where the proce~s ~or the prepsretion o~ a ~ÇLeL~_3~ - 7 !

~3~735~

compound of for~ula I includes a re~uction step, suitable dilu~nts for this .step are p~lar organic solvent~. These include, preferably9 alcohols, such as methanol, ethanol, butanol and isopropanol, and ethers, such as diethyl ether or tetrahydrofurane. In general, the reduction i9 carried out at from 0 to 30C, preferably at 0 to 20C. ~or the reaction, generally about 1 mol of a borohydride9 such a~
sodium borohydride or lithium borohydride, is employed per 1 ; mol o~ the compound o~ the ~ormula ~II). Isolation of the compounds o~ the formula (I) after reduction may be effected by taking up the residue in, for e~ample, dilute hydrochloric acid and rendering the resulting solution alkaline and then extracting with an organic solvent~ Alternatively onl~ water may be added and the resulting mixture extracted by shaking with an organic solvent~ The mixture ma~ then be further wor~ed up by conv~ntional techniquesr ~xamples which may be mentioned of particularly activ~
repre~entatives of the active compounds of formula I according to the invention, in addition to those o~ the Preparation E~amples and the ~amples in ~able 1, are ~he following:
1-(2-chlorophenoxy)-2-(2,4~diohlorophenyl)-1-(imidazol-1-yl~-ethan-2-one and -ol, 1-(2 i~opropylpheno~y)-2-(2~4-dichloro-ph~nyl)-l-(imidazol~ ethan-2-one and -ol, 1-(2~methylphen-o~y)-2~(2,4-dichlorophenyl)~ da~ol-1-yl~-ethan-2 one and ~5 -ol and 1w(2-chloro~4-methylpheno~y~-2-~2 9 4-dichloroph~nyl)-l-(imidazol-1-yl)-ethan-2-one and -ol~
The compounds of the formula (I), whi~h can be used according to the invention, and their ~alts, show antimicro-bial, in particular powerful anti~ycotic effects. The~ ~
possess a v~ry broad spectrum of antimycotic activity, ~ 8 _ ~9~

especially against d~rmatophyte~ and bla~tomyce~ as ~ell a~
biphase fungi, ~or e~ample again~t varieties o~ Candida, such as Candida albicans, Y~rieties o~ ~pidermophyton, ~uch as 1 3pidermophyton floccosum, v2~ieties of As~ergillu3, such as A~pergillus niger and A~pergillus fumigatus, varietie~ o~
Trichophyton, such as Trichophyton mentagrophyte~, varieties o~ Micro3poron, such as ~;cro~poron felineum and varieties o~
Penicillium, such as Penicillium communeO The recital of these I micro-organisms in no wa~ Lmplie~ a limitation of the germ~
I which can be combated but i9 only 0~ illustrati~e character.
~he iollowing may be mentioned as ex~mple~ o~ field~
o~ indication in human medicine: dermatomyco~es and sy~temic myco~e~ caused by Trichopyton m~ntagrophytes and other varie-tie~ of ~richsphyton, varietie~ of Micro~poron, Epidermophyto~
I flocco~ bla~tom~ces and biphase ~ungi as well a~ mould~g The ~ollowislg may be mentioned as e~cample~ o~ ~lelds of indication in ~eterinary medicine: all dermatomycoses and 8y5temiC myc08e~ especi 11~ tho3e cau~ed by the above mention-ed pathogen~.
~8 ~tated above? the in~ention al~o relates to the use in human and veterln~ry medici~e o~ the compound~ o~ the ln-~en~ion~
~he présent i~ention pro~ide~ a pharmaceutical composi-tio~ containing a~ acti~e ingredie~t a c~mpound o~ the inve~-~on ~n admixture with a ~olid or liquefied gaseous diluentg or in admixture with a liquid diluent other than a ~olvent o~ a mslecular weight le~ than 200 (pre~erably le~ than 350) except in the presence o~ a sur~ace active agent.
~he invention further provide~ a pharmaceutical compo-3~ sition containing a~ active in~redient a compound of the ~ _ g _ ~73~i~

invention in the ~orm o~ a 6terile and/or l~otonic aqueous solution.
~he invention alss provides a medicament in do~age unit form comprising a compound of the invention.
I The invention also provide~ a medicament in the ~onm ,~ . o~ tablet~ (including lozenge~ and granules), drageeo, cap-sule~ pill~, ampoules or suppo~itories comprising a compound I o~ the in~ention~
'~Medicament" as used in thi~ Specification me~
lQ I physically discrete coherent portion~ ~uitable ~or medical adm~nistra~ion. "Medicament in do~ge unit ~orm" a~ u~ed in this Specification means physically di~crete coherent unit~
~uitable ~or medical administration each containing a daily do~e or a multiple (up to four times) or ~ub-multiple (down to a ~ortieth) OI a daily do8e of the compound of the in~ention in a~sociation with a carrier ~nd/or enclosed within an enYelope. Whether the med~cament contain~ a daily dose or, ~or e~ample, a hal~ a third~ or a quarter o~ a daily dose will depend on whe~her the medic~ment i~ to be admini~tered once or~ ~or ~ample, twi¢e~ three time~ or ~our times a day re~p~cti~ely~
~hs pharmace~ti~al compo~ikio~ a~cording to the-in~en-t~on may7 ior ex~mp~e, take the fo~m of ointments7 gels, past-e~ cream~, ~pray~ (including aero301~9 lotions, ~uspen~ion~, ~olutlons and emul~ion3 of ~he active ingredient in aqueou~ or non-a~ueou~ dilue~t~ ~yrups, granul~te~ or powders.
; ~he diluent~ to be u~ed in pharmaceutical compo~ition~
(e.g. granulate~) adapted to be formed into tabl~t~, dragee~, cap ule~ and plll~ inolude the *ollowing:
(a~ r~ and a~te~ders~ e.g~ ~tarch, sugar~, mannitol, ~ - 10 ~

~3g73S~ ~ ~

and ~ilicic acid;
(b) binding agents, e.gO carbox~methyl cellulose and other cellulose d~rivatives, alginate~, gelatine and pslyvinyl pyrrolidone;
(c) moisturizing age~t~, e.g. glycerol;
(d) disintegrating agent~, e.g. agar-agar, calcium carbonate and sodium bicarbonate;
(e) agents for retarding dissolution e.g. paraffin;
I (~) resorption accelerators, e.gO quPte~ary ammonium 10 I compound~;
(g) sur~ace asti~e age~ts~ e.g, cetyl alcohol, glycerol monost~arate;
I (h) adsorptive carrier~7 e.g. ~aolin and bentonit2;
- (i) lubricants7 e.g. talc, calcium and magnesium stearate 15 1 a~d solid polyethylene ~lycols.
I The tablets~ dragees, capsule~ and pille ~ormed ~rom I the ph~rmaceutical compo6ition~ o~ the inYe~tion can have ¦ the cu~tomary coating~, e~v~lopes and protective matrice~9 Il ~hiQh may contain opaci~ier~, ~hey can ba ~o conætituted that they relea~e the actiYe ingredie~t cnly or preferably in a particular pa~t o~ the i~te~tinal tract, po6~ibly over a period o~ time N ~he coatings 7 e~elopes and protective matrlces may be maae, for e~ample, of polym~ric sub-~tances or waxe~.
?5 ~he ingredient can alæo be made up in microencapsulated form together with one or several o~ the 2bo~e mentioned diluents.
The diluent~ to be u~ed in pharmaceu~ical compositions adapted to be ~ormed into suppositorie can, ~or e~ample, be tha u~u~l water-soluble or water-in~oluble diluents, such as .
' ' . '- ' ' 1~9~35~

polyethylene glycols and ~ats (P.g. cocoa oil and high es~er~
~e.g. C14 alcohol with ~16-fatty acid3 ) or mixtures o~ these diluents ~, ~he ~harmaceutical compositions ~Jhich are ointment~, paete~, creams and gel~ can, for e~ample, contain the usual diluents, e.g. animal and vegetable ~ats9 wa~es, para~ins, 8tarch, tragacanth, cellulo3e derlvatives9 polyethylene glycols, silicone~, bentonite~, silicic acid, talc and zinc I o~ide or mlxtures of the8e au~tance9-I The pharmaceutical compo~ition~ which are powder~ and spray6 can, ~or e~ple, contain the usual diluent3, e.g.
lactose, talc, silicic acid, aluminium hydro~ide, calcium silicate, and polyamide powder or mixtures o~ these substance~. Aero~ol ~pray~ can, for example, contain the usual propellant~ e.~. chloro~luorohydrocarbonsO
¦ The pharmaceutical compo~itlon~ which are solutions I ana emul~lon~ can, ~or e~ample, contain the customary dil-ue~t8 (wi~h, o~ ~our~e9 the abo~e mentioned e~clu~ion o~
sol~ent~ haYir~g a molecular ~eight below 200 e~cept in the 20 I prese~ce o~ a ~ur~ace~acti~e agent)9 ~uch as ~olvent~, di85~1-ving agents and emul~ flerR, ~peci~io ex~mple~ o~ such diluent~ are water~ eth~l alcohol, i~opropyl alcohol, ethyl car~onate~ ethyl acetate~ benzyl alcohol, benzyl benzoate~
propylene glycol, 1,3~butylene glycol, dimethyl~orm~mide, oil~
~or example ~round nut oilJ, glycerol, tetrahydro~ur~uryl alc~hol, polyethylene ~lycol8 and fa~ty acid ester8 of ~orbit-ol or mi~ture~ thereo~.
For parenteral administration, solution~ and emulsion~
should be aterile, and, i~ appropriate 9 blood-i30tonic.
~0 The pha~maoeutical compo~i~ion~ which are su~pen8ions 35~

can contain the u~ual diluents, such as liquid diluent~, I e.g. water, ethyl alcohol, propylene glycol, sur~ace-acti~e I agents (e.g. ethoxylated i~ostearyl alcohol~, polyoxyethy-lene sorbite and sorbitane e~ters), microcry~talline cellu-~ lose, alllm~nium metahydro~ide, bentonite, agar-agar and tragacanth or mixtures thereo~.
All the pharmaceutical compo~ition~ according to the invention can al~o contain oolouring a~ents and preserva-ti~es a~ ~ell a~ perfumes and ~lavouring additions (2,g.
peppermint oil and eucalyptus oil) ~nd sweetening agents (e.g~ ~accharin)u ~he pharmaceutical compo~itions according to the invention generally contai~ ~rom 0.1 to 9995~ uaually ~rom 095 to 95% o~ the acti~e ingredient by weight o~ the total I compo~itio~
In addition to a compound o~ the inve~tion, ~he pharmaceutioal.co~po~ition6 and medieaments according to th~
invention ~n al~o contain other pharmaoeuticall~ acti~e ~ compounds~ They may al~o co~tain a plurality o~ compound~ .
I D~ the i~ve~tionO
dilue~ in the medic ments 9~ the present in~e~tion ma~ be any o~ tho~e me~tioned above in relation to the pharma-ceutical compositione o~ the pre~ent in~ention. Such medica-I ment~ may ~ncluae ~olYents of molecular ~sight le~s than 200 1 as ~ole diluent~
. The discrete coherent portionæ con~tituting the medica-ment acco~ding to the invention will generally be adapted, by virtue of their ~hape or packaging, for medical admini3tra-tion and may be7 ~or e~ample, any o~ ~he followin~: tablets, (including lo~enge~ and granulate~, pill~, dragee~, capsules, ~ L3~ - 13 -~7~5~

suppositorie~ and a~poulesO Some of the~e ~orm8 may be mad~
up for delayed relea~e of the active ingredient. 50me, ~uch as capsules, include a protective envelope which renders the portion~ o~i~he medicament physically discrete and coherent.
5 , ~he preferred daily do~e for admini~tration o~ the medicament~ o~ the invention i~ ~rom 0.5 to 15g. pre~erably from 2.5 to lOg. o~ active ingredient.
The production of the above mentioned pharmaceutical ~ compo~ition~ and medicaments is carried out by any method 10 I known in the ar~, for example, by mi~ing the active ingred ient(s) with the diluent(s) to ~orm a pharmaceutical compo-! sitlon (~.g~ a granulate) and then ~ormlng the composition.
~ into the mediGament (e.g. tablets)~
j This invention further provide~ a method o~ combating ~i~cluding pre~ention, relie~ and cure of) the above mentioned di~ea~es in hu~an and non-human animals, which comprise~ admi~i~terin~ to the animal~ a csmpound of the in~ention alon~ or ln a~m~3ture with a diluent or in the j ~orm of a medicament according to the inventio~.
20 1 ~t is en~i~aged that *he~e active compo~ds will be I administered perorally~ parsnterally (~or e~ample int~a-~u~cularly, i~traperitoneal~y.or intra~enously), rectally or loc~lly, preferably parenterally e~pecially intravenously~
, Pre~erred pharmaceu~ical compoeitions and medicaments are there~ore tho~e adapted ~or intra~enou~ admini~tration, such aB sterile and blood-i~otonic solution~ and emulsions and ampoules containing them. Adminl~tration in the method o~ the i~vention i~ preferably intraYenou~ly~
. In general it ha3 p~oved advantageou~ to admini~ter Pmounts o~ ~rom lO mg to 300mg/kg o~ body weight most ~ L~ 14 -~'''.~f~'73ff~'~f preferably from 50 to 200mg/kg of body weifght per dav to æc~ieve effec~Jive re~fults. Neverthfele~cf, it can at time~ be necessa~ to deviatfef from those dosage ratee, and in particular to do so aæ a function of the nature ~nd body weight oi the human or animal fsubject to be treated, the individual reaction of this subjeot to the treatment, the type o~ ~ormulation in which the active ingredient iB
administered and the mode in which the administration is carr-ied out, and the point in the progress o~ the disease or 1 interral at which it is to be administered. Thus it may ~n some case ~fuffice to use less than the above mentioned minlmum dosage rate, whil~3t other cases the upper limit mefn-tioned must be fe~cfefeded to achieve the de~ired rf~sultsff, I Where larger amounts are afdministered it can be ad~isable to I divide thfese into 6everal individfflal aff~minif~ftrations over the course o~ the day.

Il _~
De~criptiof~ oi the e cperimf~nt:
I Th~ in ~itro te~ts Nerfe carri0d out in a ~eries dilution t28t with ge~m inooula o~ ~ a~erage of 5 x 104 germs~ml of cfubstratfefO 'I'he nutrient medium was (a) ~affr dermatophytes and mould~: ~absuraud'~ milieu d'épreuve ~nd (b) Yor yea~ts: meat extract~gluco~e broth9 Thfef incu~fation temper~ure was 28~ and thfe durat~on ; of incubation was 24 to 96 hours~
I '~'he resultsf of the te~ts of the activity o~ ~ariou~
compound~ of the in~ention against diverse micro-organisms are given in the following '~'able A.
~0 !

~a~Q - 15 _ ~7;~6 4l ~ td El ~I h ~ O ~
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_ 17 ~L~3~7~5~ s , : Antimxcotic in Yivo activit.~_~oral3 in candidosi8 o~ mice Description o~ the experiment:
Mice of the type SPF-CF1 were infected intra~enously 5 I with 1-2 x 106 logarithmically growing Candida cell~, which were suspended in physiolo~ical ~odium ch~oride ~olution.
I The an~mals were treated orally one hour before and seven ¦ hourc after the in~ection with, in each ca~e, 100 mg/kg o~
bod~ weight of the fo2mulatio~O
19 1 Untreated an~mal~ died ~rom the in~ection 3 to 6 day~
I a~ter infection~ The ~urvi~al rate on the 6th da~ a~er infection ~as about 5~ in the ca~e of untreated control a~lima18 .

~5 1 ~+ o ~ery good action = ~ 90~o of survi~ors on th~ 6th day a~ter in~ection t- = good actio~ -~80~o of ~urvivors on the 6th d~y aiter in~ection ~+~ = action -- ~ 60~ o~ ~urYivor~ on the 6th day after infeotiQn = poor a~tion = ~ 4~% of eur~i~ors on the 6th day a~ter in~ection + - trace o~ action I n.a~ = no actio~

Tab ~ v h c t i v e c o m p o u n d A c t i o n ~ ~ -0-l -C0-C(CH3)3 nOaO

(known) ~

~ ~ ~ -CH-cH-c(cH3)3 n~a9 (known) ~ ~
;

(Compounds ~rom Example No~) 1.5 2 +~+

B~
C~;~
~0 Cl- ~ - 0 - ~ - C0 - ~ - Cl HCl I~L
10~ g (0026 mol) o~ 1-bromo-1-(4-chloropheno~y~-2-(2,4-dichlorophenyl)-ethan-2~-o~e are added dropwise~ at the boil, to 65g (1 mol) of imidazole in 650 ml o~ acetonitrile.
q'he ~ixtuxe is heated under reflu~ for 40 hours. Thereafter, the solvent is distilled off in vaouo~ the residue is taken up in 500 ml of methylene ohloride and the methylene chloride solution i~ extracted by ~haking ~our times with 250 ml o~
~0 water each time. The organi¢ phase is dri~d over sodium 1~3~ 7 ~ ~ ~

sulphate and concentrated by di~tilling off the ~olYent in vacuo. The residue is taken up in 1,000 ml o~ acetone, and 47 g ~0.26 mol) o~ 1,5-naphthalenediaulphonic acid in 100 ml of acetone are added. ~he precipitate which form8 i~ filtered off and boiled up with lCO ml of acetone. 2~0 ml of sodium bicarbonate solution and 500 ml of methylene chlorid~ are added to the residue~ The organic phase is separated o~
I wa~hed ~ith 200 ml of water and concentrated by di3tilling o~f I the ~olvent in vacuo. ~he re~idue i9 taken up in 200 ml o~
~ther and dry hydrogen chloride i~ added in exce3~ ter di~tillin~ o~ the ether in vacuo, the oily residue is recry-st~llised from acetone. This giV~9 31.6 g (~9% o~ theory~
oi 1-(4-chlorophe~o~ 2-(274-dichlorophenyl)-l-imidazol-l-I yl-ethan-2~one hydrochloride of melting point 146 - 148C.
C~

Cl ~ ~ Cl f~ OH

45~5 g (0~108 mol) o~ 1-(4-chloropheno~y)-2-(2~4-di chlorophenyl~-1 imidazol-1~yl-ethan-2-o~e hydrochloride (E~ample 1) are dissolved i~ 100 ml o~ methanol and 4.32 g ~O.lOB mol) o~ ~odium hydro~ide are added~ 4.5 g (0.12 mol) oi ~odium borohydride are added in portion3 at O to 5C ~nd ~5 ; the mi~ture iæ stirred ~sr 15 hours at room ~emperature.
~0 ml o~ aoncentrated h~drochloric acid are then added drop-wi~e at 0C9 and the mi~ture i~ again ~tirred ~or 15 hours at room temperatureO ~he reaction mixture is then stirred into ~DO ml o~ saturated ~odium bicarbonate solution and 3~ extracted by shaking with 500 ml of methylene chloride. The , .
~ 20 -~3~735~

organic pha~e is dried over sodium sulphate and concentrated by distilling o~ the 901vent in vacuo. The residue i~ recry-stallised ~rom ether. ~his gives 30 g (72,5% of theory) of l-(4~chlorophenoxy)-2-(2,~-d~chlorophenyl)-l-imida~ol-1-yl-ethan-2-ol as an lsomer mixture oi melting point 108 -110~.
The follo~ing compounds in Table 1 are obtained by method~ analOgOU8 to tho~e the ~xamples given above.

~L~_a~ 21 -3~i }~xaDlple Xn A Melting point (a) 3 2,4-al2 C0 205-215(x HCl)

4 4-~-C1 C0 145 148(x HCl) ~-~ C0 160-162(:c HCl~
~ 4-~ C0 160(x HCl) 7 C0 162-16~C~ ) 8 2,S-~1 C~) 180(x ~ICl) 9 3-Cl C0 168-171(x ECl~
4 t~I~ Cû ~10(x ~ICl) 11 4-C192~El3 C0 177~178(~: HCl) 12 294-al ~I(O~I) 208~`218 (i~omer mi~cture) (:c HCl) 13 4_~ aH(~I) 158-17t)(isomer(ml t 3e) 14 .. C~(0~) 156~159(isomer rn;~ are) 3~Cl CEI(~g) 165-i67(isome~ ture]
(æ HCl~

Claims (18)

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

1. A process for the preparation of a 2,4-dichlorophenyl-imidazolyl-ethanone or -ol of the general formula (I) in which A is a keto group or a CH(OH) group, X is halogen, straight-chain or branched alkyl with 1 to 4 carbon atoms or phenyl optionally substituted by halogen, and n is an integer from 0 to 3, or a pharmaceutically acceptable salt thereof, which comprises reacting a 1-bromo-2-(2,4-dichlorophenyl)-1-phenoxy-ethan-2-one of the general formula (II) in which X and n have the same meaning as defined above, with imidazole in the presence of a diluent and an acid-binding agent, and where required reducing the resulting imidazolyl-ethanone compound with a complex borohydride so as to produce the corresponding imidazolyl-ethanol compound, and where re-quired converting the imidazolyl-ethanone or -ethanol compound of formula I
or a salt thereof into a pharmaceutically acceptable salt thereof or the corresponding free imidazolyl-ethanone or -ethanol compound, respectively.

2. A process according to claim 1 in which the reaction is carried out at from 0 to 150°C.

3. A process according to claim 2 wherein when reduction is carried out, it is effected at a temperature of from 0 to 30°C.

4. Compounds of formula (I) according to claim 1 and their pharma-ceutically acceptable salts, whenever prepared by a process according to claim 1, 2 or 3 or by an obvious chemical equivalent thereof.

5. A process according to claim 1 in which in the starting material of formula (II) X is fluorine, chlorine, bromine, iodine, straight-chain or branched alkyl having 1 to 4 carbon atoms or phenyl optionally substituted by chlorine, and n is 0, 1 or 2.

6. Compounds of formula (I) given in claim 1 wherein A is a keto group or a CH(OH) group and X and n are as defined in claim 5, and their pharmaceutically acceptable salts, whenever prepared by a process according to claim 5 or by an obvious chemical equivalent thereof.

7. A process according to claim 1 in which Xn represents 4-chloro, 2,4-dichloro or 4-phenyl and where the initial reaction can be followed by the additional step of reduction of an imidazol ethanone compound so obtained, and where a base can be isolated as such or converted to the corresponding hydrochloride.

8. A compound of the formula:

(Ia) or a hydrochloride thereof, in which A is a keto or a -CH(OH)- group, and R is a 4-chlorophenyl, 2,4-dichlorophenyl or 4-phenyl whenever prepared by the process of claim 7 or by an obvious chemical equivalent thereof.

9. A process according to claim 1 in which 1-(4-chlorophenoxy)-2-(2,4-dichlorophenyl)-1-imidazol-1-yl-ethan-2-one hydrochloride is prepared by reacting1-bromo-1-(4-chlorophenoxy)-2-(2,4-dichlorophenyl)-ethan-2-one with imidazole and reacting the base so obtained with hydrogen chloride.

10. 1-(4-chlorophenoxy)-2-(2,4-dichlorophenyl)-1-imidazol-1-yl-ethan 2-one hydrochloride whencver prepared by the process of claim 9 or by an obvious chemical equivalent thereof.

11. A process according to claim 1 in which 1-(4-chlorophenoxy)-2-(2,4-dichlorophenyl)-1-imidazol-1-yl-ethan-2-ol is prepared by reacting 1-bromo-1-(4-chlorophenoxy)-2-(2,4-dichlorophenyl)-ethan-2-one with imidazole and reducing the product so obtained.

12. 1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-1-imidazol-1-yl-ethan-2-ol whenever prepared by the process of claim 11 or by an obvious chemical equivalent thereof.

13. A process according to claim 1 in which 1-(2,4-dichlorophenoxy)-2-(2,4-dichlorophenyl)-1-imidazol-1-yl-ethan-2-one hydrochloride is prepared by reacting 1-bromo-1-(2,4-dichlorophenoxy)-2-(2,4-dichlorophenyl)-ethan-2-one with imidazole and reacting the base so obtained with hydrogen chloride.

14. 1-(2,4-dichlorophenoxy)-2-(2,4-dichlorophenyl)-1-imidazol-1-yl-ethan-2-one hydrochloride wilenever prepared by the process of claim 13 or by an obvious chemical equivalent thereof.

15. A process according to claim 1 in which 1-(2,4-dichlorophenoxy)-2-(2,4-dichlorophenyl)-1-imidazol-1-yl-ethan-2-ol hydrochloride is prepared by reacting 1-bromo-1-(2,4-dichlorophenoxy)-2-(2,4-dichlorophenyl)-ethan-2-one with imidazole reducing the product so obtained, and reacting the base so obtained with hydrogen chloride.

16. 1-(2,4-dichlorophenoxy)-2-(2,4-dichlorophenyl)-1-imidazol-1-yl ethan-2-ol hydrochloride whenever prepared by the process of claim 15 or by an obvious chemical equivalent thereof.

17. A process according to claim 1 in which 1-(4-phenylphenoxy)-2-(2,4-dichlorophenyl)-1-imidazol-1-yl-ethan-2-ol hydrochloride is prepared by reacting 1-bromo-1-(4-phenylphenoxy)-2-(2,4-dichlorophenyl)-ethan-2-one with imidazole, reducing the product so obtained, and reacting the base so obtained with hydrogen chloride.

18. 1-(4-phenylphenoxy)-2-(2,4-dichlorophenyl)-1-imidazol-1-yl-ethan-2-ol hydrochloride whenever prepared by the process of claim 17 or by an obvious chemical equivalent thereof.