NO140009B - ANALOGICAL PROCEDURES FOR THE PREPARATION OF ANTIMYCOTIC ACTIVITY (1-IMIDAZOLYL- (1)) - (2- (4`- (4`-CHLORO-PHENYL) -PHENOXY) -4,4-DIMETHYL-PENTAN-3-ONE AND ITS SALT - Google Patents

ANALOGICAL PROCEDURES FOR THE PREPARATION OF ANTIMYCOTIC ACTIVITY (1-IMIDAZOLYL- (1)) - (2- (4`- (4`-CHLORO-PHENYL) -PHENOXY) -4,4-DIMETHYL-PENTAN-3-ONE AND ITS SALT Download PDF

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NO140009B
NO140009B NO75752017A NO752017A NO140009B NO 140009 B NO140009 B NO 140009B NO 75752017 A NO75752017 A NO 75752017A NO 752017 A NO752017 A NO 752017A NO 140009 B NO140009 B NO 140009B
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imidazolyl
dimethyl
phenoxy
pentan
preparation
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NO140009C (en
NO752017L (en
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Wolfgang Kraemer
Karl Heinz Buechel
Manfred Plempel
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Bayer Ag
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles

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  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
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  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
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  • Veterinary Medicine (AREA)
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Description

Oppfinnelsen vedrører fremstilling av nye /1-imidazolyl-( l) J-{ 2-(4'-(4"-klorfenyl)-fenoksy7-4/4-dimetyl-pentan-3- The invention relates to the preparation of new /1-imidazolyl-(l)J-{2-(4'-(4"-chlorophenyl)-phenoxy7-4/4-dimethyl-pentane-3-

on og dets salter som har antimykotisk virkning. on and its salts which have antifungal action.

Det er allerede kjent at noen N-tritylimidazoler har It is already known that some N-tritylimidazoles have

en antimykotisk virkning (sammenlign belgisk patent nr. 720.801). an antifungal effect (compare Belgian patent no. 720,801).

Antimykotisk virksomme imidazolyl-(1)-eter-ketoner Antimycotic active imidazolyl-(1)-ether ketones

er likeledes allerede kjent (sammenlign DOS nr. 2.105.49 0 og belgisk patent nr. 804.092). Disse viser imidlertid fremfor' is likewise already known (compare DOS No. 2,105,490 and Belgian Patent No. 804,092). However, these show rather than'

alt meget lave doser etter oral inngivning ikke alltid en til-fredsstillende virkning. Dessuten er deres virkningsspektrum ofte ikke meget bredt. all very low doses after oral administration not always a satisfactory effect. Moreover, their spectrum of action is often not very broad.

Det er funnet at den nye imidazolyl-(1)-eter-keton It has been found that the new imidazolyl-(1)-ether ketone

med formel I with formula I

samt dets salter har sterke antimykotiske virkninger. as well as its salts have strong antifungal effects.

Videre ble det funnet at man får imidazolyl(1)-eter-keton med formel I når man omsetter forbindelsen med formel II med imidazol i nærvær av vanntiltrekkende midler og fra den dannede base etter vanlige metoder fremstiller et salt. Furthermore, it was found that imidazolyl(1)-ether-ketone of formula I is obtained when the compound of formula II is reacted with imidazole in the presence of water-attracting agents and a salt is prepared from the base formed by usual methods.

Overraskende viser imidazolyl(1)-eter-ketonet fremstilt ifølge oppfinnelsen og dets salter en betraktelig høyere antimykotisk virkning, fremfor alt ved oral inngivning, men også ved parenteral og lokal applikasjon, enn de fra teknikkens stand kjente imidazolderivater og også enn de kjente handels-produkter som f.eks. Griseofulvin, Tolnaftan og Nystatin. Stoffene ifølge oppfinnelsen er således en berikning av farmasien. Surprisingly, the imidazolyl(1)-ether-ketone produced according to the invention and its salts show a considerably higher antifungal effect, above all by oral administration, but also by parenteral and local application, than the imidazole derivatives known from the state of the art and also than the known commercial products such as Griseofulvin, Tolnaftan and Nystatin. The substances according to the invention are thus an enrichment of the pharmacy.

Anvender man _/—l-hydroksy7 l~ 2-( k ' , (4"-klor-fenyl)-fenoksy_/-4,4-dimetyl-pentan-2-on og imidazol som utgangsstoffer, så kan reaksjonsforløpet gjengis med følgende formelskjema: If _/—1-hydroxy7 l~ 2-( k ' , (4"-chloro-phenyl)-phenoxy_/-4,4-dimethyl-pentan-2-one and imidazole are used as starting substances, the course of the reaction can be reproduced by the following formula form:

Som salter av imidazolyl (l')-eter-ketonet med formel I skal det fortrinnsvis nevnes slike med fysiologisk tålbare syrer. Eksempler på slike syrer er halogenhydrogen-syrene, spesielt klorhydrogensyre, fosforsyre, salpetersyre, mono- og bifunksjonelle karboksylsyrer og hydroksykarboksy1-syrer, som f.eks. eddiksyre, maleinsyre, ravsyre, fumarsyre, vinsyre, sitronsyre, salicylsyre, sorbinsyre, melkesyre, 1,5-naftalindisulfonsyre. Salts of the imidazolyl (1')-ether ketone of formula I are preferably those with physiologically tolerable acids. Examples of such acids are the halohydrogen acids, especially hydrochloric acid, phosphoric acid, nitric acid, mono- and bifunctional carboxylic acids and hydroxycarboxylic acids, such as e.g. acetic acid, maleic acid, succinic acid, fumaric acid, tartaric acid, citric acid, salicylic acid, sorbic acid, lactic acid, 1,5-naphthalenedisulfonic acid.

Hydroksyderivatet med formel II som skal anvendes som utgangsstoff er ikke kjent, kan imidlertid fremstilles etter kjente fremgangsmåter. Det fåes eksempelvis når de fra forbindelsene III og IV The hydroxy derivative of formula II which is to be used as starting material is not known, but can be prepared according to known methods. It is obtained, for example, when those from compounds III and IV

hvori in which

Hal betyr halogen, Hal means halogen,

kondenserte eterketon med formel V condensed ether ketone of formula V

etter vanlige metoder omsettes i nærvær av alkali, f.eks. vandig natronlut, med formaldehyd eller formaldehydavgivende midler, f.eks. en H0%- ig vandig formaldehydoppløsning, i et inert, organisk oppløsningsmiddel, f.eks. etanol, ved forhøyet temperatur, f.eks. reaksjonsblandingens koketempe-ratur. by usual methods is reacted in the presence of alkali, e.g. aqueous caustic soda, with formaldehyde or formaldehyde-releasing agents, e.g. a H0% aqueous formaldehyde solution, in an inert, organic solvent, e.g. ethanol, at elevated temperature, e.g. the boiling temperature of the reaction mixture.

Som fortynningsmiddel kommer det på tale alle inerte, høyerekokende, med vann ikke blandbare organiske oppløsningsmidler. Hertil hører fortrinnsvis fra ca. 50°C kokende alifatiske og aromatiske hydrokarboner som ligroin, benzen eller toluen. Diluents include all inert, higher-boiling, water-immiscible organic solvents. This preferably includes from approx. 50°C boiling aliphatic and aromatic hydrocarbons such as naphtha, benzene or toluene.

Omsetningen foretas fortrinnsvis i nærvær av et vanntiltrekkende middel, som brent kalsiumkarbonat eller tørr natriumsulfat eller ved hjelp av en vannutskiller. The reaction is preferably carried out in the presence of a water-attracting agent, such as burnt calcium carbonate or dry sodium sulphate or with the aid of a water separator.

Reaksjonstemperaturen kan varieres innen et stort område. Vanligvis arbeider man mellom ca. 50°C til ca. 180°C, fortrinnsvis ved 80°C til 140°C. The reaction temperature can be varied within a large range. Usually you work between approx. 50°C to approx. 180°C, preferably at 80°C to 140°C.

Ved gjennomføring av fremgangsmåten ifølge oppfinnelsen anvender man 1 mol av forbindelsen med formel II, fortrinnsvis 1 til 5, spesielt 1 til 1,5 mol imidazol og eventuelt 0,5 til 20, spesielt 1 .til 5 mol av det vanntiltrekkende middel. When carrying out the method according to the invention, 1 mol of the compound of formula II is used, preferably 1 to 5, especially 1 to 1.5 mol of imidazole and optionally 0.5 to 20, especially 1 to 5 mol of the water-attracting agent.

Isoleringen av forbindelsen med formel I foretas etter generelt kjente, vanlige metoder. Eksempelvis kan oppløsningsmidlet avdestilleres i vakuum og residuet opptas med metylenklorid. Den organiske fase adskilles deretter. Etter tørkning over natriumsulfat avdestilleres oppløsnings-midlet i vakuum. Det dannede residu renses ved omkrystallisering. Hvis rensing ved omkrystallisering ikke er tilstrekkelig, kan etter første avdestillering av oppløsningsmidlet saltet fremstilles og dette renses ved omkrystallisering. Fra saltet kan det på kjent måte ved hjelp av en base frigjøres forbindelse med formel I i form av basen. The isolation of the compound of formula I is carried out according to generally known, common methods. For example, the solvent can be distilled off in a vacuum and the residue taken up with methylene chloride. The organic phase is then separated. After drying over sodium sulphate, the solvent is distilled off in a vacuum. The residue formed is purified by recrystallization. If purification by recrystallization is not sufficient, after first distilling off the solvent, the salt can be prepared and this purified by recrystallization. A compound of formula I can be released from the salt in a known manner with the aid of a base in the form of the base.

Den nye forbindelse med formel I samt dens salter har meget sterke antimykotiske virkninger. De viser et bredt virkningsspektrum, eksempelvis overfor dermatofyter og gjær som også overfor blfasisk sopp og myggsopp samt overfor stafylokokker og trikomonader. De kan derfor med godt resultat anvendes mot sopp-infeksjon hos dyr og mennesker. The new compound of formula I as well as its salts have very strong antifungal effects. They show a broad spectrum of action, for example against dermatophytes and yeasts, as well as against blphasic fungi and mosquito fungi as well as against staphylococci and trichomonads. They can therefore be used with good results against fungal infection in animals and humans.

Som indikasjonsområde i humanmedisinen kan det eksempelvis nevnes: Dermatomykoser og systemmykoser ved Trichophyton mentagrophytes og andre trikofytonarter, mikrosporon-arter, Epidermophyton floccosum, sporesopp og bifasisk sopp samt muggsopp. As an indication area in human medicine, for example, dermatomycoses and systemic mycoses with Trichophyton mentagrophytes and other trichophyton species, microsporon species, Epidermophyton floccosum, spore fungi and biphasic fungi as well as molds can be mentioned.

Som indikasjonsområde i dyremedisinen kan det eksempelvis anføres: Alle dermatomykoser og systemmykoser, spesielt slike som frembringes ved ovennevnte frembringere. As an indication area in veterinary medicine, the following can be mentioned, for example: All dermatomycoses and systemic mycoses, especially those produced by the above-mentioned producers.

Den vir<kso>mme forbindelse eiler de farmasøytiske tilbered-ninger kan appliseres lokalt, oralt, parenteralt, intrapertone-alt og/eller rektalt, fortrinnsvis oralt eller lokalt. The active compound or the pharmaceutical preparations can be applied locally, orally, parenterally, intravenously and/or rectally, preferably orally or locally.

Vanligvis har det vist seg fordelaktig såvel i human-som også i veterinærmedisinen å administrere det eller de virksomme stoffer i mengder fra ca. 10 til 300, fortrinnsvis 50 til 200 mg/kg legemsvekt pr. 24 timer, fortrinnsvis i form av flere enkeltinngivninger for oppnåelse av de ønskede resultater. Det kan imidlertid være nødvendig å avvike fra de nevnte doseringer, nemlig i avhengighet av type og tyngde av sykdom, type av tilbe-redning og applikasjon av legemidlet samt tidsrom resp. intervall, innen hvilke administrering foregår. Således kan det i noen tilfeller være tilstrekkelig å komme ut med mindre enn ovennevnte mengde virksomt stoff, mens i andre tilfeller overskrides den ovenfor anførte virksomme stoffmengde. Fastleggelsen av den hver gang nødvendige optimale dosering og applikasjonstype av det virksomme stoff kan lett foregå av enhver fagmann på grunn av hans fagkunnskap. Generally, it has proven beneficial both in human and veterinary medicine to administer the active substance(s) in amounts from approx. 10 to 300, preferably 50 to 200 mg/kg body weight per 24 hours, preferably in the form of several individual submissions to achieve the desired results. However, it may be necessary to deviate from the dosages mentioned, namely depending on the type and severity of the disease, the type of preparation and application of the medicine as well as the time period or interval, within which administration takes place. Thus, in some cases it may be sufficient to come out with less than the above-mentioned amount of active substance, while in other cases the above-mentioned amount of active substance is exceeded. The determination of the optimal dosage and type of application of the active substance required in each case can easily be carried out by any expert due to his professional knowledge.

Den gode mikrobiologiske virkning av de ifølge oppfinnelsen fremstilte, anvendbare virksomme forbindelser kan demonstreres ved følgende in vitro- og in vivo-forsøk. The good microbiological effect of the usable active compounds produced according to the invention can be demonstrated by the following in vitro and in vivo tests.

Etter disse angivelser kan forbindelsen fremstilt ifølge oppfinnelsen betegnes som godt tålbare og meget god antimykotisk virkning med bredt virkningsspektrum såvel for den orale som også for den parenterale og lokale applikasjon. Sammenlignet med teknikkens stand viser de seg som overlegne over Clotrimazol, Miconazol og alle andre azolderivater ved deres virkning ved meget lave doser etter oral inngivning overfor Griseofulvin, Tolnaftat, Nystatin og Pimaricin ved deres meget bredere virkningsspektrum og overfor Amphotericin B ved deres vesentlige mindre toksisitet. According to these indications, the compound produced according to the invention can be described as well tolerated and very good antifungal action with a broad spectrum of action both for the oral as well as for the parenteral and local application. Compared to the state of the art, they prove to be superior to Clotrimazole, Miconazole and all other azole derivatives by their effect at very low doses after oral administration to Griseofulvin, Tolnaftate, Nystatin and Pimaricin by their much broader spectrum of action and to Amphotericin B by their substantially lower toxicity.

1) In vitro-virkning: 1) In vitro effect:

Forbindelser fremstilt ifølge oppfinnelsen viser in vitro en bred virkning overfor human- og dyrepatogen sopp, gram-positive bakterier og trikomonader. I følgende tabell er det oppstilt MHK-verdien av forbindelsen overfor representative sopp-typer, Staph, aureus og Trichomonas vaginalis: Virkningsundersøkelsene ble gjennomført i rekke-fortynningsprøve på Sabouraud's Milieu d'épreuve, kjøttvann-druesukker-buljong, blodagar og ifølge Francis og maltekstrakt-peptonmedium ifølge Kimmig. Dyrkningstemperaturene var 28 og 37°C, dyrkningsvarighet 2H- U8- 96 timer. Inokulum utgjorde en-hetlig 5 x 10^ kimer/ml substrat. Compounds produced according to the invention show in vitro a broad effect against human and animal pathogenic fungi, gram-positive bacteria and trichomonads. The following table lists the MHK value of the compound against representative fungal types, Staph, aureus and Trichomonas vaginalis: The effectiveness studies were carried out in a serial dilution test on Sabouraud's Milieu d'épreuve, broth-grape sugar-broth, blood agar and according to Francis and malt extract -peptone medium according to Kimmig. The cultivation temperatures were 28 and 37°C, cultivation duration 2H- U8- 96 hours. The inoculum consisted of a single 5 x 10^ germ/ml substrate.

Forsøksresultatene er sammenfattet i Tabell A og sammenlignet med to handelspreparater. The trial results are summarized in Table A and compared with two commercial preparations.

Virkningen av noen allerede kjente imidazolyl(1)-eterderivater viser tabell B. Table B shows the effect of some already known imidazolyl(1) ether derivatives.

Ifølge disse resultater virker forbindelsen fremstilte ifølge oppfinnelsen såvel overfor dermatofyter og gjær som også overfor bifasisk sopp og muggsopp samt overfor stafylokokker og trikomonader. According to these results, the compound produced according to the invention works both against dermatophytes and yeasts as well as against biphasic fungi and molds as well as against staphylococci and trichomonads.

Den antimykotiske virkningstype er primært fungi-statisk. Fungisider med en redusering av inokulum mer enn 99% er oppnåelig in vitro og in vivo med 2-4 ganger mini-mal hemmekonsentrasjoner. The antifungal mode of action is primarily fungistatic. Fungicides with a reduction of inoculum more than 99% are achievable in vitro and in vivo with 2-4 times the minimum inhibitory concentrations.

I passasjefremgangsmåter og i Szibalsky-teknikken kunne det ikke finnes noen resistensutvikling av primært følsomme kimer. Dermed er det tillatt en konklusjon at resistensutvikling - hvis overhodet - inntrer langsomt og etter multippeltrinn-skjema. In passage procedures and in the Szibalsky technique, no resistance development of primarily susceptible germs could be found. Thus, it is permissible to conclude that resistance development - if at all - occurs slowly and according to a multiple-step scheme.

2) In vivo-virkning. 2) In vivo action.

Forbindelsene fremstilt ifølge oppfinnelsen er også kurativt virksomme in vivo på infiserte forsøksdyr såvel ved oral som også ved parenteral og lokal applikasjon ved dermato-fytoser og systemmykoser. The compounds produced according to the invention are also curatively effective in vivo on infected laboratory animals both by oral as well as by parenteral and local application in dermatophytoses and systemic mycoses.

a) Virkning ved oral applikasjon. a) Effect by oral application.

I) På modell av eksperimentell candidose hos mus. I) On model of experimental candidosis in mice.

g Hvite mus av stammen CF--, LSPE infiseres med 1-3 g White mice of the strain CF--, LSPE are infected with 1-3

x 10 Candida albicans-celler intravenøst ved punksjon av nålevenen. Ubehandlede kontrolldyr dør av den organcandidose som utvikler seg fra 3. - 6. dag p.i. Gir man preparatene ifølge oppfinnelsen i doser på 2 x 6,25 - 2 x 150 mg/kg legemsvekt oralt, begynnende med infeksjonsdagen til 5- dag etter infeksjonen, så fremkommer følgende overlevningsgrader (tabell C): x 10 Candida albicans cells intravenously by needle vein puncture. Untreated control animals die from the organ candidiasis that develops from the 3rd - 6th day p.i. If the preparations according to the invention are given in doses of 2 x 6.25 - 2 x 150 mg/kg body weight orally, starting with the day of infection until 5 days after the infection, the following survival rates appear (table C):

De allerede kjente imidazolyl(l)-eter-derivater i tabell B viser ved en dose på 50 mg/kg legemsvekt til 125 mg/kg legemsvekt to ganger daglig overlevningsgrader på ca. 75% til 85% ved 6. dag etter infeksjon. The already known imidazolyl (l)-ether derivatives in table B show, at a dose of 50 mg/kg body weight to 125 mg/kg body weight twice a day, survival rates of approx. 75% to 85% by the 6th day after infection.

II) På modell av eksperimentell mus- og marsvin-trikofyti ved Trich. mentagrophytes og Trich. Quinckeanum: Mus (CP-j^SPP) og marsvin (Pearl-bright-white) infiseres på ryggen med sporesuspensjoner av Trich. ment. eller Trich. Quinckeanum. Ved de ubehandlede kontrolldyr utvikler det seg i løpet av 12 dager p.i. frembringertypiske sykdomsbilder av en dermatofytose. II) On model of experimental mouse and guinea pig trichophyta at Trich. mentagrophytes and Trich. Quinckeanum: Mice (CP-j^SPP) and guinea pigs (Pearl-bright-white) are infected on the back with spore suspensions of Trich. intended. or Trich. Quinckeanum. In the untreated control animals, it develops within 12 days p.i. produces typical disease pictures of a dermatophytosis.

Med orale doser på 1 x 25 til 1 x 100 mg/kg legemsvekt appliseres fra 3. - 12. dag p.i. undertrykker preparatene ifølge oppfinnelsen utviklingen fullstendig av den eksperimentelle dermatofytose. With oral doses of 1 x 25 to 1 x 100 mg/kg body weight applied from the 3rd - 12th day p.i. the preparations according to the invention completely suppress the development of the experimental dermatophytosis.

De allerede kjente imidazolyl(l)-eter-derivater ifølge B viser ikke denne totale virkning. b) Virkning ved lokal applikasjon på modell av eksperimentell marsvin-trikofyti. The already known imidazolyl(1)-ether derivatives according to B do not show this overall effect. b) Effect of local application on model of experimental guinea pig trichophyta.

Hvite marsvin av 400 - 500 g vekt infiseres på ryggen med en sporesuspensjon av Trich. ment. i den vanlige form. Til lokal terapi påføres preparatene ifølge oppfinnelsen - 1%- ig oppløst i polyetylenglykol 400 fra 4. - 13. dag p.i. en gang daglig tynt på infeksjonsstedet og ut-drives lett med en hornspatel. I følgende tabell er det vist den kurative effekt av preparatene sammenlignet til ubehandlede kontroller (tabell D): White guinea pigs weighing 400 - 500 g are infected on the back with a spore suspension of Trich. intended. in the usual form. For local therapy, the preparations according to the invention are applied - 1% dissolved in polyethylene glycol 400 from the 4th - 13th day p.i. once daily thinly on the site of infection and easily expelled with a horn spatula. The following table shows the curative effect of the preparations compared to untreated controls (table D):

c) Orienterende angivelser til farmakokinetikk etter oral inngivning. Forbindelsene ifølge oppfinnelsen resorberes godt etter oral inngivning hos mus og marsvin og gir etter doser på 50 mg/kg legemsvekt serumtoppkonsentrasjoner på c) Indicative indications for pharmacokinetics after oral administration. The compounds according to the invention are well absorbed after oral administration in mice and guinea pigs and after doses of 50 mg/kg body weight give peak serum concentrations of

Eliminasjonshalveringstiden utgjør ca. 4,5 - The elimination half-life is approx. 4.5 -

5,5 timer, eliminasjonen foregår til ca. 20% renalt og til ca. 70% fekalt via galle.. 5.5 hours, the elimination takes place until approx. 20% renally and to approx. 70% fecal via bile..

d) Akutt toksisitet og tålbarhet. d) Acute toxicity and tolerability.

Den nevnte forbindelse viste hos mus, rotte og The said compound showed in mouse, rat and

marsvin etter oral applikasjon en LD^q mellom 750 og 1200 mg/ kg KG. Hudtålbarheten ved lokal applikasjon lSS-ig oppløs-ninger var utmerket. guinea pigs after oral application an LD^q between 750 and 1200 mg/kg KG. Skin tolerability with local application of ISS-ig solutions was excellent.

Fremstillingseksempler. Manufacturing examples.

Eksempel 1. Example 1.

30,3 g (0,1 mol) _ ll-(4 •-(4"-klorfenyl)-fenoksy/- 3,3-dimetyl-butan-2-on suspenderes i 200 ml etanol. Hertil haes 30 ml 30$-ig formalinoppløsning og 3 ml 10i?-ig natronlut. Etter 4 timers oppvarmning under tilbakeløp avdestilleres opp-løsningsmidlet i vakuum. Den gjenblivne olje opptas i 200 ml toluen og oppvarmes etter tilsetning av 10 g (0,15 mol) imidazol natten over under tilbakeløp. Deretter avdestilleres opp-løsningsmidlet i vakuum, residuet opptas i eter og vaskes flere ganger med vann. Den organiske fase tørkes over natrium-sulf at og blandes med 30 ml eterisk saltsyre. Etter oppløs-ningsmidlets avdestillering i vakuum tilsettes 100 ml dietyl-eter og 50 ml eddikester. Man omrører til starting av kry-stallisering. Krystallene frasuges, vaskes med en eter- 30.3 g (0.1 mol) of 11-(4•-(4"-chlorophenyl)-phenoxy/-3,3-dimethyl-butan-2-one is suspended in 200 ml of ethanol. To this is added 30 ml of 30$ -ig formalin solution and 3 ml of 10 µg caustic soda. After 4 hours of heating under reflux, the solvent is distilled off in vacuo. The remaining oil is taken up in 200 ml of toluene and heated after the addition of 10 g (0.15 mol) of imidazole overnight under reflux. The solvent is then distilled off in a vacuum, the residue is taken up in ether and washed several times with water. The organic phase is dried over sodium sulfate and mixed with 30 ml of ethereal hydrochloric acid. After the solvent has been distilled off in a vacuum, 100 ml of diethyl ether and 50 ml of acetic acid. Stir until crystallization starts. The crystals are suctioned off, washed with an ether

eddikester-blanding og tørkes. vinegar mixture and dried.

Man får 13,8 g (33% av det teoretiske) /I-imidazolyl-{ l) J-/' 2- (4 1 - (4"-klorfenyl) -fenoksy7-4 ,4-dimetyl-pentan-3-on-hydroklorid av smeltepunkt 178-180°C. One obtains 13.8 g (33% of the theoretical) /I-imidazolyl-{1)J-/' 2-(4 1 -(4"-chlorophenyl)-phenoxy7-4,4-dimethyl-pentane-3- on-hydrochloride of melting point 178-180°C.

Eksempel 2 Example 2

Den fri base ifølge eksempel 1 får man etter den der omtalte måte, idet man danner hydrokloridet med den beregnede mengde trietylamin i eddikester og frasuger det utfelte tri-etylaminhydroklorid og avdestillerer oppløsningsmidlet i vakuum. Smeltepunkt utgjør 115-116°C. The free base according to example 1 is obtained according to the method described there, forming the hydrochloride with the calculated amount of triethylamine in acetic acid and sucking off the precipitated triethylamine hydrochloride and distilling off the solvent in a vacuum. Melting point is 115-116°C.

På analog måte får man Analogously, you get

Claims (1)

Analogifremgangsmåte til fremstilling av det antimykotisk virksomme /1-imidazolyl- (l)_7-/2- (4 ' - (4 "-klorfenyl) - f enoksy_7-4 , 4-dimetyl-pentan-3-on med formelAnalogous process for the preparation of the antifungally active /1-imidazolyl-(1)_7-/2-(4'-(4"-chlorophenyl)-phenoxy_7-4,4-dimethyl-pentan-3-one with formula og dets salter /karakterisert ved at forbindelser med formel: omsettes med imidazol i nærvær av vanntiltrekkende midler og eventuelt fremstilles av de dannede baser på i og for seg kjent måte salter.and its salts / characterized in that compounds of formula: are reacted with imidazole in the presence of water-attracting agents and optionally salts are prepared from the bases formed in a manner known per se.
NO75752017A 1974-06-20 1975-06-06 ANALOGICAL PROCEDURES FOR THE PREPARATION OF ANTIMYCOTIC ACTIVITY (1-IMIDAZOLYL- (1)) - (2- (4`- (4`-CHLORO-PHENYL) -PHENOXY) -4,4-DIMETHYL-PENTAN-3-ONE AND ITS SALT NO140009C (en)

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DE2429513A DE2429513A1 (en) 1974-06-20 1974-06-20 SQUARE CLAMP ON 1-IMIDAZOLYL- (1) SQUARE BRACKET TO-SQUARE BRACKET ON 2- (4 '(4' '- CHLOROPHENYL) -PHENOXY SQUARE CLAMP FOR -4,4-DIMETHYL-PENTANE-3-ON AND ITS SALTS, A METHOD OF MANUFACTURING IT AND ITS USE AS A MEDICINAL PRODUCT

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CA1048512A (en) 1979-02-13
FR2275204A1 (en) 1976-01-16
EG11806A (en) 1977-11-30
AU8222175A (en) 1976-12-23
SE7507014L (en) 1975-12-22
AR205746A1 (en) 1976-05-31
FI751818A (en) 1975-12-21
CH617682A5 (en) 1980-06-13
JPS5817466B2 (en) 1983-04-07
NL7507326A (en) 1975-12-23
AT340410B (en) 1977-12-12
GB1456180A (en) 1976-11-17
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NO140009C (en) 1979-06-20
NO752017L (en) 1975-12-23
DK137644B (en) 1978-04-10
IL47502A0 (en) 1975-08-31
PL94003B1 (en) 1977-07-30

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