NO830655L - DIAZOLYL ALKANOLS, THE PROCEDURE FOR THEIR PREPARATION AND THEIR USE AS AN ANTIMYCOTIC AGENT - Google Patents

DIAZOLYL ALKANOLS, THE PROCEDURE FOR THEIR PREPARATION AND THEIR USE AS AN ANTIMYCOTIC AGENT

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NO830655L
NO830655L NO830655A NO830655A NO830655L NO 830655 L NO830655 L NO 830655L NO 830655 A NO830655 A NO 830655A NO 830655 A NO830655 A NO 830655A NO 830655 L NO830655 L NO 830655L
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carbon atoms
acid
formula
diazolyl
alkanols
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Norwegian (no)
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Erik Regel
Karl Heinz Buechel
Manfred Plampel
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Bayer Ag
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • 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
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
    • C07C29/36—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring increasing the number of carbon atoms by reactions with formation of hydroxy groups, which may occur via intermediates being derivatives of hydroxy, e.g. O-metal
    • C07C29/38—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring increasing the number of carbon atoms by reactions with formation of hydroxy groups, which may occur via intermediates being derivatives of hydroxy, e.g. O-metal by reaction with aldehydes or ketones
    • C07C29/42—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring increasing the number of carbon atoms by reactions with formation of hydroxy groups, which may occur via intermediates being derivatives of hydroxy, e.g. O-metal by reaction with aldehydes or ketones with compounds containing triple carbon-to-carbon bonds, e.g. with metal-alkynes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C33/00—Unsaturated compounds having hydroxy or O-metal groups bound to acyclic carbon atoms
    • C07C33/40—Halogenated unsaturated alcohols
    • C07C33/46—Halogenated unsaturated alcohols containing only six-membered aromatic rings as cyclic parts
    • C07C33/48—Halogenated unsaturated alcohols containing only six-membered aromatic rings as cyclic parts with unsaturation outside the aromatic rings
    • C07C33/483—Monocyclic
    • 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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Abstract

1. Diazolylalkanols of the general formula I see diagramm : EP0104300,P9,F1 in which R represents alkenyl and alkynyl, each having 2 to 6 carbon atoms, and represents phenylalkenyl, having 2 to 4 carbon atoms in the alkenyl part, or phenylalkynyl, having 2 to 4 carbon atoms in the alkynyl part, each optionally identically or differently substituted once to three times, the phenyl substituents which may be mentioned in each case being : halogen, alkyl having 1 to 4 carbon atoms, alkoxy and alkylthio each having 1 to 2 carbon atoms, alkoxyalkyl having 1 to 2 carbon atoms in each alkyl part and phenyl which is optinally substituted by halogen and physiologically tolerated acid addition salts thereof.

Description

Oppfinnelsen vedrører, nye diazolyl-alkanoler, en fremgangsmåte til deres fremstilling samt deres anvendelse som antimykotika. The invention relates to new diazolyl alkanols, a process for their preparation and their use as antifungals.

Det er allerede kjent at hydroksypropyl-imidazoler som eksempelvis 2-(4 .-Mfenylyl)-1-( 2 i4-diklorfenyl)-3-(imidazol-l-yl ) -2 -propanol resp. 1-hydroksyetyl-azol-derivater, som eksempelvis 2-(4-klorfenoksymetyl)-3,3-dimetyl-l-(imidazol-l-yl)-butan-2-ol eller 2-(2-metylfenoksymetyl)-3,3-dimetyl-l-(1,2,4-triazol-l-yl)- og (imidazol-l-yl)-butan-2-ol, har gode antimykotiske egenskaper (sml. DE-OS 2 820 489 resp. DE-OS 3 018 865). Virkningån av disse forbindelser er imidlertid ikke alltid helt tilfreds-stillende, spesielt in vivo. It is already known that hydroxypropyl imidazoles such as for example 2-(4.-Mphenylyl)-1-(2.4-dichlorophenyl)-3-(imidazol-1-yl)-2-propanol resp. 1-hydroxyethyl-azole derivatives, such as 2-(4-chlorophenoxymethyl)-3,3-dimethyl-1-(imidazol-1-yl)-butan-2-ol or 2-(2-methylphenoxymethyl)-3, 3-dimethyl-1-(1,2,4-triazol-1-yl)- and (imidazol-1-yl)-butan-2-ol, have good antifungal properties (cf. DE-OS 2 820 489 resp. DE-OS 3 018 865). However, the effect of these compounds is not always completely satisfactory, especially in vivo.

Det er funnet nye diazolyl-alkanoler med den generelle formel New diazolyl alkanols with the general formula have been found

hvori in which

A og B betyr et nitrogenatom eller CH-gruppen, ogA and B mean a nitrogen atom or the CH group, and

R betyr alkenyl- alkinyl., eventuelt substituert fenylalkinyl eller eventuelt substituert fenylalkenyl, R means alkenyl-alkynyl, optionally substituted phenylalkynyl or optionally substituted phenylalkenyl,

og deres fysiologisk tålbare syreaddisjonssalter.and their physiologically tolerable acid addition salts.

Videre ble det funnet at diazolyl-alkanoler med formel I fåes når dihalogenalkanoler med formel Furthermore, it was found that diazolylalkanols of formula I are obtained when dihaloalkanols of formula

hvori in which

R har overnevnte betydning, og R has the above meaning, and

Hal' betyr halogen,Hal' means halogen,

omsettes med azoler med formel is reacted with azoles of formula

hvori in which

A har overnevnte betydning, ogA has the above meaning, and

M betyr hydrogen eller et alkalimetall,M means hydrogen or an alkali metal,

i nærvær av et fortynningsmidde1, og eventuelt i nærvær av et syrebindende middel. in the presence of a diluent1, and optionally in the presence of an acid-binding agent.

Til de således dannede forbindelser med formel ITo the thus formed compounds of formula I

kan det eventuelt deretter adderes en syre.an acid can optionally then be added.

De nye diazolyl-alkanoler med formel I har sterke antimykotiske egenskaper. Derved viser overraskende forbindelsene ifølge oppfinnelsen en bedre terapeutisk nyttbar in vivo-virkning enn de fra teknikkens stand kjente forbindelser 2-(4-bifenylyl)-1-(2,4-diklorfenyl)-3-(imidazol-l-yl)-2-propanol; 2-(4-klor-fenoksy-metyl)-3,3-dimetyl-l-(imidazol-l-yl)-butan-2-ol og 2-(2-metylfenoksymetyl)-3,3-dimetyl-l-(1,2,4-triazol-l-yl)- resp. The new diazolyl alkanols of formula I have strong antifungal properties. Thereby, the compounds according to the invention surprisingly show a better therapeutically useful in vivo effect than the compounds known from the state of the art 2-(4-biphenylyl)-1-(2,4-dichlorophenyl)-3-(imidazol-1-yl)-2 - propanol; 2-(4-chloro-phenoxy-methyl)-3,3-dimethyl-1-(imidazol-1-yl)-butan-2-ol and 2-(2-methylphenoxymethyl)-3,3-dimethyl-1- (1,2,4-triazol-1-yl)- resp.

(imidazol-l-yl)-butan-2-ol, som er kjemisk nærliggende forbindelser. Forbindelsene ifølge oppfinnelsen betyr således en berikning av farmasien. (imidazol-1-yl)-butan-2-ol, which are chemically close compounds. The compounds according to the invention thus mean an enrichment of the pharmacy.

Dessuten er de nye diazolyl-alkanoler interessante mellomprodukter. Således kan f..eks. forbindelsen med den generelle formel. I ved hydroksygruppen på vanlig måte overføres i de tilsvarende etere. Videre kan det ved omsetning med f. eks. acetylhalogenider eller karbamoylhalogenider på prinsipielt kjent måte fåes acyl- eller karbamoylderivater av forbindelsen med den generelle formel I. Moreover, the new diazolyl alkanols are interesting intermediates. Thus, e.g. the connection with the general formula. I at the hydroxy group is transferred in the usual way in the corresponding ethers. Furthermore, in the case of turnover with e.g. acetyl halides or carbamoyl halides in principle known way, acyl or carbamoyl derivatives of the compound with the general formula I are obtained.

Diazolyl-alkanoler ifølge oppfinnelsen er definert generelt ved formel I. I denne formel betyr fortrinnsvis A og B et nitrogenatom eller CH-gruppe, og Diazolyl-alkanols according to the invention are defined generally by formula I. In this formula, A and B preferably mean a nitrogen atom or CH group, and

R.alkenyl og alkinyl med hver gang 2 til 6 karbonatomer, samt eventuelt enkelt til tre-ganger like eller forskjellige substi-tuerte fenylalkinyl med 2 til 4 karbonatomer i alkinyldelen, og fenylalkenyl med 2 til 4 karbonatomer i alkenyldelen, idet hver gang som fenylsubstituenter skal det fortrinnsvis nevnes: Halogen, alkyl med 1 til 4 karbonatomer, alkoksy og alkyltio med hver gang 1 til 2 karbonatomer, alkoksyalkyl med 1 til 2 karbonatomer i hver alkyldel, samt eventuelt med halogen substituert fenyl. R.alkenyl and alkynyl with each time 2 to 6 carbon atoms, as well as optionally singly to three times equally or differently substituted phenylalkynyl with 2 to 4 carbon atoms in the alkynyl part, and phenylalkenyl with 2 to 4 carbon atoms in the alkenyl part, each time as phenyl substituents should preferably be mentioned: Halogen, alkyl with 1 to 4 carbon atoms, alkoxy and alkylthio with each time 1 to 2 carbon atoms, alkoxyalkyl with 1 to 2 carbon atoms in each alkyl part, as well as optionally halogen-substituted phenyl.

Anvender man eksempelvis 4-klor-3-klormetyl-3-hydroksy- 1-fenyl-l-butin og 1,2,4-triazol som utgangsstoffer, samt kaliumkarbonat som syrebindende middel, så kan reaksjonsforløpet av fremgangsmåten ifølge oppfinnelsen gjengis ved følgende formel-skjerna: If, for example, 4-chloro-3-chloromethyl-3-hydroxy-1-phenyl-l-butene and 1,2,4-triazole are used as starting materials, as well as potassium carbonate as an acid-binding agent, the course of the reaction of the method according to the invention can be reproduced by the following formula -kernel:

De for fremgangsmåten ifølge oppfinnelsen som utgangsstoffer anvendbare dihalogenalkanoler er generelt definert med formel II. I denne formel betyr R fortrinnsvis de rester som allerede ble nevnt i forbindelse med omtalen av stoffene med formel I ifølge oppfinnelsen, fortrinnsvis for disse sub-stituenter. Hal<1>betyr fortrinnsvis klor. The dihaloalkanols which can be used as starting materials for the process according to the invention are generally defined by formula II. In this formula, R preferably means the residues that were already mentioned in connection with the description of the substances with formula I according to the invention, preferably for these substituents. Hal<1> preferably means chlorine.

De halogenalkanolene med formel II er ennå ikke kjent, de kan fåes på generelt kjent måte, idet 1,3-dihalogenaceton som spesielt 1,3-dikloraceton omsettes med et tilsvarende Grignard-reagens (sml. hertil også J. Org. Chem. 27, 2242 (1961) samt fremstillingseksemplene). The haloalkanols of formula II are not yet known, they can be obtained in a generally known manner, whereby 1,3-dihaloacetone such as 1,3-dichloroacetone in particular is reacted with a corresponding Grignard reagent (cf. also J. Org. Chem. 27 , 2242 (1961) as well as the manufacturing examples).

De dessuten for fremgangsmåten ifølge oppfinnelsenThey also for the method according to the invention

som utgangsstoffer anvendbare azoler er generelt definert med formel III. I denne formel betyr A fortrinnsvis det som er angitt i oppfinnelsens definisjon. M betyr fortrinnsvis hydrogen, natrium eller kalium. azoles that can be used as starting materials are generally defined by formula III. In this formula, A preferably means what is stated in the definition of the invention. M preferably means hydrogen, sodium or potassium.

Azolene med formel III er generelt kjente forbindelser i organisk kjemi. Alkalisaltene fåes ved omsetning av imida- The azoles of formula III are generally known compounds in organic chemistry. The alkali salts are obtained by reacting imida-

zol resp. 1,2,4-triazol med natrium- eller kaliumetylat eller ved omsetning av imidazol resp. 1,2,4-triazol med den ekvivalente mengde tilsvarende alkalihydrid. zol or 1,2,4-triazole with sodium or potassium ethylate or by reacting imidazole resp. 1,2,4-triazole with the equivalent amount of corresponding alkali hydride.

Som fortynningsmiddel kommer det for fremgangsmåten ifølge oppfinnelsen fortrinnsvis på tale inerte organiske opp-løsningsmidler. Hertil hører fortrinnsvis ketoner som spesielt aceton, og. metyletylketon, nitriler som spesielt acetonitril, alkoholer, som spesielt etanol og isopropanol, etere som spesielt tetrahydrofuran eller dioksan, formamider som spesielt dimetyl-formamid, samt aromatiske og halogenerte hydrokarboner. Inert organic solvents are preferably used as diluents for the method according to the invention. These preferably include ketones such as acetone in particular, and. methyl ethyl ketone, nitriles such as acetonitrile in particular, alcohols such as ethanol and isopropanol in particular, ethers such as tetrahydrofuran or dioxane in particular, formamides such as dimethylformamide in particular, as well as aromatic and halogenated hydrocarbons.

Fremgangsmåten ifølge oppfinnelsen foretas eventuelt i nærvær av et syrebindende middel. Man kan tilsette alle vanligvis anvendbare uorganiske eller organiske syrebindere som alkalikarbonater, eksempelvis natrium- og kaliumkarbonat, eller som lavere tertiære alkylaminer, cykloalkylaminer eller aralkyl-aminer, eksempelvis trietylamin, N,N-dimetylcykloheksylamin, dicykloheksylamin, N,N-dimetylbensylamin, videre pyridin og diazabicyklooktan, samt også et tilsvarende overskudd av imida- The method according to the invention is optionally carried out in the presence of an acid-binding agent. You can add all commonly used inorganic or organic acid binders such as alkali carbonates, for example sodium and potassium carbonate, or as lower tertiary alkylamines, cycloalkylamines or aralkylamines, for example triethylamine, N,N-dimethylcyclohexylamine, dicyclohexylamine, N,N-dimethylbenzylamine, further pyridine and diazabicyclooctane, as well as a corresponding excess of imida-

zol resp. triazol.zol or triazole.

Reaksjonstemperaturene kan ved gjennomføring av fremgangsmåten ifølge oppfinnelsen varieres i et stort område. Vanligvis arbeides mellom ca. 20 til ca. 150°C, fortrinnsvis 2 0 til 120°C. When carrying out the method according to the invention, the reaction temperatures can be varied over a large range. Usually work between approx. 20 to approx. 150°C, preferably 20 to 120°C.

Ved gjennomføring av fremgangsmåten ifølge oppfinnel-v:.,i sen anvender man på 1 mol av dihalogenalkanoler med formel II 2 til 4 mol azol med formel III og evnetuelt 2 til 4 mol syre-binder. Isoleringen av forbindelsene med formel I foregår på vanlig måte. When carrying out the method according to the invention, 2 to 4 mol of azole of formula III and possibly 2 to 4 mol of acid binder are used for 1 mol of dihaloalkanols of formula II. The isolation of the compounds of formula I takes place in the usual way.

I en spesiell gjennomføringsform av fremgangsmåten ifølge oppfinnelsen til fremstilling av forbindelsen.med formel I, hvori A er forskjellig fra B, anvender man på 1 mol av dihalogenalkanoler med formel II i første rekke 1 mol alkalimetall-salt av et azol med formel III, idet det danner seg den tilsvarende 2-azolylmetyl-oksiran, og deretter anvendes 1 til 4 mol av det andre azol med formel III og eventuelt 1 til 4 mol syre-binder. Isoleringen av forbindelsene med formel I foregår like-ledes på vanlig måte. In a special embodiment of the method according to the invention for the preparation of the compound with formula I, in which A is different from B, 1 mol of dihaloalkanols with formula II is used primarily with 1 mol of an alkali metal salt of an azole with formula III, the corresponding 2-azolylmethyl oxirane is formed, and then 1 to 4 mol of the second azole of formula III and optionally 1 to 4 mol of acid binder are used. The isolation of the compounds of formula I likewise takes place in the usual way.

Til fremstilling av syreaddisjonssalter av forbindelsen med formel I, kommer det på tale alle fysiologiske tålbare syrer. Hertil hører fortrinnsvis halogenhydrogensyrene, som f. eks. klorhydrogensyre og bromhydrogensyre, spesielt klorhydrogensyre, videre fosforsyre, salpetersyre, svovelsyre,.mono- og bifunksjonelle karboksylsyrer og hydroksykarboksylsyrer, som f. eks. eddiksyre, maleinsyre, ravsyre, fumarsyre, vinsyre, sitronsyre, salicylsyre, sorbinsyre, melkesyre, samt sulfonsyrer, som f. eks. p-toluensulfonsyre og 1,5 —naftalindisulfonsyre. For the preparation of acid addition salts of the compound of formula I, all physiologically tolerable acids are suitable. This preferably includes the halogen hydrogen acids, which e.g. hydrochloric acid and hydrobromic acid, especially hydrochloric acid, further phosphoric acid, nitric acid, sulfuric 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, as well as sulphonic acids, such as p-toluenesulfonic acid and 1,5 -naphthalene disulfonic acid.

Saltene av forbindelsen med formel I, kan fåes på. enkel måte etter vanlig saltdannelsesmetode, f. eks. ved opp-løsning av en forbindelse med formel I i et egnet inert opp-løsningsmiddel, og tilsetning av syrer, f. eks. klorhydrogensyre, og isolere på kjent måte f. eks. ved frafiltrering og eventuelt renses ved vasking med inert organisk oppløsningsmiddel. The salts of the compound of formula I can be obtained. simple way according to the usual salt formation method, e.g. by dissolving a compound of formula I in a suitable inert solvent, and adding acids, e.g. hydrochloric acid, and isolate in a known manner, e.g. by filtration and possibly purified by washing with an inert organic solvent.

De ifølge oppfinnelsen anvendbare forbindelser med formel I og deres syreaddisjonssalter har antimikrobielle spesielt sterke antimykotiske virkninger. De har et meget bredt antimykotisk virkningsspektrum, spesielt mot dermatofyter og spross-sopp, samt bi-fasisk sopp, f.eks. mot Candida-arter, som Candida albicans, Epidermophyton-typer, som Epidermophyton flocco.sum, Aspergillus-typer, som Aspergillus niger og Aspergillus fumigatus, Tricophyton-typer, som Tricophyton mentagrophythes, Microsporon-typer, som Microsporon-felinium samt Torulopsis-typer, som Torulopsis glabrata. Oppramsningen av disse mikro-organismer er ingen begrensning av de bekjempbare kimer, men har forklarende karakter. The compounds of formula I which can be used according to the invention and their acid addition salts have antimicrobial particularly strong antimycotic effects. They have a very broad spectrum of antifungal activity, especially against dermatophytes and slat fungi, as well as biphasic fungi, e.g. against Candida species, such as Candida albicans, Epidermophyton types, such as Epidermophyton flocco.sum, Aspergillus types, such as Aspergillus niger and Aspergillus fumigatus, Tricophyton types, such as Tricophyton mentagrophythes, Microsporon types, such as Microsporon felinium and Torulopsis types , such as Torulopsis glabrata. The collection of these micro-organisms is not a limitation of the germs that can be combated, but is of an explanatory nature.

Som indikasjonsområder i humanmedisinen kan det eksempelvis nevnes: Dermatomykoser og systemmykoser på grunn av tricophyton mentagrophyte og andre Trichophytonarter, Mikrosporon-arter, Epidermophyton floccosum, Sprosse-sopp og bifasisk.sopp, samt muggsopp. Indication areas in human medicine include, for example: Dermatomycoses and systemic mycoses due to trichophyton mentagrophyte and other Trichophyton species, Microsporon species, Epidermophyton floccosum, Sprousse fungi and biphasic fungi, as well as molds.

Som indikasjonsområde i veterinærmedisinen kan det eksempelvis oppføres: Alle dermatomykoser og systemmykoser, spesielt slike som frem-bringes med de overnevnte frembringere. As an indication area in veterinary medicine, the following can be listed, for example: All dermatomycoses and systemic mycoses, especially those caused by the above-mentioned agents.

Oppfinnelsen omfatter også farmasøytiske tilberedninger som ved siden av ikke-toksiske inerte farmasøytiske egnede bærestoffer, inneholder et eller flere virksomme stoffer ifølge oppfinnelsen ,, eller som består av et eller flere virksomme stoffer ifølge oppfinnelsen, samt fremgangsmåte til fremstilling av disse tilberedninger. The invention also includes pharmaceutical preparations which, in addition to non-toxic inert pharmaceutical suitable carriers, contain one or more active substances according to the invention, or which consist of one or more active substances according to the invention, as well as methods for producing these preparations.

Til oppfinnelsen hører også farmasøytiske tilberedninger i doseringsenheter. Dette betyr at tilberedningene fore-ligger i form av enkelte deler, f. eks. tabletter, drageer, kapsler, piller, suppositorier, og ampuller, hvis virksomme stoff- The invention also includes pharmaceutical preparations in dosage units. This means that the preparations are available in the form of individual parts, e.g. tablets, dragees, capsules, pills, suppositories and ampoules, if the active substances

innhold tilsvarer en brøkdel eller et ijmltiplum av en enkelt-content corresponds to a fraction or multiple of a single

dose. Doseringsenhetene kan f. eks. inneholde 1,2,3 eller 4 enkeltdoser eller 1/2, 1/3 eller 1/4 av en enkeltdose. En enkeltdose inneholder fortrinnsvis den mengde virksomt stoff som administreres ved en applikasjon og som vanligvis tilsvarer en hel, en halv, eller en tredjedel eller en fjerdedel av en dags-dose. Med ikke-toksiske, inerte farmasøytiske egnede bærestoffer er det å forstå faste, halvfaste eller flytende for-tynningsmidler, fyllstoffer og formuleringshjelpemidler av enhver type. dose. The dosage units can e.g. contain 1,2,3 or 4 single doses or 1/2, 1/3 or 1/4 of a single dose. A single dose preferably contains the amount of active substance that is administered in one application and which usually corresponds to a whole, a half, or a third or a quarter of a daily dose. By non-toxic, inert pharmaceutical suitable carriers is meant solid, semi-solid or liquid diluents, fillers and formulation aids of any type.

Som foretrukkede farmasøytiske tilberedninger skal det nevnes tabletter, drageer, kapsler, piller, granulater, suppositorier, oppløsninger,, suspensjoner, og emulsjoner, pastaer, salver, geleer, kremer, lotion, pudder og spray. Preferred pharmaceutical preparations include tablets, dragees, capsules, pills, granules, suppositories, solutions, suspensions and emulsions, pastes, ointments, gels, creams, lotions, powders and sprays.

Tabletter/drageer, kapsler, piller og granulaterTablets/drakes, capsules, pills and granules

kan inneholde det eller eller de virksomme stoffer ved siden av de vanlige bærestoffer som (a) fyll- og drøyemidler, f. eks. stivelse, melkesukker, rørsukker, glukose, mannit og kiselsyre, :(b) bindemidler, f. eks. karboksymetylcellulose, alginater, gelatiner, polyvinylpyrrolidon, (c) fuktighetsholdemidler, f. eks. glycerol, (d) sprengmidler, f. eks. agar-agar, kalsiumkarbonat og natriumbikarbonat, (e) oppløsningsforsinkere, f. eks. parafin, og (f) resorpsjonsakselleratorer, f. eks. kvaternære ammonium-forbindelser, (g) fuktemidler, f. eks. cetylalkohol, glycerol-monostearat, (h) adsorpsjonsmidler, f. eks. kaolin og bentonitt, og (i) glidemidler, f. eks. talkum, kalsium- og magnesiumstearat og faste polyetylenglykoler eller blandinger av de under (a) til (i) oppførte stoffer. may contain the active substances in addition to the usual carriers such as (a) fillers and thickeners, e.g. starch, milk sugar, cane sugar, glucose, mannitol and silicic acid, :(b) binders, e.g. carboxymethylcellulose, alginates, gelatins, polyvinylpyrrolidone, (c) humectants, e.g. glycerol, (d) explosives, e.g. agar-agar, calcium carbonate and sodium bicarbonate, (e) dissolution retarders, e.g. paraffin, and (f) resorption accelerators, e.g. quaternary ammonium compounds, (g) wetting agents, e.g. cetyl alcohol, glycerol monostearate, (h) adsorbents, e.g. kaolin and bentonite, and (i) lubricants, e.g. talc, calcium and magnesium stearate and solid polyethylene glycols or mixtures of the substances listed under (a) to (i).

Tablettene, drageene, kapslene, pillene og granulatene kan være utstyrt med de vanlige eventuelt opakiseringsmiddel-holdige overtrekk og hylser, og også være sammensatt således at de avgir eventuelt forsinket det eller de virksomme stoffer bare eller foretrukket i en bestemt del av fordøyelseskanalen, idet som innleiringsmasser kan det for eksempel.^.anvendes poly-merstoffer og voks. The tablets, dragees, capsules, pills and granules can be equipped with the usual coverings and sleeves, possibly containing an opacifying agent, and also be composed in such a way that they release the active substance(s) only or preferentially in a specific part of the digestive tract, possibly delayed embedding compounds, for example, polymer substances and wax can be used.

Det eller de virksomme stoffer kan eventuelt foreligge med et eller flere av de ovenfor angitte bærestoffer, også The active substance(s) may possibly be present with one or more of the carriers stated above, as well

i mikroforkapslet form.in microencapsulated form.

Suppositorier kan ved siden av den eller de virk-Suppositories can, in addition to the

somme stoffer inneholde de vanlige vannoppløselige eller vann-uoppløselige bærestoffer, f. eks. polyetylenglykoler, fett, f. eks. kakaofett av høyere estere (f. eks. C-^-alkohol med C-^-fett-syrer), eller blandinger av disse stoffer. some substances contain the usual water-soluble or water-insoluble carriers, e.g. polyethylene glycols, fats, e.g. cocoa fat of higher esters (e.g. C-^-alcohol with C-^-fatty acids), or mixtures of these substances.

Salver,.pastaer, kremer og geleer kan ved siden avOintments, pastes, creams and gels can be used alongside

den eller de virksomme'stoffer inneholde de vanlige bærestoffer,the active substance(s) contain the usual carriers,

f. eks. dyrisk og plantefett, voks, parafiner, stivelse, tragant, cellulosederivater, polyetylenglykol, silikon, bento- e.g. animal and vegetable fats, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycol, silicone, bento-

niter, kiselsyre, talkum og sinkoksyd eller blandinger av disse stoffer. nites, silicic acid, talc and zinc oxide or mixtures of these substances.

Pudder og spray kan ved siden av den eller de virksomme stoffer inneholde de vanlige bærestoffer, f. eks. melkesukker, talkum, kiselsyre, aluminiumhydroksyd, kalsiumsilikat og polyamidpulver eller blandinger av disse stoffer. Sprays kan i tillegg inneholde vanlig drivmiddel, f. eks. klorfluorhydro-karboner. Powders and sprays can contain the usual carrier substances, e.g. milk sugar, talc, silicic acid, aluminum hydroxide, calcium silicate and polyamide powder or mixtures of these substances. Sprays can also contain common propellant, e.g. chlorofluorohydrocarbons.

Oppløsninger og emulsjoner kan ved siden av den eller de virksomme stoffer inneholde de vanlige bærestoffer, som opp-løsning smidler , oppløsningsformidlere og emulgatorer, f. eks. vann, etylalkohol, isopropylalkohol, etylkarbonater, etylacetat, bensyl-alkohol, bensylbensoat, propylenglykol, 1,3-butylenglykol, dimetyl-formamid, oljer, spesielt bomullsfrøolje, jordnøttolje, mais-kiimolje, olivenolje, risinusolje og sesamolje, glycerol, glycerol-formal, tetrahydrofurylalkohol, polyetylenglykoler og fettsyre-estere av sorbitan eller blandinger av disse stoffer. Solutions and emulsions can contain, in addition to the active substance(s), the usual carriers, such as solvents, dissolution agents and emulsifiers, e.g. water, ethyl alcohol, isopropyl alcohol, ethyl carbonates, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethyl formamide, oils, especially cottonseed oil, peanut oil, corn-chime oil, olive oil, castor oil and sesame oil, glycerol, glycerol formal , tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan or mixtures of these substances.

For parenteral applikasjon kan oppløsningen og emul-sjonene også foreligge i steril og blodisotonisk form. For parenteral application, the solution and emulsions can also be available in sterile and blood isotonic form.

Suspensjoner kan ved siden av den eller de virksomme stoffer inneholde de vanlige bærestoffer som flytende fortynnings-midler, f. eks. vann, etylalkohol, propylenglykol, suspenderings-midler, f. eks. etoksylerte isostéarylalkoholer, polyoksyetylen-sorbit- og sorbitanestere, mikrokrystallinsk cellulose, alu-miniummetahydroksyd, bentonit, agar-agar og tragant eller blandinger av disse stoffer. Suspensions can contain, in addition to the active substance(s), the usual carriers such as liquid diluents, e.g. water, ethyl alcohol, propylene glycol, suspending agents, e.g. ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth or mixtures of these substances.

De nevnte formuleringsformer kan også inneholde farve-midler, konserveringsstoffer, samt lukt- og smaksforbedrende til- setninger, f. eks. peppermynteolje og eukalyptusolje og søt-ningsmiddel, f. eks. sakkarin. The aforementioned forms of formulation may also contain coloring agents, preservatives, as well as odor and taste-enhancing additives, e.g. peppermint oil and eucalyptus oil and sweetener, e.g. saccharin.

De terapeutisk virksomme forbindelser skal være til stede i de ovenfor nevnte farmasøytiske tilberedninger, fortrinnsvis i en konsentrasjon på ca.' ,0,1 til 99,5, fortrinnsvis på ca. 0,5 til 95 vekt% av den samlede blanding. The therapeutically active compounds must be present in the above-mentioned pharmaceutical preparations, preferably in a concentration of approx. ,0.1 to 99.5, preferably of approx. 0.5 to 95% by weight of the overall mixture.

De ovenfor anførte farmasøytiske tilberedninger kan for uten virksomme stoffer i oppfinnelsen også inneholde ytterligere farmasøytiske virksomme stoffer. The above-mentioned pharmaceutical preparations may, without active substances in the invention, also contain additional pharmaceutical active substances.

Fremstillingen av de ovenfor oppførte farmasøytiske tilberedninger foregår på vanlig måte etter kjente metoder, f. eks. ved blanding av det eller de virksomme stoffer med bærestoffene eller stoffet. The production of the pharmaceutical preparations listed above takes place in the usual way according to known methods, e.g. by mixing the active substance(s) with the carrier substances or substance.

Til foreliggende oppfinnélse' hører også anvendelsenThe application also belongs to the present invention

av de virksomme stoffer ifølge oppfinnelsen samt av farmasøytiske tilberedninger som inneholder et eller flere av de virksomme stoffer ifølge oppfinnelsen i human- og veterinærmedisinen til å hindre,forbedre eller helbrede de ovenfor nevnte sykdommer. of the active substances according to the invention as well as of pharmaceutical preparations containing one or more of the active substances according to the invention in human and veterinary medicine to prevent, improve or cure the above-mentioned diseases.

De virksomme stoffer eller de farmasøytiske tilberedninger kan appliseres lokalt, oralt, parenteralt, intra-peritonealt og/eller rektalt, fortrinnsvis parenteralt, spesielt intravenøst. The active substances or the pharmaceutical preparations can be applied locally, orally, parenterally, intra-peritoneally and/or rectally, preferably parenterally, especially intravenously.

Generelt har det såvel i human- og som også i veterinærmedisinen vist seg fordelaktig å administrere det eller de virksomme stoffer ifølge oppfinnelsen i samlede mengder fra ca. In general, both in human and veterinary medicine it has proven advantageous to administer the active substance(s) according to the invention in total amounts from approx.

10 til ca. 300, fortrinnsvis 50 til 200 mg/kg legemsvekt pr. 24 timer, eventuelt i form av flere enkeltinngivninger for å oppnå 10 to approx. 300, preferably 50 to 200 mg/kg body weight per 24 hours, possibly in the form of several individual submissions to achieve

de ønskede resultater.the desired results.

Det kan imidlertid være nødvendig å avvike fra de nevnte doseringer, nemlig i avhengighet av type og legemsvekt, However, it may be necessary to deviate from the dosages mentioned, namely depending on the type and body weight,

av objektet som skal behandles, typen og tyngden av sykdommen, typen og tilberedningen og applikasjonen av legemidlet, samt tidsrommet resp. intervallet, inntil hvilke administreringen foregår. Således kan det i noen tilfelle være tilstrekkelig å komme ut med mindre enn overnevnte mengde virksomt stoff, mens i andre tilfelle overnevnte virksomme stoffmengde må overskrides. Fast-leggelsen av den hver gang nødvendige optimale dosering og appli-kasjonstype av de virksomme stoffer kan foregå av hver fagmann på grunn av hans fagkunnskaper. of the object to be treated, the type and severity of the disease, the type and preparation and application of the medicine, as well as the time period or the interval, until which the 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 must be exceeded. The determination of the optimal dosage and application type of the active substances required each time can be carried out by each professional due to his professional knowledge.

Fremstillingseksempler Manufacturing examples

Eksempel 1Example 1

Til en blanding av 2 7,6 g (0,4 mol) 1,2,4-triazol To a mixture of 2 7.6 g (0.4 mol) 1,2,4-triazole

og 55,2 g (0,4 mol) kaliumkarbonat i 3 00 ml aceton dryppes 22,9 g (0,1 mol) 4-klor-3-klormetyl-3-hydroksy-l-fenyl-l-butiri. Man lar reaksjonsblandingen omrøre 12 timer under tilbakeløp. Etter avkjøling filtreres. Filtratet inndampes i vakuum og det olje-aktige residuet renses kromatografisk (kiselgel 60 Merck, kloro-form) . Man får 8 g (27 % av det teoretiske) 3-hydroksy-l-fenyl-4-(1,2,4-triazol-l-yl)-3-(1,2,4-triazol-l-yl-metyl)-1-butin av sm.p. 140°C. and 55.2 g (0.4 mol) of potassium carbonate in 300 ml of acetone, 22.9 g (0.1 mol) of 4-chloro-3-chloromethyl-3-hydroxy-1-phenyl-1-butyric acid are added dropwise. The reaction mixture is allowed to stir for 12 hours under reflux. After cooling, filter. The filtrate is evaporated in vacuo and the oily residue is purified chromatographically (silica gel 60 Merck, chloroform). 8 g (27% of the theoretical) of 3-hydroxy-1-phenyl-4-(1,2,4-triazol-1-yl)-3-(1,2,4-triazol-1-yl- methyl)-1-butyne of m.p. 140°C.

Utgangsproduktets fremstillingThe production of the starting product

En suspensjon av fenylacetylenyl-magnesiumbromid i dietyleter fremstillet av 12 g (0,5 mol) magnesium, 54,5 g (0,5 mol) etylbromid og 51 g (0,5 mol) fenylacetylen i 500 ml dietyleter dryppes ved 6Q°C i en oppløsning av 63,5'g (0,5 mol) 1,3-dikloraceton i 300 ml dietyleter. Etter 2 timer lar man reaksjons- A suspension of phenylacetylenyl magnesium bromide in diethyl ether prepared from 12 g (0.5 mol) magnesium, 54.5 g (0.5 mol) ethyl bromide and 51 g (0.5 mol) phenylacetylene in 500 ml diethyl ether is dropped at 6Q°C in a solution of 63.5 g (0.5 mol) of 1,3-dichloroacetone in 300 ml of diethyl ether. After 2 hours, the reaction

o o

blandingen oppvarme til 0 C, og blander med 4 9,3 g (0,82 mol) eddiksyre, idet det foregår ytterligere oppvarming til ca. 2 0°C. Etter tilsetning av 2 00 ml vann, adskilles eterfasen, vaskes med heat the mixture to 0 C, and mix with 4 9.3 g (0.82 mol) acetic acid, further heating to approx. 20°C. After adding 200 ml of water, the ether phase is separated, washed with

vann, tørkes over natriumsulfat og inndampes i vakuum. Man får 114 g (99 % av det teoretiske) 4-klor-3-klormetyl-3-hydroksy-l-2 0 water, dried over sodium sulfate and evaporated in vacuo. 114 g (99% of the theoretical) of 4-chloro-3-chloromethyl-3-hydroxy-1-2 0 are obtained

fenyl-l-butin av brytningsindeks nD = 1,5575.phenyl-l-butyne of refractive index nD = 1.5575.

På tilsvarende måte ifølge fremgangsmåten ifølge oppfinnelsen, fåes følgende forbindelse med den generelle formel I In a similar way according to the method according to the invention, the following compound with the general formula I is obtained

Tilsvarende eksempel 1 fåes følgende mellomprodukter med den"generelle formel Ila ' Corresponding to example 1, the following intermediate products are obtained with the "general formula Ila"

Anvende1seseksempler Use 1s examples

I følgende eksempel anvendes nedenstående angitte forbindelser som sammenligningsforsøk: In the following example, the compounds specified below are used as comparison tests:

Eksempel A Example A

Antimykotisk- in vivo- virkning ( oral) ved musecandidose Forsøksbeskrivning: Mus av typen SPF-CF, ble infisert intravenøst med 1 - 2 x 10 6 logaritmisk voksende Candida-celler, som suspenderes i fysiologisk kokesaltoppløsning. En time før og syv timer etter infeksjonen, behandles dyrene oralt hver gang 50-100 mg/kg legemsvekt av preparatene. Antimycotic- in vivo- effect (oral) in mouse candidosis Test description: Mice of the SPF-CF type were infected intravenously with 1 - 2 x 10 6 logarithmically growing Candida cells, which are suspended in physiological saline solution. One hour before and seven hours after the infection, the animals are treated orally each time with 50-100 mg/kg body weight of the preparations.

Resultat; Result;

Ubehandlede dyr døde 3 til 6 dager post infeksjonem. Overlevningsgraden på 6 dag post infeksjonem utgjorde ved ubehandlede kontrolldyr ca. 5 %. Untreated animals died 3 to 6 days post infection. The survival rate at 6 days post infection in untreated control animals was approx. 5%.

I denne prøve viser f. eks. forbindelsen ifølge oppfinnelsen en bedre virkning enn de fra teknikkens stand kjente forbindelser 1 og 3. In this sample, e.g. the compound according to the invention has a better effect than the prior art compounds 1 and 3.

Tegnforklaring:Legend:

+++++ = meget god virkning = 90 % overlevende på 6 dag p.i.+++++ = very good effect = 90% survival at 6 days p.i.

++++ = god virkning = 80 % overlevende på 6 dag p.i.++++ = good effect = 80% survival at 6 days p.i.

+++ = virkning = 60 % overlevende på 6 dag p.i.+++ = efficacy = 60% survival at 6 days p.i.

++ = svak virkning = 40 % overlevende på 6 dag p.i.++ = weak effect = 40% survival at 6 days p.i.

+ = spor virkning =+ = trace effect =

i.v. = ingen virkningi.v. = no effect

Forbindelse ifølge fremstillingseksempel Connection according to manufacturing example

1 +++ 3 +++++ 1 +++ 3 +++++

Eksempel B / formuleringer 1.) oppløsning: Example B / formulations 1.) solution:

2.) krem: 1. Diazolyl-alkanoler med den generelle formel 2.) cream: 1. Diazolyl-alkanols of the general formula

hvori in which

A og B betyr et nitrogenatom eller CH-gruppen, ogA and B mean a nitrogen atom or the CH group, and

R betyr alkenyl, alkinyl, eventuelt substituert fenylalkenylR means alkenyl, alkynyl, optionally substituted phenylalkenyl

eller eventuelt substituert fenylalkinyl,or optionally substituted phenylalkynyl,

og deres fysiologisk tålbare syreaddisjonssalter.and their physiologically tolerable acid addition salts.

2. Diazolyl-alkanoler med den .generelle formel I ifølge krav 1, hvori A og B betyr et nitrogenatom eller CH-gruppen, og R betyr alkenyl og alkinyl med hver gang 2 til 6 karbonatomer, for hver gang eventuelt enkelt til tre-ganger lik eller forskjellig substituert fenylalkenyl med 2 til 4 karbonatomer i alkenyldelen eller fenylalkinyl med 2 til 4 karbonatomer i alkinyldelen, idet hver gang som fenylsubstituenter fortrinnsvis skal nevnes: Halogen, alkyl med 1 til 4 karbonatomer, alkoksy og alkyltio med hver gang 1 til 2 karbonatomer, alkoksy og alkyltio med hver gang 1 til 2 karbonatomer, alkoksyalkyl med 1 til 2 karbonatomer i hver alkyldel samt evnetuelt med halogen substituert fenyl. 3. 3-hydroksy-l-(p-klorfenyl)-4-(1,2,4-triazol-l-yl)-3-(1,2,4-triazol-l-yl-metyl)-1-butin, 4. Fremgangsmåte til fremstilling av diazolyl-alkanoler med formel I i krav 1,karakterisert vedat dihalogenalkanoler med formel 2. Diazolyl-alkanols with the general formula I according to claim 1, in which A and B mean a nitrogen atom or the CH group, and R means alkenyl and alkynyl with each time 2 to 6 carbon atoms, for each occasion singly to triply substituted phenylalkenyl with 2 to 4 carbon atoms in the alkenyl part or phenylalkynyl with 2 to 4 carbon atoms in the alkynyl part, each time as phenyl substituents should preferably be mentioned: Halogen, alkyl with 1 to 4 carbon atoms, alkoxy and alkylthio with each time 1 to 2 carbon atoms, alkoxy and alkylthio with each time 1 to 2 carbon atoms, alkoxyalkyl with 1 to 2 carbon atoms in each alkyl part and optionally with halogen substituted phenyl. 3. 3-hydroxy-1-(p-chlorophenyl)-4-(1,2,4-triazol-1-yl)-3-(1,2,4-triazol-1-yl-methyl)-1- butyne, 4. Process for the preparation of diazolyl alkanols of formula I in claim 1, characterized in that dihaloalkanols of formula

hvori in which

R har overnevnte betydning, ogR has the above meaning, and

Hal' betyr halogen, omsetter i nærvær av et fortynningsmiddel og eventuelt i nærvær av et syrebindende middel med azoler med formel Hal' means halogen, reacts in the presence of a diluent and optionally in the presence of an acid-binding agent with azoles of formula

hvori in which

A har overnevnte betydning, ogA has the above meaning, and

M betyr hydrogen eller et alkalimetall.M means hydrogen or an alkali metal.

5.. Legemiddel,karakterisert vedet innhold av minst et diazolylalkanol ifølge krav 1. 6. Fremgangsmåte til behandling av mykoser,karakterisert vedat diazolylalkanoler ifølge krav 1 appliseres på mennesker eller, dyr som er syke av mykose. 5. Medicine, characterized by the content of at least one diazolylalkanol according to claim 1. 6. Method for treating mycoses, characterized in that diazolylalkanols according to claim 1 are applied to humans or animals that are ill with mycosis.

NO830655A 1982-08-03 1983-02-24 DIAZOLYL ALKANOLS, THE PROCEDURE FOR THEIR PREPARATION AND THEIR USE AS AN ANTIMYCOTIC AGENT NO830655L (en)

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GB8819308D0 (en) * 1988-08-13 1988-09-14 Pfizer Ltd Triazole antifungal agents
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DK74683A (en) 1984-02-04
JPS5929671A (en) 1984-02-16
FI830152L (en) 1984-02-04
CA1198117A (en) 1985-12-17

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