DE2510130A1 - Imidazolyl alkyl-phenyl - (thio) ethers - active against dermatophytes, yeasts, protozoa bacterial and fungal diseases - Google Patents

Imidazolyl alkyl-phenyl - (thio) ethers - active against dermatophytes, yeasts, protozoa bacterial and fungal diseases

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Publication number
DE2510130A1
DE2510130A1 DE19752510130 DE2510130A DE2510130A1 DE 2510130 A1 DE2510130 A1 DE 2510130A1 DE 19752510130 DE19752510130 DE 19752510130 DE 2510130 A DE2510130 A DE 2510130A DE 2510130 A1 DE2510130 A1 DE 2510130A1
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Germany
Prior art keywords
alkyl
phenyl
general formula
compounds
imidazole
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DE19752510130
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German (de)
Inventor
Hans-Joachim Dr Kessler
Ulrich Redmann
Peter Dr Strehlke
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Bayer Pharma AG
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Schering AG
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Application filed by Schering AG filed Critical Schering AG
Priority to DE19752510130 priority Critical patent/DE2510130A1/en
Priority to IE780/75A priority patent/IE40911B1/en
Priority to CS752431A priority patent/CS194221B2/en
Priority to DD185337A priority patent/DD121515A5/xx
Priority to AT268675A priority patent/AT341518B/en
Priority to YU00898/75A priority patent/YU89875A/en
Priority to DK153075A priority patent/DK139909C/en
Priority to HU75SC00000516A priority patent/HU172895B/en
Priority to IL7547061A priority patent/IL47061A/en
Priority to AU80025/75A priority patent/AU496423B2/en
Priority to SE7504123A priority patent/SE418498B/en
Priority to CH457575A priority patent/CH612185A5/xx
Priority to JP50044147A priority patent/JPS6018654B2/en
Priority to ES75436546A priority patent/ES436546A1/en
Priority to CA224,402A priority patent/CA1051908A/en
Priority to NL7504387A priority patent/NL7504387A/en
Priority to FR7511415A priority patent/FR2267101B1/fr
Priority to US05/567,361 priority patent/US4006243A/en
Priority to GB15012/75A priority patent/GB1510016A/en
Publication of DE2510130A1 publication Critical patent/DE2510130A1/en
Priority to AT80677A priority patent/AT352117B/en
Pending legal-status Critical Current

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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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
    • C07C205/27—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by etherified hydroxy groups
    • C07C205/35—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by etherified hydroxy groups having nitro groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
    • C07C205/36—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by etherified hydroxy groups having nitro groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton to carbon atoms of the same non-condensed six-membered aromatic ring or to carbon atoms of six-membered aromatic rings being part of the same condensed ring system
    • C07C205/37—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by etherified hydroxy groups having nitro groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton to carbon atoms of the same non-condensed six-membered aromatic ring or to carbon atoms of six-membered aromatic rings being part of the same condensed ring system the oxygen atom of at least one of the etherified hydroxy groups being further bound to an acyclic carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
    • C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
    • C07C45/70—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction with functional groups containing oxygen only in singly bound form
    • C07C45/71—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction with functional groups containing oxygen only in singly bound form being hydroxy groups
    • 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

Abstract

Imidazole derivs. (I) their salts and medicaments contg. (I): (where X is a direct bond or -(CH2)n-CH-R1; n is 0, 1 or 2; R1 is H, 1-6C alkyl, phenyl opt. substd. by halogen, 1-6C alkyl or -alkoxy or NO2; R2 and R3 are H, 1-10C alkyl, 1-6C alkoxy or alkylthio, halogen or NO2 or R2+R3 is C4H4; R4 is 3-6C alkynyl, phenyl opt. substd. by halogen, NO2, CF3, 3-6C alkynyl, 1-6C alkyl or alkoxy, phenyl (1-4C alkyl) opt. substd. in the ring by halogen, NO2, CF3, 1-6C alkyl or alkoxy; R4 is also 1-6C alkyl when n is O, and X is O, S or NH) are active against dermatophytes, yeasts, protozoa, Gram-positive and negative bacteria and diseases caused by fungi.

Description

Imidazolderivate und Verfahren zu ihrer Herstellung (Zusatz zur Patentanmeldung P 24 18 502.2) Im Hauptpatent . . . . . . . (Patentanmeldung P 24 18 502.2) werden Verbindungen der allgemeinen Formel worin R1 ein Wasserstoffatom, eine Alkylgruppe mit 1 - 6 C-Atomen oder einen Phenylrest, der gegebenenfalls durch Halogenatome, Alkylgruppen mit 1 - 6 C-Atomen, Alkoxygruppen mit 1 - 6 C-Atomen oder Nitrogruppen substituiert sein kann, bedeutet, R2 und R5 gleich oder verschieden sina und Wasserstoffatome, Alkylgruppen mit 1 - 10 C-Atomen, Alkoxygruppen mit 1 - 6 C-Atomen, Alkylmercaptogruppen mit 1 - 6 C-Atomen, Halogenatome oder Nitrogruppen bedeuten oder R2 und R3 zusammen mit dem Benzolring einen Naphthalin ring bilden, R4 eine Alkylgruppe mit 1 - 6 C-Atomen, eine Alkenyl--- gruppe mit 3 - 6 C-Atomen, eine Alkinylgruppe mit 3 - 6 C-Atomen, einen Phenylrest, der gegebenenfalls durch Halogenatome, Nitrogruppen, Trifluormethylgruppen, Alkylgruppen mit 1 - 6 G-Atomen oder Alkoxy-- gruppen mit 1 - 6 C-Atomen substituiert ist, oder einen Phenylaflylrest mit 7 - 10 C-Atomen, der gegebenenfalis am Phenylring durch Halogenatome, Nitrogruppen, Trifluormethylgruppen, Alkylgruppen mit 1 - 6 .C-Atomen oder Alkoxygruppen mit 1 - 6 C-Atomen substituiert ist, und X ein Sauerstoff- oder Schwefelatom bedeutet, sowie deren Salze mit physiologisch verträglichen Säuren beschrieben.Imidazole derivatives and processes for their preparation (addendum to patent application P 24 18 502.2) In the main patent. . . . . . . (Patent application P 24 18 502.2) are compounds of the general formula wherein R1 is a hydrogen atom, an alkyl group with 1-6 carbon atoms or a phenyl radical which can optionally be substituted by halogen atoms, alkyl groups with 1-6 carbon atoms, alkoxy groups with 1-6 carbon atoms or nitro groups, R2 and R5, identically or differently, are hydrogen atoms, alkyl groups with 1-10 carbon atoms, alkoxy groups with 1-6 carbon atoms, alkyl mercapto groups with 1-6 carbon atoms, halogen atoms or nitro groups, or R2 and R3 together with the benzene ring represent a naphthalene ring R4 is an alkyl group with 1 - 6 carbon atoms, an alkenyl group with 3 - 6 carbon atoms, an alkynyl group with 3 - 6 carbon atoms, a phenyl radical, optionally replaced by halogen atoms, nitro groups, trifluoromethyl groups, alkyl groups is substituted with 1-6 carbon atoms or alkoxy groups with 1-6 carbon atoms, or a phenylaflyl radical with 7-10 carbon atoms, which is optionally attached to the phenyl ring by halogen atoms, nitro groups, trifluoromethyl groups, alkyl groups with 1-6. C- Atoms or alkoxy groups with 1-6 carbon atoms is substituted, and X is an oxygen or sulfur atom, and their salts with physiologically acceptable acids are described.

Diese Verbindungen sind wirksam gegen Dermatophyten, sowie gegen Candida albicans.These compounds are effective against dermatophytes, as well as against candida albicans.

Tn Weiterentwicklung der obengenannten Erfindung wurde nun gefunden, daß Verbindungen der allgemeinen Formel I, in denen NH für X steht, ebenfalls eine gute Wirkung gegen Dermatophyten und Candida albicans aufweisen.A further development of the above-mentioned invention has now been found that compounds of general formula I, in where NH stands for X, also have a good effect against dermatophytes and Candida albicans.

Die Erfindung betrifft Verbindungen der allgemeinen Formel I des Hauptpatentes . . . . . . . . . . (Patentanmeldung P 24 18 502.2) sowie deren Salze mit physiologisch verträglichen Säuren, worin X NH bedeutet und R1, R2, R5 und R4 die im Hauptpatent angegebene Bedeutung haben.The invention relates to compounds of the general formula I. of the main patent. . . . . . . . . . (Patent application P 24 18 502.2) and their salts with physiologically acceptable acids, in which X is NH and R1, R2, R5 and R4 have the meaning given in the main patent.

De-r Alkylrest in den Phenylalkylgruppen mit 7 - 10 C-Atomen des Substituenten R4 kann ein geradkettiger oder verzweigter 1 - 4 C-Atome enthaltender Alkylrest sein, wie z. B. in den Phenylalkylresten l-Phenyläthyl-, l-Phenyl-2-propyl-, 2-Phenyl-l-propyl-, 2-Phenyl-2-propyl -, l-Phenyl-l-butyl-, l-henyl-2-butyl-, 2-Phenyl-2-butyl-, 3-Phenyl-2-butyl-, 1!-Phenyl-2-butyl-, 2-Methyl-l-phenyl-l-propyl- und 4-Phenyl-lbutyl-. Bevorzugt sind Phenylmethyl-, Phenyläthyl-und Phenylpropylgruppen und insbesondere solche mit 1 - 2 C-Atomen in der Alkylkette.The alkyl radical in the phenylalkyl groups with 7-10 carbon atoms of the substituent R4 can be a straight-chain or branched alkyl radical containing 1 to 4 carbon atoms be, such as B. in the phenylalkyl radicals l-phenylethyl, l-phenyl-2-propyl, 2-phenyl-l-propyl, 2-phenyl-2-propyl -, l-phenyl-l-butyl-, l-henyl-2-butyl-, 2-phenyl-2-butyl-, 3-phenyl-2-butyl-, 1! -Phenyl-2-butyl-, 2-methyl-1-phenyl-1-propyl- and 4-phenyl-1-butyl-. Phenylmethyl, phenylethyl and phenylpropyl groups are preferred, and in particular those with 1 - 2 carbon atoms in the alkyl chain.

Als physiologisch verträgliche Säuren kommen anorganische Säuren, wie Salzsäure, Schwefelsäure, Salpetersäure oder Phosphorsäure und organische Säuren, wie Essigsäure, Propionsäure, Milchsäure, Bernsteinsäure, Weinsäure, Zitronensäure, Benzoesäure, Salicylsäure, Nikotinsäure und Heptagluconsäure, in Frage.The physiologically compatible acids are inorganic acids, such as hydrochloric acid, sulfuric acid, nitric acid or phosphoric acid and organic acids, such as acetic acid, propionic acid, lactic acid, succinic acid, tartaric acid, citric acid, Benzoic acid, salicylic acid, nicotinic acid and heptagluconic acid.

Die neuen Verbindungen können in Analogie zu dem im Hauptpatent angegebenen Verfahren hergestellt werden, wobei man von den entsprechenden Ausgangsprodukten mit X in der Bedeutung NH ausgeht.The new compounds can be analogous to that specified in the main patent Process are produced, one of the corresponding starting materials with X meaning NH.

So kann man a) Verbindungen der allgemeinen Formel II worin R1, R2, R3 und R4 die oben angegebene Bedeutung haben und Y eine Hydroxylgruppe, ein Halogenatom oder eine reaktive Estergruppe bedeutet, mit Imidazol oder einem Alkalisalz des Imidazols umsetzen oder b) Verbindungen der allgemeinen Formel III worin R1, R2 und R3 die oben angegebene Bedeutung haben mit einer Verbindung der allgemeinen Formel TV Q - R4 (IV), worin R4 die obenangegebene Bedeutung hat und Q ein Halogenatom oder eine reaktive Estergruppe bedeutet, umsetzen und anschließend gegebenenfalls die nach a) und b) erhaltenen Verbindungen in ihre physiologisch verträglichen Salze überführt.So you can a) compounds of the general formula II in which R1, R2, R3 and R4 have the meaning given above and Y is a hydroxyl group, a halogen atom or a reactive ester group, react with imidazole or an alkali metal salt of imidazole or b) compounds of the general formula III in which R1, R2 and R3 have the meaning given above with a compound of the general formula TV Q - R4 (IV), in which R4 has the meaning given above and Q is a halogen atom or a reactive ester group, and then optionally react with those according to a) and b) the compounds obtained are converted into their physiologically acceptable salts.

Als reaktive Estergruppen kommen vorzugsweise Sulfonyloxygruppen, wie Methansulfonyloxy- und Toluolsulfonyloxygruppen, in Frage.The reactive ester groups are preferably sulfonyloxy groups, such as methanesulfonyloxy and toluenesulfonyloxy groups.

Die Imidazolderivate der allgemeinen Formel I lassen sich sowohl nach Reaktion a) als auch nach Reaktion b) darstellen, vorzugsweise nach b).The imidazole derivatives of the general formula I can be both according to Represent reaction a) as well as after reaction b), preferably according to b).

Die Umsetzung einer Verbindung der allgemeinen Formel II mit Imidazol entsprechend Reaktion a) erfolgt in einem Lösungsmittel, wie z. B. Dimethylformamid, Hexamethylphosphorsäuretriamid, einem aromatischen KohlenwasserstoS wie Benzol oder Toluol, einem äther, wie Diäthyläther, Dioxan, Tetrahydrofuran oder 1,2-Dimethoxyäthan oder einem niederen Alkohol oder in Wasser bei Temperaturen zwischen 0° C und dem Siedepunkt des verwendeten Lösungsmittels, vorzugsweise bei Temperaturen zwischen 200 0 und dem Siedepunkt des verwendeten Lösungsmittels, oder ohne Lösungsmittel bei Temperaturen zwischen 800 C und 2000 C, vorzugsweise zwischen 100 C und 1800 C, gegebenenfalls in Gegenwart eines Katalysators, wie p-Toluolsulfonsäure.The reaction of a compound of the general formula II with imidazole according to reaction a) takes place in a solvent, such as. B. dimethylformamide, Hexamethylphosphoric triamide, an aromatic hydrocarbon such as benzene or Toluene, an ether such as diethyl ether, dioxane, tetrahydrofuran or 1,2-dimethoxyethane or a lower alcohol or in water at temperatures between 0 ° C and the Boiling point of the solvent used, preferably at temperatures between 200 0 and the boiling point of the solvent used, or without a solvent at temperatures between 800 C and 2000 C, preferably between 100 C and 1800 C, optionally in the presence of a catalyst such as p-toluenesulfonic acid.

Das Imidazol kann entweder in freier Form oder in Form des Alkalisalzes, das aus Imidazol und einem Alkalihydrid, Alkaliamid, AlkaliaJkoholat oder Alkalihydroxyd erhalten werden kann, eingesetzt werden.The imidazole can either be in free form or in the form of the alkali salt, that of imidazole and an alkali hydride, alkali amide, alkali alcoholate or alkali hydroxide can be obtained.

Die Umsetzung entsprechend Reaktion b) erfolgt in an sich bekannter Weise, indem die freie Verbindung oder das Alkalisalz der Verbindung der allgemeinen Formel III, das mit einer Alkalibase, wie z. B. einem Alkalihydrid, Alkaliamid, Alkalialkoholat oder Alkalihydroxyd gebildet wird, mit einer Verbindung der allgemeinen Formel IV in einem der obenangegebenen Lösungsmittel bei Temperaturen zwischen 0° C und dem Siedepunkt des verwendeten Lösungsmittels, vorzugsweise zwischen 200 und 700 C, umgesetzt wird, wobei die Reaktion mit der freien Verbindung der allgemeinen Formel III bevorzugt abläuft.The implementation according to reaction b) takes place in a manner known per se Way by adding the free compound or the alkali salt of the compound of general Formula III, with an alkali base, such as. B. an alkali hydride, alkali amide, Alkali alcoholate or alkali hydroxide is formed with a compound of the general Formula IV in one of the solvents indicated above at temperatures between 0 ° C and the boiling point of the solvent used, preferably between 200 and 700 C, is reacted, the reaction with the free compound of the general Formula III preferably expires.

Die Ausgangsverbindungen der allgemeinen Formeln In II und III sind entweder literaturbekannt oder können nach analogen Verfahren aus bekannten Verbindungen dargestellt werden.The starting compounds of the general formulas In II and III are either known from the literature or can be prepared from known compounds by analogous processes being represented.

Die neuen Verbindungen der allgemeinen Formel I sind gut wirksam gegen Dermatophyten, wie Trichophyton rubrum und Trichophyton mentagrophytes, sowie gegen Candida albicans, wie aus der folgenden Tabelle I hervorgeht. Als Vergleichssubstanzen sind l-(l,2,3,4-Tetrahydro-l-naphthyl) -imidazol-5-carbonsäure-äthylester (Etonam) und das im Handel befindliche 2-Dimethylamino-6-(ß-diäthylaminoäthoxy)-benzothiazol, Dihydrochlorid (Dimazol Dihydrochlorid) angegeben. Die MIC-Werte wurden im Röhrchentest ermittelt.The new compounds of general formula I are very effective against Dermatophytes, such as Trichophyton rubrum and Trichophyton mentagrophytes, as well as against Candida albicans, as shown in Table I below. As comparison substances are l- (l, 2,3,4-tetrahydro-l-naphthyl) -imidazole-5-carboxylic acid ethyl ester (Etonam) and the commercially available 2-dimethylamino-6- (ß-diethylaminoethoxy) -benzothiazole, Dihydrochloride (Dimazole Dihydrochloride) indicated. The MIC values were in the tube test determined.

T A B E L L E I S u b s t a n z Minimale Hemmkonzentration MIC in µg/ml gegen Candida albicans Trichophyton mentagrophytes Trichophyton rubrun 1) Etonam [1-(1,2,3,4-Tetrahydro-1- naphthyl)-imidazol-5-carbonsäure- inaktiv 50 50 äthylester] 2) Dimazol Dihydrochlorid [2-Dimethyl- amino-6-(ß-diäthylaminoäthoxy)-benzo- inaktiv inaktiv inaktiv thiozol, Dihydrochlorid] 3) N-(2,4-Dichlorbenzyl)-2-(1-imidazo- 12,5 0,8 0,4 lylmethyl)-anilin 4) N-(2,4-Dichlorbenzyl)-4-(1-imida- 25 12,5 6,3 zolylmethyl)-anilin Wie aus der Tabelle I ersichtlich, weisen die Vergleichssubstanzen keine Wirkung gegen Candida albicans auf. Im Gegensatz zu den Vergleichssubstanzen, von denen eine solche Wirkung nicht bekannt ist, weisen die erfindungsgemäßen Verbinlungen weiterhin eine systemische Wirkung auf.TABLE I. S ubstance Minimum inhibitory concentration MIC in µg / ml against Candida albicans Trichophyton mentagrophytes Trichophyton rubrun 1) Etonam [1- (1,2,3,4-tetrahydro-1- naphthyl) imidazole-5-carboxylic acid inactive 50 50 ethyl ester] 2) Dimazole dihydrochloride [2-dimethyl- amino-6- (ß-diethylaminoethoxy) -benzo- inactive inactive inactive thiozole, dihydrochloride] 3) N- (2,4-dichlorobenzyl) -2- (1-imidazo-12.5 0.8 0.4 lylmethyl) aniline 4) N- (2,4-dichlorobenzyl) -4- (1-imida- 25 12.5 6.3 zolylmethyl) aniline As can be seen from Table I, the comparison substances have no activity against Candida albicans. In contrast to the comparison substances, of which such an effect is not known, the compounds according to the invention continue to have a systemic effect.

Die Anwendung kann in den pharmazeutisch üblichen Applikationsformen erfolgen. Für die orale Applikation kommen insbesondere Tabletten, Dragees, Kapseln, Pillen und Suspensionen infrage. Tabletten enthalten beispielsweise 0,05 bis 0,50 g Wirkstoff und 0,1 bis 5 g eines pharmakologisch indifferenten Hilfsstoffes. Als Hilrsstoffe werden beispielsweise für Tabletten verwendet: Milchzucker, Stärke, Talkum, Gelatine, Magnesiumstearat usw.It can be used in the usual pharmaceutical administration forms take place. Tablets, coated tablets, capsules, Pills and suspensions in question. For example, tablets contain 0.05 to 0.50 g of active ingredient and 0.1 to 5 g of a pharmacologically inert excipient. as Ingredients are used for tablets, for example: lactose, starch, Talc, gelatin, magnesium stearate, etc.

Die neuen Wirkstoffe sollen in Mengen zwischen 0,1 und 4,0 g pro Patient und pro Tag angewendet werden.The new active ingredients should be in amounts between 0.1 and 4.0 g per patient and applied per day.

Die folgenden Beispiele sollen das erfindungsgemäße Verfahren näher erläutern.The following examples are intended to explain the process according to the invention in more detail explain.

Beispiel 1 N-(2,4-Dichlorbenzyl)-2 (l-imidazolylmethyl)-anilin 6,9 g Imidazol werden in 100 ml Dimethylformamid gelöst und mit 3 g einer 80 zeigen Natriumhydrid-Ölsuspension versetzt. Nach 30 Minuten Rühren bei Raumtemperatur gibt man 17,1 g 2-Nitrobenzylchlorid, gelöst in 50 ml Dlmethylformamid, zu der Lösung und läßt eine Stunde bei Raumtemperatur rühren. Dann gießt man das Gemisch in 500 ml 1 N Salzsäure, filtriert, extrahiert die klare Lösung mit Ather und macht anschließend die wäBrige Phase mit 40 %iger Natronlauge alkalisch. Man extrahiert mit Methylenchorid, trocknet die organische Phase und erhält nach Eindampfen des Lösungsmittels ein Rohprodukt, das durch zweimalige Vakuumdestillation bei 100 - 1100 C (Luftbadtemperatur)/ 0,03 Torr am Kugelrohr gereinigt.wird. Schmelzpunkt 80 -82° C. Ausbeute 12,6 g 1-(2-Nitrobenzyl)-imidazol. Dieses Produkt wird bei 100° C in 50 ml konzentrierter Salzsäure gelöst, dann mit 60 g Zinn(II)-chlorid-dihydrat, gelöst in 50 ml konzentrierter Salzsäure, versetzt und so lange bei 1000 C erwärmt, bis die Lösung klar ist.- Nach dem Abkühlen gießt man in eine Lösung von 200 g Natriumhydroxyd in 500 ml Wasser langsam ein und extrahiert mit Methylenchlorid. Nach Destillation am Kugelrohr (120 - 1300 C/0,03 Torr) erhält man 9 g 2-(1-Imidazolylmethyl)-anilin. Das Produkt wird in 100 ml Dimethylformamid gelöst und mit 10 g 2,4-Dichlorbenzylchlorid versetzt. Nach 20 Stunden Rühren bei Raumtemperatur gießt man auf 300 ml l N Salzsäure, extrahiert mit Äther, macht die wäßrige Phase mit Natronlauge alkalisch und extrahiert mit Chloroform. Nach Trocknen und Eindampfen der organischen Phase erhält man ern Rohprodukt, das nach Umkristallisieren aus Benzol 8,5 g N-(2,4-Dichlorbenzyl) -2-(1-imidazolylmethyl)-anilin vom Sehmelzpunkt 149 - 1510 c gibt.Example 1 N- (2,4-dichlorobenzyl) -2 (1-imidazolylmethyl) aniline 6.9 g of imidazole are dissolved in 100 ml of dimethylformamide and show an 80 with 3 g Sodium hydride oil suspension added. After stirring for 30 minutes at room temperature there is 17.1 g of 2-nitrobenzyl chloride, dissolved in 50 ml of dimethylformamide, are added to the solution and let stir for one hour at room temperature. Then the mixture is poured into 500 ml of 1 N hydrochloric acid, filtered, the clear solution extracted with ether and then made the aqueous phase is alkaline with 40% sodium hydroxide solution. Extract with methylene chloride, the organic phase dries and is obtained after evaporation of the solvent Crude product obtained by vacuum distillation twice at 100 - 1100 C (air bath temperature) / 0.03 Torr on the spherical tube. Is cleaned. Melting point 80-82 ° C. Yield 12.6 g of 1- (2-nitrobenzyl) imidazole. This product is dissolved in 50 ml of concentrated hydrochloric acid at 100 ° C., then with 60 g of tin (II) chloride dihydrate, dissolved in 50 ml of concentrated hydrochloric acid, are added and heated at 1000 C until the solution is clear. After cooling, pour is slowly introduced into a solution of 200 g of sodium hydroxide in 500 ml of water and extracted with methylene chloride. Obtained after distillation on a Kugelrohr (120-1300 C / 0.03 Torr) 9 g of 2- (1-imidazolylmethyl) aniline. The product is in 100 ml of dimethylformamide dissolved and mixed with 10 g of 2,4-dichlorobenzyl chloride. After stirring for 20 hours at Room temperature it is poured into 300 ml of 1 N hydrochloric acid and extracted with ether, make the aqueous phase alkaline with sodium hydroxide solution and extracted with Chloroform. After drying and evaporation of the organic phase, a crude product is obtained, after recrystallization from benzene, 8.5 g of N- (2,4-dichlorobenzyl) -2- (1-imidazolylmethyl) aniline from Sehmelzpunkt 149 - 1510 c.

B e i s p i e l 2 N-(2,4-Dichlorbenzyl)-4-(1-imidazolylmethyl)-anilin.For example, 2 N- (2,4-dichlorobenzyl) -4- (1-imidazolylmethyl) aniline.

Analog Beispiel 1 aus 4-Nitrobenzylchlorid.Analogously to Example 1 from 4-nitrobenzyl chloride.

Schmelzpunkt bei 117 - 118° zu c (aus Methylenchlorid/Äther).Melting point at 117 - 118 ° to c (from methylene chloride / ether).

B e i s p i e l 3 N-(3,4-Dichlor-α-methyl-benzyl)-2-(1-imidazolylmethyl)-anilin.For example 3 N- (3,4-dichloro-α-methyl-benzyl) -2- (1-imidazolylmethyl) aniline.

6,9 g Imidazol werden in 100 ml Dimethylformamid gelöst und mit 3 g einer 80 %igen Natriumhydrid-Ölsuspension versetzt. Nach 30 Minuten Rühren bei Raumtemperatur gibt man 17,1 g 2-Nitrobenzylchlorid, gelöst in 50 ml Dimethylformamid, zu der Lösung und läßt eine Stunde bei Raumtemperatur rühren. Dann gießt man das Gemisch in 500 ml 1 N Salzsäure, filtriert, extrahiert die klare Lösung mit Äther und macht anschließend die wäßrige Phase mit 40 %iger Natronlauge alkalisch. Man extrahiert mit Methylenchlorid, trocknet die organische Phase und erhält nach Eindampfen des Lösungsmittels ein Rohprodukt, das durch zweimalige Vakuumdestillation bei 100 - 110° C (Luftbadtemperatur)/0,03 Torr am Kugelrohr gereinigt wird. Schmelzpunkt 80 - 820 C. Ausbeute 12,6 g 1-(2-Nitrobenzyl)-imidazol. Dieses Produkt wird bei 1000 C in 50 ml konzentrierter Salzsäure gelöst, dann mit 60 g Zinn(II)-chlorid-dihydrat, gelöst in 50 ml konzentrierter Salzsäure, versetzt und so lange bei 100° C erwärmt, bis die Lösung klar ist.6.9 g of imidazole are dissolved in 100 ml of dimethylformamide and mixed with 3 g of an 80% sodium hydride oil suspension are added. After stirring for 30 minutes at 17.1 g of 2-nitrobenzyl chloride, dissolved in 50 ml of dimethylformamide, are added to room temperature, to the solution and allowed to stir for one hour at room temperature. Then you pour that Mixture in 500 ml of 1N hydrochloric acid, filtered, and the clear solution extracted with ether and then makes the aqueous phase alkaline with 40% sodium hydroxide solution. Man extracted with methylene chloride, the organic phase is dried and obtained after evaporation of Solvent a crude product, which by vacuum distillation twice at 100 - 110 ° C (air bath temperature) / 0.03 Torr is cleaned on the bulb tube. Melting point 80 - 820 C. Yield 12.6 g of 1- (2-nitrobenzyl) imidazole. This product is sold at 1000 C dissolved in 50 ml of concentrated hydrochloric acid, then with 60 g of tin (II) chloride dihydrate, dissolved in 50 ml of concentrated hydrochloric acid, added and heated at 100 ° C for so long, until the solution is clear.

Nach dem Abkühlen gießt man in eine Lösung von 200 g Natriumhydroxld in 500 ml Wasser langsam ein und extrahiert mit Methylenchlorid. Nach Destillation am Kugelrohr (120 -1300 C/0,03 Torr) erhält man 9 g 2-(1-Imidazolylmethyl)-anilin. Das Produkt wird in 100 ml Dimethylformamid gelöst und mit 11 g 3,4-Dichlor-α-methyl-benzylchlorid versetzt. After cooling, it is poured into a solution of 200 g of sodium hydroxide slowly in 500 ml of water and extracted with methylene chloride. After distillation 9 g of 2- (1-imidazolylmethyl) aniline are obtained on a bulb tube (120-1300 C / 0.03 Torr). The product is dissolved in 100 ml of dimethylformamide and mixed with 11 g of 3,4-dichloro-α-methyl-benzyl chloride offset.

Nach 20 Stunden Rühren bei Raumtemperatur gießt man auf 300 ml 1 N Salzsäure, extrahiert mit Äther, macht die wäßrige Phase mit Natronlauge alkalisch und extrahiert mit Ch.loroform Nach Trocknen und Eindampfen der organischen Phase erhält man 7,1 g des gewünschten Produkts als gelbliches Öl. After stirring for 20 hours at room temperature, it is poured into 300 ml of 1 N hydrochloric acid, extracted with ether, makes the aqueous phase alkaline with sodium hydroxide solution and extracted with chloroform. After drying and evaporation of the organic phase 7.1 g of the desired product are obtained as a yellowish oil.

Analyse berechnet C 61,0 H 5,10 N 12,6 gefunden C 59,5 H 5,25 N 12,9 Analysis calculated C 61.0 H 5.10 N 12.6 found C 59.5 H 5.25 N 12.9

Claims (5)

Patentansprüche Verbindungen der allgemeinen Formel I gemäß Hauptpatent * . . . . . . . . (Patentanmeldung P 24 18 502.2), worin X NH bedeutet und R1, R2, R3 und R4 die im Hauptpatent angegebene bedeutung haben sowie deren Salze mit physiologisch verträglichen Säuren.Claims Compounds of the general formula I according to main patent *. . . . . . . . (Patent application P 24 18 502.2), in which X is NH and R1, R2, R3 and R4 have the meaning given in the main patent and their salts with physiologically acceptable acids. 2) N-(2,4-Dichlorbenzyl)-2-(1-imidazolylmethyl)-anilin.2) N- (2,4-dichlorobenzyl) -2- (1-imidazolylmethyl) aniline. 3) N-(2,4-Dichlorbenzyl)-4-(1-imidazolylmethyl)-ani lin .3) N- (2,4-dichlorobenzyl) -4- (1-imidazolylmethyl) ani lin. 4) N-(3,4-Dichlor-α-methyl-benzyl)-2-(1-imidazolylmethyl)-anilin.4) N- (3,4-dichloro-α-methyl-benzyl) -2- (1-imidazolylmethyl) aniline. 5) Arzneimittel, gekennzeichnet durch den Geahlt an einer oder mehrerer Verbindungen der Ansprüche 1 - 6) Verfahren zur Herstellung von Imidazolderivaten der allgemeinen Formel I durch gekennzeichnet, daß man a) Verbindungen der allgemeinen Formel II worin R1, R2, H3 und R4 die obenangegebene Bedeutung haben und Y eine Hydroxylgruppe, ein Halogenatom oder eine reaktive Estergruppe bedeutet, mit Imidazol oder einem Alkalisalz des Imidazols umsetzt oder b) Verbindungen der allgemeinen Formel III worin R1 R2 und R3 die obenangegebene Bedeutung haben mit einer Verbindung der allgemeinen Formel IV Q - R4 (IV), worin R4 die obenangegebene Bedeutung hat und Q ein Halogenatom oder eine reaktive Estergruppe bedeutet, umsetzt und anschließend gegebenenfalls die nach a) und b) erhaltenen Verbindungen in ihre physiologisch verträglichen Salze überführt.5) Medicines, characterized by the fact that one or more compounds of claims 1-6) Process for the preparation of imidazole derivatives of the general formula I, characterized in that a) compounds of the general formula II in which R1, R2, H3 and R4 have the meaning given above and Y is a hydroxyl group, a halogen atom or a reactive ester group, is reacted with imidazole or an alkali metal salt of imidazole, or b) compounds of the general formula III in which R1, R2 and R3 have the meaning given above with a compound of the general formula IV Q - R4 (IV), in which R4 has the meaning given above and Q is a halogen atom or a reactive ester group, and then optionally reacts the according to a) and b) The compounds obtained are converted into their physiologically acceptable salts.
DE19752510130 1974-04-11 1975-03-06 Imidazolyl alkyl-phenyl - (thio) ethers - active against dermatophytes, yeasts, protozoa bacterial and fungal diseases Pending DE2510130A1 (en)

Priority Applications (20)

Application Number Priority Date Filing Date Title
DE19752510130 DE2510130A1 (en) 1975-03-06 1975-03-06 Imidazolyl alkyl-phenyl - (thio) ethers - active against dermatophytes, yeasts, protozoa bacterial and fungal diseases
IE780/75A IE40911B1 (en) 1974-04-11 1975-04-08 Imidazole derivatives and process for their manufacture
CS752431A CS194221B2 (en) 1974-04-11 1975-04-09 Method of producing novel derivatives of aryl-and aralkylimidazole
DD185337A DD121515A5 (en) 1974-04-11 1975-04-09
AT268675A AT341518B (en) 1974-04-11 1975-04-09 PROCESS FOR THE PREPARATION OF NEW IMIDAZOLE DERIVATIVES AND THEIR SALT
YU00898/75A YU89875A (en) 1974-04-11 1975-04-09 Process for obtaining imidazole derivatives
DK153075A DK139909C (en) 1974-04-11 1975-04-09 ANALOGICAL PROCEDURE FOR PREPARING IMIDAZOLE DERIVATIVES
AU80025/75A AU496423B2 (en) 1975-04-10 Imidazole derivatives and process for their manufacture
IL7547061A IL47061A (en) 1974-04-11 1975-04-10 1-aryl and aralkyl imidazole derivatives and process for their manufacture
HU75SC00000516A HU172895B (en) 1974-04-11 1975-04-10 Process for producing imidazol derivatives
SE7504123A SE418498B (en) 1974-04-11 1975-04-10 SET TO MAKE IMIDAZOLD DERIVATIVES
CH457575A CH612185A5 (en) 1974-04-11 1975-04-10
CA224,402A CA1051908A (en) 1974-04-11 1975-04-11 Imidazole derivatives and process for their manufacture
ES75436546A ES436546A1 (en) 1974-04-11 1975-04-11 Amino-, mercapto- and -oxy-substituted-phenyl and -phenalkyl imidazoles
JP50044147A JPS6018654B2 (en) 1974-04-11 1975-04-11 Production method of imidazole derivatives
NL7504387A NL7504387A (en) 1974-04-11 1975-04-11 PROCEDURE FOR THE PREPARATION OF A MEDICINAL PRODUCT INCLUDING ANTI-DERMATOPHYTIC AND ANTI-BACTERIA ACTION.
FR7511415A FR2267101B1 (en) 1974-04-11 1975-04-11
US05/567,361 US4006243A (en) 1974-04-11 1975-04-11 Amino-, mercapto- and -oxy-substituted-phenyl and -phenalkyl imidazoles
GB15012/75A GB1510016A (en) 1974-04-11 1975-04-11 Imidazole derivatives and process for their manufacture
AT80677A AT352117B (en) 1974-04-11 1977-02-07 PROCESS FOR THE PRODUCTION OF NEW IMIDAZOLE DERIVATIVES AND THEIR SALT

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0003796A1 (en) * 1978-02-24 1979-09-05 Bayer Ag Substituted diphenylmethyl-imidazoles, their preparation and medicaments containing them
DE3235589A1 (en) 1982-09-25 1984-03-29 Hoechst Ag, 6230 Frankfurt BENZYL ETHER FROM PHENOL-MANNICH-BASEN, METHOD FOR THE PRODUCTION THEREOF, THEIR USE AND PHARMACEUTICAL PREPARATIONS BASED ON THESE COMPOUNDS, INTERMEDIATE PRODUCTS AND METHOD FOR THE PRODUCTION THEREOF
EP0186190A2 (en) * 1984-12-24 1986-07-02 Sumitomo Chemical Company, Limited Benzimidazole derivatives, and their production and use

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0003796A1 (en) * 1978-02-24 1979-09-05 Bayer Ag Substituted diphenylmethyl-imidazoles, their preparation and medicaments containing them
DE3235589A1 (en) 1982-09-25 1984-03-29 Hoechst Ag, 6230 Frankfurt BENZYL ETHER FROM PHENOL-MANNICH-BASEN, METHOD FOR THE PRODUCTION THEREOF, THEIR USE AND PHARMACEUTICAL PREPARATIONS BASED ON THESE COMPOUNDS, INTERMEDIATE PRODUCTS AND METHOD FOR THE PRODUCTION THEREOF
EP0186190A2 (en) * 1984-12-24 1986-07-02 Sumitomo Chemical Company, Limited Benzimidazole derivatives, and their production and use
EP0186190A3 (en) * 1984-12-24 1988-04-06 Sumitomo Chemical Company, Limited Benzimidazole derivatives, and their production and use

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