DD214129A5 - PROCESS FOR THE PREPARATION OF NEW ARYLPHENYL ETHER DERIVATIVES - Google Patents

Abstract

The invention relates to a process for the preparation of novel arylphenyl ether derivatives for use as medicaments. The aim of the invention is to provide novel compounds with anticonvulsant and / or anxiolotic and antidepressant and / or antifungal activity. According to the invention, arylphenyl ether derivatives of the formula I are prepared in which, for example: R is C-lower-C-lower-alkyl; Rtiefa and Rtiefb independently of one another are hydrogen, halogen, or Ctief1-Ctief3-alkyl; Ar unsubstituted or substituted by halogen, Ctief1-Ctief3-alkoxy and / or trifluoromethyl mono- or polysubstituted phenyl; U and V independently of each other optionally substituted by halogen or Ctief1-Ctief12-alkyl u.a. Formula.

Description

Berlin, 30.3.1984 AP G 07 D / 256 720/6 63 196/11

Process for the preparation of novel arylphenyl ether derivatives Field of application of the invention

The present invention relates to a process for the preparation of novel substituted arylphenyl ether derivatives having valuable pharmacological, in particular anticonvulsive and / or cariolotic and antidepressant and / or antifungal properties,

The compounds according to the invention are used as medicaments, for example, j aur control of parasitic on warm-blooded animals Plzen and / or for the treatment of various Pormen epilepsy, you anxiety, tension and Erregungsauständen and / or manic states of mind "

Characteristic of the known technical solutions

U.S. Patent Nos. 3,575,999, 3,936,470, 3,101,664, 4,101,666, 4,156,008 cite 1- (3-aryl) ethyl imidazolyl ketals in which aryl is substituted phenyl or naphthyl as fungicides and bactericides ,

Aim of the invention;

The aim of the invention is to provide novel compounds with valuable pharinakologischen properties, in particular with anticonvulsive and / or anxiolotic and antidepressant and / or antimycotic effect »

-1- 30.3 »1984

AP C 07 D / 256 720/6 63 196/11

presentation; the essence of the invention; , ,

The invention has the object augrunde to find new Arylphenylether-Berivate with the desired properties and processes au their preparation »

According to the invention, arylphenyl ether derivatives of the formula I

R IL

L ⁷ \

Ar-O- ί ° -C 0

V-4- J

GH ₀ -IJR (I)

R _b

made, v / orin

R is Cj-Cg-alkyl;

R_ and Κ independently of one another are hydrogen, halogen or

e U.

C.-G - alkyl;

Ar is phenyl which is unsubstituted or phenyl which is monosubstituted or polysubstituted by halogen, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy and / or trifluoromethyl;

U and V independently of each other optionally by halogen or

C -, - C, alkoxy-substituted C ₁ -C ₁₀ -AlkVl or together are an i. ο 1 lz

the following alkylene bridges

/ \, 1 -j-R or ^β H, where

R and R independently of one another represent hydrogen, C 1 -C 4 -alkyl, C 1 -C 4 -alkyl which is monosubstituted or polysubstituted by halogen, phenyl,

i. Lu

one or more times, are by halogen and / or C -C alkyl-substituted phenyl or represents the group -CH ₀ -ZR, wherein Z is oxygen or sulfur and

R _{7 is} hydrogen, C -C -alkyl, a C 1 -C 4 -alkoxy-substituted LZ

C 1 -C 4 -alkyl, C 2 -C 4 -alkenyl, 2-propynyl, 3-halogeno-2-propynyl, phenyl, a halogen by halogen, C 2 -C 4 -alkyl, C 2 -C 4 -alkoxy, nitro and / or CF_ or polysubstituted phenyl, benzyl or benzyl mono- or polysubstituted by halogen, C 1 -C 4 -alkyl and / or C 1 -C 4 -alkoxy;

R, R, and R_ are independently hydrogen or C, -C _y alkyl, wherein the total number of carbon atoms in R, R, and R_ not exceed the number 6, and

R is hydrogen or C ₁ -C -alkyl; including their acid addition salts.

The substituent Ar has, for example, the formula

R η ι c

- "5 -

wherein R R and R are independently hydrogen, halogen, cd e

C ₁ -C 4 alkyl, C ₁ -C 4 alkoxy or trifluoromethyl.

The term alkyl itself or as a constituent of another substituent, depending on the number of carbon atoms given, is understood to mean, for example, the following groups: methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl or dodecyl and their isomers such as Isopropyl, isobutyl, tert -butyl, sec -butyl, isopentyl, etc. Alkenyl is e.g. for propenyl (1), allyl, butenyl (1), butenyl (2) or butenyl (3). Halogen is here and in the following fluorine, chlorine, bromine or iodine, preferably chlorine or bromine, mean.

The invention relates both to the free compounds of formula I, as well as their addition salts with inorganic and organic acids.

Salts according to the invention are in particular addition salts with physiologically acceptable inorganic or organic acids.

Physiologically acceptable acids, i. pharmaceutically acceptable acids are, for example, pharmaceutically acceptable mineral acids such as hydrohalic acids, e.g. Hydrochloric, hydrobromic or hydroiodic acid, nitric acid, sulfuric acid or phosphoric acid, pharmaceutically acceptable carboxylic and sulphonic acids, such as aliphatic mono- and optionally hydroxylated dicarboxylic acids, e.g. Acetic acid, fumaric acid, maleic acid, malic acid or tartaric acid, as well as aliphatic or aromatic sulfonic acids, such as lower alkane or optionally substituted benzenesulfonic acid, z.3. Methane, ethane, benzene, p-toluene and p-bromobenzenesulfonic acid, further sulfamic acids, e.g. N-Cyclohexylsulphamic.

The compounds of formula I are stable at room temperature oils, resins or solids, which are characterized by valuable pharmacological,

03/30/1984

AP G 07 D / 256 720/6

63 196/11

especially anticonvulsive and / or anxiolotic, also antidepressant and / or antifungal properties. They can therefore be used as anticonvulsants and / or anxiolytics, as well as antidepressants and / or antimycotics, for example for controlling parasitic pests on warm-blooded animals and / or for the treatment of various forms of epilepsy, anxiety, tension and excitation states and / or of use manic states of mind *

The invention relates, for example, to the preparation of compounds of the formula I in which R, R and R have the meanings indicated, Ar is a group of the formula

represents, in which R ^, R, and R _{0 are} independently hydrogen, halogen, irifluoromethyl, G -C., - Alkyl or C ₁ -G - alkoxy and Ü and V independently of each G.-Gg-alkyl or by Halogen or C.-C ₂ alkoxy-substituted Gp-G ^ alkyl or together one of the following Aikyiengruppen

or

, wherein R ^, R ^ _p5 R, R, and R.- independently hydrogen or C.-C, alkyl, wherein the total number of carbon atoms of R _Q, R ₁ and R 6 does not exceed

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A? C 0? D / 256 720/6 63 196/11

or R _{1 is} hydrogen and R is a group of the formula CH ₂ OR "in which R _{7 is} C 1 -C 4 -alkyl, C ₂ -C -alkyl substituted by G ₁ -C ₂ -alkoxy, C ₃ -C 4 -alkyl, C4 alkenyl or prop-2-ynyl, including their acid addition salts.

Compounds with markedly useful anticonvulsant and anxiolytic properties are those in which R has the meaning given under formula I, R and R independently of one another are hydrogen, methyl, chlorine or bromine, Ar is phenyl which is unsubstituted or substituted by halogen, methyl or trifluoromethyl and U and Y independently of one another are C ₁ -C -alkyl, C ₂ -C -alkyl optionally substituted by halogen or C ₁ -C ₂ -alkyl, or together one of the following alkylene groups

RR ₂ \ / or

form, wherein R .., R _2, R, R. and R are each independently hydrogen or C -C.-alkyl, wherein the total number of carbon atoms in R _0, R, and R _c, the number 4 is not

J 4 Ό

should exceed.

As 3ine v / urther preferred group of pronounced anticonvulsive and anxiolytic compounds are the highlight, wherein R has the meaning given under the Pormel I, R ^ and R, _Q are hydrogen, Ar is unsubstituted or substituted by halogen or methyl substituted phenyl and U as well as V together a group of the formula

- ζ _

/ 2, · · · or

in which R is C -C -alkyl, such as methyl or ethyl, hydroxy

C 1 -C 4 -alkyl, such as hydroxymethyl or 2-hydroxyethyl, or C 2 -C 4 -alkoxy-X-J 12

C is -C -alkyl, such as methoxymethyl or ethoxymethyl.

The following compounds may be mentioned as examples of compounds which are particularly preferred with regard to their anticonvulsant, antidepressant and / or anxiolytic properties:

2- [p-ip-chlorophenoxy) phenyl] -2- [1- (2-methylimidazolyDmethyl] -4-ethyl-l, 3-dioxolane,

2- (p-phenoxyphenyl) -2- [1- (2-methylimidazolyDmethyl] -4-methyl-l, 3-dioxane,

2- [4- (p-chlorophenoxy) -2-methyl-pheny1] -2- [1- (2-methylimidazolyl) methyl] -4-methyl-l, 3-dioxolane,

2- [4- (p-chlorophenoxy) -2-methyl-phenyl] -2- [l- (2-methylimidazolyl) methyl] -4-ethy1-1,3-dioxolane,

2- [p- (m-chlorophenoxy) phenyl] -2- [1- (2-methylimidazolyl) methyl] -4-ethyl-1,3-dioxolane,

2- (2-chloro-4-phenoxy-phenyl) -2- [l- (2-methylimidazolyl} methyl] -4-ethyldioxolan,

2- [p- (p-chlorophenoxy) phenyl] -2- [1- (2-methylimidazolylmethyl) -1,3-dioxane,

2- [p- (4-chloro-3-methyl-phenoxy) phenyl] -2- [l- (2-methylimidazolyl) methyl] -4-methoxymethyl-l, 3-dioxolane,

- 6 - 2- (p-phenoxyphenyl) -2- [l- (2-methyli _m idazolyl) methyl] -4-propyl-di-

οχοlan and

2- [p- (2,4-dichlorophenoxy) phenyl] -2- [1- (2-methylimidazolyl) methyl] -4-ethyl-1,3-dioxolane

and in each case their pharmaceutically usable acid addition salts. More particularly, the invention relates to these, to processes for their preparation, to pharmaceutical compositions containing them and to their use as pharmaceutical active ingredients.

The compounds of the formula I can be prepared by reacting A) a compound of the formula II

(ID

wherein Y represents hydrogen or a metal cation, with a compound of formula III

wherein X represents a nucleofugic leaving group, condensed or B) in a compound of formula IV

Ar-O-, - C-

R a

• N =

- / - f-R (IV)

H °

the carbonyl group into a group of the formula V

! I U -ν

convicted, or

C) for the preparation of compounds of formula I, wherein U and V together represent a group of the formula -CH-CH (CH ZR ^.) - and R 'is a radical other than hydrogen R ₇ , compounds de:

Formulas VI and .VII R

I ^a Ar-O- ·

X, / / \ "" 2 'XTK (VI) and X ₀ -R ₇ (VII), 10 0

Tj X ^ S

wherein one of the radicals X ₁ and X "optionally present in salt hydroxy or mercapto, for example of the formula -ZY in which Y is hydrogen or preferably a metal cation, and other a nucleofuge leaving group X, or both X, and X-hydroxy groups represent, condensed with each other or

D) Compounds of the formulas VIII and IX

Ar-X ₃ (VIII) and X ₄ - ^{7 X} , & CH "- <- f" * (IX),

U V

wherein one of X_ and X represents a group -O-Y in which Y 'is hydrogen or preferably a metal cation and the other represents an aryloxy-substitutable radical, or E) a compound of the formula

R_

a 0 I 0

_Ar _ ₀ _ _c _0-. _{: Ä} cH "- <L (X)

decarboxylated intramolecularly and, if desired, converts a compound obtainable according to the method into another compound of the formula I and / or a free compound obtainable in accordance with the method in an acid addition salt, an acid addition salt obtainable according to the method into the free compound or into another acid addition

transferred salt.

Metal cations Y are, for example, alkali metal, e.g. Lithium, sodium or potassium cations, or alkaline earth metal, e.g. Magnesium, calcium, strontium or barium cations.

N ^T ukleofuge leaving groups are, for example, reactive esterified hydroxy groups, such as, Rait a hydrohalic acid, for example with fluorine, chlorine, bromine or hydriodic acid, or a lower alkanoic, optionally substituted benzene or halosulfonic acid, for example with methane-, ethane-, benzene- p-toluene or fluorosulfonic acid, esterified hydroxy groups.

The reaction of an azole of the formula II, wherein R has the meaning given under formula I and Y is preferably a metal atom, in particular an alkali metal atom, with a compound of formula III, wherein Ar, R, IL, U and V are the lower formula I have the meanings given and X is, for example, halogen, in particular chlorine, bromine or iodine, or benzenesulfonyloxy, p-tosyloxy, trifluoroacetyloxy or preferably lower alkylsulfonyloxy, for example Mesyloxy, is preferably carried out in a relatively polar but reaction-inert organic solvent, e.g. Ν, Ν-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide, acetonitrile, benzonitrile and others. Such solvents may be used in combination with other reaction inert solvents such as aliphatic or aromatic hydrocarbons, e.g. Benzene, toluene, xylene, hexane, petroleum ether, chlorobenzene, nitrobenzene, and the like. be used.

If X is chlorine or bromine, then zirconium may be added to alkali iodide (such as NaJ or KJ) to accelerate the reaction. Elevated temperatures of 0 to 22O ° C, preferably S0-170 ° C, are advantageous. The reaction mixture is expediently heated under reflux.

In cases where in formula II Y is hydrogen, the process is carried out in the presence of a base. Examples of such bases are inorganic bases such as the oxides, hydroxides, hydrides, carbonates and bicarbonates of alkali and alkaline earth metals and e.g. tert. Amines such as triethylamine, triethylenediamine, piperidine, pyridine, 4-dimethylaminopyridine, 4-pyrrolidylpyridine, etc.

In this and the following preparation variants, the intermediate and final products can be isolated from the reaction medium and, if desired, purified by one of the commonly used methods, e.g. by extraction, crystallization, chromatography, distillation etc.

The conversion of the carbonyl group in compounds of formula IV into the group of formula V is carried out by reaction with an orthocarboxylic acid tri-C, -C-alkyl esters, whose C, -C alkyl groups optionally substituted by halogen or C, -C.-alkoxy are, or in the presence of an acid with at least 2 moles of a monohydric alcohol of the formula U-OH (Va), wherein compounds of formula I are obtained wherein U and V are the same, optionally substituted C .. -C "alkyl groups, or by reaction with a diol of the formula Vb

HO-U V-OH (Vb) ₅

wherein compounds of the formula I are obtained, wherein U and V commonly represent one of the above-defined alkylene bridges. there

Ar, R, R, R, U and V have the meanings given under formula I, a D

This ketalization reaction can be carried out analogously to previously known ketalization reactions, for example analogously to the preparation of 2-3rommethyl-2,4-diphenyl-1,3-dioxolane [Synthesis, 1974 (D, 23].

- 10 -

In the preferred embodiment of ketalization, both reactants are refluxed for several hours together with an azeotrope former in one of the common organic solvents. As azeotrope formers, e.g. Benzene, toluene, xylene, chloroform or carbon tetrachloride, with the addition of a strong acid, e.g. p-Toluolsulfonsaure, may be advantageous. Useful organic solvents in this case are e.g. aromatic hydrocarbons, such as benzene, toluene, xylene, etc., saturated hydrocarbons, such as η-hexane or saturated halogenated hydrocarbons, e.g. 1,1,1-trichloroethane.

Other ways of ketalization are also feasible, e.g. by reacting a ketone IV, which is ketalized with an alcohol or phenol other than alkanols or diols of the formulas Va or Vb, and reprecipitates this by reaction with excess alkanol Va or the diol Vb to give (I). The starting product is e.g. according to one of the process variants A), D) and E) accessible.

The preparation of compounds of the formula I in which substituents U and V according to variant C) together represent TCH ₇ -CH (CK ₇ ZR ₇ ) - takes place, for example, by reaction of a compound of the formula VI with a compound of the formula VII in which X is _{1 is} a group -ZH and X _{7 is} a group X. The reaction is preferably carried out in reaction-inert organic solvents. N, N-dimethylformamide, N, N-dimethylacetamide, hexamethylphosphortriamide, dimethylsulfoxide, 4-methyl-3-pentanone, etc. are also suitable for this purpose. Mixtures with other reaction-inert solvents, for example with aromatic hydrocarbons such as benzene, toluene, xylene, etc . can be used. In some cases it may be advantageous to work to accelerate the reaction rate in the presence of a base. Such bases are, for example, alkali metal hydrides or alkali metal carbonates. In certain cases, it may also be advantageous that the compound VI is first converted in a known manner into a suitable metal salt.

- 11 -

This is preferably done by reaction of VI with a Na compound, for example, sodium hydride, sodium hydroxide, etc. Subsequently, this salt of VI is reacted with the compound of formula VII. To increase the reaction rate can be used in some cases, even at elevated temperature, preferably 80 ⁰ C to 130 ⁰ C, or at the boiling point of the solvent.

In an analogous manner, compounds of the formulas VI and VII in which X is a group X and X "is a group -ZH can also be reacted.

In the condensation reaction of compounds of formulas VI and VII wherein X and X are hydroxy leading to products of formula I wherein Z is oxygen, the reactants can be refluxed in a suitable solvent, with concomitant azeotropic evolution of the resulting water is distilled off from the reaction mixture. Suitable solvents are aromatic hydrocarbons, such as toluene or alcohol HO-R itself. In this reaction, it is convenient to work in the presence of a strong acid, e.g. p-toluene sulfonic acid.

In variant D), preference is given to compounds of the formulas VIII and IX in which X- is a group -OY and X, a nucleofugic leaving group or vice versa, X_ represents the nucleofuge leaving group and X, the group -OY. Here, R, R, U, V, R and Ar have the meanings given under formula I; Y is preferably hydrogen. The reaction is advantageously carried out under the conditions described in variant A).

In variant E), the compound of the formula X to be decarboxylated, obtainable by ketalization of a compound of the formula XI,

analogously as described under B),

i ^a ° Ar-OCOf Vc-CH -N ^ (XI),

- 12 -

which in turn is prepared by reacting a compound of the formula Ar-OH XII with a difunctional derivative of carbonic acid, e.g. with phosgene, a Halogenameisensäureniederalkylester or a Diniederallyl- or diphenyl carbonate and further reaction with a compound of formula XIII fa ο

T *

HO- '' NC-CH ₂ -N 1 -J -R (XIII)

can be obtained, dry or in a high boiling solvent, such as a high boiling ether, e.g. Diphenyl ether or ethylene glycol dimethyl ether, heated to about 120 ° to 22O ° C.

Compounds available in the process can be converted into other compounds of the formula I by methods known per se.

Thus, it is possible, for example, to quaternize compounds obtainable according to the method according to the invention with other compounds of the formula I. For example, in compounds of the formula I in which U and V are identical, optionally substituted, C 1 -C 4 -alkyl radicals U, by reaction with 10 mol of another, optionally substituted C ₁ -C 6 -alkanol of the formula V-OH (Vc), a group U replaced by a group V or by reaction with a diol of the formula Vb both groups U by a bivalent radical. The Umketalisierung carried out in a conventional manner, for example in the presence of an acidic condensing agent such as a mineral, sulfonic or strong carboxylic acid, for example of chloro or hydrobromic acid, sulfuric acid, p-toluenesulfonic acid or trifluoroacetic acid, - advantageously with distillative or azeotropdestillativer removal of volatile reaction products.

Further, in the carbocyclic aryl parts according to the method obtainable compounds optionally additional substituents

- 13 -

into the radical Ar and / or the groups R and K, respectively. For example, by reaction, it is never possible to introduce halogen into a halogen in the presence of a Lewis acid, such as an iron, zinc, boron or antimony halide, or by treatment with N-chlorosuccinimide.

Furthermore, nitro groups, e.g. by means of suitable complex hydrides, e.g. with lithium aluminum hydride, reduce to amines, these, e.g. by means of nitrous acid, diazotize and replace the diazonium group formed in the usual way by halogen or alkoxy. Similarly, halogen may be reacted by reaction with an alkyl metal compound, e.g. with an alkyllithium or alkylmagnesium halide, replace with alkyl.

The starting ketals of the formula III can be prepared from the underlying methylaryl ketone of the formula XIV

^ a _Ar _ ₀ _. / ^ \ ._ _CO _ _{CH3 (XIV)}

^R b

by reaction with the desired diol in an inert solvent z.3. a halogenated hydrocarbon (such as methylene chloride, ethylene chloride, chloroform, carbon tetrachloride, etc.) and simultaneous or subsequent halogenation win. To accelerate the reaction, an addition of p-toluenesulfonic acid is advantageous.

The ketones of formula IV can be obtained by halogenation of the starting

ketone XIV to XV R l ^a

Ar-O-... CO-CH ₉ -HaI (XV)

R.

and further reaction of XV, analogously to variant A, with an azole of formula II. Here, shark is preferably chlorine or 3rom.

- 14 -

The ketals III, VI, IX and X are obtained analogously to variant 3 by reaction of the starting ketone, e.g. of the formula IV with a suitable alcohol or diol.

Obtained free compounds of the formula I can be converted into salts in a manner known per se, i.a. by treatment with a base or with a suitable salt of a carboxylic acid, usually in the presence of a solvent or diluent.

Salts obtained can be converted into the free compounds in a manner known per se, e.g. by treating with an acidic reagent, such as a mineral acid.

The compounds, including their salts, can also be obtained in the form of their hydrates or include the solvent used for the crystallization.

As a result of the close relationship between the novel compounds in free form and in the form of their salts, the corresponding salts or free compounds are to be understood as meaningful and appropriate in the preceding and following among the free compounds or their salts.

The invention also relates to those embodiments of the process starting from a compound obtainable as an intermediate at any process stage and carrying out the missing process steps, or forming a starting material under the reaction conditions or in the form of a derivative thereof, optionally a salt.

The process of the present invention preferably uses those starting materials which are among the. initially referred to as particularly valuable connections lead. New starting materials and processes for their preparation are included in the invention.

- 15 -

In all described ketalization reactions of a ketone with a substituted α, β or α, γ-diol, predominantly mixtures of diastereomers of the resulting ketal are formed. Correspondingly, diastereomer mixtures of the end products I are generally formed from the starting ketones. The compounds of the formula I can be present, for example, in the following two diastereomeric forms:

Ar-O _x "" Ar-O,

G _x A types A

(XVI). CH ₂ ZR ₇ (XVII) R ₃

The configuration of type A is here and hereinafter referred to as the "trans" isomer.

Ar-O \ I D • B grades y • = · ⁷ ei Λ.1 -

 0 · = Ν

/ V · XJ.

X / .c £, ^Y

(XVIII) _ ₂ _ _{7 (XIX)}

4 ^H

The symbols in the spatially rendered structures should have the following meanings:

• ··· = behind

- = in i® ⁸ "* · = in front of the drawing plane.

The configuration of type B shall accordingly be referred to as the "cJ3" isomer . The separation of the two diastereomers can

- 16 -

for example, by fractional crystallization or by chromatography (thin, thick-layer, column, liquid high-pressure chromatography, etc.). The two isomers show different biological effects. In general, the diastereomer mixtures are used for practical purposes.

The invention relates to all isomeric compounds of the formula I and their salts.

L- (β-aryl) ethyl imidazolyl ketals in which aryl is substituted phenyl or naphthyl are cited in the following references as fungicides and bactericides: U.S. Patents: 3,575,999, 3,936,470, 4,101,664, 4,101,666, 4 156 008.

The antimycotic properties of the usefulness of the compounds of the formula I and their pharmaceutically usable acid addition salts for combating warm-blooded parasitic fungi, for example, in vitro by conventional microbiological examination methods, for example by their toxic effect on fungi parasitizing warm-blooded animals, such as Trychophyton mentagryphites, Microsporum canis, Sporotrichum schenkii, Aspergillus fumigatus and Candida albicans, as well as in vivo on the guinea pig on the basis of the healing effect on experimental infestations of the dorsal skin with Trychophyton, eg T. rubrum, after peroral or local application.

The anticonvulsant activity of the compounds of formula I and their pharmaceutically acceptable acid addition salts can be in vivo in, for example, the mouse in the pentatetrazole spasm test in the dose range of about 10 to about 100 mg / kg po, as well as in the electroshock test in the dose range of about 10 to about 100 mg / kg po be demonstrated. The anxiolytic activity can be, for example, in the mouse

- 17 -

and other small rodents using the Gellert test and the Quatre plaque test in the dose range of about 10 to about 100 mg / kg p.o. demonstrate. It is also possible to conclude that the new compounds have a significant antimanic effect.

Accordingly, the invention likewise relates to the use of compounds of the formula I and their pharmaceutically usable acid addition salts for topical or local and systemic control of warm-blooded parasitic fungi or for systemic treatment of various forms of epilepsy, states of anxiety and tension and of manic states of mind in particular as active ingredient in or for the preparation of pharmaceutical preparations for enteral, parenteral, topical or local administration, as well as such pharmaceutical preparations.

The pharmaceutical compositions according to the invention which contain compounds of the formula I or pharmaceutically acceptable salts thereof are accordingly those for enteral, such as oral or rectal, and parenteral administration and for topical administration to warm-blooded animals, which alone are the pharmacologically active substance or together with a pharmaceutically acceptable carrier material. The dosage of the active ingredient depends on the species of warm-blooded animals, the age and the individual condition as well as the mode of administration.

Normally, an approximately daily dose of about 50-500 mg, advantageously distributed in several equal sub-doses, is to be estimated for a warm-blooded animal weighing about 75 kg when administered orally.

The new pharmaceutical preparations contain e.g. from about 10% to about 80%, preferably from about 20% to about 60% of the active ingredient. Pharmaceutical preparations according to the invention for oral or parenteral administration are e.g. those in unit dosage forms such as dragees,

- 18 -

Tablets, capsules or suppositories, and ampoules. These are produced in a manner known per se, e.g. produced by conventional mixing, granulation, coating, solution or lyophilization process. Thus, one can obtain pharmaceutical preparations for oral use by combining the active ingredient with solid carriers, optionally granulating a mixture obtained, and the mixture or granules, if desired or necessary, after addition of suitable excipients, processed into tablets or dragee cores ,

Suitable carriers are, in particular, fillers, such as sugars, e.g. Lactose, sucrose, mannitol or sorbitol, cellulose preparations and / or calcium phosphates, e.g. Tricalcium phosphate or CalcLum hydrogen phosphate, further binders such as starch pastes using e.g. corn, wheat, rice or potato starch, gelatin, tragacanth, methylcellulose and / or polyvinylpyrrolidone, and / or, if desired, disintegrating agents such as the abovementioned starches, furthermore carboxymethyl starch, cross-linked polyvinylpyrrolidone, agar, alginic acid or a salt thereof, like sodium alginate. Auxiliaries are primarily flow regulators and lubricants, for example silicic acid, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and / or polyethylene glycol Dragee cores are provided with suitable coatings, which may be enteric-coated, inter alia concentrating Sugar solutions which may contain arabic gum, talc, polyvinylpyrrolidone, polyethylene glycol and / or titanium dioxide, lacquer solutions in suitable organic solvents or solvent mixtures or, for the production of enteric coatings, solutions of suitable cellulose preparations, such as acetylcellulose phthalate or hydroxypropylmethylcellulose phthalate. Coatings may be added to dyes or pigments, for example for identifying or labeling different doses of active substance.

Other orally applicable pharmaceutical preparations are sinrf capsules

- 19 -

of gelatin, as well as soft, closed capsules of gelatin and a plasticizer, such as glycerol or sorbitol. The capsules may contain the active ingredient in the form of granules, e.g. in admixture with fillers, such as lactose, binders, such as starches, and / or lubricants, such as talc or magnesium stearate, and optionally stabilizers. In soft capsules, the active ingredient is preferably dissolved or suspended in suitable liquids, such as fatty oils, paraffin oil or liquid polyethylene glycols, it likewise being possible for stabilizers to be added.

As rectally applicable pharmaceutical preparations are e.g. Suppositories which consist of a combination of the active ingredient with a suppository base. As suppository base, e.g. natural or synthetic triglycerides, paraffin hydrocarbons, polyethylene glycols or higher alkanols. Furthermore, gelatin rectal capsules containing a combination of the active ingredient with a matrix may also be used; as basic materials there are e.g. liquid triglycerides, polyethylene glycols or paraffinic hydrocarbon in question.

For parenteral administration, aqueous solutions of an active ingredient in water-soluble form, e.g. a water-soluble salt, further suspensions of the active ingredient, such as corresponding oily injection suspensions, whereby suitable lipophilic solvents or vehicles such as fatty oils, e.g. Sesame oil, or synthetic fatty acid esters, e.g. Echyl oleate, or triglycerides, or aqueous injection suspensions containing viscosity increasing agents, e.g. Sodium carboxymethyl cellulose, sorbitol and / or dextran and optionally also stabilizers.

As topically applicable pharmaceutical preparations are primarily cream, ointments, pastes, foams, tinctures and solutions in question, which contain from about 0.5 to about 20% of the active ingredient.

- 20 -

Creams are oil-in-water emulsions containing more than 50% water. The oily basis used is primarily fatty alcohols, z.3. Lauryl, cetyl or stearyl alcohol, fatty acids, e.g. Palmitic or stearic acid, liquid to solid waxes, e.g. Isopropyl myristate, wool wax or beeswax, and / or hydrocarbons, e.g. Vaseline (petrolatum) or paraffin oil. Suitable emulsifiers are surfactants having predominantly hydrophilic properties, such as corresponding nonionic emulsifiers, z.3. Fatty acid esters of polyhydric alcohols or ethylene oxide adducts thereof, such as polyglycerol fatty acid esters or polyoxyethylene fatty alcohol ethers or fatty acid esters, or corresponding ionic emulsifiers, such as alkali metal salts of fatty alcohol sulfates, e.g. Sodium lauryl sulphate, sodium cetyl sulphate or sodium stearyl sulphate, usually in the presence of fatty alcohols, e.g. Ceryl alcohol or stearyl alcohol used. Additives to the water phase are u.a. Agents which reduce dehydration of the cream, e.g. Polyalcohols, such as glycerol, sorbitol, propylene glycol and / or. Polyethylene glycols, preservatives, fragrances etc.

Ointments are water-in-oil emulsions containing up to 70%, but preferably from about 20% to about 50% water or aqueous phases. The fatty phase is primarily hydrocarbons, e.g. Vaseline, paraffin oil and / or hard paraffins in question, the preferably water-binding capacity suitable hydroxy compounds, such as fatty alcohols or esters thereof, e.g. Cetyl alcohol or wool wax alcohols or wool wax included. Emulsifiers are corresponding lipophilic substances, such as sorbitan fatty acid esters (Spans), e.g. Sorbitan oleate and / or sorbitan isostearate. Additives to the water phase are u.a. Humectants, such as polyalcohols, e.g. Glycerol, propylene glycol, sorbitol and / or polyethylene glycol, as well as preservatives, fragrances etc.

Fatty ointments are anhydrous and contain, in particular, hydrocarbons, e.g. Paraffin, vaseline and / or liquid paraffins, also natural or partially synthetic fats, e.g. coconut oil

- 21 -

acid triglyceride, or preferably hydrogenated oil, z.3. hydrogenated peanut or castor oil, also fatty acid partial esters of glycerol, e.g. Glycerol mono- and distearate, as well as e.g. the mentioned in connection with the ointments, the water absorbency enhancing fatty alcohols, emulsifiers and / or additives.

Pastes are cream and ointments with secretion absorbing powder ingredients, such as metal oxides, e.g. Titanium oxide or zinc oxide, further talc and / or aluminum silicates, which have the task to bind existing moisture or secretion.

Foams are administered from pressure vessels and are aerosolized liquid oil-in-water emulsions wherein halogenated hydrocarbons such as chlorofluoro-lower alkanes, e.g. Dichlorodifluoromethane and dichlorotetrafluoroethane, be used as blowing agent. The oil phase used u.a. Hydrocarbons, e.g. Paraffin oil, fatty alcohols, e.g. Cetyl alcohol, fatty acid esters, e.g. Isopropyl myristate, and / or other waxes. As emulsifiers u.a. Mixtures of those having predominantly hydrophilic properties, such as polyoxyethylene sorbitan fatty acid esters (Tweens), and those having predominantly lipophilic properties, such as sorbitan fatty acid esters (Spans). There are also the usual additives, such as preservatives, etc.

Tinctures and solutions mostly have an aqueous-ethanolic base, which i.a. Polyalcohols, e.g. Glycerol, glycols, and / or polyethyleneglycol, as humectants to reduce evaporation, and replenishers, such as fatty acid esters, with low polyethyleneglycols, i. lipophilic substances which are soluble in the aqueous mixture as a substitute for the fatty substances removed from the skin with the ethanol and, if necessary, other auxiliaries and additives are added.

 22-

30.3 * 1934

Λ? G 07 D / 256 72Q / 6

63 196/11

It is carried out the preparation of the topically administrable pharmaceutical preparations in "per se known manner, for" B _e by dissolving or suspending the active ingredient in the base or in a part thereof, if, necessary case of processing the active ingredient as a solution, it is generally in front of the in one of the two phases, when processed as a suspension it is mixed after mixing with a part of the base and then added to the rest of the formulation,

embodiment

The following examples serve to illustrate the invention without limiting it, temperatures are given in ceices, pressures in mbar, percent and parts are by weight. RT means room temperature, h stands for hour «

Example 1: Preparation of

² \

e *

(1.3)

2- (p-Phenoxyphenyl) -2- / 1- (2-methyl-imidazole), ethyl. 7-4-methyl-1,3-dioxane

a) Zvvischenprodukt

a) 2- (p-? -heoxyphnyl) -2-bromoethyl-4-methyl-1,3-dioxane

-22- 30.3.1984

AP G 07 D / 256 720/6 S3 196/11

10 parts of 2- (p-phenoxyphenyl) -2-oxo-1-bromomethane and 4 parts of 1 _? 3-Butanediol are refluxed in 40 ml of absolute toluene in the presence of 0.2 part of catalytically active p-Toluolsuifonsäure for 3 hours, with formed water is separated with a Wasserabscheider »After cooling to room temperature, the reaction mixture is twice with 20 ml of water washed, dried over sodium sulfate, filtered, the solvent evaporated and the crude product recrystallized from isopropanol * Parblose crystals »mp 96-106 ⁰ G,

- 23 -

b) end product

3.8 parts of 2-Methyliiiiidazol Natriunisalz and a catalytic amount of potassium iodide are dissolved in 40 ml of dimethylformamide together with 10.2 parts of the prepared according to a) 2- (p-phenoxyphenyl) -2-bromomethyl-4-methyl-l, 3rd -dioxane for 30 h at an internal temperature of + 120 °. After cooling to room temperature, 300 ml of water are added, extracted three times with 30 ml of ethyl acetate, the combined extracts washed twice with 20 ml of water, dried over sodium sulfate, filtered and the solvent evaporated. The oily residue is purified by column chromatography (silica gel / ethyl acetate). The eluent is evaporated. A viscous mass is obtained with n £ '= 1.5634.

Example 2: Preparation

(1.50)

2- [p- (m-chlorophenoxy) phenyl] -2- [1- (2-methyl-imidazoIyI) methyl] -4-ethyl-1,3-dioxolane

1.4 parts of 2-methylimidazole sodium salt and a catalytically active amount of potassium iodide are dissolved in 50 ml of dimethylformamide together with 4 parts of 2- [p- (3-chlorophenoxy) phenyl] -2-bromomethyl-4-ethyl-1,3-dioxolane Stirred for 17 h at an internal temperature of 125 °. After cooling, the brown reaction mixture is mixed with 150 ml of water, extracted three times with 50 ml of ethyl acetate, the combined extracts washed twice with 50 ml of water, dried over sodium sulfate, filtered and the solvent evaporated. The oily crude product is chromatographed over a 35 cm long silica gel column using acetone / ethyl acetate (1: 1). The eluent is evaporated. This gives a viscous

Mass with ru = 1.5685.

- 24 -

Example 3: Preparation of

(1.2)

2- [ρ- (p-Chlorophenoxy) phenyl] -2- [1- (2-methyl thyimidazolylmethyl] -1-ethyl-1,3-dioxolane

a) intermediates

α) 2- [ρ- (p-Chlorophenoxy) phenyl] -2-methyl-4-ethyl- 1,3 -dioxolane 37 parts of 4- (p-chlorophenoxy) acetophenone and 18 parts of 1,2-butanediol are dissolved in 400 ml absolute toluene in the presence of 2 parts of catalytically active p-toluenesulfonic acid for 14 h under reflux at the water. After cooling to RT, the reaction mixture is washed twice with 400 ml of water, dried over sodium sulfate, filtered, the solvent evaporated and the crude product for purification over a 1 m long silica gel column using ligroin / hexane / ethyl acetate / toluene (5: 3: 1 : 1) chromatographed. The product is shown as slightly yellow

22 ·

gel, il: 1.5527.

β) 2- [p- (p-chlorophenoxy) phenyl] -2-bromomethyl-4-ethyl- 1,3- dioxolane 36.8 parts of the 2- [p- (p-chlorophenoxy) phenyl-2 prepared under α) Methyl 4-ethyl-1,3-dioxolane are boiled in 350 ml of chloroform. Under illumination by means of a 150 Watt spot lamp 19.4 parts of bromine, dissolved in 50 ml of chloroform, added dropwise and then heated under reflux for 2 h. After cooling to RT, the reaction mixture is washed twice with 200 ml of water, dried over sodium sulfate, filtered and the solvent removed in a water jet vacuum. For purification, the crude product is chromatographed over a 1 m long silica gel column using toluene. The product

23 is obtained as yellow OeI with η = 1.5805.

- 25

b) end product

5.0 parts of 2-methylimidazole sodium salt and a catalytically active amount of potassium iodide are dissolved in 80 ml of dimethylformamide together with 14.7 parts of the 2- [p- (p-chlorophenoxy) phenyl] -2-bromomethyl-4 prepared according to ethyl-l, 3-dioxolane for 17 h at a bath temperature of 125 ° C stirred. After cooling to room temperature, the reaction mixture is poured into 600 ml of water, extracted three times with 200 ml of ethyl acetate, the combined organic phases washed twice with 200 ml of water, dried over sodium sulfate, filtered and the solvent evaporated. The oily residue is chromatographed over a 50 cm long silica gel column using acetone / ethyl acetate (1: 1). After evaporation of the eluent, the product is as brown

23

OeI obtained with the il = 1.5721.

Example 4: Preparation of

(1.1)

2- (p-phenoxyphenyl) -2- [l- (2-methyl imidazoIyDmethyl] -4-ethy1-1,3-dioxolane

17 parts of 2- (p-henoxyphenyl) -3-bromomethyl-4-ethyl-l, 3-dioxolane, 8.4 parts of potassium carbonate, 5.0 parts of 2-methylimidazole and a catalytic amount of sodium iodide are dissolved in 100 ml of dimethyl sulfoxide 24 Stirred at an internal temperature of 125 °. After cooling to RT, the reaction mixture is poured into 600 ml of water, extracted three times with 200 ml of ethyl acetate, the combined extracts washed twice with 200 ml of water, dried over sodium sulfate, filtered and the solvent evaporated. This gives a viscous mass with the n ^ ² ' ⁵ = 1.5562.

- 26 -

Example 5: Preparation of

2- (p-Phenoxyphenyl) -2- [1- (2-methylimidazolyl) methyl] -1,3-dioxane 14 parts 2- (p-Phenoxyphenyl) -2-bromomethyl-1,3-dioxane, 7.2 parts Potassium carbonate, 4.2 parts of 2-methylimidazole and a catalytically active amount of potassium iodide are stirred in 100 ml of dimethyl sulfoxide for 20 h at an internal temperature of 140 °. After cooling to RT, 600 ml of water are added, extracted three times with 200 ml of ether, the combined extracts washed twice with 200 ml of water, dried over sodium sulfate, filtered and the solvent evaporated. The oily residue is chromatographed over a 50 cm long silica gel column using chloroform / ether (1: 1). The eluent is used

23

evaporated. This gives a viscous mass with the il = 1.5632.

Example 6: Preparation of

2- (p-Phenoxyphenyl) -2- [1- (2-methylimidazolymethyl) 1,3-dioxolane 4.5 parts 2- (p-Phenoxyphenyl) -2-bromomethyl-4-hydroxymethyl-1,3-dioxolane, 2 , 2 parts of potassium carbonate, 1.3 parts of 2-methylimidazole and a catalytically active amount of potassium iodide are stirred in 50 ml of dimethyl sulfoxide for 4 hours at an internal temperature of 140 ° C. After cooling to RT, 600 ml of water are added, twice with 200 ml of ethyl acetate The combined extracts are washed twice with 200 ml of water each time, dried over sodium sulfate, filtered and the solvent is evaporated off, and the oily residue is passed through a 50 cm long pad.

* Λ

- 27 -

gel column chromatographed by acetone. After evaporation of the eluent, the oily residue crystallizes after addition of petroleum ether. Beige crystals from the snip. 166 - 170 °.

Example 7: Preparation of

(1.29)

^ .- η-. , -fi γη -ν I

2- (p-phenoxyphenyl) -2- [1- (2-methy1imidazoIy1) methyl] -4-n-propy1-1,3-dioxolan

10.3 parts of the nitrate of 1- (p-phenoxyphenyl) -2- [1- (2-methyliniidazolyl)] ethanone, 6.1 parts of 1,2-pentanediol, 6.9 parts of p-toluenesulfonic acid, 20 parts of 1 -Pentanol and 200 parts of xylene are refluxed for 6 days on a water and washed after cooling to RT twice with 200 ml of dilute sodium hydroxide solution and twice with 200 ml of water. The organic phase is dried over sodium sulfate, filtered and the solvent evaporated. The oily residue is chromatographed over a 1 m long silica gel column using ethyl acetate. After evaporation of the eluent remains

22 5 a yellowish OeI with the ru '= 1.5565 back.

Example 8: Preparation of

· = · 0 0

2- (2-methyl-4-phenoxy-phenyl ·) -2- [l- (2-methyIimidazoIyI) methyl] -4-ethy1-1,3-dioxolan

a) intermediates

- 28 -

α) 2-methyl-4-phenoxy-phenacyl bromide

36.6 parts of 2-methyl-4-phenoxy-acetophenone are dissolved in 160 ml of acetic acid dissolved heated to 35 ° and treated dropwise with stirring over 1.5 h with 25.9 parts of bromine. The mixture is stirred for 1 h, poured into ICOO ml of ice water and shaken twice with 100 ml of diethyl ether. The combined extracts are washed with water, dried over sodium sulfate, filtered and evaporated. The oily residue crystallized from hexane to brownish crystals of mp. 60 - 61 °.

β) 2- (2-Methyl-4-phenoxyphenyl) -2-bromomethyl-4-ethyl -1,3- dioxolane 85.4 parts of 2-methyl-4-phenoxy-phenacyl bromide and 25.2 parts of butane-1 , 2-Diol are dissolved in 250 ml of toluene. 1 part of p-toluenesulfonic acid is added and the mixture is heated to boiling point on a water separator for 25 hours. It is allowed to cool to RT, washed three times with 250 ml of water, dried over sodium sulfate and filtered. The solvent is evaporated under reduced pressure. It remains a red-brown OeI back.

b) end product

9.5 parts of 2- (2-methyl-4-phenoxyphenyl) -2-bromomethyl-4-ethyl-1,3-dioxolane according to β), 2.9 parts of 2-methylimidazole and 4 parts of potassium tert-butoxide are dissolved in 50 ml Dimeth ' Ylsulfoxid stirred for 30 h at 110 °. It is allowed to cool to RT, diluted with 300 ml of water and shaken out three times with 150 ml of ethyl acetate. The ethyl acetate extracts are combined, washed neutral with water, dried over sodium sulfate, filtered and evaporated to dryness. The crude product is purified on a silica gel column (50 cm long) with Essigaster as eluent. After evaporation of the same remains with a viscous mass

22 5 back to the rC '= 1.5640.

Example 9: Preparation of 2- [p- (m-chlorophenoxy) phenyl] -2- [1- (2

methylimidazolyDmethylj ^ ethyl-l ^ dioxolane hydrochloride

9.8 parts of 2- [p- (m-chlorophenoxy) phenylj-2- [1- (2-methylimidazolyl) methyl] -4-ethyl-l, 3-dioxolane are dissolved in 80 ml of diethyl ether and under

- 29 -

Stirring was added dropwise with 2.5 parts of concentrated hydrochloric acid. The yellowish precipitate formed is filtered off after 1 h, washed with ice-cold diethyl ether and dried: white crystals, mp. 153 - 162 °.

Example 10; The end products described in the table below (Table I) can also be prepared in an analogous manner (if not particularly noted, diastereomer mixtures having different mixing ratios) of the formula I:

Table 1: Compounds of the formula

^R i4 \ _. A3 al ¹

20 \

• N =

^R 15-

• t-6 5-f t J

(Ia)

16

12

Verb. R _n ^R 12 ^R 13 ^R 14 ^R 15 ^R 16 U V ^R 20 salt Physical. Characteristic data (O ⁰ C) No. 1.1 H H H H H Il / ^C 2 ^H 5 * - ♦ / \ CH ₃ - 22 5 viscous mass, η '1,5562 1.2 H H H H Cl II .- / ^C 2 ^H 5 / * \ CH ₃ - 23 viscous mass, η 1.5721 1.3 H Il H H Il H / \ / ^H 3 ii CII ₃ - 22 5 viscous mass, η '1,5634 1.4 H H H Cl Cl H / * "\ CH ₃ - 1.5 H H H Cl Cl H / ^C 2 ^H 5 • - O / \ CH ₃ - viscous mass, 1.6 II H H Cl Cl H / ^# ~ \ C ₂ H ₅ - 1.7 2-CII ₃ H H H H H / * "* \ CH ₃ - 22 5 viscous mass, η '1,5640 1.8 2-CIl ₃ H H H Cl Il / "\ ^CH 3 - viscous mass, η 1.5767

Table 1: (continued)

Verb no. "η ^R 12 ^R 13 ^R 14 ^R 15 ^R 16 U V ^R 20 j salt Physical. Characteristics (0 ° C) 1.9 2-CH ₃ H H H Cl H _ / ^C 2 ^H ₅ / * \ CH ₃ CH ₃ - OeI, 11 ^ 1,57Il 1.10 H H II Cl H H / ^C 2 ^H 5 • - Φ / \ CH ₃ - 22 viscous mass, η 1.5685 1.11 2-CH ₃ H H H P H CH ₃ CH ₃ - 1.12 H H H H H H CH ₃ - Snip. 166 - 170 ° 1.13 H Il H H Cl H ^ / CH ₂ OCH ₃ CH ₃ - 1.14 H H H H H H / ^CH 3 CH _ / * 1.15 2-Cl H H H H H / \ - OeI, η 1.5708 1.16 2-Cl H H H Cl H / \ - 1.17 H H H H H H / \ i viscous mass, η 1.5632

Table 1: (continued)

Verb no. H ^R 12 ^R 13 ^R 14 R ₁₅ ^R 16 U V ^R 20 salt Physical. Characteristics (0 ° C) 1.18 2-CH ₃ H H II F H _# / \ ϊ ί CH ₃ - 1.19 H 6-CH ₃ H H H H ._ / 2 ^H 5 CH ₃ - 1.20 H H CH ₃ H Cl H _ _φ / ° 2 ^Η 5 CH ₃ - 1.21 II Il H H Cl H CH ₃ - 1.22 2-CH ₃ H H H F H / CH ₂ OH ^CH 3 - 1.23 11 H II H F H .- / ° 2 ^H 5 / \ CH ₃ - 1.24 2-CH ₃ H II H Cl H i i CH ₃ - Snip. 88 - 90 ° 1.25 2-CH ₃ H H H F H ϊ ί CH ₃ - 1.26 H H II br H < / \ CH ₃ -

Table 1: (continued)

Verb no. "π ^R 12 ^R 13 ^R 14 ^R 15 ^R 16 U V ^R 20 salt Physical. Characteristics (0 ° C) 1.27 2-CH ₃ H H H Cl H _# _ / ^H 3 CH ₃ ENT ₃ Mp. 181-183 ° 1.28 H II H CH ₃ Cl H ^ CH ₂ OCH ₃ * - »/ \ CH ₃ - 22 OeI, η 1.5599 1.29 II H H H H II / \ CH ₃ - OeI, η ²² ' ⁵ I, 5565 1.30 II H Cl H Cl H / * CH ₃ - Oei, η ^{22 '5!,} 5732 1.31 H H H H Cl H CH ₂ OH β - · / \ CH ₃ - 1:32 2-Cl H H H F H .- / ^C 2 ^H 5 / \ ^CH 3 - 1:33 II H H Cl H H ti - · / \ CH ₃ - 1:34 2-CH ₃ H H Cl H II m ϊ ΐ CH ₃ - 1:35 2-CH ₃ 5-CH ₃ H Cl H H CII ₃ -

Table 1: (continued)

Verb no.  · " ^R 12 ^R 13 ^R 14 ^R 15 ^R 16 U V ^R 20 salt Physical. Characteristics (0 ⁰ C) 1:36 2-CH ₃ H H H H H CH ₃ - 1:37 2-CIl ₃ 5-CH ₃ II H H H / CH ₂ OH CH ₃ - 1:38 2-CIL 5-CH ₃ H H H H / \ CH ₃ - 1:39 2-CH ₃ 5-CH ₃ H H Cl H ^C 2 ^H 5 HCl 1:40 2-C ₂ H ₅ H II H Cl H _# _ _# / ^C 2 ^H 5 CH ₃ - η ²⁴ ' ⁵ 1.5678 1:41 2-CH ₃ H H H H H CH ₃ ENT ₃ Snip. 124-126 ° 1:42 H H Cl H II H * - · / \ CH ₃ - η ²² 1.5682 1:43 Il H Cl H H H / \ CH ₃ - OeI, η 1.5690 1:44 H H II Cl H H CH ₃ HCl Mp 158-162 °

Table 1: (continued)

Verb no. H ^R 12 ^R 13 ^R 14 ^R 15 ^R 16 U V ^R 20 salt Physical characteristics (0 ⁰ C) 1:45 H H H H H H / * ^C 2 ^H 5 , - OeI, η 1.5596 1:46 H II H CH ₃ Cl H κ * ~ * \ C ₂ H ₅ - 1:47 II H H H H H _V I ₇ -n 23 5 OeI, η ^ ' ³ 1.5631 1:48 H H H H H II / \ / ^CH 3 ί ι ^C 2 ^H 5 - 23 viscous mass, η 1.5638 1:49 II H H CH ₃ Cl H C ₃ H ₇ -I - 1:50 II H Cl H H H / * "\ C ₃ II ₇ -X _ 1:51 II H H H H H C ₃ H ₇ -I 1:52 H H II H H II  · « C ₂ H ₅ - 1:53 H II H H H / CH ₂ OCH ₃ A- -

Table 1: (continued)

Verb.

1:54

11

13

15

16

U V

20

salt

Physical. Characteristics (0 ⁰ C)

1:55

II

1:56

II

Cl

/ \ / ^CH 3

• *

/ ^C 3 ^H 7- ⁿ

CH. I CH ₂ CH

CH.

H .

- 37 -

Example 11: Gelatin capsules containing 200 mg of [p- (p-chlorophenoxy) phenyl] -2- [1- (2-methylimidazolyl) methyl-4-ethyl-1,3-dioxolane as active ingredient can be prepared, for example, as follows :

Composition (for 1000 capsules) Active substance 100 g

Lactose, ground 100 g

The active ingredient and the lactose (finely ground) are mixed well with each other. The resulting powder is sieved and bottled in portions of 0.20 g each in gelatine capsules.

Example 12 Tablets containing 25 mg of active ingredient, for example 2- [p- (p-chlorophenoxy) phenyl 3-2- [1- (2-methylimidazolylmethyl] -4-ethyl-1,3-dioxolane, can be obtained as follows:

Ingredients (for 1000 tablets)

Active ingredient 25, Og

Lactose 100.7 g

Wheat starch 7.5 g

Polyethylene glycol 6000 5.0 g

Talc 5.0 g

Magnesium stearate 1.8 g

demineralised water q.s.

Preparation : All solid ingredients are first driven through a sieve of 0.6 mm mesh size. Then the active ingredient, the lactose, the talc, the magnesium stearate and half of the starch are mixed. The other half of the starch is suspended in 40 ml of water and this suspension is added to a boiling solution of the polyethylene glycol in 100 ml of water and the mixture is granulated, if necessary adding water. The granules are dried overnight at 35 °, passed through a sieve of 1.2 mm mesh size

- 38 -

and compressed on both sides concave tablets of about 6 mm in diameter.

Example 13 Tablets containing 75 mg of active ingredient, for example 2- [p- (p-chlorophenoxy) phenyl] -2- [1- (2-methylene-1-thyido] -dimethyl-4-yl-1-1,3-dioxolane , can be produced as follows:

Ingredients (for 1000 tablets)

Active ingredient 75.0 g

Lactose 100.7 g

Wheat starch 7.5 g

Polyethylene glycol 6000 5.0g

Talc 5.0 g

Magnesium stearate 1.8 g

demineralised water q.s.

Preparation: All solid ingredients are first driven through a sieve of 0.6 mm mesh size. Then the active ingredient, the lactose, the talc, the magnesium stearate and half of the starch are mixed. The other half of the starch is suspended in 40 ml of water and this suspension is added to a boiling solution of the polyethylene glycol in 100 ml of water and the mixture is granulated, if necessary adding water. The granules are dried overnight at 35 °, forced through a sieve of 1.2 mm mesh size and pressed on both sides concave tablets of about 6 mm in diameter.

Example 14: In a manner analogous to those described in Examples 11 to 13, pharmaceutical preparations containing another of the compounds obtainable according to Table 1 can also be prepared.

Claims (12)

R and R-. independently of one another are hydrogen, halogen or C.-C-alkyl: Ar is phenyl which is unsubstituted or phenyl which is monosubstituted or polysubstituted by halogen, G, -C-alkyl, G-C-alkoxy and / or trifluoromethyl; ¹ J and V are independently of each other optionally substituted by halogen or G ₁ -C - alkoxy 0 ^ -G. _o -alkyl IO lic. stand or together one of the following alkylene bridges R ₂ bilaen, where or R. and R ₂ are independently hydrogen, 0, -Q ^ - alkyl, mono- or poly-substituted by halogen Gj-Gp-alkyl, phenyl, mono- or polysubstituted by halogen and / or G. G - alkyl substituted Phenyl or the group -GHp-ZR ₇ , where Oxygen or sulfur means and -40- 30.3.1384 AP G 07 D / 256 720/6 63 196/11 R _{7 is} hydrogen, C.-Cg-alkyl, a through. G.-Cp-alkoxy substituted G -, - Gq-alkyl, Cy-G, -alkenyl, 2-propynyl, 3-halo-2-propynyl, phenyl, a by halogen, C ^ -C ^ alkyl, C. -C, -alkoxy, nitro and / or GJ ¹ ^ mono- or polysubstituted phenyl, benzyl or benzyl mono- or polysubstituted by halogen, G ..- C - alkyl and / or Q ^ -G ^ - alkoxy stands $ R-, R ^ and R, - independently of one another denote hydrogen or G.-G.-alkyl, the total number of carbon atoms in R, R. and Rj- not exceeding 6 and R 1 is hydrogen or C 1 -C 4 alkyl; under the inclusion of their acid addition salts in that one A) a compound of Poraiel II Y-Itf-I-R (II), v4 wherein ϊ 7 / sa material or a Lletallkation represents, with a compound of formula III 0-1-9. / 7 ^υ ^ ^ ² ^ ^ ¹¹¹ ) » »== ^ρ ο ο wherein Σ is a microfuge leaving group, condensed or, 3) in a compound of formula 17  40a 30.3 * 1934 A? G 07 D / 256 720/6 63 196/11 it V · ⁷ > -0-OHo-iI (IV) ax Garbony! group in a ^G roup of Pormel 7 convicted, or C) aur a preparation of compounds of the SOrmei I, wherein U and V together represent a group of the formula -CHp-CHCGH ₉ ZRL) -and RL is a radical other than hydrogen R ₇ , compounds of formula VI and VII - 41 - R a ! ^a .1. .1. ^Ar "°" \ / ^7C \ " ^H 2" \ - 4-R (VI) and X - R ₇ (VII), t/ y ' ^{2 7} , / 7 \ 2 \ 4 (VI) and XR ₇ • t *ς / y ' ⁼ - ^{2 7} H -X wherein one of the radicals X, and X optionally present in salt form Hydroxy or mercapto, ζ.B '. of the formula -Z-Y, in which Y is hydrogen or preferably a metal cation, and the other represents a nucleofugic leaving group X or both X-j and X-hydroxy groups, condensed together or D) Compounds of the formulas VIII and IX Ar-X- (VIII) and X- ( "> --- C-CH-N ^ 4-3 (IX), R, I ι 0 υ ν wherein one of the radicals X, and X is a group -O-Ύ, in which Y is hydrogen or preferably a metal cation, and the other is an aryloxy-exchangeable radical, condensed together or E) a compound of the formula A ₁ -OCO- /; \ C-CH ₂ - ^ I ₅ (X) OIOOO _L t ν decar oxylated intramolecularly and, if desired, converts a compound obtainable according to the process into another compound of the formula I and / or converts a free compound obtainable by the process into an acid addition salt, an acid addition salt obtainable by the process into the free compound or into another acid addition salt. -42- 30.3.1384 AP 0 07 D / 256 720/6 63 196/11 2ο method according to item 1, characterized in that one äaß of compounds of formulas II and III is used in which Y is an alkali metal or iSrdalkaliraetallocation and 1 is a reactive esterified hydroxyl group, such _a J3 _S with a hydrohalic acid, a Hiederalkyl- or unsubstituted or substituted benzenesulfonic acid or Hydroxy esterified with fluorosulphonic acid means » 3. The method according to item 1, characterized by reacting a compound of formula IV with an orthocarbon-3-tri ~ G. -G-p-alkyl ester, the C.-C ^ alkyl groups optionally substituted by halogen or C, , -C, - Alkoxy substituted, or in the presence of an acid with at least 2 moles of a monohydric alcohol of the formula U-OH (Va), wherein compounds of formula I are obtained, wherein 'U and V are the same, optionally substituted C ^ -G ₁₂ alkyl groups, or with a diol of the formula Vb HO-U V-OH (Vb), wherein compounds of the formula I are obtained, in which U and V together represent one of the aikylenbrücken defined in item 1, » 4 * Process according to item 1, characterized in that starting from compounds of formulas VI and VII, wherein X. a group -2H and Z _{2 is} a reactive esterified hydroxy group, s, 3. with a hydrohalic acid, a Nieäeralkan- or optionally substituted Benzenesulfonic or fluorosulfonic acid esterified hydroxy 5 * Process according to item 1, characterized in that starting from compounds of formula VIII and 12, wherein -43- 30.3 «1334 AP G 07 D / 256 720/6 63 196/11 one of the radicals X "and X. one group -OY and another is a reactive esterified Hydrozygruppe, z» B, with a hydrohalic acid, a Kiederalkan- or optionally substituted Benzolsuifonsäure or with luorsulfonsäure esterified hydroxy, means 6. A process as claimed in one of the items 1 to 5, which comprises starting from a compound obtainable as an intermediate at any process stage and carrying out the missing process steps, or forming a starting material under the reaction conditions or in the form of a derivative thereof, optionally a saleaea. used " 7. The method according to any one of items 1 to 6, characterized in that one produces compounds of Porsiel I or their acid addition salts, wherein R, R and E, in 'a o Point 1, Ar has a group of the formula ^S e represents, in the R. R-. and R independently Cu e "hydrogen, halogen, trifluoromethyl, C.-C - alkyl or C \ -C" alkoxy and Ii and V are independently G -0 _r - alkyl or by halogen or »G. G ₉ alkoxy-substituted C ^ -C ^ alkyl or gsmeinsam one of the following alkyl groups -44- 30,3.1934 AP C 07 D / 256 720/6 63 196/11 \ 1/2 \ / or R rr and wherein R, R ₂ , R-, each other hydrogen or G.-0.-alkyl, wherein the total irrespective of the carbon atoms of R, R, and R- 6 not R _{1 is} hydrogen and R is a group of the formula GH ₂ OR ₇ in which R _{7 is} C 1 -C 4 -alkyl, C 1 -C 4 -alkyl substituted by C ₁ -C ₄ -alkoxy, G ₀ -G.- Alkenyl or prop-2-inyl means. 3. Method according to one of the items 1 to 6, characterized in that compounds of the formula I, in which R has the meaning given under the formula I, R and R independently of one another denote hydrogen, methyl, chlorine or bromine, Ar are unsubstituted or phenyl which is substituted by halogen, methyl or irifluoromethyl and U and Y are, independently of each other, C... G-alkyl, C ₂ -C -alkyl optionally substituted by halogen or G 1 to C ₄ -alkoxy, or together one of the following alkylene groups OAER R, R and Rc are independent of each other form, wherein R ₁ , R,
are hydrogen or C.-G.-alkyl, wherein the total number of carbon atoms in R_, R ^ and Rr- should not exceed the number 4, or produce their acid addition salts * -45-. 30.3 * 1984 AP C 07 D / 25o 720 / δ 63 196/11 A method according to any one of items 1 to 6, characterized in that compounds of the formula I, wherein R has the meaning given under the Pormel I, R and Second R, mean hydrogen, Ar for unsubstituiartes or ο. phenyl substituted by halogen or methyl, and U and V together represent a group of the formula / j ^c : _fl - β ^or ! ι in which R _{2 is} G.G.-alkyl, hydrozy-C.sub.1-C.sub.4-alkyl or G.G.sub.p-Zilkosy G.G.sub.-alkyl, or the acid addition salts thereof are prepared. Method according to one of the items 1 to 6, characterized in that 2- / p- (p-chlorophenoxy) phenyl7-2- / T- (2-methylimidazolyl) meth3O.7-4-ethyl-1,3- diozolane or an acid addition salt thereof « 11. The method according to any one of items 1 to 6, characterized in that 2- (p-phenoxyphenyl) -2- / ~ - (2-methyliraida-3olyl) ~ methyl7-4-methyl-1,3-diozane or a Acid addition salt thereof produces, 12. The method according to any one of the items 1 to 6, characterized in that 2 - ^ - (p-Ghlorphenoxy) -2-methyl-phenyl7- -2- / T- (2-methylimidazolyl) meth.yl7-4-niethyl -1,3-dioxoian or an acid addition salt thereof. -46- 30.3.1984 A? G 07 D / 256 720/6 63 196/11 13. The method according to any one of items 1 to 6, characterized by reacting 2- _- / 4- (p-chlorophenoxy) -2-methyl-phenyl] _: 7- -2-Z "T- (2-niethyl.imidazolyl ) methyl 7-4-ethyl-1,3-dio: colan or an acid addition salt thereof a 14. The method according to any one of items 1 to 6, characterized in that 2 -_ / p- (m-Ghlorphenoxy) phenyl7-2- / T- (2-methylimidazolyl) methyl7-4-ethyl-1j3-dioxolane or "produces an acid addition salt thereof. 15. The method according to any one of items 1 to 6, characterized in that 2- (2-chloro-4-phenoxy-phenyl) -2- / l- (2-methylimidazolyl) methy] .7-4-ethyl dio: colan or an acid salt thereof. 16 »A method according to any one of the items 1 to 6, characterized in that 2- / p- ^G hlorphenoxy) pheny_l7-2- / T- (2-methylimidazolyl) methy] -7-1,3-dioxane or an acid ~ addition salt thereof produces. 17. The method according to any one of the items 1 to 6, characterized in that 2- ^ p- (4-chloro-3-niethyl-phenoxy) phenyl7- 2- / 1- (2-methylimidaaolyl) methyl7-4-aethoxymethyl 1,3-diozolane or an acid addition salt thereof » 18. Process according to any one of items 1 to 6, characterized in that 2- (p-phenozyphenyl) -2- / 1 '- (2-methylimidazolyl) -methyl7-4-propyi-dioxolane or an acid addition salt thereof is prepared » 19. The method according to any one of the items 1 to 6, characterized in that 2- / p- (2,4-dichlorophenoxy) oneny 1.7-2- / T- (2-methylimidazolyl) methyl7-4 ~ ethyl-1 _} 3rd -dioxolane or an acid addition salt thereof «