NO834188L - PROCEDURE FOR THE PREPARATION OF NEW ARYL PHENYLETER DERIVATIVES - Google Patents

Description

The invention relates to a process for the production of new substituted arylphenyl ether derivatives with the following formula I as well as their acid addition salts.

Arylphenyl ether derivatives obtainable according to the invention have formula I,

in which

R means C 1 -C -alkyl,

R^ and R, independently of each other mean hydrogen, halogen

or C 1 -C 4 -alkyl,

Ar means unsubstituted or with halogen, C₁-C₁-alkyl,

C 1 -C 4 -alkoxy<y>and/or trifluoromethyl mono- or polysubstituted phenyl;

U and V independently of each other mean C^-C^2~ alkyl optionally substituted by halogen or C₁-C₂-Alkoxy or together mean one of the following alkylene bridges

R^ and R 2 independently of each other mean hydrogen, C^-C^2~alkYl'

one or more times with halogen substituted C^-C^2-alkyl, phenyl, one or more times with halogen and/or C^-C^-alkyl substituted phenyl or the group -CH2-Z-R^, wherein

Z means oxygen or sulfur and

R 7 means hydrogen, C 1 -C 8 -alkyl, a C 1 -C 8 -alkyl substituted with C 1 -C 2 -Alkoxy, C 1 -C 3 -alkenyl, 2-propynyl, 3-halo-2-propynyl, phenyl, one with halogenxC₂-C₂-alkyl, C₁-C₂-alkyl, nitro and/or CF₂ one or more substituted phenyl, benzyl or with halogen, C₂-C₂-alkyl and/or C₂-C 3-Alkoxy

mono- or polysubstituted benzyl;

R^, R^ and Rj. independently means hydrogen or C₁-C₂-alkyl, the total number of carbon atoms

in R^ 1 R^and R,- does not exceed the number 6, and

Rg means hydrogen or C₁-C₁-alkyl,

as well as their acid addition salts.

The substituent Ar, for example, has the formula

wherein R , R , and R independently of one another mean hydrogen, halogen, C 1 -C 4 -alkyl, C 1 -C 4 -alkyl or trifluoromethyl.

By the term alkyl itself or as a component of another substituent, depending on the number of carbon atoms indicated, for example, the following groups are understood: 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 means e.g. propenyl-(1), allyl, butenyl-(1), butenyl-(2) or butenyl-(3). Halogen shall here and in the following mean fluorine, chlorine, bromine or iodine, preferably chlorine or bromine.

The invention also relates to the free compounds with formula

I, as also their addition salts with inorganic or organic acids.

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

Physiologically tolerable acids, i.e. pharmaceutically usable

acids are, for example, pharmaceutically usable mineral acids,

as hydrohalic acid, e.g. hydrochloric, bromic or hydroiodic acid, nitric, sulfuric or phosphoric acid, pharmaceutically usable 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 sulphonic acids, such as lower alkane or optionally substituted benzene sulphonic acids, e.g. methane-, ethane-, benzene-, p-toluene-

and p-bromobenzenesulfonic acid, further sulfamic acids, e.g. N-cyclohexylsulfamic acid.

The compounds of formula I are at room temperature stable oils, resins or solids, which are distinguished by valuable pharmacological, especially anticonvulsant and/or anxiolytic, likewise antidepressant and/or antifungal properties. They can therefore be used as anticonvulsants and/or anxiolytics, as well as antidepressants and/or antifungals, for example to combat parasitic fungi on warm-blooded animals and/or to treat various forms of epilepsy, anxiety, tension and excitement and/or mania states of mind.

Compounds with distinctly useful anticonvulsant and anxiolytic properties are those, in which R has the meaning given under formula I, R and R, means regardless of

cl -D

each other hydrogen, methyl, chlorine or bromine, Ar means unsubstituted or with halogen, methyl or trifluoromethyl substituted phenyl and U and V mean independently of each other

C^-C^-alkyl, optionally C^-C^-alkyl substituted with halogen or C^-C^-alkyl or together form one of the following alkylene groups

in which R^, R2>R2/R4 and R^ independently of each other mean hydrogen or C^-C^-alkyl, the total number of carbon atoms in R.j f R^ and R^- shall not exceed the number 4. The invention relates, for example, to the production of compounds with formula I, in which R, R^ and R^ have the indicated meaning, Ar means a group of the formula in which Rc, R^ and Rg independently of each other mean hydrogen, halogen, trifluoromethyl, C^-C^-alkyl or C^- C₁-Alkoxy, and U and V independently of each other means C₁-C₆-alkyl or with halogen resp. C₁-C₂-Alkoxy substituted C₁-C₂-alkyl together means one of the following alkylene groups

wherein R^, R2, R^/R^°9R independently of each other means hydrogen or C^-C^-alkyl, the total number of carbon atoms of R^, R^ and R^ not exceeding 6, or R^ means hydrogen and R means a group with Cr^OR^, in which R^ means: C^-C4~alkyl with C^-C2-alkoxy-substituted C^-C^-Alkyl, C^-C^-alkenyl or prop-2- inyl as well as their acid addition salts.

A further preferred group of distinctly anticonvulsant and anxiolytic-acting compounds which are to be highlighted,

in

IN

in which R has the meaning given under formula I, R^ and R^ mean hydrogen, Ar means unsubstituted or halogen- or methyl-substituted phenyl and U and V together mean a group of formula

in which R^ means C^-C^-alkyl, such as methyl or ethyl, hydroxy-C^-C^-alkyl, such as hydroxymethyl or 2-hydroxyethyl, or C^-C^-alkoxy-C-^-C^- alkyl, such as methoxymethyl or ethoxymethyl.

The following compounds should be mentioned as examples of particularly preferred compounds with regard to their anticonvulsant, antidepressant and/or anxiolytic properties: 2-/_p-(p-chlorophenoxy)phenyl_1/-2-/ 1-(2-methylimidazolyl)methyl7- 4-ethyl-1. 3-dioxolane,

2-(p-phenyl)-2-(1-(2-methylimidazolyl)methyl)-4-methyl-1,3-dioxane.

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

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

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

2-(2-chloro-4-phenoxyphenyl)-2-[1-(2-methylimidazolyl)methyl]-4-ethyldioxolane,

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

2-[p-(4-chloro-3-methyl-phenoxy)phenyl]-2-[1-(2-methylimidazolyl)-methyl]-4-methoxymethyl-1,3-dioxolane,

2-(p-phenoxyphenyl)-2-[1-(2-methylimidazolyl)methyl]-4-propyl-dioxolane and

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

and each their pharmaceutically acceptable acid addition salts. The invention relates in particular to methods for their production.

The compound of formula I can be prepared by

A) a compound of formula II

in which Y is hydrogen or a metal cation, is condensed with a compound of formula III in which X is a nucleofuge leaving group, or B) a compound of formula IV the carbonyl group is transferred to a group of formula V

or

C) for the preparation of compounds of formula I, in which U and V together represent a group of the formula

-CH2-CH(CH2ZR^)- and R^ means a residue different from hydrogen R^, compounds with the formulas VI and VII are condensed with each other

in which one of the residues X₂ and X₂ optionally means hydroxy or mercapto present in salt form, e.g. of the formula

-Z-Y, wherein Y means hydrogen or preferably a metal cation

and the other means a nucleofuge leaving group X, or as well as also X2 means hydroxy groups, or

D) the compounds of formula VIII and IX

in which one of the radicals X^ and X^ means a group -O-Y, in which Y means hydrogen or preferably a metal cation, and the other means an aryloxy-exchangeable residue, condense with each other or

E) a compound of formula

is decarboxylated intramolecularly and

if desired, a compound obtained according to the method is converted into another compound of formula I and/or a free compound obtained according to the method is transferred into an acid addition salt, an acid addition salt obtained according to the method is converted into a free compound or into another acid addition salt.

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

Nucleofuge leaving groups are, for example, reactive esterified hydroxy groups, such as hydroxy groups esterified with a halogen hydrogen acid, e.g. with hydrofluoric, chloric, bromic or hydroiodic acid, or a lower alkane, optionally substituted benzene or halosulfonic acid, e.g. with methane, ethane, benzene, p-toluene or fluorosulfonic acid.

The reaction with an azole of formula II, in which R is the meaning given under formula I and Y preferably means a metal atom, especially an alkali metal atom, with a compound of formula III, in which Ar, R a , R, b , U and ^ V have the meaning given under formula I and X for example means halogen, especially chlorine, bromine or iodine, or benzenesulfonyloxy, p-tosyloxy, trifluoroacetyloxy or preferably lower alkylsulfonyloxy such as e.g. mesyloxy, is preferably carried out in a relatively polar, however reaction-inert organic solvent, e.g. N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, acetonitrile, benzonitrile and others. Such solvents can 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, etc.

If X is chlorine or bromine, alkali iodide (such as NaJ or KJ) can conveniently be added to accelerate the reaction. Increased temperatures from 0 to 220°C, preferably 80-170°C, are advantageous. The reaction mixture is suitably heated under reflux.

In those cases where in formula II Y means hydrogen, the method is carried out in the presence of a base. Examples of such bases are inorganic bases such as oxides, hydroxides, hydroxides, the hydrides, carbonates and hydrogen carbonates of alkali and iodo-alkaline metals as well as e.g. tart. amines such as triethylamine, triethylenediamine, piperidine, pyridine, 4-dimethylaminopyridine, 4-pyrrolidylpyridine, etc.

With these and the following manufacturing variants, the intermediate products and end products can be isolated from the reaction medium, if desired, purified using one of the generally common methods, e.g. by means of extraction, crystallization, chromatography, distillation, etc.

Transfer of the carbonyl groups in connection with formula IV

in the group with formula V takes place by reaction with an orthocarboxylic acid tri-C^-C^2-alkyl ester/if C^-C^2~ alkyl groups optionally substituted with halogen or C^-C^- alkoxy or in the presence of - an acid with at least 2 mol of a monohydric alcohol of formula U-OH (Va), whereby compounds of formula I are obtained, in which U and V mean the same, optionally substituted C^-C^2~ alkyl groups, or by reaction with a diol of formula Vb

as compounds of formula I in which U and V are obtained

together means one of the initially defined alkylene bridges. Thereby, Ar, R, R , R , U and V have the meaning given under formula 1.

The ketalization reaction can be carried out analogously to those

already known ketalization reactions, for example analogous to the already known catalysis reactions, for example analogous to the production of 2-bromomethyl-2,4-diphenyl-1,3-dioxolane [Synthesis, 1974 (I) , 23] .

In the preferred embodiment of ketalization is heated

both reaction partners several hours together with- an azeotrope-former in one of the usual organic solvents. under reflux. As an azeotrope-former, e.g. namely benzene, toluene, xylene, chloroform or carbon tetrachloride,

in that to accelerate the reaction it may be advantageous to add a strong acid, such as e.g. p-toluenesulfonic acid. Usable organic solvents in this case are e.g. aromatic hydrocarbons, such as benzene, toluene, xylene, etc., saturated hydrocarbons, such as n-hexane or saturated halogenated hydrocarbons such as 1,1,1-trichloroethane.

Other ketalization routes are also feasible, e.g. by reacting a ketone IV, which is ketalized with one from alkanols resp. diols with the formulas Va or Vb different alcohol or phenol and re-ketalizes these by reaction excess alkanol Va resp. diols Vb to (I). The output product is e.g. available according to one of the method variants A), D) and E).

Preparation of compounds of formula I, in which the substituents U and V according to variant C) together mean -C^-CH (CI^ZR^)-, takes place, for example, by reaction of a compound of formula VI with a compound of formula VII, wherein a group means -ZH and X2 means a group X. The reaction is preferably carried out in a reaction-inert organic solvent. It is suitable for this e.g. N,N-dimethylformamide, N,N-dimethylacetamide, hexamethylphosphoric triamide, dimethyl sulfoxide, 4-methyl-3-pentanone, etc. Also mixtures with other reaction-initiated solvents, e.g. with aromatic hydrocarbons such as benzene, toluene, xylene, etc. can be used. In many cases, working in the presence of a base can prove beneficial for accelerating the reaction rate. Such bases are e.g. alkali metal hydrides or alkali metal carbonates. In certain cases, it may also be advantageous to first transfer the compound VI in a known manner into a suitable metal salt.

This preferably takes place by reacting VI with a Na compound, e.g. sodium hydride, sodium hydroxide, etc. This salt of VI is then reacted with the compound of formula VII. To increase the reaction rate, in many cases it is also possible to work at an elevated temperature, preferably 80°C to 130°C, resp. at the boiling point of the solvent.

In an analogous way, one can also react with compounds of the formula VI and VII, in which X 1 means a group X and X 2 a group -ZH.

By that to the products of formula I where Z is oxygen,

leading condensation reaction of compounds with the formula VI and VII, in which and X~means hydroxy, the reaction participants can be heated in a suitable solvent under reflux, while at the same time the water formed is distilled off azeotropically from the reaction mixture. Solvents include aromatic hydrocarbons such as toluene or alcohol HO-R^self. With this reaction, one works appropriately in the presence of a strong base, e.g. p-toluenesulfonic acid.

In the case of variant D), the starting point is preferably connections

with the forms VIII and IX, in which X^ means a group -0Y and X^ means a nucleofuge leaving group or vice versa, X^ means

a nucleofuge leaving group and X^ forms the group -0Y. Hereby, R cL , R, JD, U, V, R and Ar have the meanings indicated under formula I; Y preferably means hydrogen. The reaction is preferably carried out under the conditions mentioned in variant A).

In variant E), the compound of formula X, which is to be decarboxylated, becomes available by ketalization of a compound of formula XI. analogously to that discussed under B),

which in turn can be obtained by reacting a compound of formula Ar-OH XII with a difunctional derivative of carbonic acid, e.g. with phosgene, haloformic acid lower alkyl ester or a divalereallyl or diphenyl carbonate and further reaction with a compound of formula XIII

heated dry or in a boiling solvent, such as a high-boiling ether, e.g. diphenyl ether or ethylene glycol dimethyl ether, to approx. 120 to 220°C.

According to the method, compounds obtained can be transferred into other compounds of formula I by methods known per se.

Thus, for example, compounds obtained according to the method can be reketalized to other compounds of formula I. For example, in compounds of formula I, in which U and V mean the same optionally substituted, C]_~C]_2~alkyl residues U, by reaction with 1 mol of another, optionally substituted C 1 -C 12 -alkanol of formula V-OH (Vc) ,

replace a group U with a group V or, by reaction with a diol of formula Vb, replace both groups U with a divalent residue. The reketalization takes place in the usual way, for example in the presence of an acidic condensation agent such as a mineral, sulphonic or strong carboxylic acid, e.g. of hydrochloric or bromic acid, sulfuric acid, p-toluenesulfonic acid or trifluoroacetic acid, preferably under distillative resp. azeotropic distillation removal of volatile reaction products.

Furthermore, in the carbocyclic aryl part of compounds obtained according to the method, additional substituents can possibly be introduced in the residue Ar and/or the group Rg or R^. Thus, one can e.g. by reaction with a halogen in the presence of a Lewis acid, such as an iron, zinc, boron or antimony halide, or by treatment with N-chlorosuccinimide,

introduce halogen.

Furthermore, the nitro group can be reduced, e.g. with help

of suitable., complex ...hydrides,_. for example with lithium aluminum hydride, to amines, diazotize these e.g. by means of nitric acid, and replace the formed diazonium groups in the usual way with halogen or alkoxy. Likewise, halogen can be replaced by reaction with an alkyl metal compound, e.g. with an alkyllithium or alkylmagnesium halide with alkyl.

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

by reaction with the desired diol in an inert solvent, e.g. a halogenated hydrocarbon (such as methylene chloride, ethylene chloride, chloroform, carbon tetrachloride, etc.) and simultaneous or subsequent halogenation. To accelerate the reaction, it is advantageous to add p-toluenesulfonic acid. The ketones of formula IV can be prepared by halogenation of the starting ketones XIV to XV

and further reaction of XV, analogous variant A with an azole of formula II. Herein, Hal preferably means chlorine or bromine.

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

Formed free compounds of formula I can in and of themselves

known manner is transferred to salts, among other things by treatment with a base or with a suitable salt of a carboxylic acid, usually in the presence of a dissolving or diluting

medium.

Formed salts can be converted in a manner known per se

free connections, e.g. by. treatment with an acidic reagent such as a mineral acid.

The compounds, including their salts, can also be obtained in form

of their hydrates or contain the solvent used for crystallization.

Because of the narrow relationship between the new connections

in free form and in the form of their salts, in the preceding and following food free compounds or their salts may also mean the corresponding salts resp. free connections.

The invention also relates to the embodiments of the method where one starts from a compound obtained at an arbitrary process step as an intermediate and carries out the missing process steps or forms a starting material under the reaction conditions or uses it in the form of a derivative thereof, possibly a salt.

In the method according to the invention, such starting materials are preferably used, which lead to the compounds initially described as particularly valuable. New starting materials and methods for their production are covered by the invention.

In all mentioned ketalization reactions of a ketone with a substituted α,3~ or α,y-diol, predominantly mixtures of diastereomers of the resulting ketal occur. Correspondingly, diastereomeric mixtures of the end products I are usually formed from the starting ketones. The compounds of formula I can exist, for example, in the following two diastereomeric forms:

The configuration of type A shall here and in the following be referred to as "trans" isomers.

The symbols in the spatially reproduced structures shall have the following meaning

• *' •= rear

in

= in front of the drawing plane.

The configuration of type B shall be designated accordingly as "cis" isomers. The separation of the two diastereomers can, for example, take place by fractional crystallization or by chromatography (thin-, thick-layer, column chromatography, liquid-high-pressure chromatography, etc.). The two isomers show different biological effects. Generally, for practical purposes, diastereomer mixtures are used. The invention relates to all isomeric compounds of formula I and their salts.

1-(3-aryl)-ethyl imidazolyl ketals in which aryl means substituted phenyl or naphthyl are cited in the following references as fungicides and bactericides: US patents: 3,575,999, 3,936,470, 4,101,664,- 4,101,666, 4,156 .008.

The antifungal properties which justify the applicability of the compound of formula I and their pharmaceutically usable acid addition salts for combating warm-blooded parasitizing fungi can, for example, be determined in vitro by means of standard microbiological examination methods, e.g. by means of their toxic effect on warm-blooded parasitizing fungal strains, such as trychophyton mentagryphites, Microsporum canis, Sporotrichum schenkii, Aspergillus fumigatus and Candida albicans, as well as in vivo on guinea pigs. help

of preparation effect on experimental infestations of the dorsal skin with Trychophyton, e.g. T.rubrum, after oral resp. local application.

The anticonvulsant effect of the compound of formula I and their pharmaceutically usable acid addition salts can be demonstrated in vivo, for example on mice in the Pentatetrazol seizure test in the dose range from approx. 10 to approx. 100 mg/kg p.o., likewise in the electroshock test in the dose range from approx. 10 to approx.

100 mg/kg p.o. The anxiolytic effect can be shown, for example, on mice and other small rodents using the Gellert test and the quatre-Plaques test in the dose range from approx. 10 to approx. 100 mg/kg p.o~r One can also infer a significant antimanic effect of the new compounds.

The compounds of formula I and their pharmaceutically usable acid addition salts are used for topical, resp. local and systemic control of warm-blooded animals parasitizing fungi resp. for the systemic treatment of various forms of epilepsy, of anxiety and tension states and of manic states of mind, especially as an active substance in resp. for the production of pharmaceutical preparations for enteral, parenteral, topical resp. local application.

The pharmaceutical preparations containing the compound of formula I or pharmaceutically usable salts thereof are therefore those for enteral, such as oral or rectal and parenteral administration as well as for topical use on warm-blooded animals, and which contain pharmacologically active substances alone or together with a pharmaceutically usable carrier material. The dosage of the active substance depends on the type of warm blood, age and individual condition as well as the method of application.

Normally, it is approx. 75 kg heavy warm-blooded animal wood

oral application to suggest an approximate daily dose of approx.

50-500 mg, preferably divided into several equal partial doses.

The new pharmaceutical preparations contain e.g. from approx.

10% to approx. 80%, preferably from approx. 20% to approx. 60% of the active substance. Pharmaceutical preparations for etheral or parenteral administration are e.g. such dosage unit forms as dragees, tablets, capsules or suppositories, further ampoules. These are produced in a manner known per se, e.g. using conventional mixing, granulating, coating, dissolving or lyophilizing methods. Thus, pharmaceutical preparations for oral use can be obtained by combining the active substance with solid carriers, possibly granulating a formed mixture, and processing the mixture or the granulate if desired or necessary after the addition of suitable excipients

tablets or dragon cores.

Suitable carriers are especially fillers, such as sugar,

e.g. lactose, sucrose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, e.g. tricalcium

phosphate or calcium hydrogen phosphate, further binders such as starch, adhesives during use, e.g. of corn, wheat, rice or potato starch, gelatins, tragacanth, methylcellulose and/or polyvinylpyrrolidone and/or, if desired, disintegrants such as the above-mentioned starches, further carboxymethyl starch, cross-linked polyvinylpyrrolidone, agar, alginic acid or a salt thereof, as sodium alginate. Auxiliaries are primarily flys-regulating and lubricants, e.g. silicic acid, talc, stearic acid or salts thereof such as magnesium or calcium stearate, and/or polyethylene glycol. Dragon cores are equipped with suitable, possibly gastric juice-resistant coatings, using, among other things, concentrated sugar solutions, such as possibly gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide varnish solutions in suitable organic solvents or solvent mixtures or, for the production of gastric juice three-resistant coatings, solutions of suitable cellulose preparations, such as acetyl cellulose phthalate or hydroxypropyl methyl cellulose phthalate. Dyes or pigments can be added to the tablets or kite covers, e.g. for the identification or characterization of different effective drug doses.

Further orally usable pharmaceutical preparations are capsules made of gelatin as well as soft closed capsules made of gelatin and a plasticizer such as glycerol or sorbitol. Stik capsules may contain active substances in the form of a granule, e.g. in a mixture with fillers, such as lactose, binders, such as starches and/or lubricants, such as talc or magnesium stearate and possibly stabilizers. In soft capsules, the active substance is preferably dissolved or suspended in suitable liquids such as fatty oils, paraffin oils or liquid polyethylene glycols, as stabilizers may possibly be added to them.

As rectally applicable pharmaceutical preparations, there are e.g. considering suppositories which consist of a combination of the active substance with a suppository base.

As a suppository base material, it is suitable, e.g. natural or synthetic triglycerides, paraffin hydrocarbons, polyethylene glycols or higher alkanols. Furthermore, gelatin rectal capsules can also be used which contain a combination of the active substance with base material; as base materials there are e.g. namely liquid triglycerides, polyethylene glycols or paraffin hydrocarbons.

For parenteral administration, aqueous solutions of an active substance in water-soluble form are primarily suitable, e.g. a water-soluble salt, further suspensions of the active substance as corresponding oily injection suspensions, using suitable lipophilic solvents or carriers, such as fatty oils, e.g. sesame oil, or synthetic fatty acid esters, e.g. ethyl oleate or triglycerides, or aqueous injection suspensions,

which contain viscosity-increasing substances, e.g. sodium carboxymethylcellulose, sorbitol and/or dextran and optionally also stabilizers.

As topically applicable pharmaceutical preparations it comes

primarily creams, ointments, pastes, foams, tinctures and solutions containing from approx. 0.5 to approx. 20% of the active substance.

Creams are oil-in-water emulsions that contain more than 50% water. Fatty alcohols are primarily used as oily bases, e.g. 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. petroleum jelly (petrolatum) or paraffin oil. Emulsifiers include surface-like substances with predominantly hydrophilic properties such as corresponding non-ionic emulsifiers, e.g. fatty acid esters of polyalcohols 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 sulfate, sodium cetyl sulfate or sodium stearyl sulfate, which are usually used in the presence of fatty alcohols, e.g. cetyl alcohol or stearyl alcohol. Additions to the water phase include agents that prevent drying of the creams, e.g. polyalcohols, such as glycerol, sorbitol, propylene glycol and/or polyethylene glycols, further preservatives, fragrances etc.

Ointments are water-in-oil emulsions, which contain up to

70%, preferably however from approx. 20 to approx. 50% water or aqueous phases. The fatty phase primarily includes linear hydrocarbons, e.g. vaselines, paraffin oils and/or hard paraffins, which improve the water-binding capacity, preferably contain suitable hydroxy compounds such as fatty alcohols or esters thereof, e.g. cetyl alcohol or wool wax alcohols, resp. owl wax. Emulsifiers are similarly lithophilic substances, such as sorbitan fatty acid esters (spans), e.g. sorbitan oleate and/or sorbitan isostearate. Additions to the water phase include 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 hydrocarbons in particular as a basis, e.g. paraffins, petroleum jelly and/or liquid paraffins, further natural or partially synthetic fats, e.g. coconut fatty acid triglyceride, or preferably hardened oils, e.g. hydrogenated peanut or castor oil,

further fatty acid partial esters of glycerol, e.g. glycerol mono- and -distearate, as well as~ e.g. the compounds with the ointments mentioned water absorption increasing fatty alcohols, emulsifiers and/or additives.

Pastes are creams and ointments with secretion-absorbing powder components, such as metal oxides, e.g. titanium oxide or zinc oxide, further talc and/or aluminum silicates which have the task of binding the moisture or secretions present.

Foams are administered from pressurized containers and are liquid oil-in-water emulsions present in aerosol form, halogenated hydrocarbons such as chlorofluorolower alkanes, e.g. dichlorodifluoromethane and dichlorotetrafluoroethane are used as propellants. Hydrocarbons are used as the oil phase, e.g. paraffins, fatty alcohols, e.g. cetyl alcohol, fatty acid esters, e.g. isopropyl myristate, and/or other types of wax. Emulsifiers used include mixtures with predominantly hydrophilic properties, such as polyoxyethylene sorbitan fatty acid esters (Tweens) and those with predominantly lipophilic properties, such as sorbitan fatty acid esters (spans). In addition, there are the usual additives, such as preservatives etc.

Tinctures and solutions mostly have an aqueous ethanolic base such as polyalcohols, e.g. glycerol, glycols and/or polyethylene glycol, as a humectant to reduce evaporation and fattening substances,

as fatty acid esters with lower polyethylene glycol, i.e. soluble in an aqueous mixture, lipophilic substances as a replacement for the fatty substances that have been removed from the skin with ethanol, and if necessary other aids and additives.

The preparation of the topically applicable pharmaceutical preparations takes place in a manner known per se, e.g. by dissolving or suspending the active substance in the base or in a part of it if necessary. When processing the active substance as a solution, this is usually dissolved before emulsification in one of the two phases; when processed as a suspension, it is mixed after emulsification with part of the base and then the rest of the formulation is added.

The invention will be explained in more detail with the help of some examples. Temperatures are given in degrees Celsius, pressure in mbar. Percentages and parts refer to weight.

Example i

Manufacture of

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

a) Intermediate product

a) 2-(p- phenoxyphenyl)- 2- bromomethyl- 4- methyl- 1, 3- dioxane

10 parts 2-(p-phenoxyphenyl)-2-oxo-1-bromomethane and 4 parts

1,3-Butanediol is heated in 40 ml of absolute toluene in the presence of 0.2 parts of catalytically active p-toluenesulfonic acid for 3 hours under reflux, the water formed being separated with a water separator. After cooling to room temperature, the reaction mixture is washed twice with 20 ml of water each time,

dried over sodium sulfate, filtered, the solvent evaporated and the crude product recrystallized from isopropanol. Colorless crystals. Melting point 96-106°C.

b) Final product

3.8 parts of 2-methylimidazole sodium salt and a catalytic

an effective amount of potassium iodide is stirred in 40 ml of dimethylformamide together with 10.2 parts of the 2-(p-phenoxy-phenyl)-2-bromomethyl-4-methyl-1,3-dioxane prepared according to a) for 30 hours at an internal temperature of 120°cr" After cooling to room temperature, 300 ml of water are added, extracted three times with 30 ml of ethyl acetate each time, the combined extracts are washed twice with 20 ml of water each time, dried over sodium sulphate, filtered and the solvent is evaporated. The oily

residue is purified by column chromatography (silica gel/ethyl acetate). The eluent is evaporated. You get a viscous mass with 22.5

<n>D = 1.5634.

Example 2:

Manufacture of

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

1.4 parts of 2-methylimidazole sodium salt and a catalytically effective amount of potassium iodide are stirred in 50 ml of dimethylformamide together with 4 parts of 2-[p-(3-chlorophenoxy)phenyl]-2-bromomethyl-4-ethyl-1,3-dioxolane for 17 hours at an internal temperature of 125°C. After cooling, the brown reaction mixture is mixed with 150 ml of water, extracted three times with each time 50 ml of ethyl acetate, the combined extracts are washed twice with each time with 50 ml of water, dried over sodium sulfate, filtered and the solvent is evaporated. The oily crude product is chromatographed over a 35 cm long silica gel column using acetone/ethyl acetate (1:1). The eluent for-22

steamed. You get a viscous mass with n = 1.5685.

Example 3

Manufacture of

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

a) Intermediate product

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

37 parts 4-(p-chlorophenoxy)acetophenone and 18 parts 1,2-butane-

diol is heated in 400 ml of absolute toluene in the presence of 2 parts of catalytically active p-toluenesulfonic acid for 14 hours with a water separator under reflux. After cooling to room temperature, the reaction mixture is washed twice with 400 ml of water, dried over sodium sulfate, filtered, the solvent is evaporated and the crude product is chromatographed for purification over a 1 m long silica gel column using ligroin/hexane/ethyl acetate/toluene (5:3:1:1 ). The product is available as a light yellow

22

like oil. n^ : 1.5527.

2-[ p-( p- chlorophenoxy) phenyl]- 2- bromomethyl- 4- ethyl- 1, 3- dioxolane

36.8 parts of the 2-[p-(p-chlorophenoxy)phenyl]-2-methyl-4-ethyl-1,3-dioxolane produced under a) are heated in 350 ml of chloroform to boiling. Under illumination using a 150 watt spot lamp, 19.4 parts of bromine, dissolved in 50 ml of chloroform, are added dropwise, and then heated for 2 hours under reflux.

After cooling to room temperature, the reaction mixture is washed twice with 200 ml of water each time, dried over sodium sulphate, filtered and the solvent is removed using a water jet vacuum. For purification, the crude product is chromatographed over a 1 m long silica gel column using toluene. The product is obtained as a yellow oil with nQ 23 = 1.5805.

b) Final product

5.0 parts of 2-methylimidazole sodium salt and a catalytic

an effective amount of potassium iodide is stirred in 80 ml of dimethylformamide together with 14.7 parts of the 2-[p-(p-chlorophenoxy)phenyl]-2-bromomethyl-4-ethyl-1,3-dioxolane prepared according to 3) for 17 hours at a bath temperature of 125°C. After cooling to room temperature, the reaction mixture is poured into 600 ml of water, extra-

is stirred three times with each time 200 ml of ethyl acetate, combined organic phases are washed twice with each time with 200 ml of water, dried over sodium sulphate, filtered and the solvent is evaporated. The oily residue is chromatographed over a 50 cm long silica gel column using acetone/ethyl acetate (1:1). After the eluent evaporates, the product is obtained

23

as brown oil with nQ '= 1.5721.

Example 4

Manufacture of

2-(p-phenoxyphenyl)-2-[1-(2-methylimidazolyl)methyl]-4-ethyl-1,3-di6xolane 17 parts 2-(p-phenoxyphenyl)-3-bromomethyl-4-ethyl-1, 3-dioxolane, 8.4 parts of potassium carbonate, 4.0 parts of 2-methylimidazole and a catalytic amount of sodium iodide are stirred in 100 ml of dimethylsulfoxide for 24 hours at an internal temperature of 125°C.

After cooling to room temperature, the reaction mixture is poured into 600 ml of water, extracted three times with 200 ml of ethyl acetate each time, the combined extracts are washed twice with 200 ml of water each time, dried over sodium sulfate, filtered and the solvent is evaporated. You get a viscous

22 5

mass with nQ ' = 1.5562.

Example 5

Manufacture 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 effective amount of potassium iodide are stirred in 100 ml of dimethylsulfoxide for 20 hours at an internal temperature of 140°C. After cooling to room temperature, 600 ml of water are added, extracted three times with 200 ml of ether each time, the combined extracts are washed twice with 200 ml of water each time, dried over sodium sulfate, filtered and the solvent is evaporated.

The oily residue is chromatographed over a 50 cm long silica gel column using chloroform/ether (1:1). Elution-23

the agent evaporates. You get a viscous mass with nQ = 1.5632.

Example 6

Manufacture of

2-( p-phenoxyphenyl)- 2-[ 1-( 2- methylimidazolyl) methyl]- 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 effective amount of potassium iodide are stirred in 50 ml of dimethylsulfoxide for 4 hours at an internal temperature of 140°C. After cooling to room temperature, 600 ml of water are added, extracted twice with 200 ml of ethyl acetate each time, the combined extracts are washed twice with 200 ml of water each time, dried over sodium sulfate, filtered and the solvent is evaporated. The oily residue is chromatographed over a 50 cm long silica gel column using acetone. After evaporation of the eluent, the oily residue crystallizes after the addition of petroleum ether. Beige crystals of melting point 166 - 170°C. Example 7 Preparation of 2-(p-phenoxyphenyl)-2-[1-(2-methylimidazolyl)methyl]-4-n-propyl-1,3-dioxolane 10.3 parts of the nitrate of 1-(p-phenoxyphenyl) -2-[1-(2-methylimidazolyl)]-ethanone, 6.1 parts of 1,2-pentadiol, 6.9 parts of p-toluenesulfonic acid, 20 parts of 1-pentanol and 200 parts of xylene are heated for 6 days with a water separator under reflux and washed after cooling to room temperature twice with each time 200 ml of diluted caustic soda and twice with each time 200 ml of water. The organic phase is dried over sodium sulphate, filtered and the solvent is evaporated. The oily residue is chromatographed over a lm long silica gel column using ethyl acetate. After the eluent has evaporated, a yellowish oil with nD' = 1.5565 remains.

Example 8

Manufacture of

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

a) Intermediate products

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

36.6 parts of 2-methyl-4-phenoxy-acetophenone are heated dissolved in 160 ml of acetic acid to 35°C and mixed with stirring for 1.5 hours dropwise with 25.9 parts of bromine. It is then allowed to stir for 1 hour, rather in 1000 ml of ice water and shaken twice with 100 ml of diethyl ether each time. The combined extract is washed with water, dried over sodium sulfate, filtered and evaporated. The oily residue crystallizes from hexane to a brownish crystal with a melting point of 60 - 61°C.

3) 2-( 2- methyl- 4- phenoxy- phenyl)- 2- bromomethyl- 4- ethyl- 1, 3- diocolane

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. One part of p-toluenesulfonic acid is added and heated with a water separator for 25 hours until boiling. It is allowed to cool to room temperature, washed three times with 250 ml of water each time, dried over sodium sulphate and filtered. The solvent is evaporated under reduced pressure. A red-brown oil remains.

b) Final product

9.5 parts of 2-(2-methyl-4-phenoxyphenyl)-2-bromomethyl-4-ethyl-1,3-dioxolane according to 3) 2.9 parts of 2-methylimidazole and 4 parts of potassium tertiary butanolate are stirred in 50 ml of dimethylsulfoxide for 30 hours at 110 °C. Allow it to cool to room temperature, dilute with 300 ml of water and shake three times with 150 ml of vinegar each time. The acetate extracts are combined, washed neutrally with water, dried over sodium sulphate, filtered and evaporated to dryness. The crude product is purified on a silica gel column (50 cm long) with vinegar as eluent. After this evaporates, a viscose remains

22 5

mass with nD ' =1.5640.'

Example 9

Preparation of 2-[p-(m-chlorophenoxy)phenyl]-2-[1-(2-methylimidazolyl)methyl]-4-ethyl-1,3-dioxolane hydrochloride 9.8 parts 2-[p-(m -chlorophenoxy)phenyl]-2-]1-(2-methylimidazolyl)methyl]-4-ethyl-1,3-dioxolane is dissolved in 80 ml of diethyl ether and mixed dropwise with 2.5 parts of concentrated hydrochloric acid while stirring. The yellowish precipitate formed is filtered off after 1 hour, washed with ice-cold diethyl ether and dried:

white crystals of melting point 158 - 162°C.

Example 10

In an analogous way, it is also possible to prepare the end products mentioned in the following table.. (Table I) (if nothing else is specifically noted, diastereomer mixtures with different mixing ratios) of formula I;

Example 11

Gelatin capsules containing 200 mg [p-(p-chlorophenoxy)-phenyl]-2-[2-methylimidazolyl)methyl-4-ethyl-1,3-dioxolane as active substance can_ e.g. is produced as follows:-

Composition (for 1000 capsules)

The active substance and the lactose (finely ground) mix well with each other. The resulting powder is sieved and filled in portions of 0.20 g each in gelatin capsules.

Example 12

Tablets containing 25 mg of active substance, e.g. 2-[p-(p-chlorophenoxy)phenyl]-2-[1-(2methylimidazolylmethyl]-4-ethyl-1,3-dioxolane, can be prepared as follows:

Ingredients (for 1000 tablets)

Manufacturing:

All solid ingredients are first run through a sieve

of 0.6 mm mesh size. The active ingredient, lactose, talc, magnesium stearate and half of the starch are then mixed. The other starch half is suspended in 40 ml of water and this suspension is added to a boiling solution of polyethylene glycol in 100 ml of water and the mixture is granulated if necessary while adding water. The granulate is dried overnight at 35°C. Drive through a sieve with a mesh size of 1.2 mm and press to form concave tablets on both sides

about. 6 mm diameter.

Example 13

Tablets containing 75 mg of active substance, e.g. 2-[p-(p-chlorophenoxy)phenyl]-2-[1-(2-methylimidazolyl)methyl]-4-ethyl-1,3-dioxolane can be prepared as follows:

Ingredients for 1000 tablets)

Manufacturing:

All solid ingredients are first run through a sieve

of 0.6 mm mesh size. The active substances, lactose, talc, magnesium stearate and half of the starch are then mixed. The other starch half is suspended in 40 ml of water and this suspension is added to a boiling solution of polyethylene glycol and 100 ml of water and the mixture is granulated if necessary while adding water. The granulate is dried overnight at 35°C, passed through a sieve with a mesh size of 1.2 mm and pressed into concave tablets of approx. 6 mm diameter.

Example 14

Analogous to examples 11 to 13, pharmaceutical preparations can also be prepared containing another of the compounds obtained according to table 1.

Claims (11)

1. Process for the preparation of new arylphenyl ether derivatives of formula I in which R means C 1 -C 8 alkyl, R and R independently mean hydrogen, halogen a o or C 1 -C 4 -alkyl, Ar means unsubstituted or with halogen, C₁ -C₁ -alkyl, C₁ -C₁ ₂ - alkoxy and/or trifluoromethyl or polysubstituted phenyl, U and V stand independently of each other, optionally with halogen or C₁ -C₁ ₂ -Alkoxy substituted C₁ -C₂₂₂ alkyl or form together one of the following alkylene bridges R 1 and R 2 independently of each other mean hydrogen, C 1 -C 2 -alkyl, one or more times with halogen substituted C^-C^2~ alkyl, phenyl, one or more times with halogen and/or C^-C-^-alkyl substituted phenyl or the group -CP^ -Z-R^ , ie Z means oxygen or sulfur and R 1 means hydrogen, C 1 -C 8 -alkyl, a C 1 -C 8 -alkyl substituted with C 1 -C 6 -C 8 -alkyl, C 1 -C 3 -alkenyl, 2-propynyl, 3-halo-2-propynyl, phenyl, one with halogen, C 1 -C 3 -alkyl, C 1 -C 3 - alkoxy, nitro and/or CF 3 one or more times substituted phenyl,. benzyl or a benzyl substituted with halogen, C 1 -C 4 -alkyl and/or C 1 -C 4 -alkyl one or more times, R^ , R^ and R^- independently mean hydrogen or C^ -C^ -alkyl, as the total number of carbon atoms in Ry R^ and R^ exceeds the number 6, and Rg means hydrogen or C^ -C^ -alkyl, as well as their acid addition salts, characterized by A) a compound of formula II wherein Y is hydrogen or a metal cation, is condensed with one compound of formula III in which X means a nucleofuge leaving group, orE) in a compound of formula IV, the carbonyl group is transferred to a group of formula V or C) for the preparation of compounds of formula I, in which U and V together mean a group of formula -CH2 -CH(CH2 ZR^)- and means a residue different from hydrogen R-, condenses with each other compounds with formula VI and VII in which one of the residues and X2 means optionally present in salt form hydroxy or mercapto, e.g. of formula -Z-Y, in which Y means hydrogen or preferably a metal cation, and the other means a nucleofuge leaving group X or both X^ and also X2 means hydroxy groups, or D) Compounds of formula VIII and IX are condensed together in which one of the residues X., and X^ means a group -O-Y, in which Y means hydrogen or preferably a metal cation, and the other means a residue exchangeable with aryloxy, orE) a compound of formula decarboxylated intramolecularly and, if desired, a compound formed according to the method is converted into another compound of formula I and/or a free compound obtained according to the method is transferred into an acid addition salt, an acid addition salt formed according to the method is transferred into the free compound or into another acid addition salt. 2. Process according to claim 1, characterized in that compounds of formula I or their acid addition salts are prepared, in which R, R& and R^ have the in the meaning given in claim 1, Ar means a group of formula wherein Rc , R^ , and Rg independently of one another mean hydrogen, halogen, trifluoromethyl, C₁-C₁-alkyl or C₁-C₁- alkoxy, and U and V independently of one another mean C₁-C₆-alkyl or with halogen or C 1 -C 3 -Alkoxy substituted C 2 -C 3 ~ alkyl together means one of the following alkylene groups wherein , R_, R^ , R^ and R^, independently of each other mean hydrogen or C^ -C^ -alkyl, the total number of carbon atoms of R^ , R^ and R^ not exceeding 6, or R^ means hydrogen and R.. means a gr.up.p_e with CH^ OR-, in which R^ means C^ -C^ -alkyl with C^ -C2 -alkyl substituted C^ -C^ -alkyl, C^ -C^ - alkenyl or prop-2-inyl. 3. Process according to claim 1, characterized in that compounds of formula I are prepared in which R has the meaning given under formula I, R^ and R^ independently mean hydrogen, methyl, chlorine or bromine, Ar means unsubstituted or with halogen, methyl or trifluoromethyl substituted phenyl and U and V independently mean C₁ - C₃ -alkyl, optionally with halogen or C₁ -C₂₂ alkoxy substituted C₁ -C₂ -alkyl or together one of the following alkylene groups wherein R^ , R2/ R3/ R^ and Rj. independently of each other means hydrogen or C₂ -C₂ -alkyl, the total number of carbon atoms in R₂, R₂ and R₂ shall not exceed the number 4, or their acid addition salts. 4. Method according to claim 1, characterized in that compounds of formula I are prepared, in which R has the meaning given under formula I, R& and R&^ mean hydrogen, Ar means unsubstituted or halogen or methyl substituted phenyl and U and V together mean a group with formula in which R 2 means C 1 -C 4 -alkyl, hydroxy-C 1 -C 4 -alkyl or C 1 -C 6 -p -alkyl C 1 -C 4 -alkyl, or their acid addition salts. 5. Method according to claim 1, characterized in that 2-_/p-(p-chlorophenoxy)phenyl7-2-/1-(2-methyl-imidazolyl)methyl7-4-ethyl-1,3-dioxolane is prepared or an acid addition salt thereof. 6. Process according to claim 1, characterized in that 2-(p-phenoxyphenyl)-2-[1-(2-methylimidazolyl)-methyl]-4-methyl-1,3-dioxane is produced. 7. Method according to claim 1, characterized in that 2-/4-(p-chlorophenoxy)-2-methyl-phenyl7-2-/1-(2-methylimidazolyl)methyl/-4-methyl-1, 3- dioxolane or an acid addition salt thereof. 8. Process according to claim 1, characterized in that 2-/4-(p-chlorophenoxy)-2-methyl-phenyl7-2-(1-(2-methylimidazolyl7methyl7-4-ethyl-1-3-dioxolane) is produced or a acid addition salt thereof. 9. Process according to claim 1, characterized in that 2-/p-(m-chlorophenoxy)phenyl/- 2-/1-(2-methyl-imidazolyl)methyl7-4-ethyl-1,3-dioxolane or a acid addition salt thereof. 10. Process according to claim 1, characterized in that 2-β-(2,4-dichlorophenoxy)phenyl/-2-/T-(2-methylimidazolyl)methyl/-4-ethyl-1,3-dioxolane is produced or an acid addition salt thereof. 11. Method according to claim 1, characterized in that 2-(2-chloro-4-phenoxy-phenyl)-2-(T-(2-methyl-imidazolyl)methyl-7-4-ethyl-dioxolane or an acid addition salt thereof is produced.