LU83138A1 - TOPICAL PHARMACEUTICAL PREPARATIONS, CONTAINING SALTS OF ALKANCARBONIC ACIDS AND NEW CARBONIC ACID SALTS AND METHOD FOR THE PRODUCTION THEREOF - Google Patents

Description

* i - 1 - 4-13267

Topical pharmaceutical preparations * containing salts of alkane carboxylic acids and new carhonic acid salts and process for their preparation * "The invention relates to topically applicable pharmaceutical preparations containing salts of alkane carboxylic acids, in particular compounds of? Formula V §> ^ CH-C ^ lP-N-R (I), r /% 0, 4;

Xl \ Λ • - · where R ^ represents a group of the formula - · ^ / * ~ X3, · = · in which X ^ and X ^ are hydrogen and X ^ isobutyl or X ^ and X ^ are hydrogen and X ^ eenzoyl represent or X ^ hydrogen, X ^

Chlorine and X ^ 3-pyrrolin-l-yl mean or X ^, hydrogen, X2 is a group of the formula -CH = CH-C (001 ^) = CH-X ^ and X ^ together with X ^ represent a bond, and R ^ each represents methyl, or in which X2 and X ^ represent hydrogen and X ^ 2,6-dichloroanilino, and R2 represents hydrogen, or in which R ^ represents a group of the formula. ’Ϊ *

X8 \ / Y \ / S

) —Î (Ilb) '*, - xx \ / X6 means in which X ^ represents the common bond with the methine group in formula I, X and X represent hydrogen, X represents p-methyl-07 o benzoyl, Y is a Is nitrogen atom and XQ represents a methyl group y or in which X,. is a methyl group, X ^ is a common / t - 2 - •

Represents bond with methine group in formula I, X ^ represents a group of the formula -CH = C (OCHg) -CH = CH-X ^, Xg together with X ^ represents a bond, Y is a nitrogen atom and p-chlorobenzoyl means or in which there is a methyl group, Xg represents the common bond with the methine group in formula 1, X ^ a group of the formula -CH = C (F) -CH = CH-X1., XQ together with X., a bond il ö 11 means Y is a C atom and X ^ (p-methanesulfinylphenyl) methylene *. represents, and each represents hydrogen, and wherein Rg, R ^ and R ^ independently of one another hydrogen, an aliphatic radical or 1 two of the radicals Rg, R ^ and Rg together form a divalent, unsubstituted or substituted or interrupted by aza, oxa or thia represent aliphatic radical, with the proviso that at least one of the radicals Rg, R ^ and Rg is different from hydrogen, optionally in the form of an isomer, in addition to the auxiliaries and / or additives customary for topical application, the use of compounds of the formula I, as topically applicable anti-inflammatory and / or analgesic, new compounds of formula I and processes for their preparation.

Topically administrable pharmaceutical preparations are to be understood in particular to be those in which the active ingredient is in a form that can be absorbed by the skin, e.g. together with the auxiliaries and / or additives customary for topical application.

"An aliphatic radical Rg, R ^ or Rg primarily means an unsubstituted or optionally by amino, a group of

Formula NH ®®0CC-C / 1 or hydroxy-substituted lower alkyl.

-3 nR

4 2 'Such radicals are, for example, lower alkyl, amino lower alkyl,

Hydroxy-lower alkyl or oligo-hydroxy-lower alkyl.

A divalent aliphatic radical is to be understood, for example, to mean 4- to 7-membered lower alkylene, while a divalent aliphatic radical interrupted by optionally substituted aza or oxa or thia is, for example, 4- to 7-membered 3-aza- , 3-oxa- or 3-thia-lower alkylene, wherein aza, for example can be substituted by lower alkyl.

Above and below, organic radicals and compounds denoted by “lower” are preferably to be understood as those which contain up to and with 7, especially up to and with 4, carbon atoms.

’E The general definitions used in the context of this text primarily have the following meanings:

Lower alkyl is e.g. Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl and also includes corresponding pentyl, hexyl or heptyl radicals.

»

Amino lower alkyl is primarily aminomethyl, 2-amino-alkyl, 3-aminopropyl or 4-aminobutyl.

Hydroxy lower alkyl contains in particular a hydroxy group and is e.g. Hydroxymethyl, 2-hydroxyethyl, 2- or 3-hydroxypropyl or 2-, 3- or 4-hydroxybutyl.

Oligohydroxy-lower alkyl contains at least two hydroxy groups and is e.g. 1,2-dihydroxyethyl, 2,3-di- or 1,2,3-trihydroxypropyl,! . 2,3,4-trihydroxybutyl, 2,3,4,5-tetrahydroxypentyl or especially 2,3,4,5,6-pentahydroxyhexyl derived from D-glucamine

Di- (hydroxymethyl) methyl, tri- (hydroxymethyl) methyl or 2- (di-. 'Hydroxymethyl) ethyl.

’, 4- to 7-membered lower alkylene is primarily 1,4-butylene, 1,5-pentylene, 1,6-hexylene and also 1,7-heptylene.

4- to 7-membered 3-aza, 3-0xa or 3-thia-lower alkylene is primarily 3-aza, 3-N-lower alkyl-aza-, such as 3-N-methyl-aza-, and 3-0xa- or 3-thia-l, 5-pentylene, furthermore corresponding butylene, / hexylene or heptylene.

V

- 4 -

The compounds of the formula CH-COOH (purple) or their salts are known R2. These compounds or their salts with bases are used, for example, as non-steroidal anti-inflammatory agents in the treatment of inflammatory processes. The corresponding preparations are predominantly administered orally, also enterally or parenterally, but side effects can be observed with the mode of application, especially in the gastrointestinal area, for example ulcer bil-3 _ fertilizer on the mucous membranes of the gastrointestinal tract. The

The aim of treating different forms of inflammatory diseases, in particular of "soft tissue rheumatism", is to reduce the side effects, which are mainly associated with systemic therapy; largely bypassed. A topical is particularly suitable for this

Therapy begins when it is possible to ensure that the active ingredient is transported to the area of inflammation. However, the success of therapy by percutaneous application often fails because the active ingredients of the formula (purple) are only insufficiently able to channel the active substance through the skin into the diseased tissue in a therapeutically effective amount.

The invention is based on the surprising finding that the compounds of the formula (I) are distinguished by excellent percutaneous penetration and absorption properties.

In addition, the compounds of formula I to be used according to the invention have pronounced anti-inflammatory and analgesic properties. The anti-inflammatory efficacy can be demonstrated, for example, by the significant reduction in rat paw swelling in the kaolin paw edema model, created according to Helv. Physiol. Acta 25, 156 (1967), on the rat, in which, for example, a gel containing about 0.5 to 5% of the active ingredient is massaged into the clipped back skin of the test animals. (Lit .: drug research 21_ (X) _, 1326, 1977). In addition, the anti-inflammatory / / / - 5 -

Activity of topical application of the active substance, for example in the form of a gel containing about 0.5 to 5% of the active substance, can be derived from the inhibition of abscess formation which is initiated by subcutaneous injection of carragenin in the rat (Lit .: Pharm. Research 27 (1), 1326, 1977).

Investigations of compounds of the formula I on the model of the phenyl-p-benzoquinone writhing test (method: J. Pharmacol. Exp. Therap. 125, "237, 1959) in the dose range from about 0.1 to about 120 mg po.o. indicate a clear analgesic effectiveness.

The compounds of the formula I are therefore particularly suitable as percutaneously applicable anti-inflammatory agents and can also be used as analgesics.

The invention relates in particular to topically applicable pharmaceutical preparations containing a compound of the formula I in which R ^ and R2 have the meanings given at the outset, R ^, R ^ and R ^ independently of one another are hydrogen, an unsubstituted or, through amino, a group of the formula - N ^^^ OCC-CH ^ 1 or hydroxy substituted

Represent lower alkyl radical or two of the radicals R ^, R ^ and R ^ _ 4- to 7-membered lower alkylene, or 4- to 7-membered lower alkylene interrupted by aza or oxa or thia optionally containing lower alkyl, with the proviso that at least one of the radicals R.sup.1, R. and R.sup.2 where hydrogen is different, and the 3 4 5

Use of these compounds as topically applicable anti-inflammatory agents and / or analgesics.

‘This includes, for example, topical pharmaceuticals

Preparations containing a compound of formula I, wherein R ^ and R ^ have the meanings given above and R ^, R ^ and R, - independently of one another hydrogen, lower alkyl, amino-lower alkyl, through / - 6 - a group of the formula -NH ® Q) CC -CH ^^ substituted lower alkyl,

Hydroxy-lower alkyl, oligohydroxy-lower alkyl or two of the radicals R3, R ^, and R5 mean 4- to 7-membered lower alkylene or 4- to 7-membered lower alkylene interrupted by optionally N-lower alkylated aza or by oxa or thia.

The invention relates above all to topically applicable pharmaceutical preparations containing a compound of the formula X, in which R ^ and R ^ have the meanings given above and R ^, R ^ and, independently of one another, lower alkyl having up to and with 4 carbon atoms, such as methyl or Ethyl, or hydroxy lower alkyl with up to and including 4 carbon atoms, such as. 2-Hydroxyethyl, or one of the radicals R ^, R ^ and R ^ represents hydrogen and the others independently of one another lower alkyl having up to and with 4 carbon atoms, such as ethyl, hydroxy lower alkyl having up to and 4 carbon atoms, such as 2- Hydroxyethyl or 2-hydroxypropyl, or together 4 to 7-membered lower alkylene, such as 1,4-butylene or 1,5-pentylene, 4 to 7-membered, optionally N-lower alkylated aza- or oxa- or thia-lower alkylene, such as 3-aza, 3-0xa- or 3-thia-l, 5-pentylene, or one of the other lower alkyl having up to and with 4 carbon atoms, such as methyl, and the third oligohydroxy-lower alkyl, such as that derived from D-glucamine derivative 2,3,4,5,6-pentahydroxy-l-hexyl, or two of the radicals R ^, R ^ and R ^ represent hydrogen and the other lower alkyl having up to and with 4 carbon atoms, such as ethyl, hydroxy lower - Alkyl with up to and with 4 C atoms, such as 2-hydroxyethyl, oligohydroxy lower alkyl with up to and with 4 C atoms, such as tris (hydroxymethyl) methyl, amino lower alkyl with up to and with 4 C atoms, such as 2-A mino-ethyl, or a group of the formula -alk-NH ^^ CC-CH ^ *, in which alk is lower alkylene with up to and with 4 carbon atoms, such as ethylene, and the use of these compounds as topically applicable anti-inflammatory agents and / or analgesics.

a - 7 -

The invention relates primarily to topically applicable pharmaceutical preparations containing a compound of the formula I in which R ^ is a group of the formula Ha in which hydrogen, X2 is a group of the formula -CH-CH-C (OCH3) = CH-X ^ and X3 together represent a bond, and R2 is methyl or wherein Rj ^ represents a group of the formula Ha in which 2,6-dichloroanilino is, X ^ and X3 represent hydrogen, and R2 is hydrogen or wherein R1 is a »group of the formula Ilb means in which X ^ is a methyl group, Xg * is the common bond with the methine group of formula I, X ^ is a group of the formula -CENCCOCH ^ -CH ^ CH-X ^ q, Xg together with Χ ^ 0 represents a bond, Y is a nitrogen atom and X ^ p-chlorobenzoyl, and R2 is hydrogen and R ^, R ^ and R ^ have the immediately preceding meanings, and the use of these compounds as topically applicable anti-inflammatory and / or analgesics.

The invention relates primarily to topically applicable pharmaceutical preparations containing a compound of the formula I in which R ^ and R2 have the meanings given above and R ^, R ^ and R ^ hydroxy-lower alkyl having up to and with 4 carbon atoms, such as 2- Hydroxy-ethyl, or one of the radicals Rg, R ^ and R ^ is hydrogen and the other lower alkyl having up to and with 4 carbon atoms, such as ethyl, hydroxy-lower alkyl having up to and with 4 carbon atoms, such as 2-hydroxyethyl, or 4th up to 7-membered oxa-lower alkylene, such as 3-0xa-l, 5-pentylene, and the use of these compounds as topically applicable anti-inflammatory and / or analgesic agents.

The invention preferably relates to topically applicable pharmaceutical preparations containing a compound of the formula I in which R ^ is a group of the formula Ha in which X ^ is 2,6-dichloroanilino and X2 and X3 are hydrogen, and R2 is hydrogen and R3, R ^ and R ^ have the meanings given above, and the use of these compounds as topically applicable anti-inflammatory and / or analgesic.

- 8th -

Pharmaceutical preparations which can be used topically are particularly preferred, comprising a compound of the formula I in which R 1 and R 2 have the meanings mentioned immediately above, and one of the radicals R 1, R 4 and R 1. Means hydrogen and the other lower alkyl with up to and with 4 carbon atoms, such as ethyl, or 4- to 7-membered 3-0xa-lower alkylene, such as 3-0xa-l, 5-pentylene, and the use of these Compounds as topically applicable anti-inflammatory and / or analgesic.

The invention relates in particular to the topically applicable pharmaceutical preparations mentioned in the examples and the use of these compounds as topically applicable anti-inflammatory and / or analgesics.

The invention further relates to a method for producing topically administrable pharmaceutical preparations. The process is characterized in that a compound of the above-mentioned compound of the formula I is used with those customary for topical application

Auxiliaries and / or additives mixed.

The invention also relates to new compounds of the formula I in which R ^ is a group of the formula Ha in which X ^ is hydrogen

Group of the formula -CH ^ H-CCOCH ^^ CH-X ^ and X ^ together means a bond, R ^ is methyl and R ^, R ^ and R ^

Represent ethyl or 2-hydroxyethyl, or one of the radicals R ^, R ^ and Rç. Hydrogen and the other ethyl, 2-hydroxyethyl or 3-0xa-l, 5-; , pentylene or where R ^ is a group of the formula Ha in which 2,6-dichloroanilino, X2 and X ^ are hydrogen, R2 is hydrogen and one of the radicals R ^, R ^ and R ^ is hydrogen and the others

Represent ethyl or the radicals R ^, R ^ and R ^ each represent 2-hydroxyethyl or in which R ^ is a group of the formula IIb in which X ^

Methyl means Xg is a common bond with the methine group of the

Formula I represents, X ^ is a group of the formula -CH = C (OCH ^) - CH = CH-X ^ q, X0 together with X is a bond, Y is a nitrogen! o 10 .. \ - 9 - is atom and represents p-chlorobenzoyl, R2 is hydrogen and R ^, R ^ and R ^ hydroxy lower alkyl with up to and including 4 carbon atoms, such as 2-hydroxyethyl, or ethyl or two of the radicals R ^, R ^ and R ^ represent hydroxy lower alkyl with up to and with 4 carbon atoms, such as 2-hydroxyethyl, or ethyl and the other is hydrogen or one of the radicals R ^, R ^ and R ,. Hydroxy-lower alkyl having up to and with 4 carbon atoms, such as 2-hydroxyethyl, or ethyl and the other being hydrogen, or an isomer thereof, their use, pharmaceutical preparations containing them and processes for their preparation.

The invention further relates to new compounds of the formula I, in particular those compounds in which R ^ is a group of the formula Ha in which X ^ is hydrogen, and is a group of the formula -CH = CH-C (OCH ^) = CH-X ^ and X ^ together with a bond, R2 is methyl and R3, R ^ and R5 are ethyl or 2-hydroxyethyl, or one of the radicals R ^, R ^ and R ^ is hydrogen and the other ethyl, 2-hydroxyethyl or 3 Represent -0xa-1,5-pentylene.

. The invention further relates to new compounds of the formula I, in particular those compounds in which R ^ is a group of the formula Ha in which X ^ is 2,6-dichloroanilino, X2 and X ^ are hydrogen, R "is hydrogen and one of the radicals R «, R, and R_ are hydrogen and 2 J 4 5 are the other ethyl or the radicals R ^, R ^ and R, _ 2-hydroxyethyl.

The invention further relates to new compounds of formula I, in particular! especially those in which R ^ represents a group of the formula IIb in which X ^

Methyl means, X ^ represents a bond with the methine group of the formula I, X-, a group of the formula -CH = C (OCH3) -CH = CH-X ^, X together with X means a bond, Y is a nitrogen -s is atom and X ^ is p-chlorobenzoyl, R2 is hydrogen and R ^, R ^ and R ^ are hydroxy-lower alkyl having up to and with 4 carbon atoms, Îj - 10 - such as 2 hydroxyethyl, or ethyl or two of the radicals R. ^, R ^ and R ,. Hydroxy lower alkyl with up to and with 4 carbon atoms, such as 2-hydroxyethyl, or ethyl and the other is hydrogen or one of the radicals R ^, R ^ and R ,. Hydroxy-lower alkyl with up to 4 carbon atoms, such as 2-hydroxyethyl, or ethyl and the other is hydrogen.

The invention relates in particular to the new compounds obtainable according to the examples and to the production processes described there.

Depending on the choice of starting materials and procedures, the compounds of the formula dr can be in the form of a possible isomer or a mixture thereof, for example as optical optical isomers, such as enantiomers or diastereomers, or geometric isomers, such as cis-trans isomers. The optical isomers are present in the form of pure antipodes and / or as racemates. Racemates or mixtures of geometric isomers obtained can be separated into the pure constituents on the basis of chemical-physical differences in the components. For example, racemates of optical antipodes can be prepared by methods known per se, e.g. using chromatographic methods, by fractional crystallization, microorganisms or enzymes, to separate into the appropriate anti-mers. Furthermore, optical anti. pode by converting the other antimer into a racemic

Enrich mixture. The more effective of the isomers in question is advantageously isolated. The isomers of new compounds of the formula I also form an object of the invention.

The compounds of the formula I can also be obtained in the form of their hydrates or include other solvents used for the crystallization.

The invention further relates to processes for the production of

L

- 11 - new compounds of formula I, which are prepared by processes known per se.

A preferred process variant is characterized, for example, in that an organic carboxylic acid of the formula

Rl \ CH-COOH (purple) '. R2 or a base salt thereof other than a salt of the formula I with an at least equimolar amount of the amine of the formula EV4 I (Illb) R5 or an acid addition salt thereof and, if desired,> a compound of the formula I obtainable according to the process in another compound of the Formula I converts and / or separates an isomer mixture obtainable according to the process into the components.

The molar ratio of acids of the formula purple and amines of the formula Illb depends on the choice of the desired salts or on the number. of the substituted amino groups in the corresponding compound of

Formula Illb.

Appropriate hydrohalides, such as hydrochlorides, are used, for example, as acid addition salts of amines of the formula IIIb.

- 12 -

The reaction of compounds of the formula purple with compounds of the formula IIIb is advantageously carried out in an inert solvent or diluent, if necessary with cooling and heating, e.g. in a temperature range from approximately 0 ° to approximately 100 ° C., preferably at room temperature, in a closed vessel and / or under an inert gas atmosphere. e.g. Nitrogen.

Suitable solvents and diluents are, for example, water, alcohols, such as lower alkanols, e.g. Methanol or ethanol,

Ethers, such as di-lower alkyl ethers, e.g. Diethyl ethers such as cyclic ethers e.g. Dioxane or tetrahydrofuran, ketones such as di-lower alkyl ketones, e.g. Acetone, carboxylic acid esters such as lower alkane carboxylic acid esters e.g. Ethyl acetate, amides such as Ν, Ν-di-lower alkylamides, e.g. N, N-dimethylformamide, suifoxides such as di-lower alkyl sulfoxides, e.g. Dimethyl sulfoxide, or mixtures thereof in question.

The starting materials of the formulas purple and Illb are known.

The invention also relates to those embodiments of the process according to which the starting materials are prepared in situ, or in which a starting material is obtained from a derivative under the reaction conditions and / or used in the form of a mixture of isomers or a pure isomer.

The starting compounds of the formula purple can be obtained, for example, under the reaction conditions from corresponding esters, such as lower alkyl esters, by hydrolysis in the presence of a base, such as an amine, e.g. Diethylamine, are formed. An amine of formula IIIb may, for example, be in the form of an acid addition salt, such as a hydrohalide, e.g. Hydrochloride used and released in the presence of a base such as an amine.

/ - 13 -

In the process of the present invention, those starting materials which lead to particularly valuable compounds are preferably used.

The topically applicable pharmaceutical preparations according to the invention contain the pharmaceutically usable compounds of the formula I together with a pharmaceutically usable additive or auxiliary material. "The daily dosage of the active ingredient depends on the age and the individual condition, and on the mode of administration.

The topical pharmaceutical preparations that can be used are primarily cream, ointments and gels, as well as pastes, foams, tinctures and solutions, which contain from about 0.5 to about 5% of the active ingredient.

Creams or lotions are oil-in-water emulsions that contain more than 50% water. Fatty alcohols, 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. Vaseline (petrolatum) or paraffin oil. Suitable emulsifiers are surface-active substances with predominantly hydrophilic properties, such as corresponding nonionic emulsifiers, e.g. Fatty acid esters of polyalcohols or ethylene oxide adducts thereof, such as polyglycerol fatty acid esters or polyoxyethylene sorbitan fatty acid esters (Tweens), also 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 commonly used in the presence of fatty alcohols, e.g. Cetyl alcohol or stearyl alcohol. Additions to the water phase include Agents which prevent the creams from drying out, e.g. Polyalcohols, such as glycerol, sorbitol, propylene glycol and / or polyethylene glycols, also preservatives, - 14 -

Fragrances, etc.

Ointments or lotions are water-in-oil emulsions that contain up to 70%, but preferably from about 20% to about 50%, water or aqueous phase. The fatty phase is primarily hydrocarbons, e.g. Petroleum jelly, paraffin oil and / or hard paraffins, which preferably contain suitable hydroxy compounds, such as fatty alcohols or esters thereof, e.g. Cetyl alcohol or wool wax alcohols or wool wax. Emulsifiers are corresponding lipophilic 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. Glycerin, propylene glycol, sorbitol and / or polyethylene glycol, as well as preservatives, fragrances, etc.

Microemulsions are isotropic systems, the basis of which consists of the following four components: water, an emulsifier, such as a surfactant, e.g. eumulgin, a lipid, such as a non-polar oil, e.g. Paraffin oil, and an alcohol with a lipophilic group, e.g. 2-0ctyldodecanol. If desired, other additives can be added to the microemulsions.

Fatty ointments are anhydrous and contain hydrocarbons, e.g. Paraffin, petroleum jelly and / or liquid paraffins, also natural or partially synthetic fat, e.g. Coconut fatty acid triglyceride, or preferably hardened oils, e.g. hydrogenated peanut or castor oil, also fatty acid partial esters of glycerin, e.g. Glycerol mono- and distearate, as well as e.g. the fatty alcohols, emulsifiers and / or additives mentioned in connection with the ointments, which increase the water absorption capacity.

In the case of the gels, a distinction is made between aqueous, anhydrous or low-water gels which are made from swellable, gel-forming materials.

L

- 15 - stand. Transparent hydrogels based on inorganic or organic macromolecules are primarily used. High-molecular inorganic components with gel-forming properties are predominantly water-containing silicates, such as aluminum silicates, e.g. Betonite, magnesium aluminum silicates, e.g. Veegum, or colloidal silica, e.g. Aerosil. Natural, semisynthetic or synthetic macromolecules, for example, are used as high-molecular organic substances. Natural and semi-synthetic polymers are derived, for example, from polysaccharides with a wide variety of carbohydrate components, such as celluloses, starches, tragacanth, arabic gum, agar-agar, gelatin, alginic acid and their salts, e.g. Sodium alginate, and their derivatives such as lower alkyl celluloses, e.g. Methyl or ethyl celluloses, carboxy or hydroxy lower alkyl cellulose, e.g. Carboxymethyl or hydroxyethyl celluloses. The building blocks of synthetic, gel-forming macromolecules are, for example, appropriately substituted unsaturated aliphatics, such as vinyl alcohol, vinyl pyrrolidine, acrylic or methacrylic acid. Examples of such polymers are polyvinyl alcohol derivatives, such as polyviol, polyvinylpyrrolidines, such as Kollidon, polyacrylates or polymethacrylates, such as Rohagit S or Eudispert. Common additives, such as preservatives or fragrances, can be added to the gels.

Pastes are creams and ointments with secretion-absorbing powder components such as metal oxides, e.g. Titanium oxide or zinc oxide, also talc * and / or aluminum silicates, which have the task of existing

Bind moisture or secretions.

Foams are e.g. administered from pressure vessels and are in the form of aerosol liquid Oe1-in-water emulsions, halogenated hydrocarbons such as chlorofluoro lower alkanes, e.g. Dichlorodifluoromethane and dichlorotetrafluoroethane can be used as blowing agents. The oil phase used includes Hydrocarbons, e.g.

f - 16 -

Paraffin oil, fatty alcohols, e.g. Cetyl alcohol, fatty acid esters, e.g. Isopropyl myristate, and / or other waxes. The emulsifiers used include Mixtures of those 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 usually have an ethanol base, to which water may be added and which, among other things. Polyalcohols, e.g. Glycerin, glycols, and / or polyethylene glycol, as humectants to reduce evaporation, and refatting substances, such as fatty acid esters with low polyethylene glycols, i.e. lipophilic substances soluble in the aqueous mixture as a substitute for the fatty substances extracted from the skin with the ethanol, and, if necessary, other auxiliaries and additives are added.

The topical pharmaceutical preparations are prepared in a manner known per se, e.g. by dissolving or suspending the active ingredient in the base or in a part thereof, if necessary. When the active ingredient is administered as a solution, it is usually dissolved in one of the two phases before emulsification; when processed as a suspension, it is mixed with part of the base after emulsification and then added to the rest of the formulation.

? The invention also encompasses the use of the new compounds of the

Formula I as a percutaneously usable anti-inflammatory and / or analgesic. tics, preferably in the form of corresponding pharmaceutical preparations.

The following examples illustrate the invention described above. However, you should not restrict their scope in any way.

^ The temperatures are given in degrees Celsius.

- 17 -

Example 1: 2 ml of diethylamine are added to a solution of 2 g of 2- (2,6-dichloroanilino) phenylacetic acid in 40 ml of ether. The solution is heated under reflux for 10 minutes, cooled and concentrated under reduced pressure, the diethylanmonium 2- (2,6-dichloroanilino) phenylacetate crystallizing out. The colorless crystals are filtered off (mp. 110 ° -155e, decomp.) And dried in a high vacuum at room temperature.

{YXCOOefH2 (C2H5) 2 V> cli V1 V * * Analogously, starting from diethylamine and 2- (6-

Methoxy-2-naphthyl) -propionic acid the diethylammonium- [2- (6-methoxy-2-naphthyl)] - propionate, mp. 72 ° -83 ° (decomp.) And starting from diethylamine and [1- (p-chlorobenzoyl ) -5-methoxy-2-methyl-3-indoly1] -acetic acid, the diethy lammonium- [1- (p-chlorobenzoy 1) -5-methoxy-2-methyl-3-indolyl] acetate, mp. 98 ° - 125 ° (dec.).

Example 2: 4.53 g of tris (hydroxymethyl) methylamine are added to a solution of 10 g of 2- (2,6-dichloroanilino) phenyl acetic acid in 230 ml of ethyl acetate at room temperature and with vigorous stirring within 10 minutes. dissolved in 10 ml of water, added dropwise. A salt precipitates immediately. The mixture is then stirred for a further half an hour at room temperature and the solvent is removed on the Rotavap. The white, crystalline residue is dissolved in 1 l of acetone / water (1: 1) at about 50 °. The hot solution is concentrated on the Rotavap until the first crystals fail. Then allow to crystallize at 0 °.

The precipitated white, flaky crystals are filtered off and dried under high vacuum. The tris (hydroxymethyl) methyl ammonium 2- (2,6-dichloroanilino) phenylacetate thus obtained has a melting point of 202 ° -204 °.

/

iS

v - 18 -

EXAMPLE 3 5.52 g of triethanolamine, dissolved in 30 ml of ethyl acetate, are added to a solution of 10 g of 2- (2,6-dichloroanilino) phenyl acetic acid in 230 ml of ethyl acetate at room temperature and with vigorous stirring within 10 minutes. dripped. A salt precipitates immediately. The mixture is then stirred for a further half an hour at room temperature and the solvent is removed on the Rotavap. The white, crystalline residue is dissolved in a little hot ethanol and crystallized out at 0 °. The white crystals are filtered off and dried under high vacuum. The triethanolammonium-2 - (- 2,6-dichloroani- • lino) -phenylacetate melts at 137 ° -138e.

Example 4: 3.89 g of diethanolamine, suspended in 30 ml of ethyl acetate, are added to a solution of 10 g of 2- (2,6-dichloroanilino) phenylacetic acid in 230 ml of ethyl acetate at room temperature and with vigorous stirring within 10 minutes. dripped. The salt that is formed precipitates immediately. The mixture is then stirred for half an hour at room temperature and the solvent is removed on a Rotavap. The yellowish, crystalline residue is dissolved in a little boiling ethanol. The solution is left to stand at 0 °, during which the diethanolammonium 2- (2,6 ~ dichloranilino) phenylacetate crystallizes, which has a melting point of 130 ° -132 °.

Example 5: 3.22 g of morpholine in 30 ml of ethyl acetate are added dropwise at room temperature and with vigorous stirring within 10 minutes to a solution of 10 g of 2- (2,6-dichloroanilino) phenyl acetic acid in 230 ml of ethyl acetate. Approx. A salt precipitates 10 minutes after the addition of the morpholine. The mixture is then stirred for 1 hour at room temperature and the solvent is removed on the Rotavap. The white, crystalline residue is then dissolved in boiling ethanol.

At 0 ° the morpholinium 2- (2,6-dichloroanilino) phenyl acetate crystallizes out, which melts at 162 ° -165 °.

4 - 19 -

In an analogous manner, starting from morpholine and 2- (6-methoxy-2-naphthyl) propionic acid or [l- (p-chlorobenzoyl) -5-methoxy-2-methyl-3-indolyl] acetic acid, morpholinium- [ 2- (6-methoxy-2-naphthyl -)] - prapionate and morpholinium- [1- (p-chlorobenzoyl) -5-methoxy-2-methyl-3-indoly1] acetate.

Example 6: 4.93 g of diisopropanolamine in 30 ml of ethyl acetate are added dropwise to a solution of 10 g of 2- (2,6-dichloroanilino) phenylacetic acid in 230 ml of ethyl acetate at room temperature and with vigorous stirring within 5 minutes. After a short time, a salt precipitates. The mixture is stirred for 1 hour and the solvent is removed on a Rotavap and the white, crystalline residue is dissolved in a little boiling ethanol. The solution is left to stand at 0 °, during which the diisopropanolammonium 2- (2,6-dichloroanilino) phenylacetate crystallizes out, with a melting point of 165-170 °.

Example 7; A suspension of 6.64 g of N-methyl-D-glucamine in 100 ml of ethanol is stirred together with 10 g of 2- (2,6-dichloroanilino) phenylacetic acid in 230 ml of ethyl acetate at room temperature under nitrogen overnight. After 2 hours, white, fine crystals precipitate. The solvent is then removed on the Rotavap and the white, sticky residue is dissolved in a little hot water. Then the clear solution is allowed to slowly cool to 0 ° and stand at 0 ° overnight. An oily, semi-crystalline mass precipitates, which is filtered off over a 2-day period using a Celite and cloth filter. The filter cake is dried for one week at 60 ° / 100 mmHg and then pulverized. The N-methyl-D-glucamrnonium-2- (2,6-dichloroanilino) phenylacetate melts at 127 ° -130 °.

Example 8: An ointment containing 5 Z of diethylammonium 2- (2,6-dichloroanilino) phenylacetate is produced as follows: / 1 4 v - 20 -

composition

Propylene glycol 10-44%

Polyalkylene glycol, high molecular weight 10%

Paraffin oil, viscous 12%

Vaseline, white 22%

Wax, microcrystalline 7%

Glycerin 0-34 t

Parabens 0.2 T

Active ingredient 5 Z

The active ingredient is dissolved in a mixture of glycerin and propylene glycol and the other components are melted together. The active ingredient solution is then emulsified into the pett phase. After this . Cold stirring is added, if desired, fragrance (0.1 Z).

An ointment containing 0.5 Z or 2 Z of the active ingredient is obtained in an analogous manner.

Example 9: A transparent hydrogel containing 5 Z diethylammonium 2- (2,6-dichloroanilino) phenylacetate is produced as follows:

composition

Active ingredient 5 Z

Propylene glycol 10-20 t

’Isopropanol 20 t

Hydroxypropyl methyl cellulose 2 Z

; Water ad 100 Z

The hydroxypropyl methyl cellulose is swollen in the water. The active ingredient is dissolved in a mixture of isopropanol and propylene glycol. The active ingredient solution is then mixed with the swollen cellulose derivative and, if desired, with fragrances (0.1%).

/ λ t - 21 -

In a similar manner, a gel is obtained containing 0.5 Z or 2 Z of the active ingredient.

Example 10: A transparent hydrogel containing 5 Z of diethylammonium-2- (2,6-dichloroanilino) phenylacetate is produced as follows:

composition

Active ingredient 5%

Propylene glycol 20%

Isopropanol 20 t

Acetic acid polymer 2%

Triethanolamine 3 Z.

Water ad 100 Z

Acrylic acid polymer and water are dispersed and neutralized with triethanolamine. The active ingredient is dissolved in a mixture of isopropanol and propylene glycol. The active ingredient solution is then mixed with the gel, it being possible, if desired, to add fragrance (0.1%).

In an analogous manner, gels containing 0.5 Z or 2 Z of the active ingredient are obtained.

Example 11: A transparent microemulsion containing 5% diethylammonium 2- (2,6-dichloroanilino) phenylacetate is prepared as follows:

composition

Active ingredient 5%

Cetylstearyl alcohol 27 t

Polyol fatty acid ester 15 Z.

Glycerin 4Z

Water ad 100 Z

/ - 22 -

Cetylstearyl alcohol and polyol fatty acid esters are heated to 95 ° and the active ingredient is dissolved in them. For this purpose, a mixture of water and glycerin heated to 95 ° and, if desired, preservative (0.2%) is added. The microemulsion formed is cooled with stirring and, if appropriate, fragrance (0.1%) is added.

In an analogous manner, transparent microemulsions containing 0.5% or 2% of the active ingredient are obtained.

Example 12; A lotion containing 5% diethyl ammonium 2- (2,6-dichloroanilino) phenylacetate is made as follows:

Composition "active ingredient 5%

Mono- and diglycerides of higher saturated 6%

Fatty acids with potassium stearate

Polyoxyethylene cetyl stearyl ether 2%

Oleic acid decyl ester 5%

Propylene glycol 20%

Parabens 0.2%

Water, demineralized ad 100%

The active ingredient and the parabens are dissolved in water and propylene glycol. Then polyoxyethylene cetyl stearyl ether is added to the drug solution. Oleic acid decyl ester and the glycerides of the fatty acids with potassium stearate are melted together and emulsified into the water phase. The lotion is stirred cold and, if necessary, fragrances (0.1%) are added.

Example 13: A solution containing 5% diethylammonium-2- (2,6-

Dichloranilino) phenylacetate is produced as follows:

A

- 23 - h

composition

Active ingredient 5 Z

Polyoxyethylene sorbitan fatty acid ester 10 Z.

Ethanol 20 t

Triglyceride, liquid 65%

The active ingredient is dissolved in ethanol and polyoxyethylene sorbitan fatty acid ester in liquid .Triglyceride. The two solutions are '' mixed. If desired, additional fragrances (0.1 Z) are added.

I In an analogous manner, solutions containing 0.5% or 2% of the

Active ingredient.

Example 14; An ointment containing 5 Z diethylammonium-2- (2,6-di-. Chloroanilino) phenylacetate is prepared as follows:

composition

Active ingredient 5 Z

Mono- and diglycerides of higher saturated 17 Z

Fatty acids with potassium stearate

Oleic acid decyl ester 5 Z.

Propylene glycol 20 t

Water, demineralized ad 100%

The active ingredient is dissolved in propylene glycol and water. Mono- and diglycerides of higher saturated fatty acids with potassium stearate are melted together with oleic acid decyl ester. The water phase is then added to the fat phase and emulsified and, if desired, fragrances (0.1%) are added.

In an analogous manner, a cream containing 0.5 Z and 2 Z of the active ingredient is obtained.

fi - 24 -

Example 15; An ointment containing 5 Z of diethylammonium 2- (2,6-di-chloroanilino) phenylacetate is prepared as follows:

composition

Active ingredient 5%

Propylene glycol 12 t

Vaseline, white 28 t

Wax, microcrystalline 2T

Sorbitan fatty acid ester 25 T.

Water, demineralized ad 100 Z

The active ingredient is dissolved in propylene glycol and water. The fat components petroleum jelly, wax and sorbitan fatty acid esters are melted together. The active ingredient solution is then emulsified into the fat phase and, if desired, fragrances (0.1%) are added.

An ointment containing 0.5% and 2% of the active ingredient is obtained in an analogous manner.

Example 16: A lotion containing 2 Z diethylammonium 2- (2,6-dichloroanilino) phenylacetate is produced as follows:

composition

Active ingredient 2 Z

Polyalkylene glycol, high molecular weight 14 t

Triglyceride, liquid 5 t

Paraffin oil, viscous 13 t

Glycerol sorbitan fatty acid ester 10 Z.

Water, demineralized ad 100 Z

The active ingredient is dissolved in polyalkylene glycol and water. Triglyceride, paraffin oil and glycerin-sorbitan fatty acid ester are combined

A

i -25- melted. The water phase is then emulsified into the fat phase. If desired, fragrances (0.1%) are added.

A lotion containing 0.5% of the active ingredient is obtained in an analogous manner.

In an analogous manner as in Examples 8 to 16, ointments, creams, gels, microemulsions, lotions and solutions containing 0.5%, 2% or 5% of the compounds listed in Examples 1 to 7 are obtained.

V

Claims (44)

1. Topically administrable pharmaceutical preparations containing compounds of the formula Rl) cff — c (° "Η®-Μ (X), X1X A · - · Λ \ where R is a group of the formula / *” ^ 3, in which X ^ and X ^ are hydrogen and Xg isobutyl or X ^ and Xg are hydrogen and X ^ benzoyl or X ^ is hydrogen, X ^ chlorine and Xg are 3-pyrrolin-l-yl or X ^ is hydrogen, a group of the formula -CH = CH-C (OCHg) = CH-X ^ and Xg together with X ^ represent a bond, and Rg each represents methyl, or in which X ^ and Xg represent hydrogen and X ^ represent 2,6-dichloro-anilino, and R ^ Is hydrogen, or in the R ^ - is a group of the formula Xn | 9 X8 \ Λ Λ l] _II (Ilb) v \, in which Xg is the common bond with the methine group in the formula I, Xc and X_ are hydrogen , XQ represents p-methylbenzoyl “D / O, Y is a nitrogen atom and XQ represents a methyl group or in which Xg is a methyl group, X ^ is a common bond with the methine group in the formula I X ^ represents a group of the formula -CH = C (OCHg) “CH = CH-X ^ q, Xg together with X represents a bond, Y is a nitrogen atom and X ^ represents p-chlorobenzoyl or in which X is a methyl group, X. represents the common bond with the methine group in the formula I, X ^ a group of the formula -CH = C (F) -CH = CH-X .., X_ together with X. _ one Bin- 11 o 11 fertilizes, Y is a C atom and X represents (p-methanesulfinylphenyl) -methyl- / 'Ί ^ / - 27 - len, and each represents hydrogen, and wherein R ^, R ^ and R ^ independently of one another represent hydrogen, an aliphatic radical or two of the radicals R ^, R ^ and together a divalent, unsubstituted or substituted or interrupted by aza, oxa or thia aliphatic radical, with the proviso that at least one of the radicals R ^, R ^ and R ,. is different from hydrogen, optionally in the form of an isomer, in addition to the auxiliaries and / or additives customary for topical> application. 2. Topically administrable pharmaceutical preparations according to claim 1, containing a compound of formula I, wherein R ^ and R ^ have the meanings given above, R ^, R ^ and R ^ independently of one another hydrogen, an unsubstituted or by amino, a group of Formula R 3 or hydroxy substituted Nie deralkylrest or two of the radicals R ^, R ^ and R, _ 4- to 7- * membered lower alkylene, or interrupted by optionally lower alkyl ent containing aza or oxa or thia 4- to 7-membered Lower alkylene, with the proviso that at least one of the radicals R_, R, and R_ is different from hydrogen, in addition to the auxiliaries and additives customary for 3 4 5. 3. Topical pharmaceutical preparations according to claim 1, containing a compound of formula I, wherein R ^ and R ^ have the meanings given above and R ^, R ^ and R ,. independently of one another, other lower alkyl with up to and with 4 carbon atoms, such as methyl or ethyl, or hydroxy lower alkyl with up to and with 4 carbon atoms or hydroxy lower alkyl with up to and with 4 carbon atoms, or one of the radicals R 1, R 1 and R 1 are hydrogen and the other, independently of one another, lower alkyl with up to and with 4 carbon atoms, hydroxy lower alkyl with up to and with 4 carbon atoms or together 4- to 7-membered lower alkylene, 4- to 7-membered, optionally N-lower alkylated Aza or oxa or thia-lower alkylene or one of the other lower alkyls with up to and with 4 carbon atoms and the third oligohydroxy-lower alkyl, or - 28 -> two of the radicals R_, R, and R_ represent hydrogen and the other 3 4 5 Lower alkyl with up to and with 4 carbon atoms, hydroxy lower alkyl with up to and with 4 carbon atoms, oligohydroxy lower alkyl with up to and with 4 carbon atoms, amino lower alkyl with up to and with 4 carbon atoms or a group of the formula ™ -alk-NH ^ ®®0CC-CI1 * represents, in which alk * 2 lower alkylene mi t up to and including 4 carbon atoms means, in addition to the auxiliaries and additives customary for topical application. 4 is C atoms or ethyl and the others are hydrogen or an isomer thereof. 4. Topically administrable pharmaceutical preparations according to claim 1, containing a compound of formula I, wherein R ^ is a group of the formula Ha, in which hydrogen, X2 is a group of the formula -CH = CH-C (OCH ^) = CH-X ^ and X ^ together with X ^ represent a bond, and R2 is methyl or in which R ^ represents a group of formula Ia in which X ^ is 2,6-dichloroanilino, X2 and X3 represent hydrogen, and R2 is hydrogen or in which R ^ is a group of the formula IIb, in which Xc is a methyl group, X is a bond with the methine group of the formula I, X ^ is a group of the formula -CH = C (OCH ") - CH = CH-CH -X. means, X together with X ^ q represents a bond, Y is a nitrogen atom and X ^ p-chloro-benzoyl, and R2 is hydrogen and R ^, R ^ and the immediately preceding meanings have besides the auxiliaries customary for topical application - and additives. 5. Topically administrable pharmaceutical preparations according to claim 1, containing a compound of the formula I, in which R ^ and R2 have the * meanings above and R ^, R ^ and R are hydroxy lower alkyl having up to and with 4 carbon atoms, or one of the radicals R, R and R_ is hydrogen and the other 3 4 o / - v - 29 - ren lower alkyl with up to and with 4 carbon atoms, hydroxy lower alkyl with up to and with 4 carbon atoms or 4- to 7-membered oxa mean lower alkylene, in addition to the auxiliaries and additives customary for topical application. 6. Topically administrable pharmaceutical preparations according to claim 1, containing a compound of formula I, wherein R ^ is a group of formula Ha in which 2,6-dichloroanilino and and X ^ are hydrogen, and is hydrogen and R ^, R ^ and R ,. the meanings given above have, in addition to the auxiliaries and additives customary for topical application. 7. Topically administrable pharmaceutical preparations according to claim 1, containing a compound of formula I, wherein and R ^ have the meanings given above, and one of the radicals R ^, R ^ and hydrogen and the other lower alkyl with up to and with 4 C. -Atoms. or 4- to 7-membered 3-0xa-lower alkylene, in addition to the auxiliaries and additives customary for topical application. 8. Topically administrable pharmaceutical preparations according to claim 1, containing diethylammonium 2- (2,6-dichloroanilinio) phenylacetate in addition to the auxiliaries and additives customary for topical application. 9. Z represents -CH = CH-C (OCH ^) ”CH-X ^ and X ^ together with X ^ represents a bond, R2 is methyl and R ^, and R ^ are ethyl or 2-hydroxyethyl, or one of the residues R ^, R ^ and R ,. Represent hydrogen and the other ethyl, 2-hydroxyethyl or 3-oxa-l, 5-pentylene or in which R ^ is a group of the formula Ia in which X ^ 2,6-di-chloroanilino, X ^ and X ^ are hydrogen , R2 is hydrogen and one of the radicals R ^, R ^ and R ,. Represent hydrogen and the other ethyl or the radicals R ^, R ^ and R ,. are each 2-hydroxyethyl or in which a group of the formula is Hb, in which methyl is, X ^ is a common bond with the methine group of the formula I, X ^ is a group of the formula -CH = C (0CH2) -CH = CH- X ^ q is, X together with X is a bond, Y is a nitrogen? o is 10 atoms and X ^ represents p-chlorobenzoyl, R2 is hydrogen and R ^, R ^ and hydroxy-lower alkyl with up to 4 carbon atoms or ethyl or two of the radicals R ^, R ^ and hydroxy-lower alkyl with up to 4 Represent carbon atoms or ethyl and the other is hydrogen or one of the radicals R ^, R ^ and R ,. t Hydroxy-lower alkyl with up to and / / Λ - 33 - b 9. Topically administrable pharmaceutical preparations according to claim 1, containing diethylammonium [2- (6-methoxy-2-naphthyl)] propionate in addition to the auxiliaries and additives customary for topical application. 10. Topically administrable pharmaceutical preparations according to claim 1, containing diethylammonium [1- (p-chlorobenzoyl) -5-methoxy-2-methyl-3-indolyl] acetate in addition to the auxiliaries and additives customary for topical application. '\ s - 30 - 11. Topically administrable pharmaceutical preparations according to claim 1, containing tris (hydroxymethyl) methylammonium-2- (2,6-dichloro-anilino) phenyl acetate in addition to the auxiliaries and additives customary for topical application. 12. Topically administrable pharmaceutical preparations according to claim 1, containing triethanolammonium 2- (2,6-dichloroanilino) phenyl acetate in addition to the auxiliaries and additives customary for topical application. 13. Topically administrable pharmaceutical preparations according to claim 1, containing diethanolaxmonium-2- (2,6-dichloroanilino) phenyl acetate in addition to the auxiliaries and additives customary for topical application. 14. Topically administrable pharmaceutical preparations according to claim 1, containing morpholinium-2- (2,6-dichloroanilino) phenyl acetate in addition to the auxiliaries and additives customary for topical application. 15. Topically administrable pharmaceutical preparations according to claim 1, containing morpholinium [2- (6-methoxy-2-naphthyl -)] - propionate in addition to the auxiliaries and additives customary for topical application. 16. Topically administrable pharmaceutical preparations according to claim 1, containing morpholinium- [1- (p-chlorobenzoyl) -5-methoxy-2 ~ methyl-3-indolyl] acetate in addition to the auxiliaries and additives customary for topical application. 17. Topically administrable pharmaceutical preparations according to claim 1, containing diisopropanolammonium 2- (2,6-dichloroanilino) phenylacetate in addition to the auxiliaries and additives customary for topical application. / L - 31 - 18. Topically administrable pharmaceutical preparations according to claim 1, containing N-methyl-D-glucammonium-2- (2,6-dichloroanilino) phenyl acetate in addition to the auxiliaries and additives customary for topical application. 19. A process for the preparation of topically administrable pharmaceutical preparations, characterized in that a compound of the formula R1 \ I3 ^ CH-c (Hw-H-R4 (I), R2 R5 in which a group of the formula / * “^ 3 (Ha) represents, • S · in which X ^ and hydrogen and Xg represent isobutyl or X ^ and Xg represent hydrogen and X ^ benzoyl or X ^ represents hydrogen, X ^ chlorine and X ^ 3-pyrrolin-l-yl mean or hydrogen, X ^ is a group of the formula -CH = CH “C (OCH ^) = CH-X ^ and X ^ together with X ^ represent a bond, and each is methyl, or in which and Xg is hydrogen and X ^ 2,6-dichloro-anilino, and R ^ means hydrogen, or in the R ^ a group of the formula%.: V /! / \ X7 6 means in the X ^ the common bond with the methine group in the formula I represents, Xg and X ^ represent hydrogen, Xg represents p-methylbenzoyl, Y is a nitrogen atom and Xg represents a methyl group or in which X ^ represents a methyl group, Xg represents a common Bi is the group with the methine group in the formula I, X ^ is a group of the formula -CH = C (OCH_) - CH = CH-X n, X together with X is a> j 1U o 10 - 32 bond, Y is a Is nitrogen atom and X ^ p -chlorobenzoyl or in which X, _ is a methyl group, Xg represents the common bond with the methine group in the formula I, a group of the formula -CH "C (F) -CH = CH-X, XQ together with X represents a bond, Y is a C atom and X represents ^ (p-methanesulfinylphenyl) methylene, and R2 each represents hydrogen, and where R ^> * and Rj. Independently of one another are hydrogen, an aliphatic radical or two the radicals R, R. and R_ together represent a divalent, un- * OJ substituted or substituted or interrupted by aza, oxa or thia aliphatic radical, with the proviso that at least one of the radicals R ^, R ^ and R ^ of hydrogen is different, optionally in the form of an isomer, with auxiliaries and Z customary for topical application additives mixed. 20. Compounds of the formula I, in which a group of the formula Ia represents, in which X is hydrogen, X is a group of the formula 21. Compounds of formula I according to claim 20, wherein R ^ is a group of formula Ha in which X ^ is hydrogen, a group of formula -CH = CH-C (OCHg) = CH-X ^ and Xg together with X ^ means a bond, R £ is methyl and Rg, R ^ and R, ethyl or 2-hydroxyethyl represent, or one of the radicals Rg, and Rg is hydrogen and the other ethyl, 2-hydroxyetnyl or 3-0xa-l Represent 5-pentylene. 22. Compounds of the formula I according to claim 20, in which R ^ is a group of the formula Ha in which X ^ is 2,6-dichloroanilino and Xg is hydrogen, Rg is hydrogen and one of the radicals Rg, R ^ and Rg is hydrogen and represent other ethyl or the radicals Rg, R ^ and Rg each represent hydroxyethyl. 23. Compounds of formula I according to claim 20, wherein R ^ represents a group of formula Ilb, in which Xg is methyl, Xg represents a bond with the methine group of formula I, X ^ represents a group of the formula —CH = C (OCH ^) —011 = 011 — is, Xg together with X ^ is a bond, Y is a nitrogen atom and X ^ is p-chlorobenzoyl, R2 is hydrogen and Rg, R ^ and R_ are hydroxy-lower alkyl with up to 4 C- Are atoms or ethyl or represent two of the radicals Rg, R ^ and R_ hydroxy lower alkyl with up to and with 4 C atoms * or ethyl and the other is hydrogen or one of the radicals Rg, R ^ and Rg hydroxy lower alkyl with up to and with 4 C- Is atoms or ethyl and the others are hydrogen. 24. Diethylammonium 2- (2,6-dichloroanilino) phenylacetate. 25. Diethylammonium [2- (6-methoxy-2-naphthyl)] propicnate or an isomer thereof. L * * - 34 - b 26. Methylammonium [1- (p ~ chlorobenzoyl) -5-methoxy-2-methyl-3-indolyl] acetate. 27. Triethanolammonium 2- (2,6-dichloroanilino) phenylacetate. 28. Methanol ammonium 2- (2,6-dichloroanilino) phenylacetate. - 29. Morpholinium 2- (2,6-dichloroanilino) phenylacetate. 30. Pharmaceutical preparations containing as active ingredient a compound of formula I according to one of claims 20 to 29 in addition to conventional pharmaceutical auxiliaries and / or carriers. 31. Pharmaceutical preparations according to claim 30 for topical application. 32. Pharmaceutical preparations according to one of claims 1 to 18 and 30 and 31, containing from about 0.5 to about 5 weight percent Λ of the active ingredient in addition to conventional pharmaceutical auxiliaries and carriers. 33. Compound according to one of claims 20 to 29 for use in a method for the therapeutic treatment of the human or animal body. H 34. A compound according to any one of claims 20 to 29 for use according to claim 33 as an anti-inflammatory and / or analgesic. î 35. A process for the preparation of compounds of the formula I according to one of claims 20 to 29, characterized in that an organic carboxylic acid of the formula Λ 4 - 35 - v 'CH-COOH (Ilia) R2 or one of a salt of the formula I various base salt thereof with an at least equimolar amount of the amine of the formula VR * T (Illb) _ * 5 »or an acid addition salt thereof and, if desired,» converting a compound of the formula I obtainable according to the process into another compound of the formula I and / or separates an isomer mixture obtainable according to the process into the components. "36. Process according to claim 35, characterized in that the starting materials are prepared in situ or a starting material is obtained from a derivative and / or in the form under the reaction conditions! ' a mixture of isomers or a pure isomer and / or salt! 37. Use of compounds of the formula I according to one of claims 20 to 29 for the production of pharmaceutical preparations. 38. Use according to claim 37 for the manufacture of topically administrable pharmaceutical preparations. Λ p 39. Use of compounds of formula I according to one of claims 20 to 29 as anti-inflammatory and / or analgesic. 40. The compounds described in Examples 1 to 7. - 41. The procedure of Examples 1 to 7. 42. The formulations described in Examples 8 to 16. l ^ \ Μ - 36 - 43. The processes for producing topically administrable pharmaceutical preparations described in Examples 8 to 16. 44. A process for the preparation of topically administrable pharmaceutical preparations, characterized in that a compound of the formula I according to one of claims 20 to 29 is mixed with auxiliaries and excipients customary for topical application. ΙλΛλΚϋ 'MT * i w iw v *